abstract - john l. wood
TRANSCRIPT
Abstract
Synthesis of Syringolides, Syributins and Analog Compounds,
a Family of Metabolites from Pseudomonas syringae:
The Total Synthesis of (-)-Syringolide 1, (-)-Syringolide 2,
(-)-Syringolide 3, (+)-Syringolide 1, (+)-Syringolide 2, (+)-Syringolide 3,
(-)-N-(Carbobenzyloxy)-8-aminosyringolide 1, (+)-Syributin 1, (+)-Syributin 2,
(+)- Syributin 3, (-)-Syributin 1, (-)-Syributin 2 and (-)-Syributin 3
Mauricio Navarro Villalobos
2000
The first total synthesis of (-)-syringolide 3 and its unnatural enantiomer (+)-
syringolide 3 following a biomimetic procedure is described. In addition, total syntheses
of (-)- and (+)-syringolides 1 and 2 were achieved using the same methodology. This
biomimetic route was easily modified to obtain (-)-N-(carbobenzyloxy)-8-
aminosyringolide 1, a good candidate for the preparation of affinity columns designed for
isolation of the soybean protein that binds to syringolide.
Model studies towards the total synthesis of syringolides using a rhodium-
catalyzed intramolecular C-H insertion reaction as the key step are described. A highly
stereospecific synthesis of spirolactones was achieved employing this methodology.
The first total synthesis of (+)-syributin 3 and its unnatural enantiomer (-)-
syributin 3 using an intermediate of the syringolide synthesis as starting material is
described. In addition, total syntheses of (-)- and (+)-syributins 1 and 2 were
accomplished by means of the same methodology.
Synthesis of Syringolides, Syributins and Analog Compounds,
a Family of Metabolites from Pseudomonas syringae:
The Total Synthesis of (-)-Syringolide 1, (-)-Syringolide 2,
(-)-Syringolide 3, (+)-Syringolide 1, (+)-Syringolide 2, (+)-Syringolide 3,
(-)-N-(Carbobenzyloxy)-8-aminosyringolide 1, (+)-Syributin 1,
(+)-Syributin 2, (+)- Syributin 3, (-)-Syributin 1, (-)-Syributin 2 and
(-)-Syributin 3
A Dissertation
Presented to the Faculty of the Graduate School
of
Yale University
in Candidacy for the Degree of
Doctor of Philosophy
by
Mauricio Navarro Villalobos
Dissertation Director: John Louis Wood
December, 2000
ii
© 2000 by Mauricio Navarro Villalobos
All rights reserved.
iii
A mi familia de Oradores:
Gaspar
Rosita
Rosa María
Erick
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Acknowledgements
I would like to thank my advisor Professor John L. Wood for all his friendship,
advice, help and support both inside and outside the walls of the Sterling Chemistry
Laboratories.
I would like to thank my thesis committee, Professors Frederick E. Ziegler and
Professor William L. Jorgensen for reviewing my thesis. I enjoyed very much working
as a Teaching Assistant for Professor Ziegler.
I would like to thank all the members of the Wood Group who worked so hard in
the Syringolide project, that is: Catherine McCarty, Susan Jeong, Cristy M. Lindberg,
Steve Zeman, Jonathan Jenkins, Analee Salcedo and, last but not least, Matthew M.
Weiss.
I would like to thank all the current and former members of the Wood Group
(a.k.a. W6) for their friendship, especially Jón T. Njarðarson for helping me to keep my
sanity during all this years and my adopted Portuguese cousin from Boston, George A.
Moniz.
I would like to thank Professor Martin Saunders for his friendship, help and
advice.
I would like to thank Professor David J. Austin and Serguey N. Savinov for their
friendship and helpful discussions about the C-H insertion part of my project.
I would like to thank Benedict W. Bangerter and Xiaoling Wu for their help in
NMR experiments and Susan De Gala for obtaining the X-ray crystal structures of this
work.
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FOR GOD
I would like to thank God Father, God Son and God Holy Spirit as well as Our
Lady of Guadalupe, St. Thomas Aquinas, St. Anthony of Padua, St. Mary Goretti, St.
Ignatius of Loyola, St. Maurice, St. Thérèse of the Child Jesus, St. Francis of Assisi, St.
Jude Thaddeus, St. Martin of Porres, St. Albertus Magnus and all the angels and saints
for delivering me from evil and keeping me from performing experiments dangerous for
myself and my labmates.
FOR COUNTRY
Mi más sincero cariño y agradecimiento a mi patria, México, porque siempre lo
he llevado en el corazón y la certeza de que tarde o temprano he de volver a él ha hecho
más llevadera en mí la pesada carga del exilio.
Así mismo quisiera agradecerle a mis padres y mis hermanos, a quienes dedico
este trabajo, por su apoyo y confianza a lo largo de toda mi vida.
FOR YALE
I would like to thank Yale University for six great years of my life. I am very
proud of being part of this institution which I will never forget since part of me remains
here and part of her I’ll bring with me.
Mauricio Navarro Villalobos
New Haven, CT
August, 2000
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Table of Contents
Dedication ......................................................................................................................... iii Acknowledgements .......................................................................................................... iv Table of Contents ............................................................................................................. vi List of Figures.....................................................................................................................x List of Schemes .............................................................................................................. xvii List of Tables .................................................................................................................. xix List of Abbreviations .......................................................................................................xx
Chapter 1, Syringolides: Background and Introduction ...............................................1
1.1 Biological Background: The Hypersensitive Response.............................................1
1.2 Syringolides: Isolation and Biological Activity.........................................................1
1.3 Syringolides as Molecular Probes..............................................................................3
1.4 Isolation and Characterization of a Syringolide-Binding Protein..............................3
1.5 Proposed Biosynthesis of Syringolides......................................................................4
1.6 Syntheses of Syringolides ..........................................................................................5 1.6.1 Wood et al.: Total Synthesis of (+)- and (-)-Syringolides 1 and 2 .....................6 1.6.2 Kuwahara et al.: Total Synthesis of (-)-Syringolides 1 and 2.............................7 1.6.3 Murai et al.: Total Synthesis of (-)-Syringolide 1...............................................8 1.6.4 Rickards and Henschke: Total Synthesis of (-)-Syringolide 2 and (-)-Deuterosyringolide 2 ....................................................................................10 1.6.5 Honda et al.: Total Synthesis of (-)-Syringolides 1 and 2.................................13 1.6.6 Sims et al.: Total Synthesis of (-)- and (+)-Syringolide 1 and (-)-∆7-Syringolide 1............................................................................................13 1.6.7 Wong et al.: Improved Synthesis of (-)-Syringolides 1 and 2 ..........................16 1.6.8 Chênevert and Dasser: Total Synthesis of (-)-Syringolide 2 ............................17 1.6.9 Yoda et al.: Formal Synthesis of (-)-Syringolide 1...........................................19
1.7 References................................................................................................................21
Chapter 2, Syringolides: Biomimetic Total Synthesis ..................................................25
2.1 Retrosynthetic analysis ............................................................................................25
2.2 Biomimetic Total Synthesis of (-)-Syringolides 1, 2 and 3 .....................................27
2.3 Biomimetic Total Synthesis of (+)-Syringolides 1, 2 and 3 ....................................29
2.4 Biomimetic Total Synthesis of (-)-N-(Carbobenzyloxy)-8-aminosyringolide 1 .....31
2.5 Conclusions..............................................................................................................32
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2.6 Experimental Section ...............................................................................................33 2.6.1 Materials and Methods......................................................................................33 2.6.2 Preparative Procedures......................................................................................34
2.7 Notes and references ................................................................................................57
Appendix 1, Spectra Relevant to Chapter 2 ..................................................................61
Appendix 2, X-ray Structure Reports Relevant to Chapter 2 ...................................117
A.2.1 X-ray Structure Report for (-)-Syringolide 3 .....................................................117 A.2.1.1 Crystal Data.................................................................................................117 A.2.1.2 Intensity Measurements ..............................................................................118 A.2.1.3 Structure Solution and Refinement .............................................................118 A.2.1.4 Atomic coordinates and Biso/Beq...............................................................119
Chapter 3, Syringolides: C-H Insertion Synthetic Studies.........................................120
3.1 Retrosynthetic analysis ..........................................................................................120
3.2 General Strategy.....................................................................................................121
3.3 C-H Insertion: Tetrahydrofurfuryl Esters ..............................................................123 3.3.1 Initial Studies with Tetrahydrofurfuryl Esters of 113.....................................123
3.3.1.1 Diazoacetoacetate ....................................................................................123 3.3.1.2 2-Diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate.................................124 3.3.1.3 Diazomalonate .........................................................................................125 3.3.1.4 3-Methoxyphenyldiazoacetate .................................................................125 3.3.1.5 Vinyldiazoacetate.....................................................................................126 3.3.1.6 Cyclohexenyldiazoacetate........................................................................127
3.4 C-H Insertion: 2,5-Dihydrofurfuryl Esters ............................................................129 3.4.1 Studies with 2,5-Dihydrofurfuryl Esters.........................................................129
3.4.1.1 Diazoacetoacetate ....................................................................................129 3.4.1.2 2-Diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate.................................130 3.4.1.3 Diazoacetate.............................................................................................131 3.4.1.4 3-Methoxyphenyldiazoacetate .................................................................132 3.4.1.5 4-Methoxyphenyldiazoacetate .................................................................133
3.5 C-H Insertion: 1,4-Anhydroarabinityl Esters.........................................................134 3.5.1 Studies with 2,3-di-O-Protected 1,4-Anhydroarabinityl Esters ......................134
3.5.1.1 Masked Diols: 2,3-di-O-(t-Butyldimethylsilyl)-1,4-anhydro-DL-arabinityl Esters............................................................................................................134
3.5.1.1.1 Diazoacetoacetate .............................................................................135 3.5.1.1.2 2-Diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate..........................136 3.5.1.1.3 Diazoacetate......................................................................................137
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3.5.1.1.4 3-Methoxyphenyldiazoacetate ..........................................................138 3.5.1.2 Masked Diols: 1,4-Anhydro-2,3-di-O-benzyl-D-arabinityl Esters ..........139
3.5.1.2.1 Diazoacetoacetate .............................................................................139 3.5.1.2.2 2-Diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate..........................140 3.5.1.2.3 Diazoacetate......................................................................................141 3.5.1.2.4 3-Methoxyphenyldiazoacetate ..........................................................141
3.5.1.3 Masked Diols: 1,4-Anhydro-2,3-di-O-methyl-DL-arabinityl Esters........142 3.5.1.3.1 Diazoacetoacetate .............................................................................143 3.5.1.3.2 2-Diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate..........................143 3.5.1.3.3 Diazoacetate......................................................................................144 3.5.1.3.4 3-Methoxyphenyldiazoacetate ..........................................................145
3.5.2 Unmasked Diols: 1,4-Anhydroarabinityl Esters .............................................146 3.5.2.1 Diazoacetoacetate ....................................................................................146 3.5.2.2 3-Methoxyphenyldiazoacetate .................................................................147
3.6 C-H Insertion: Stereochemistry .............................................................................149
3.7 Conclusions............................................................................................................150
3.8 Experimental Section .............................................................................................152 3.8.1 Materials and Methods....................................................................................152 3.8.2 Preparative Procedures....................................................................................153
3.9 References..............................................................................................................208
Appendix 3, Spectra Relevant to Chapter 3 ................................................................212
Appendix 4, X-ray Structure Reports Relevant to Chapter 3 ...................................315
A.4.1 X-ray Structure Report for Spirolactone 127 .....................................................315 A.4.1.1 Crystal Data.................................................................................................315 A.4.1.2 Intensity Measurements ..............................................................................316 A.4.1.3 Structure Solution and Refinement .............................................................316 A.4.1.4 Atomic coordinates and Biso/Beq...............................................................317
A.4.2 X-ray Structure Report for Spirolactone 149 .....................................................318 A.4.2.1 Crystal Data.................................................................................................318 A.4.2.2 Intensity Measurements ..............................................................................319 A.4.2.3 Structure Solution and Refinement .............................................................319 A.4.2.4 Atomic coordinates and Biso/Beq...............................................................320
A.4.3 X-ray Structure Report for Spirolactone 153.....................................................321 A.4.3.1 Crystal Data.................................................................................................321 A.4.3.2 Intensity Measurements ..............................................................................322 A.4.3.3 Structure Solution and Refinement .............................................................322 A.4.3.4 Atomic coordinates and Biso/Beq...............................................................323
A.4.4 X-ray Structure Report for Spirolactone 168.....................................................324 A.4.4.1 Crystal Data.................................................................................................324
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A.4.4.2 Intensity Measurements ..............................................................................325 A.4.4.3 Structure Solution and Refinement .............................................................325 A.4.4.4 Atomic coordinates and Biso/Beq...............................................................326
Chapter 4, Syributins: Background and Introduction ...............................................328
4.1 Syributins and Secosyrins: Isolation and Characterization....................................328
4.2 Proposed Biosynthesis of Syributins and Secosyrins ............................................329
4.3 Syntheses of Secosyrins and Syributins.................................................................330 4.3.1 Honda et al.: Total Synthesis of (+)-Syributin 1.............................................331 4.3.2 Wong et al.: Total Syntheses of (+)-Syributins 1 and 2 and (+)-Secosyrins 1 and 2 .....................................................................................332 4.3.3 Mukai and co-workers: Total Syntheses (+)-Syributins 1 and 2 and (+)-Secosyrins 1 and 2 .....................................................................................334 4.3.4 Yoda et al.: Total Synthesis of (+)-Syributin 1...............................................338 4.3.5 Carda et al.: Formal Synthesis of (+)-Secosyrins and (+)-Syributins.............338
4.4 References..............................................................................................................339
Chapter 5, Syributins: Total Synthesis ........................................................................341
5.1 Retrosynthetic analysis ..........................................................................................341
5.2 Total Synthesis of (+)-Syributins 1, 2 and 3..........................................................342
5.2 Total Synthesis of (-)-Syributins 1, 2 and 3...........................................................343
5.3 Conclusions............................................................................................................344
5.4 Experimental Section .............................................................................................344 5.4.1 Materials and Methods....................................................................................344 5.4.2 Preparative Procedures....................................................................................346
5.5 References..............................................................................................................360
Appendix 5, Spectra Relevant to Chapter 5 ................................................................362
Appendix 6, Notebook Cross Reference.......................................................................383 Bibliography ...................................................................................................................388 Index................................................................................................................................392 About the Author ...........................................................................................................393
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List of Figures
Chapter 1 Figure 1.1 Syringolide elicitors...........................................................................................2 Figure 1.2 Syringolide 1 derivatives ...................................................................................4 Chapter 2 Figure 2.1 (-)-11 and Precursors .......................................................................................27 Figure 2.2 1H NMR (500 MHz, CDCl3) Comparison of (-)-Syringolide 2 ......................30 Appendix 1 Figure A.1.1 1H NMR (500 MHz, CDCl3) of Compound (-)-12 ......................................62 Figure A.1.2 FTIR Spectrum (thin film/NaCl) of Compound (-)-12................................63 Figure A.1.3 13C NMR (125 MHz, CDCl3) of Compound (-)-12 .....................................63 Figure A.1.4 1H NMR (500 MHz, CDCl3) of Compound (+)-12 .....................................64 Figure A.1.5 FTIR Spectrum (thin film/NaCl) of Compound (+)-12...............................65 Figure A.1.6 13C NMR (125 MHz, CDCl3) of Compound (+)-12 ....................................65 Figure A.1.7 1H NMR (500 MHz, CDCl3) of Compound (-)-13 ......................................66 Figure A.1.8 FTIR Spectrum (thin film/NaCl) of Compound (-)-13................................67 Figure A.1.9 13C NMR (125 MHz, CDCl3) of Compound (-)-13 .....................................67 Figure A.1.10 1H NMR (500 MHz, CDCl3) of Compound (+)-13 ...................................68 Figure A.1.11 FTIR Spectrum (thin film/NaCl) of Compound (+)-13.............................69 Figure A.1.12 13C NMR (125 MHz, CDCl3) of Compound (+)-13 ..................................69 Figure A.1.13 1H NMR (500 MHz, CDCl3) of Compound (-)-16a ..................................70 Figure A.1.14 FTIR Spectrum (thin film/NaCl) of Compound (-)-16a............................71 Figure A.1.15 13C NMR (125 MHz, CDCl3) of Compound (-)-16a .................................71 Figure A.1.16 1H NMR (500 MHz, CDCl3) of Compound (+)-16a .................................72 Figure A.1.17 FTIR Spectrum (thin film/NaCl) of Compound (+)-16a...........................73 Figure A.1.18 13C NMR (125 MHz, CDCl3) of Compound (+)-16a ................................73 Figure A.1.19 1H NMR (500 MHz, CDCl3) of Compound (-)-16b..................................74 Figure A.1.20 FTIR Spectrum (thin film/NaCl) of Compound (-)-16b ...........................75 Figure A.1.21 13C NMR (125 MHz, CDCl3) of Compound (-)-16b.................................75 Figure A.1.22 1H NMR (500 MHz, CDCl3) of Compound (+)-16b.................................76 Figure A.1.23 FTIR Spectrum (thin film/NaCl) of Compound (+)-16b...........................77 Figure A.1.24 13C NMR (125 MHz, CDCl3) of Compound (+)-16b................................77 Figure A.1.25 1H NMR (500 MHz, CDCl3) of Compound (-)-16c ..................................78 Figure A.1.26 FTIR Spectrum (thin film/NaCl) of Compound (-)-16c ............................79 Figure A.1.27 13C NMR (125 MHz, CDCl3) of Compound (-)-16c .................................79 Figure A.1.28 1H NMR (500 MHz, CDCl3) of Compound (+)-16c .................................80
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Figure A.1.29 FTIR Spectrum (thin film/NaCl) of Compound (+)-16c ...........................81 Figure A.1.30 13C NMR (125 MHz, CDCl3) of Compound (+)-16c ................................81 Figure A.1.31 1H NMR (500 MHz, acetone-d6) of Compound (-)-1................................82 Figure A.1.32 1H NMR (500 MHz, CDCl3) of Compound (-)-1 ......................................83 Figure A.1.33 FTIR Spectrum (thin film/NaCl) of Compound (-)-1................................84 Figure A.1.34 13C NMR (125 MHz, acetone-d6) of Compound (-)-1...............................84 Figure A.1.35 1H NMR (500 MHz, CDCl3) of Compound (-)-51a ..................................85 Figure A.1.36 FTIR Spectrum (thin film/NaCl) of Compound (-)-51a............................86 Figure A.1.37 13C NMR (125 MHz, CDCl3) of Compound (-)-51a .................................86 Figure A.1.38 1H NMR (500 MHz, acetone-d6) of Compound (+)-1...............................87 Figure A.1.39 1H NMR (500 MHz, CDCl3) of Compound (+)-1 .....................................88 Figure A.1.40 FTIR Spectrum (thin film/NaCl) of Compound (+)-1...............................89 Figure A.1.41 13C NMR (125 MHz, acetone-d6) of Compound (+)-1..............................89 Figure A.1.42 1H NMR (500 MHz, CDCl3) of Compound (+)-51a .................................90 Figure A.1.43 FTIR Spectrum (thin film/NaCl) of Compound (+)-51a...........................91 Figure A.1.44 13C NMR (125 MHz, CDCl3) of Compound (+)-51a ................................91 Figure A.1.45 1H NMR (500 MHz, acetone-d6) of Compound (-)-2................................92 Figure A.1.46 1H NMR (500 MHz, CDCl3) of Compound (-)-2 ......................................93 Figure A.1.47 FTIR Spectrum (thin film/NaCl) of Compound (-)-2................................94 Figure A.1.48 13C NMR (125 MHz, acetone-d6) of Compound (-)-2...............................94 Figure A.1.49 1H NMR (500 MHz, CDCl3) of Compound (-)-51b..................................95 Figure A.1.50 FTIR Spectrum (thin film/NaCl) of Compound (-)-51b ...........................96 Figure A.1.51 13C NMR (125 MHz, CDCl3) of Compound (-)-51b.................................96 Figure A.1.52 1H NMR (500 MHz, acetone-d6) of Compound (+)-2...............................97 Figure A.1.53 1H NMR (500 MHz, CDCl3) of Compound (+)-2 .....................................98 Figure A.1.54 FTIR Spectrum (thin film/NaCl) of Compound (+)-2...............................99 Figure A.1.55 13C NMR (125 MHz, acetone-d6) of Compound (+)-2..............................99 Figure A.1.56 1H NMR (500 MHz, CDCl3) of Compound (+)-51b...............................100 Figure A.1.57 FTIR Spectrum (thin film/NaCl) of Compound (+)-51b.........................101 Figure A.1.58 13C NMR (125 MHz, CDCl3) of Compound (+)-51b..............................101 Figure A.1.59 1H NMR (500 MHz, acetone-d6) of Compound (-)-3..............................102 Figure A.1.60 FTIR Spectrum (thin film/NaCl) of Compound (-)-3..............................103 Figure A.1.61 13C NMR (125 MHz, acetone-d6) of Compound (-)-3.............................103 Figure A.1.62 1H NMR (500 MHz, CDCl3) of Compound (-)-51c ................................104 Figure A.1.63 FTIR Spectrum (thin film/NaCl) of Compound (-)-51c ..........................105 Figure A.1.64 13C NMR (125 MHz, CDCl3) of Compound (-)-51c ...............................105 Figure A.1.65 1H NMR (500 MHz, acetone-d6) of Compound (+)-3.............................106 Figure A.1.66 FTIR Spectrum (thin film/NaCl) of Compound (+)-3.............................107 Figure A.1.67 13C NMR (125 MHz, acetone-d6) of Compound (+)-3............................107 Figure A.1.68 1H NMR (500 MHz, CDCl3) of Compound (+)-51c ...............................108 Figure A.1.69 FTIR Spectrum (thin film/NaCl) of Compound (+)-51c .........................109 Figure A.1.70 13C NMR (125 MHz, CDCl3) of Compound (+)-51c ..............................109 Figure A.1.71 1H NMR (500 MHz, CDCl3) of Compound (-)-91 ..................................110 Figure A.1.72 FTIR Spectrum (thin film/NaCl) of Compound (-)-91............................111 Figure A.1.73 13C NMR (125 MHz, CDCl3) of Compound (-)-91 .................................111 Figure A.1.74 1H NMR (500 MHz, acetone-d6) of Compound (-)-92............................112
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Figure A.1.75 1H NMR (500 MHz, CDCl3) of Compound (-)-92 ..................................113 Figure A.1.76 FTIR Spectrum (thin film/NaCl) of Compound (-)-92............................114 Figure A.1.77 13C NMR (125 MHz, acetone-d6) of Compound (-)-92...........................114 Figure A.1.78 1H NMR (500 MHz, CDCl3) of Compound (-)-93 ..................................115 Figure A.1.79 FTIR Spectrum (thin film/NaCl) of Compound (-)-93............................116 Figure A.1.80 13C NMR (125 MHz, CDCl3) of Compound (-)-93 .................................116 Appendix 2 Figure A.2.1 ORTEP plot of Syringolide 3 ....................................................................117 Chapter 3 Figure 3.1 Side Chains for Model Studies ......................................................................122 Figure 3.2 Masked Trans Diol for Model Studies ..........................................................123 Figure 3.3 2,3-di-O-1,4-Arabinitol (98) and Derivatives................................................134 Figure 3.4 Spirolactones Analyzed by X-ray Crystallography .......................................149 Figure 3.5 Proposed Relative Stereochemical Configuration for C-H Insertion Products
131, 135 and 178......................................................................................................150 Appendix 3 Figure A.3.1 1H NMR (500 MHz, CDCl3) of Compound 115 .......................................213 Figure A.3.2 FTIR Spectrum (thin film/NaCl) of Compound 115 .................................214 Figure A.3.3 13C NMR (125 MHz, CDCl3) of Compound 115 ......................................214 Figure A.3.4 1H NMR (500 MHz, CDCl3) of Compound 117 .......................................215 Figure A.3.5 FTIR Spectrum (thin film/NaCl) of Compound 117 .................................216 Figure A.3.6 13C NMR (125 MHz, CDCl3) of Compound 117 ......................................216 Figure A.3.7 1H NMR (500 MHz, CDCl3) of Compound 121 .......................................217 Figure A.3.8 FTIR Spectrum (thin film/NaCl) of Compound 121 .................................218 Figure A.3.9 13C NMR (125 MHz, CDCl3) of Compound 121 ......................................218 Figure A.3.10 1H NMR (500 MHz, CDCl3) of Compound 122 .....................................219 Figure A.3.11 FTIR Spectrum (thin film/NaCl) of Compound 122 ...............................220 Figure A.3.12 13C NMR (125 MHz, CDCl3) of Compound 122 ....................................220 Figure A.3.13 1H NMR (500 MHz, CDCl3) of Compound 125 .....................................221 Figure A.3.14 FTIR Spectrum (thin film/NaCl) of Compound 125 ...............................222 Figure A.3.15 13C NMR (125 MHz, CDCl3) of Compound 125 ....................................222 Figure A.3.16 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 126 .........................223 Figure A.3.17 FTIR Spectrum (thin film/NaCl) of Compound 126 ...............................224 Figure A.3.18 13C NMR (125 MHz, CDCl3) of Compound 126 ....................................224 Figure A.3.19 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 127 .........................225 Figure A.3.20 FTIR Spectrum (thin film/NaCl) of Compound 127 ...............................226 Figure A.3.21 13C NMR (125 MHz, CDCl3) of Compound 127 ....................................226
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Figure A.3.22 1H NMR (500 MHz, CDCl3) of Compound 129 .....................................227 Figure A.3.23 FTIR Spectrum (thin film/NaCl) of Compound 129 ...............................228 Figure A.3.24 13C NMR (125 MHz, CDCl3) of Compound 129 ....................................228 Figure A.3.25 1H NMR (500 MHz, CDCl3) of Compound 131 .....................................229 Figure A.3.26 FTIR Spectrum (thin film/NaCl) of Compound 131 ...............................230 Figure A.3.27 13C NMR (125 MHz, CDCl3) of Compound 131 ....................................230 Figure A.3.28 1H NMR (500 MHz, CDCl3) of Compound 134 .....................................231 Figure A.3.29 FTIR Spectrum (thin film/NaCl) of Compound 134 ...............................232 Figure A.3.30 13C NMR (125 MHz, CDCl3) of Compound 134 ....................................232 Figure A.3.31 1H NMR (500 MHz, CDCl3) of Compound 135 .....................................233 Figure A.3.32 FTIR Spectrum (thin film/NaCl) of Compound 135 ...............................234 Figure A.3.33 13C NMR (125 MHz, CDCl3) of Compound 135 ....................................234 Figure A.3.34 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 140 .........................235 Figure A.3.35 FTIR Spectrum (thin film/NaCl) of Compound 140 ...............................236 Figure A.3.36 13C NMR (125 MHz, CDCl3) of Compound 140 ....................................236 Figure A.3.37 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 141 .........................237 Figure A.3.38 FTIR Spectrum (thin film/NaCl) of Compound 141 ...............................238 Figure A.3.39 13C NMR (125 MHz, CDCl3) of Compound 141 ....................................238 Figure A.3.40 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 143 .........................239 Figure A.3.41 FTIR Spectrum (thin film/NaCl) of Compound 143 ...............................240 Figure A.3.42 13C NMR (100 MHz, CDCl3) of Compound 143 ....................................240 Figure A.3.43 1H NMR (500 MHz, CDCl3) of Compound 145 .....................................241 Figure A.3.44 FTIR Spectrum (thin film/NaCl) of Compound 145 ...............................242 Figure A.3.45 13C NMR (125 MHz, CDCl3) of Compound 145 ....................................242 Figure A.3.46 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 147 .........................243 Figure A.3.47 FTIR Spectrum (thin film/NaCl) of Compound 147 ...............................244 Figure A.3.48 13C NMR (125 MHz, CDCl3) of Compound 147 ....................................244 Figure A.3.49 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 148 .........................245 Figure A.3.50 FTIR Spectrum (thin film/NaCl) of Compound 148 ...............................246 Figure A.3.51 13C NMR (125 MHz, CDCl3) of Compound 148 ....................................246 Figure A.3.52 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 149 .........................247 Figure A.3.53 FTIR Spectrum (thin film/NaCl) of Compound 149 ...............................248 Figure A.3.54 13C NMR (125 MHz, CDCl3) of Compound 149 ....................................248 Figure A.3.55 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 151 .........................249 Figure A.3.56 FTIR Spectrum (thin film/NaCl) of Compound 151 ...............................250 Figure A.3.57 13C NMR (125 MHz, CDCl3) of Compound 151 ....................................250 Figure A.3.58 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 152 .........................251 Figure A.3.59 FTIR Spectrum (thin film/NaCl) of Compound 152 ...............................252 Figure A.3.60 13C NMR (125 MHz, CDCl3) of Compound 152 ....................................252 Figure A.3.61 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 153 .........................253 Figure A.3.62 FTIR Spectrum (thin film/NaCl) of Compound 153 ...............................254 Figure A.3.63 13C NMR (125 MHz, CDCl3) of Compound 153 ....................................254 Figure A.3.64 1H NMR (400 MHz, CDCl3) of Compound 158 .....................................255 Figure A.3.65 FTIR Spectrum (thin film/NaCl) of Compound 158 ...............................256 Figure A.3.66 13C NMR (100 MHz, CDCl3) of Compound 158 ....................................256 Figure A.3.67 1H NMR (400 MHz, CDCl3) of Compound 154 .....................................257
xiv
Figure A.3.68 FTIR Spectrum (thin film/NaCl) of Compound 154 ...............................258 Figure A.3.69 13C NMR (100 MHz, CDCl3) of Compound 154 ....................................258 Figure A.3.70 1H NMR (500 MHz, CDCl3) of Compound 159 .....................................259 Figure A.3.71 FTIR Spectrum (thin film/NaCl) of Compound 159 ...............................260 Figure A.3.72 13C NMR (100 MHz, CDCl3) of Compound 159 ....................................260 Figure A.3.73 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 160 .........................261 Figure A.3.74 FTIR Spectrum (thin film/NaCl) of Compound 160 ...............................262 Figure A.3.75 13C NMR (100 MHz, CDCl3) of Compound 160 ....................................262 Figure A.3.76 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 162 .........................263 Figure A.3.77 FTIR Spectrum (thin film/NaCl) of Compound 162 ...............................264 Figure A.3.78 13C NMR (100 MHz, CDCl3) of Compound 162 ....................................264 Figure A.3.79 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 164 ........................265 Figure A.3.80 FTIR Spectrum (thin film/NaCl) of Compound 164 ...............................266 Figure A.3.81 13C NMR (100 MHz, CDCl3) of Compound 164 ....................................266 Figure A.3.82 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 165 .........................267 Figure A.3.83 FTIR Spectrum (thin film/NaCl) of Compound 165 ...............................268 Figure A.3.84 13C NMR (100 MHz, CDCl3) of Compound 165. ...................................268 Figure A.3.85 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 166 .........................269 Figure A.3.86 FTIR Spectrum (thin film/NaCl) of Compound 166 ...............................270 Figure A.3.87 13C NMR (100 MHz, CDCl3) of Compound 166 ....................................270 Figure A.3.88 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 167 .........................271 Figure A.3.89 FTIR Spectrum (thin film/NaCl) of Compound 167 ...............................272 Figure A.3.90 13C NMR (100 MHz, CDCl3) of Compound 167 ....................................272 Figure A.3.91 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 168 .........................273 Figure A.3.92 FTIR Spectrum (thin film/NaCl) of Compound 168 ...............................274 Figure A.3.93 13C NMR (100 MHz, CDCl3) of Compound 168 ....................................274 Figure A.3.94 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 169 .........................275 Figure A.3.95 FTIR Spectrum (thin film/NaCl) of Compound 169 ...............................276 Figure A.3.96 13C NMR (100 MHz, CDCl3) of Compound 169 ....................................276 Figure A.3.97 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 170 .........................277 Figure A.3.98 FTIR Spectrum (thin film/NaCl) of Compound 170 ...............................278 Figure A.3.99 13C NMR (125 MHz, CDCl3) of Compound 170 ....................................278 Figure A.3.100 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 172 .......................279 Figure A.3.101 FTIR Spectrum (thin film/NaCl) of Compound 172 .............................280 Figure A.3.102 13C NMR (100 MHz, CDCl3) of Compound 172 ..................................280 Figure A.3.103 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 174 .......................281 Figure A.3.104 FTIR Spectrum (thin film/NaCl) of Compound 174 .............................282 Figure A.3.105 13C NMR (100 MHz, CDCl3) of Compound 174 ..................................282 Figure A.3.106 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 176 .......................283 Figure A.3.107 FTIR Spectrum (thin film/NaCl) of Compound 176 .............................284 Figure A.3.108 13C NMR (125 MHz, CDCl3) of Compound 176 ..................................284 Figure A.3.109 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 177 .......................285 Figure A.3.110 FTIR Spectrum (thin film/NaCl) of Compound 177 .............................286 Figure A.3.111 13C NMR (125 MHz, CDCl3) of Compound 177 ..................................286 Figure A.3.112 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 178 .......................287 Figure A.3.113 FTIR Spectrum (thin film/NaCl) of Compound 178 .............................288
xv
Figure A.3.114 13C NMR (100 MHz, CDCl3) of Compound 178 ..................................288 Figure A.3.115 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 179 .......................289 Figure A.3.116 FTIR Spectrum (thin film/NaCl) of Compound 179 .............................290 Figure A.3.117 13C NMR (100 MHz, CDCl3) of Compound 179 ..................................290 Figure A.3.118 1H NMR (500 MHz, CDCl3) of Compound 156 ...................................291 Figure A.3.119 FTIR Spectrum (thin film/NaCl) of Compound 156 .............................292 Figure A.3.120 13C NMR (100 MHz, CDCl3) of Compound 156 ..................................292 Figure A.3.121 1H NMR (400 MHz, CDCl3) of Compound 180 ...................................293 Figure A.3.122 FTIR Spectrum (thin film/NaCl) of Compound 180 .............................294 Figure A.3.123 13C NMR (100 MHz, CDCl3) of Compound 180 ..................................294 Figure A.3.124 1H NMR (500 MHz, CDCl3) of Compound 181 ...................................295 Figure A.3.125 FTIR Spectrum (thin film/NaCl) of Compound 181 .............................296 Figure A.3.126 13C NMR (100 MHz, CDCl3) of Compound 181 ..................................296 Figure A.3.127 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 183 .......................297 Figure A.3.128 FTIR Spectrum (thin film/NaCl) of Compound 183 .............................298 Figure A.3.129 13C NMR (100 MHz, CDCl3) of Compound 183 ..................................298 Figure A.3.130 1H NMR (400 MHz, CDCl3) of Compound 185 ...................................299 Figure A.3.131 FTIR Spectrum (thin film/NaCl) of Compound 185 .............................300 Figure A.3.132 13C NMR (100 MHz, CDCl3) of Compound 185 ..................................300 Figure A.3.133 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 186 .......................301 Figure A.3.134 FTIR Spectrum (thin film/NaCl) of Compound 186 .............................302 Figure A.3.135 13C NMR (100 MHz, CDCl3) of Compound 186 ..................................302 Figure A.3.136 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 187 .......................303 Figure A.3.137 FTIR Spectrum (thin film/NaCl) of Compound 187 .............................304 Figure A.3.138 13C NMR (100 MHz, CDCl3) of Compound 187 ..................................304 Figure A.3.139 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 188 .......................305 Figure A.3.140 FTIR Spectrum (thin film/NaCl) of Compound 188 .............................306 Figure A.3.141 13C NMR (100 MHz, CDCl3) of Compound 188 ..................................306 Figure A.3.142 1H NMR (500 MHz, CDCl3) of Compound 190. ..................................307 Figure A.3.143 FTIR Spectrum (thin film/NaCl) of Compound 190 .............................308 Figure A.3.144 13C NMR (125 MHz, acetone-d6) of Compound 190 ............................308 Figure A.3.145 1H NMR (400 MHz, CDCl3) of Compound 194 ...................................309 Figure A.3.146 FTIR Spectrum (thin film/NaCl) of Compound 194 .............................310 Figure A.3.147 13C NMR (100 MHz, acetone-d6) of Compound 194 ............................310 Figure A.3.148 1H NMR (500 MHz, CDCl3) of Compound 196 ...................................311 Figure A.3.149 FTIR Spectrum (thin film/NaCl) of Compound 196 .............................312 Figure A.3.150 13C NMR (100 MHz, acetone-d6) of Compound 196 ............................312 Figure A.3.151 1H NMR (500 MHz, acetone-d6) of Compound 199 .............................313 Figure A.3.152 FTIR Spectrum (thin film/NaCl) of Compound 199. ............................314 Figure A.3.153 13C NMR (100 MHz, acetone-d6) of Compound 199 ............................314
xvi
Appendix 4 Figure A.4.1 ORTEP plot of Spirolactone 127 ...............................................................315 Figure A.4.2 ORTEP plot of Spirolactone 149 ...............................................................318 Figure A.4.3 ORTEP plot of Spirolactone 153 ...............................................................321 Figure A.4.4 ORTEP plot of Spirolactone 168 ...............................................................324 Chapter 4 Figure 4.1 Syributins and Secosyrins..............................................................................328 Appendix 5 Figure A.5.1 1H NMR (500 MHz, CDCl3) of Compound (-)-246 ..................................363 Figure A.5.2 FTIR Spectrum (thin film/NaCl) of Compound (-)-246............................364 Figure A.5.3 13C NMR (125 MHz, CDCl3) of Compound (-)-246 .................................364 Figure A.5.4 1H NMR (500 MHz, CDCl3) of Compound (+)-246 .................................365 Figure A.5.5 FTIR Spectrum (thin film/NaCl) of Compound (+)-246...........................366 Figure A.5.6 13C NMR (125 MHz, CDCl3) of Compound (+)-246 ................................366 Figure A.5.7 1H NMR (500 MHz, CDCl3) of Compound (+)-226c ...............................367 Figure A.5.8 FTIR Spectrum (thin film/NaCl) of Compound (+)-226c .........................368 Figure A.5.9 13C NMR (125 MHz, CDCl3) of Compound (+)-226c ..............................368 Figure A.5.10 1H NMR (500 MHz, CDCl3) of Compound (-)-226c ..............................369 Figure A.5.11 FTIR Spectrum (thin film/NaCl) of Compound (-)-226c ........................370 Figure A.5.12 13C NMR (125 MHz, CDCl3) of Compound (-)-226c .............................370 Figure A.5.13 1H NMR (500 MHz, CDCl3) of Compound (+)-201 ...............................371 Figure A.5.14 FTIR Spectrum (thin film/NaCl) of Compound (+)-201.........................372 Figure A.5.15 13C NMR (125 MHz, CDCl3) of Compound (+)-201 ..............................372 Figure A.5.16 1H NMR (500 MHz, CDCl3) of Compound (-)-201 ................................373 Figure A.5.17 FTIR Spectrum (thin film/NaCl) of Compound (-)-201..........................374 Figure A.5.18 13C NMR (125 MHz, CDCl3) of Compound (-)-201 ...............................374 Figure A.5.19 1H NMR (500 MHz, CDCl3) of Compound (+)-202 ...............................375 Figure A.5.20 FTIR Spectrum (thin film/NaCl) of Compound (+)-202.........................376 Figure A.5.21 13C NMR (125 MHz, CDCl3) of Compound (+)-202 ..............................376 Figure A.5.22 1H NMR (500 MHz, CDCl3) of Compound (-)-202 ................................377 Figure A.5.23 FTIR Spectrum (thin film/NaCl) of Compound (-)-202..........................378 Figure A.5.24 13C NMR (125 MHz, CDCl3) of Compound (-)-202 ...............................378 Figure A.5.25 1H NMR (500 MHz, CDCl3) of Compound (+)-203 ...............................379 Figure A.5.26 FTIR Spectrum (thin film/NaCl) of Compound (+)-203.........................380 Figure A.5.27 13C NMR (125 MHz, CDCl3) of Compound (+)-203 ..............................380 Figure A.5.28 1H NMR (500 MHz, CDCl3) of Compound (-)-203 ................................381 Figure A.5.29 FTIR Spectrum (thin film/NaCl) of Compound (-)-203..........................382 Figure A.5.30 13C NMR (125 MHz, CDCl3) of Compound (-)-203 ...............................382
xvii
List of Schemes
Chapter 1 Scheme 1.1 Proposed Biosynthesis of Syringolides............................................................5 Scheme 1.2 Wood et al.: Total Synthesis of (+)- and (-)-Syringolides 1 and 2 ..................6 Scheme 1.3 Kuwahara et al.: Total Synthesis of (-)-Syringolides 1 and 2..........................8 Scheme 1.4 Murai et al.: Total Synthesis of (-)-Syringolide 1............................................9 Scheme 1.5 Rickards and Henschke: Total Synthesis of (-)-Syringolide 2 ......................10 Scheme 1.6 Rickards and Henschke: Total Synthesis of (-)-Deuterosyringolide 2 ..........11 Scheme 1.7 Honda et al.: Total Synthesis of (-)-Syringolides 1 and 2 .............................12 Scheme 1.8 Sims et al.: Total Synthesis of (-)- and (+)-Syringolide 1 and (-)-∆7-Syringolide 1 ...................................................................................................14 Scheme 1.9 Sims et al.: Total Synthesis of (-)-Syringolide 1 ...........................................15 Scheme 1.10 Wong et al.: Synthesis of Precursor 47........................................................16 Scheme 1.11 Wong et al.: Improved Synthesis of (-)-Syringolides 1 and 2 .....................17 Scheme 1.12 Chênevert and Dasser: Total Synthesis of (-)-Syringolide 2 .......................18 Scheme 1.13 Chênevert and Dasser: Improved Total Synthesis of (-)-Syringolide 2.......19 Scheme 1.14 Yoda et al.: Formal Synthesis of (-)-Syringolide 1......................................20 Chapter 2 Scheme 2.1 Proposed Biosynthesis of Syringolides..........................................................25 Scheme 2.2 Syringolides: Retrosynthetic Analysis...........................................................26 Scheme 2.3 Biomimetic Total Synthesis of (-)-Syringolides 1, 2 and 3 ...........................28 Scheme 2.4 Biomimetic Total Synthesis of (-)-N-(Carbobenzyloxy)-8- aminosyringolide 1.....................................................................................................31 Chapter 3 Scheme 3.1 Doyle and Dyatkin: Spirolactone Synthesis ................................................120 Scheme 3.2 Syringolides: Retrosynthetic Analysis........................................................121 Scheme 3.3 C-H Insertion: General Strategy ..................................................................122 Scheme 3.4 ......................................................................................................................124 Scheme 3.5 ......................................................................................................................124 Scheme 3.7 ......................................................................................................................126 Scheme 3.8 ......................................................................................................................127 Scheme 3.9 ......................................................................................................................128 Scheme 3.10 ....................................................................................................................129 Scheme 3.11 ....................................................................................................................130 Scheme 3.12 ....................................................................................................................131 Scheme 3.13 ....................................................................................................................131
xviii
Scheme 3.14 ....................................................................................................................132 Scheme 3.15 ....................................................................................................................133 Scheme 3.16 ....................................................................................................................135 Scheme 3.17 ....................................................................................................................136 Scheme 3.18 ....................................................................................................................137 Scheme 3.19 ....................................................................................................................137 Scheme 3.20 ....................................................................................................................138 Scheme 3.21 ....................................................................................................................139 Scheme 3.22 ....................................................................................................................140 Scheme 3.23 ....................................................................................................................140 Scheme 3.24 ....................................................................................................................141 Scheme 3.25 ....................................................................................................................142 Scheme 3.25 ....................................................................................................................143 Scheme 3.27 ....................................................................................................................144 Scheme 3.28 ....................................................................................................................144 Scheme 3.29 ....................................................................................................................145 Scheme 3.30 ....................................................................................................................147 Scheme 3.31 ....................................................................................................................148 Scheme 3.30 ....................................................................................................................151 Chapter 4 Scheme 4.1 Proposed Biosynthesis of Secosyrins and Syributins ..................................330 Scheme 4.2 Honda et al.: Total Synthesis of (+)-Syributin 1..........................................331 Scheme 4.3 Honda et al.: Total Synthesis of (+)-Syributin 1..........................................332 Scheme 4.4 Wong et al.: Total Synthesis (+)-Syributins 1 and 2 ...................................333 Scheme 4.5 Wong et al.: Total Synthesis (+)-Secosyrins 1 and 2...................................334 Scheme 4.6 Mukai et al.: Total Synthesis of (+)-Syributins 1 and 2...............................335 Scheme 4.7 Mukai and co-workers: Total Synthesis of (+)-Secosyrins 1 and 2.............336 Scheme 4.8 Mukai et al.: Synthesis of (+)-Secosyrin 1 from (+)-Syributin 1 ...............337 Scheme 4.9 Yoda et al.: Total Synthesis of (+)-Syributin 1............................................337 Scheme 4.10 Carda et al.: Formal Synthesis of (+)-Secosyrins and (+)-Syributins.......338 Chapter 5 Scheme 5.1 Syributins: Retrosynthetic Analysis............................................................341 Scheme 5.2 Total Synthesis of (+)-Syributins 1, 2 and 3................................................342 Scheme 5.3 Total Synthesis of (-)-Syributins 1, 2 and 3.................................................343
xix
List of Tables
Appendix 2 Table A.2.1 Atomic coordinates and Biso/Beq for Syringolide 3 ..................................119 Appendix 4 Table A.4.1 Atomic coordinates and Biso/Beq for Spirolactone 127 .............................317 Table A.4.2 Atomic coordinates and Biso/Beq for Spirolactone 149 .............................320 Table A.4.3 Atomic coordinates and Biso/Beq for Spirolactone 153 .............................323 Table A.4.4 Atomic coordinates and Biso/Beq for Spirolactone 168 .............................326 Appendix 6 Table A.6.1 Compounds Appearing in Chapter 2...........................................................383 Table A.6.2 Compounds Appearing in Chapter 3...........................................................385 Table A.6.3 Compounds Appearing in Chapter 5...........................................................387
xx
List of Abbreviations [α]D20 specific rotation at 20 °C and wavelength of sodium D line p-ABSA 4-acetamidobenzenesulfonyl azide AcOH acetic acid app. apparent aq aqueous Bn benzyl br broad Bu butyl c concentration in g/100mL C carbon °C degrees Celsius calcd calculated CCl4 carbon tetrachloride CDCl3 chloroform-d CH3CN acetonitrile CHCl3 chloroform CH2Cl2 methylene chloride CI chemical ionization Cs2CO3 cesium carbonate δ chemical shift in ppm downfield from Me4Si d doublet DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC 1,3-dicyclohexylarbodiimide dd doublet of doublets ddd doublet of doublets of doublets DMAP 4-(dimethylamino)pyridine DMF dimethylformamide dt doublet of triplets ea. each Eds. editors EI electron impact equiv equivalent Et ethyl Et2O ethyl ether EtOAc ethyl acetate Et3N triethylamine FAB fast atom bombardment FTIR Fourier transform infrared g gram(s) h hour(s) H hydrogen Hz hertz HBF4 tetrafluoroboric acid HBr hydrobromic acid
xxi
HCl hydrochloric acid HF hydrofluoric acid HPLC high-performance liquid chromatography HR hypersensitive response HRMS high-resolution mass spectrum J coupling constant L liter(s) LDA lithium diisopropylamide LiOH lithium hydroxide lit. literature µ micro m milli, medium (FTIR), multiplet (NMR) M moles per liter Me methyl MeOH methanol Me4Si tetramethylsilane MgSO4 magnesium sulfate mp melting point MHz megahertz min minute(s) mol mole(s) mp melting point MsN3 mesyl azide m/z mass to charge ratio N normal NH4Cl ammonium chloride NaCl sodium chloride NaHCO4 sodium bicarbonate NaOH sodium hydroxide NMR nuclear magnetic resonance O oxygen OAc acetate p para P. Pseudomonas P. s. Pseudomonas syringae pv. pathovar pH hydrogen ion concentration POCl3 phosphorous oxychloride ppm parts per million ppt precipitate q quartet quint. quintuplet Rh2(cap)4 rhodium(II) caprolactam Rh2(OAc)4 rhodium(II) acetate dimer Rh2(NHCOC3F7) rhodium(II) perfluorobutyramide Rh2(tfa)4 rhodium(II) trifluoroacetate dimer
xxii
RuCl3 ruthenium(III) chloride s singlet (NMR), strong (FTIR) sext. sextuplet soln solution t triplet td triplet of doublets TBAF tetrabutylammonium fluoride TBS tert-butyldimethylsilyl TBSOTf tert-butyldimethylsilyl trifluoromethylsulfonate td triplet of doublets TMSCHN2 (trimethylsilyl)diazomethane TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TsOH toluenesulfonic acid w weak
1
Chapter 1
Syringolides: Background and Introduction.
1.1 Biological Background: The Hypersensitive Response.
The hypersensitive response (HR) of plants is an active mechanism of defense
that allows them to resist pathogen infection.1 It involves cell death in the site of
infection and a complex series of biochemical changes in the plant that restrict the
pathogen’s proliferation.
According to the gene-for-gene complementarity hypothesis, first described by
Flor in 1942,2 an HR will only occur if the pathogen contains a specific avirulence (avr)
gene and the plant has a specific resistance (R) gene. These two genes are
complementary since both are required for the HR to occur. If either the pathogen lacks
the avr gene or the plant lacks the corresponding R gene there will be no HR and
infection will not be prevented.
Pathogen avr genes are responsible for the biosynthesis of metabolites named
elicitors that trigger the HR in plants. It is believed that plant R genes encode for specific
receptors for the pathogen elicitors, however these putative receptors have not yet been
characterized and the way they interact with the elicitors and trigger the HR is not well
understood.
1.2 Syringolides: Isolation and Biological Activity.
In 1993 Sims et al.3 reported the isolation of syringolide 1 (1) and syringolide 2
(2), the first nonproteinaceous specific elicitors of a plant HR. Syringolides 1 and 2 are
2
bacterial signal molecules (elicitors) produced by the avirulence gene D (avrD) of
Pseudomonas syringae pv. tomato. The syringolides elicit an HR on soybean cultivars
carrying the resistance gene Rpg4. Through a combination of NMR experiments and X-
ray crystallography Sims et al. determined the structures illustrated in Figure 1.1.
OO
O
HO
O
OO
O
HO
O
OO
O
HO
O HO HHH HOHO
(-)-Syringolide 1 (1) (-)-Syringolide 2 (2) (-)-Syringolide 3 (3)
Figure 1.1 Syringolide elicitors.
In 1994 Yucel et al.4 reported that two different classes of avrD alleles occur in P.
syringae pathovars: class I and class II alleles. Class I alleles include the avrD allele 1
from P. s. pv. lachrimans and the avrD allele from P. s. pv. tomato. Class II alleles
include the avrD allele 2 from P. s. pv. lachrimans and the avrD allele from P. s. pv.
phaseolicola. The same year Yucel and co-workers5 reported that the two classes of
alleles direct the production of different syringolides. Class I avrD alleles are responsible
for the biosynthesis of syringolides 1 (1) and 2 (2) while class II avrD alleles direct the
production of syringolide 1 (1) and syringolide 3 (3), a new member of the syringolide
family.
3
1.3 Syringolides as Molecular Probes.
From the time syringolides were isolated it was believed that they could be used
to study their interaction with the products of soybean Rpg4 genes and help to elucidate
the molecular mechanisms of the HR and plant-pathogen interactions.
It was supposed that syringolide-like molecules could be used as molecular
probes for the isolation of the putative soybean protein receptor (presumably encoded by
the Rpg4 gene) as long as these syringolide derivatives retained their biological activity
and could bind to their receptor. This could be achieved by obtaining biologically active
syringolide derivatives that could either be fixed to a polymer support for affinity
chromatography or, alternatively, be radiolabelled for radioisotope detection.
Two approaches were used for obtaining the requisite syringolide derivatives;
these include:
a) Total synthesis of syringolides that could be easily modified for the production
of derivatives suitable for affinity chromatography6,7 (by incorporating an amino
functionality at the terminus of the aliphatic side chain) or radiolabelling experiments6,8-11
(by addition of radioactive atoms to a double bond at the end of the aliphatic side chain).
b) Derivatization of the natural product to compounds suitable for affinity
chromatography or radiolabelling experiments.12
1.4 Isolation and Characterization of a Syringolide-Binding Protein.
Using a biologically active 123I labelled derivative of natural syringolide 1, 123I-
syringolide 1 (4), Ji et al.13 discovered that syringolide binds specifically to a soluble
protein fraction from soybean leaves. In 1998 Ji et al.14 isolated and characterized a 34-
kDa soybean protein that binds to syringolide. They achieved this with the aid of 4 and
4
an affinity gel chromatography prepared with a biologically active succinyl derivative of
natural syringolide 1 (5). Ji et al. believe this protein may be the protein receptor of
syringolide, although surprisingly this protein is present in plants either harboring or
lacking the Rpg4 gene. These results suggest that initial recognition of the syringolide
elicitor is not done by proteins encoded by Rpg4 as initially presumed, but by receptors
(present in all soybean plants) which transduct a signal which results in an HR only in
plants carrying the Rpg4 gene.15
OO
O
O
OHHO
125I-Syringolide 1 (4)
O125IMeO
MeOOMe
OOO
O
OHHO
OHO
O
4'-Succinyl Syringolide 1 (5)
Figure 1.2 Syringolide 1 derivatives.
1.5 Proposed Biosynthesis of Syringolides.
Sims et al.3 proposed in the original syringolides isolation and characterization
papers a possible biosynthesis for these compounds from common metabolites (Scheme
1.1)
The first step would involve acylation of D-xylulose (6) with a β-ketoacid
derivative such as 7 to furnish the ester intermediate 8. Intramolecular Knoevenagel
condensation of 8 would result in the formation of butenolide 9. Finally, intramolecular
5
Michael addition of the primary alcohol over the α,β-unsaturated system and
hemiketalization would result in the formation of the natural product.
OH
HO
HO
OOH
SCoA
O O
n
7a, n = 37b, n = 57c, n = 1
6
OH
HO
HO
OO
O
On
8a, n = 38b, n = 58c, n = 1
OH
9a, n = 39b, n = 59c, n = 1
O
OO
HO
HOn OO
O
HO
O
n
1, n = 32, n = 53, n = 1
HHO
Scheme 1.1 Proposed Biosynthesis of Syringolides.
1.6 Syntheses of Syringolides.
Since 1995 there have been reported nine different total syntheses of syringolides
1 and 26-10,16-19 and a formal one.11 However, syringolide 3 has yet to be synthesized. As
mentioned earlier, many of these syntheses were designed to allow ready access to
syringolide derivatives suitable for affinity chromatography6-7 or radiolabelling
experiments.6,8-11 All the syringolide syntheses reported to date are outlined below.
6
1.6.1 Wood et al.: Total Synthesis of (+)- and (-)-Syringolides 1 and 2.
In 1995, Wood et al.6 published the first total synthesis of syringolides 1 and 2.
This approach (Scheme 1.2) is based on the proposed biosynthesis of syringolides
(Scheme 1.1) and confirmed the absolute stereochemistry of (-)-syringolides proposed by
Sims et al.3 (Figure 1.1).
OH
OO
14a, n = 314b, n = 5
OTBS
OO
O
On
15a, n = 315b, n = 5
n OO
O
HO
O
n
1, n = 32, n = 5
OTBS
ON2
OTBS
O
O
O
13
Br
OHOHO
O OTBSOHO
O
O
O
OTBS
O
O
O
OO
NaH, THF
TBSCl(65%)
10 11
12
n
16a, n = 316b, n = 5
O
O
1. RuCl3, NaIO42. EtOC(O)Cl, Et3N
3. CH2N2(50%, three steps)
HBr, Et2O
-78 °C(80%)
Cs2CO3, DMF(75-80%)
HCl, THF
(15%)
HO H
Scheme 1.2 Wood et al.: Total Synthesis of (+)- and (-)-Syringolides 1 and 2.
7
In this synthesis, asymmetry originated in the starting material 10 which is
commercially available in both enantiomerically pure forms. The aliphatic side chain of
the β-ketoacids 14 could be easily modified for the production of derivatives suitable for
affinity chromatography (by incorporating an amino functionality) or radiolabelling
experiments (by addition of radioactive atoms to a double bond at the end of the chain)
and this idea was incorporated in several of the subsequent syringolide syntheses. The
key step of the synthesis was the deprotection of 16 to furnish the desired syringolides.
Unfortunately this final step was problematic and low-yielding. Full details of this
synthesis are provided in Chapter 2.
1.6.2 Kuwahara et al.: Total Synthesis of (-)-Syringolides 1 and 2.
Kuwahara et al.7 published the second total synthesis of syringolides (Scheme
1.3). Their approach was very similar to the one by Wood et al., the main difference
being the type of protecting groups used. Deprotection of 22 failed to furnish directly the
syringolides since acetal 23 unexpectedly formed and a second deprotection step was
included. The potential of this approach for the synthesis of aminated syringolide
analogs suitable for affinity chromatography was recognized.
8
DCC, DMAP, CH2Cl2
OTBS
OO
O
On
21a, n = 321b, n = 5
n
OTBS
O
OO
NaH, THF
TBSCl(91%)
17 18
22a, n = 322b, n = 5
Swern
oxidation
p-TsOH
1:5 acetone:water(46-51%)
MOMOMOMO
MOMOMOMO
H
19
MOMO
MOMO
O
OTBS
20a, R = EE20b, R = H
MOMO
MOMO
OOR
MOMO
MOMO
MOMO
MOMO
OO
O
HO
O
n
23a, n = 323b, n = 5
MeO H
1. Bu3SnCH2OEE, n-BuLi, THF2. Swern oxidation
3. PPTS, EtOH(63%, four steps)
SiO2, hexanes-EtOAc
(51-56%, two steps)
Dowex 50W-X8
MeOH(30-36%)
Scheme 1.3 Kuwahara et al.: Total Synthesis of (-)-Syringolides 1 and 2.
OH
OH
OH
OTBS OTBS
OH
OO
14a, n = 314b, n = 5
n
OO
O
HO
O
n
1, n = 32, n = 5
HO H
1.6.3 Murai et al.: Total Synthesis of (-)-Syringolide 1.
Murai et al.8 reported the third syringolide synthesis in 1996 and 1997. Sharpless
asymmetric dihydroxylation of 29a was the source of asymmetry. The final deprotection
step was low-yielding as in previous syntheses. The potential of this approach for the
synthesis of radiolabelled analogs suitable for receptor studies was mentioned.
9
O
OBu
O
33
TBSO
OTBSOTBS
O
OBuO
32
TBSO
OTBSOTBS
O
OBuMPMO
31
TBSO
OTBSOTBS
O
OMPMO
30aa (38%, 90% ee)30ab (57%, 74% ee)
HO
OTBSOH
O
OBuOR
28a, R = H (68%)28b, R = H (26%)29a, R = MPM (82%)29b, R = MPM (100%)OTBS
O
O
26OTBS
O
O
OO
24
O
O
27OTBS
OBu
Cu(CN)Li
OTBS
25
THF, -78 °C
(49%)+
NaH, BuLi, BuBr;20:1 THF:HMPA, 0 °C
(80%)
1. NaBH4, MeOH, -5 °C
2. MPMOC(=NH)CCl3;TfOH, Et2O
AD-mixβMeSO2NH2
1:1 t-BuOH:H2O, 0 °C29a
30ab
TBSOTf, 2,6-lutidine
CH2Cl2 (98%)
1. DDQ, CH2Cl2-H2O
2. PDC, CH2Cl2(72%, two steps)
1. KHMDS, PhSeBr,THF, -78 °C
2. H2O2, Py, CH2Cl2(67%, two steps)
p-TsOH10:1 THF:H2O
(16%, ca. 87% ee)
Scheme 1.4 Murai et al.: Total Synthesis of (-)-Syringolide 1.
OO
O
HO
O
3
1
HO H
10
1.6.4 Rickards and Henschke: Total Synthesis of (-)-Syringolide 2 and (-)-
Deuterosyringolide 2.
Rickards and Henschke9a published the fourth syringolide synthesis in 1996
(Scheme 1.5). This approach is very short and uses D-xylulose (6) as starting material,
just as proposed for the biosynthesis of syringolides. The final step is low-yielding.
O
OO
MeO
HO
OH
O O
O O
OH
O
OO
MeO
HO
O O
5
34
p-MeOC6H4CHO
ZnCl2, sonication(64%)
35b, 0.2 equiv
THF, reflux (67%)
5
36
H2Pd(OH)2/C
AcOH (83%)
Basic Al3O3
THF (6%)
2
Scheme 1.5 Rickards and Henschke: Total Synthesis of (-)-Syringolide 2.
OH
HO
HO
OOH
6
OH
HO
HO
OO
O
O5
8b
OO
O
HO
O
5
HO H
O
11
In 1998 Rickards and Henschke9b reported the synthesis of deuterated syringolide
(41). In this approach (Scheme 1.6) they modified their original synthesis by
incorporating a terminal olefin in the Meldrum’s acid 37 used to acylate 34. In contrast
to their original approach, removal of the p-methoxybenzylidene group of 38 to furnish
39 was effected with TFA instead of 2H2 thus postponing the use of isotopic hydrogen
(2H or 3H) until after the low-yielding cyclization. Unsaturated syringolide analogue 40b
was deuterated to furnish 41 in quantitative yield .
O O
O O
OH37, 0.5 equiv
THF, reflux (38%)
5
O
OO
MeO
HO
O
O O
5
38
OH
OHHO
OO
OO
5
39
67% aq TFA
THF (64%)
O
O
HO
OHHO
40b
4
Basic Al3O3
THF (6%)
2H2, Pd(OH)2/C
AcOH (100%)OO
O
HO
OHHO
41
4
2H
2HO
Scheme 1.6 Rickards and Henschke: Total Synthesis of (-)-Deuterosyringolide 2.
O
OO
MeO
HO
OH
34
12
O
OOH
TBSO
O
O
HO
OTBSOH
O
O
44OTBS
O
O
42
B
OTBS43
+
TfO
O
O
O
O
HO
OO
O
O
TBSO
OO
OO
O
O
TBSO
OO
O
OO
O
OH
O
AD-mixβMeSO2NH2
1:1 t-BuOH:H2O, 0 °C(85%)
45
2,2-Dimethoxypropane
PPTS, DMF(80%)
46
TBSCl, imidazole
DMF (85%)
47
H
O
48a, n = 348b, n = 5
n
Bu2BOTf, i-Pr2NEt(83-87%)
n Dess-Martinperiodinate
CH2Cl2 (93-96%)
49a, n = 349b, n = 5
50a, n = 350b, n = 5
6 N HCl, THF
50a,b
+
51a, n = 3 (44%)51b, n = 5 (40%)
n
Dowex 50W-X8
MeOH(36-40%)
n
Scheme 1.7 Honda et al.: Total Synthesis of (-)-Syringolides 1 and 2.
OO
OHO
O
n23a, n = 323b, n = 5(Kuwahara et al., scheme 1.3)
MeO H
(Ph3P)2PdCl2K3PO4, THF
70 °C (48%)
OO
O
HO
O
n
1, n = 3 (10%)2, n = 5 (12%)
HO H
13
1.6.5 Honda et al.: Total Synthesis of (-)-Syringolides 1 and 2.
The fifth synthesis of syringolides was reported by Honda et al.16 in 1996. As in
the synthesis by Murai et al., Sharpless asymmetric dihydroxylation (in this case of 44)
was the source of asymmetry. The final deprotection step was low-yielding as in
previous syntheses.
1.6.6 Sims et al.: Total Synthesis of (-)- and (+)-Syringolide 1 and (-)-∆7-Syringolide
1.
In 1997, Sims et al.10 published the sixth syringolide synthesis starting with D-
xylose (52). The approach (Scheme 1.8) is short (two steps from 53) but as in previous
syntheses the final step is low-yielding. By replacing D-xylose with L-xylose they
obtained unnatural (+)-syringolide 1 and surprisingly they discovered that both
enantiomers of syringolide 1 are specific elicitors of the HR in soybean plants harboring
the Rpg4 gene. An alternative seven-step synthesis (Scheme 1.9) had a better overall
yield (14% vs. 6.3%).
14
O
OO
HO
O
O
R
O
O
O
HO
OHHO
O
O
OO
HO
OH
53
55, R = -(CH2)4CH356, R = -(CH2)3CH=CH2
1, R = -(CH2)4CH340a, R = -(CH2)3CH=CH2
R
14a, R = -(CH2)4CH354, R = -(CH2)3CH=CH2
R
O
OH
O
1. Pyridine, reflux
2. CuSO4, acetone DCC, DMAP, CH2Cl2, 0 °C(48-49%)
9:1 TFA:H2O
(12-13%)
Scheme 1.8 Sims et al.: Total Synthesis of (-)- and (+)-Syringolide 1 and(-)-∆7-Syringolide 1.
1
H2, 10% Pd/C
(100%)
40a
O
HO
HO
OHOH
52
O
O
HO
OHHO
O O
O
HO
OHHO
O
Exploring the possibility of using their methodology to synthesize radiolabelled
syringolide analogues for receptor studies, Sims et al. modified their first approach by
incorporating a terminal olefin in the β-ketoacid 54 used to acylate 53. Thus, they
obtained unsaturated syringolide analogue 40a which was quantitavely hydrogenated to
syringolide 1 (1) and accordingly it should be easily reduced with 3H to afford tritium-
labelled syringolide 1.
15
O
OO
BnO
O
O
R
O
O
O
BnO
OHHO
O
O O
O O
R OH
O
OO
BnO
OH
57
35a, R = -(CH2)4CH3
58, R = -(CH2)4CH3
60, R = -(CH2)4CH3
R
OBnO
O
O
R
O
59, R = -(CH2)4CH3
HOHO
Toluene, reflux(98%)
9:1 TFA:H2O
(80%)
H2, 10% Pd/C
(100%)
Scheme 1.9 Sims et al.: Total Synthesis of (-)-Syringolide 1.
1. Ph3CCl, pyridine2. BnCl, NaH, DMF
3. 2 N HCl(77%, three steps)
TFA, AcOH
(23%)
OHO
O
O
R
O
61, R = -(CH2)4CH3
HOHOTiCl4, CH2Cl2
-30 °C (80-84%)
pH 6, H2O
(12%)
1
O
O
HO
OHHO
O
1
O
O
HO
OHHO
O
O
OO
HO
OH
53
O
OO
R'O
O
O
R
O
55; R = -(CH2)4CH3, R' = OH58; R = -(CH2)4CH3, R' = OBn
16
O
SiMe3
TBSO
OO
O
O
TBSO
OO
TBSCl, Et3N, DMAP
DMF (96%)
47
Scheme 1.10 Wong et al.: Synthesis of Precursor 47.
OTBSO
OO
67
OHO
OO
64(70% from 62a)(62% from 62b)
OR
LiBEt3H, THF
-78 °C (100%)
1. n-BuLi, THF, -78 °C
2.
62a, R = Sn(n-Bu)362b, R = Br
HO
OO
63
OO
OO
65
PDC, CH2Cl2
(95%)
OHO
OO
66
1. n-BuLi, THF, -78 °C
2. TMSCl(82%, two steps)
68
32% AcOOH, NaOAc
CH2Cl2 (70%)
1.6.7 Wong et al.: Improved Synthesis of (-)-Syringolides 1 and 2.
In 1997 Wong et al.20 synthesized 47 as an intermediate for the total synthesis of
syributins and secosyrins (Scheme 1.10). In 1998 Wong et al.17 published an improved
synthesis of syringolides (seventh in the series) where they used the methodology
developed by Honda et al.16 to obtain syringolide precursors 50 in two steps from 47.
They greatly improved the yield of the final deprotection step to obtain syringolides by
employing 1:1 10% HF:MeCN and discovered that side products 51, obtained in several
17
of the previous syringolide syntheses, could be transformed into the corresponding
syringolides by treating them with p-TsOH in 1:1 acetone:water (Scheme 1.11).
1:1 10% HF:MeCN
Scheme 1.11 Wong et al.: Improved Synthesis of (-)-Syringolides 1 and 2.
Silica gel (60%)
p-TsOH1:1 acetone:H2O
(52%)
O
OOH
TBSOO
O
TBSO
OO
OO
O
O
TBSO
OO
O
OO
O
OH
O
47
H
O
48a, n = 348b, n = 5
n
Bu2BOTf, i-Pr2NEt(83-88%)
n
Dess-Martinperiodinate
CH2Cl2 (89-91%)
49a, n = 349b, n = 5
50a, n = 350b, n = 5
51a, n = 351b, n = 5
n
n
OO
O
HO
O
n
1, n = 3 (56%)2, n = 5 (52%)
HO H
1.6.8 Chênevert and Dasser: Total Synthesis of (-)-Syringolide 2.
The eight total synthesis of syringolides was reported by Chênevert and Dasser18
this year. They used di-O-isopropylidene-D-arabinose (69) as the source of asymmetry
(Scheme 1.12) and the final deprotection was made in two steps with good overall yield.
18
5
OMPM
O
O
O
OO
69
O
O
Scheme 1.12 Chênevert and Dasser: Total Synthesis of (-)-Syringolide 2.
O
H
OO
71
O
O OH
OO
O
O OMPM
OO
O
O OMPM
OHOH
O
O OMPM
OHOAc O
O OMPM
OOAc
O
O OMPM
OOH
NaBH4, EtOH
(90%)
70
NaH, MPMCl
DMF (91%)
MeOH, p-TsOH
(73%)
72
AcCl, 2,4,6-collidine
-78 °C (90%)
73
(COCl)2, DMSO
(87%)
74
Candida antartica lipase
EtOH, (i-Pr)2O(85%)
75
1. THF, reflux, 35b
2. SiO2, 9:1 hexanes:EtOAc(71%, two steps)
76
5
OH
O
O
O
OO
77
DDQ, CH2Cl2, H2O
(83%)
p-TsOH1:1.2 acetone:H2O
(54%)
2
OO
O
HO
O
5
HO H
O O
O O
OH5
Also this year they reported a ninth total synthesis of syringolides19 wherein the
protected D-xylulose derivative 75 was produced in three steps from aldehyde 78 and
19
dihydroxyacetone phosphate (79) (Scheme 1.13) . The key step of the synthesis is the
enantiospecific condensation of 78 and 79 in the presence of fructose 1,6-diphosphate
aldolase (FDP aldolase).
Scheme 1.13 Chênevert and Dasser: Improved Total Synthesis of (-)-Syringolide 2.
OMPM
OOHHO
HO
OOPO3
=HOOMPMH
O+
78 79
80
1. FDP aldolase, H2O, DMF
2. Acid phosphatase(65%, two steps)
Acetone, p-TsOH
(67%)
5
OMPM
O
O
O
OO
O
O OMPM
OOH
75
1. THF, reflux, 35b
2. SiO2, 9:1 hexanes:EtOAc(71%, two steps)
76
5
OH
O
O
O
OO
77
DDQ, CH2Cl2, H2O
(83%)
p-TsOH1:1.2 acetone:H2O
(54%)
2
OO
O
HO
O
5
HO H
O O
O O
OH5
1.6.9 Yoda et al.: Formal Synthesis of (-)-Syringolide 1.
In 1997 Yoda et al.11 published a formal synthesis of syringolides using 1,2-O-
isopropylidene-D-xylofuranose (81) as the source of asymmetry (Scheme 1.14). They
20
accomplished the synthesis of the syringolide precursors 23, previously reported by
Kuwahara et al.7 and the potential of this approach for the synthesis of radiolabelled
analogs suitable for receptor studies was mentioned.
Scheme 1.14 Yoda et al.: Formal Synthesis of (-)-Syringolide 1.
OO
OHO
HO OOMe
OBnBnO
BnO
OH
BnOOBn
OH
OMOM
BnOOBn
OH
OMOM
O
O
O3
OBnBnO
BnOOMOM
O
O
O3
OBnO
O
Ph
OMOM
O
O
Ph O
OO
3
1. NaH, BnBr,THF (93%)
2. MeOH, concd HCl (93%)
81 82
83 84
1. 8:1 AcOH:H2O,100 °C (91%)
2. NaBH4, EtOH(96%)
1. TBDPSCl, imidazole,DMF (92%)
2. MOMCl, (i-Pr)2Et,CH2Cl2 (97%)3. BuNF4, THF (98%)
DCC, DMAP,CH2Cl2 (92%)
85
1. 4.4% HCOOH-MeOHPd (black), 40 °C (94%)
2. PhCH(OMe)2, p-TsOH(60%)
86
1. PCC, MS4A, CH2Cl2
2. Silica gel, hexanes:EtOAc(27%, two steps)
Dowex 50W-X8
MeOH(40%)
87
OO
OHO
O
n
23a, n = 323b, n = 5
MeO H
OH
OO
14a3
OBn OBn
21
1.7 References.
(1) (a) Keen, N. T. Adv. Bot. Res. 1999, 30, 291-328. (b) Strange, R. N. Sci.
Progr. 1998, 81, 35-68. (c) Heath, M. C. Eur. J. Plant. Pathol. 1998, 104, 117-124. (d)
Staskawicz, B. J.; Ausubel, F. M.; Baker, B. J.; Ellis, J. G.; Jones, J. D. G. Science 1995,
268, 661-667. (e) Keen, N. T. In Mechanisms of Plant Defense Responses; Fritig, B.;
Legrand, M., Eds.; Kluwer Academic: Boston, 1993; pp 3-11. (f) Keen, N. T. Plant
Molecular Biology 1992, 19, 109-122. (g) Keen, N. T. Annu. Rev. Genet. 1990, 24, 447-
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(2) Flor, H. H. Phytopathology 1942, 32, 653-669.
(3) (a) Smith, M. J., Mazzola, E. P.; Sims, J. J.; Midland, S. L.; Keen, N. T.;
Burton, V.; Stayton, M. M. Tetrahedron Lett. 1993, 34, 223-226. (b) Midland, S. L.;
Keen, N. T.; Sims, J. J.; Midland, M. M.; Stayton, M. M.; Burton, V.; Smith, M. J.,
Mazzola, E. P.; Graham, K. J.; Clardy, J. J. Org. Chem. 1993, 58, 2940-2945.
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1994, 7, 131-139.
22
(5) (a) Yucel, I.; Midland, S. L.; Sims, J. J.; Keen, N. T. Mol. Plant-Microbe
Interact. 1994, 7, 148-150. (b) Keen, N.; Midland, S. L.; Boyd, C.; Yucel, I.; Tsurushima,
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Interactions; Daniels, M. J.; Downie, J. A.; Osburn, A. E., Eds.; Kluwer Academic:
Boston, 1994; Vol. 3, pp 41-48.
(6) Wood, J. L.; Jeong, S.; Salcedo, A.; Jenkins, J. J. Org. Chem. 1995, 60, 286-
287.
(7) (a) Kuwahara, S.; Moriguchi, M.; Miyagawa, K.; Konno, M.; Kodama O.
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Konno, M.; Kodama O. Tetrahedron, 1995, 51, 8809-8814.
(8) (a) Ishihara, I.; Sugimoto, T.; Murai, A.; Synlett 1996, 335-336. (b) Ishihara,
I.; Sugimoto, T.; Murai, A.; Tetrahedron 1997, 53, 16029-16040.
(9) Henschke, J. P.; Rickards, R. W. Tetrahedron Lett. 1996, 37, 3557-3560. (b)
Henschke, J. P.; Rickards, R. W. J. Labelled Cpd. Radiopharm. 1998, 41, 211-220.
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4780-4784.
23
(11) Yoda, H.; Kawauchi, M.; Takabe, K.; Hosoya, K. Heterocycles 1997, 45,
1895-1898.
(12) Tsurushima, T.; Midland, S. L.; Zeng, C.-M.; Ji, C.; Sims, J. J.; Keen, N. T.
Phytochemistry 1996, 43, 1219-1225.
(13) Ji, C.; Okinaka, Y.; Takeuchi, T.; Tsurushima, T.; Buzzell, R. I.; Sims, J. J.;
Midland, S. L.; Salymaker, D.; Yoshikawa, M.; Yamaoka, N.; Keen, N. T. The Plant Cell
1997, 9, 1425-1433.
(14) Ji, C.; Boyd; C.; Salymaker, D.; Okinaka, Y.; Takeuchi, T.; Midland, S. L.;
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(15) Ji, C.; Smith-Becker, J.; Keen, N. T. Curr. Opin. Biothechnol. 1998, 9, 202-
207.
(16) Honda, T.; Mizutani, H.; Kanai, K. J. Org. Chem. 1996, 61, 9374-9378.
(17) Yu, P.; Wang, Q.-G.; Mak, T. C. W.; Wong, H. N. C. Tetrahedron, 1998, 54,
1783-1788.
(18) Chênevert, R.; Dasser, M. Can. J. Chem. 2000, 78, 275-279.
24
(19) Chênevert, R.; Dasser, M. J. Org. Chem. 2000, 65, 4529-4531.
(20) Yu, P.; Yang, Y.; Zhang, Z. Y.; Mak, T. C. W.; Wong, H. N. C. J. Org
Chem. 1997, 62, 6359-6366.
25
Chapter 2
Syringolides: Biomimetic Total Synthesis.
2.1 Retrosynthetic analysis.
According to the proposed biosynthesis of syringolides (Scheme 2.1), these
metabolites can be formed by condensation between D-xylulose (6) and a β-ketoacid such
as 7 to produce the ester intermediate 8 which could undergo an intramolecular
Knoevenagel condensation to furnish lactone 9. Finally, intramolecular Michael addition
of the primary alcohol over the α,β-unsaturated system and hemiketalization would result
in the formation of the natural product.
OH
HO
HO
OOH
SCoA
O O
n
7a, n = 37b, n = 57c, n = 1
6
OH
HO
HO
OO
O
On
8a, n = 38b, n = 58c, n = 1
OH
9a, n = 39b, n = 59c, n = 1
O
OO
HO
HOn OO
O
HO
O
n
Syringolide 1 (1, n = 3)Syringolide 2 (2, n = 5)Syringolide 3 (3, n = 1)
HHO
Scheme 2.1 Proposed Biosynthesis of Syringolides.
26
Based on this proposed biosynthetic pathway, the retrosynthetic analysis shown
on Scheme 2.2 was devised. In this approach, the lactone required for the syringolide
synthesis would be obtained by complete deprotection of butenolide 16. This butenolide
could arise from intramolecular Knoevenagel condensation of ester 15, which would be
produced by condensation between the α-bromoketone 13 and a β-ketoacid 14. The
different syringolides would be synthesized by changing the length of the side chain of
the β-ketoacid 14. This side chain could also be easily modified for the production of
syringolide derivatives suitable for affinity chromatography (by incorporating an amino
functionality) or radiolabelling experiments (by addition of radioactive atoms to a double
bond at the end of the chain).
OH
OO
14a, n = 314b, n = 514c, n = 1
OTBS
OO
O
On
15a, n = 315b, n = 515c, n = 1
nOO
O
HO
O
n
1, n = 32, n = 53, n = 1
OTBS
ON2
O
O
OTBS
O
O
O
OO
13
n
16a, n = 316b, n = 516c, n = 1
O
O
HO H
Scheme 2.2 Syringolides: Retrosynthetic Analysis.
+
27
2.2 Biomimetic Total Synthesis of (-)-Syringolides 1, 2 and 3.
The total synthesis of (-)-syringolides 1, 2 and 3 (1, 2 and 3, respectively) is
described on Scheme 2.3. The starting material was the monoprotected alcohol (-)-111
which is commercially available in both enantiomeric forms and can be easily prepared in
quantitative yield2 from (-)-2,3-O-isopropylidene-D-threitol [(-)-10, Figure 2.1] using the
monosilylation procedure of McDougal et al.3 Moreover, (-)-10 can be obtained from (-)-
D-tartaric acid [(-)-88] on multigram scale4 and by replacing (-)-D-tartaric acid with (+)-
L-tartaric acid the alcohols (+)-10 and (+)-11 can be prepared.
OHOHO
O
(-)-10
OHOH
(-)-88
O
OHO
HO
OTBSOHO
O
(-)-11
Figure 2.1 (-)-11 and Precursors.
As illustrated in Scheme 2.3, alcohol (-)-11 was transformed into α-bromoketone
(-)-13 via a four-step procedure without purification of the intermediates. First 11 was
oxidized to the corresponding carboxylic acid 89 using the catalytic RuCl3 procedure of
Sharpless et al.5 Acid 89 was treated first with ethyl chloroformate and triethylamine and
then with excess diazomethane6 to furnish (-)-12. Halogenation6 of (-)-12 with
anhydrous ethereal HBr provided (-)-13 in 29% overall yield from (-)-11. This α-
bromoketone (-)-13 was the common intermediate for the synthesis of all three
syringolides and their amino analogue.
28
OH
OO
14a, n = 314b, n = 514c, n = 1
OTBS
OO
O
On
15a, n = 315b, n = 515c, n = 1
n
OO
O
HO
O
n
(-)-1, n = 3 (12%)(-)-2, n = 5 (8%)(-)-3, n = 1 (7%)
OTBS
ON2
OTBS
O
O
O
(-)-13
Br
OTBSOHO
O
O
O
OTBS
O
O
O
OO
(-)-11
(-)-12
n
(-)-16a, n = 3 (50%)(-)-16b, n = 5 (47%)(-)-16c, n = 1 (53%)
O
O
1. EtOC(O)Cl, Et3N
2. CH2N2
HBr, Et2O, -78 °C
(29%, four steps) Cs2CO3, DMF
HF, H2O/CH3CN
HO H
Scheme 2.3 Biomimetic Total Synthesis of (-)-Syringolides 1, 2 and 3
OTBSOHO
O
89
ORuCl3, NaIO4
CCl4/CH3CN/H2O
OO
O
OH
O
(-)-51a, n = 3 (8%)(-)-51b, n = 5 (10%)(-)-51c, n = 1 (7%)
n
+
According to the retrosynthetic analysis, different syringolides could be obtained
after several steps by changing the length of the β-ketoacid 147 used to acylate (-)-13.
29
This acylation was performed by treating (-)-13 with the cesium salts9 of β-ketoacids
14a-b10 and 14c.11 The expected ester intermediates 15a-c were not detected since they
underwent an intramolecular Knoevenagel condensation in the same pot to furnish the
desired butenolides (-)-16a-c in 47-53% yields.12
The final step of the synthesis involved complete deprotection of butenolides (-)-
16a-c using 10% aq HF in CH3CN13 to furnish the corresponding syringolides (-)-1, (-)-2
and (-)-3 in 7-12% yields, along with the side products (-)-51a-c in 7-10% yields.
Spectroscopic data for (-)-syringolides 1 and 2 were identical to that reported in the
literature.14,15 Synthetic (-)-syringolide 2 was identical in all respects with a sample
derived from natural sources16 of the natural product (Figure 2.2). There is no published
data for (-)-syringolide 3, however, spectroscopic data for this compound is similar to
that for (-)-syringolides 1 and 2 and X-ray crystallographic analysis of (-)-3 confirms that
this compound has the same relative stereochemical configuration as (-)-1 and (-)-2.14
2.3 Biomimetic Total Synthesis of (+)-Syringolides 1, 2 and 3.
The total synthesis of (+)-syringolides 1, 2 and 3 was accomplished in the same
manner as for the corresponding (-)-syringolides by replacing (-)-11 with (+)-11. Thus,
α-bromoketone (+)-13 was obtained in 35% overall yield form (+)-11 and was treated
with the β-ketoacids 14a-c to give butenolides (+)-16a-c in 42-51% yields. Deprotection
of these butenolides furnished the corresponding syringolides (+)-1, (+)-2 and (+)-3 in
10-17% yields, along with the side products (+)-51a-c in 6-10% yields.
30 30
OOO
HO
OHO H
(-)-Syringolide 2(-)-2
Top: Natural Bottom: Synthetic
Figure 2.2 1H NMR (500 MHz, CDCl3) Comparison of (-)-Siringolide 2.
31 31
OOO
HO
OHO H
(-)-Syringolide 2(-)-2
Figure 2.2 1H NMR (500 MHz, CDCl3) Comparison of (-)-Siringolide 2.
Top: Natural Bottom: Synthetic
31
2.4 Biomimetic Total Synthesis of (-)-N-(Carbobenzyloxy)-8-aminosyringolide 1.
As mentioned in Chapter 1, it was supposed that syringolide-like molecules could
be used as molecular probes for the isolation of the receptor protein in soybean provided
these derivatives retained their biological activity and could bind to their receptor.
OH
OO
NH
4
OO
O
HO
OHN
4
(-)-92 (11%)
OTBS
O
O
O
ONH
O
4
(-)-91
Cs2CO3, DMF
(45%)
HF, H2O/CH3CN
HO H
Scheme 2.4 Biomimetic Total Synthesis of (-)-N-(Carbobenzyloxy)-8-aminosyringolide 1.
OO
O
OH
O
HN
(-)-93 (5%)
4+
O
O
90
O
O
O
O
+
O
O
OTBS
O
O
O
(-)-13
Br
To this end, a synthesis of (-)-N-(carbobenzyloxy)-8-aminosyringolide 1 [(-)-92]
was initiated by incorporating β-ketoacid 9017 into the biomimetic syringolide synthesis
(Scheme 2.4). Thus, α-bromoketone (-)-13 was treated with β-ketoacid 90 to give
butenolide (-)-91 in 45% yield. Deprotection of (-)-91 furnished (-)-N-(carbobenzyloxy)-
32
8-aminosyringolide 1 [(-)-92] in 11% yield, along with the corresponding side product
(-)-93 in 5% yield. It was found that, just as syringolides, (-)-N-(carbobenzyloxy)-8-
aminosyringolide 1 is a specific elicitor of the HR in soybean plants harboring the Rpg4
gene.18 Therefore, (-)-N-(carbobenzyloxy)-8-aminosyringolide 1 would be a good
candidate for use in affinity columns designed to isolate the soybean protein that binds
syringolide.
2.5 Conclusions.
The first total synthesis of (-)-syringolide 3 and its unnatural enantiomer (+)-
syringolide 3 was successfully completed following a biomimetic procedure. In addition,
total synthesis of (-)- and (+)-syringolides 1 and 2 was achieved using the same
methodology. This biomimetic route was easily modified to obtain (-)-N-
(carbobenzyloxy)-8-aminosyringolide 1, a good candidate for the preparation of affinity
columns designed for isolation of the soybean protein that binds to syringolide.
33
2.6 Experimental Section.
2.6.1 Materials and Methods.
Unless stated otherwise, reactions were performed in flame dried glassware under
a nitrogen atmosphere, using freshly distilled solvents. Diethyl ether (Et2O) and
tetrahydrofuran (THF) were distilled from sodium/benzophenone ketyl. Methylene
chloride (CH2Cl2) and triethylamine (Et3N) were distilled from calcium hydride. All
other commercially obtained reagents were used as received.
Unless stated otherwise, all reactions were magnetically stirred and monitored by
thin-layer chromatography (TLC) using E. Merck silica gel 60 F254 precoated plates (0.25
mm). Column or flash chromatography was performed with the indicated solvents using
silica gel (230-400 mesh) purchased from Bodman. In general, the chromatography
guidelines reported by Still et al.19 were followed. When reactions were adsorbed onto
silica gel, the amount of silica gel used was equal to two times the weight of the reagents.
All melting points were obtained on a Thomas Hoover capillary melting point
apparatus and are uncorrected. Infrared spectra were recorded on a Midac M1200 FTIR.
1H and 13C NMR spectra were recorded on a Bruker AM-500, Bruker Avance DPX-500
or Bruker Avance DPX-400 spectrometer. Chemical shifts are reported relative to
internal chloroform (1H, δ 7.26 ppm; 13C, δ 77.2 ppm)20, Me4Si (1H, δ 0.00 ppm) or
acetone (1H, δ 2.05 ppm; 13C, δ 29.8 ppm).20 High resolution mass spectra were
performed at the University of Illinois Mass Spectrometry Center. High performance
liquid chromatography (HPLC) was performed on a Waters 510 solvent delivery system
using a Rainin Microsorb 80-199-C5 column, or a Rainin Dynamax SD-200 solvent
34
delivery system with a Rainin Microsorb 80-120-C5 column. Optical rotations were
measured on a Perkin Elmer 341 polarimeter. Single-crystal X-ray analyses were
performed by Susan DeGala of Yale University.
For purposes of this work, in any given reaction the number of equivalents of a
reactant A is equal to the number of mmol of A used per mmol of the limiting reagent B
employed. The phrase: “was allowed to warm to room temperature” should be taken to
mean that no more cooling agent (ice or dry-ice) was added to the insulating cooling bath.
2.6.2 Preparative Procedures.
Preparation of α-Diazoketone (-)-12.
OTBS
ON2
(-)-12
O
O
α-Diazoketone (-)-12. This compound was prepared in the same manner as its
enantiomer (+)-12 and was used without purification. An analytical sample (yellow oil)
was prepared by flash column chromatography followed by HPLC employing 9:1
hexanes:EtOAc as eluant in both cases: [α]D20 -20° (c 1.02, CHCl3); FTIR (thin
film/NaCl) 3128 (m), 2992 (m), 2956 (s), 2930 (s), 2856 (s), 2118 (m), 1621 (s), 1472
(w), 1460 (m), 1453 (m), 1380 (s), 1361 (s), 1254 (s), 1078 (s), 840 (s) cm-1; 1H NMR
(500 MHz, CDCl3) δ 5.82 (s, 1H), 4.36 (d, J=7.7 Hz, 1H), 4.09-4.08 (m, 1H), 3.95 (dd,
J=11.4, 2.6 Hz, 1H), 3.79 (dd, J=11.2, 4.0 Hz, 1H), 1.45 (s, 3H), 1.42 (s, 3H), 0.90 (s,
35
9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 194.5, 111.0, 80.4, 79.4,
62.9, 52.9, 27.0, 26.5, 26.1, 18.5, -5.1, -5.3; HRMS (CI, isobutane) m/z 315.1740 [calcd
for C14H27N2O4Si (M+H) 315.1740].
Preparation of α-Diazoketone (+)-12.
TBSO
ON2
(+)-12
O
O
α-Diazoketone (+)-12. To a stirred biphasic solution of mono-protected alcohol
(+)-11 (5.532 g, 20.01 mmol, 1 equiv), CCl4 (40 mL), CH3CN (40 mL) and water (60
mL) were added sodium periodate (12.894 g, 60.28 mmol, 3.01 equiv) and RuCl3 hydrate
(210 mg, 0.93 mmol, 0.05 equiv).5b After vigorously stirring the reaction mixture
overnight, water (165 mL) and CH2Cl2 (120 mL) were added. The phases were separated
and the aqueous one was extracted with CH2Cl2 (2 X 180 mL). The combined organic
phases were dried over MgSO4, filtered and concentrated in vacuo to furnish acid 89 as a
purple oil (3.914 g, 67% yield) which was used without purification.
Triethylamine (2.2 mL, 15.78 mmol) and ethyl chloroformate (1.4 mL, 14.64
mmol) were sequentially added to a stirred (–10 °C) solution of acid 89 (3.914 g, 13.48
mmol) in THF (17 ml). After 10 min of stirring, a white ppt formed. Excess
diazomethane in Et2O (146 mL) was added at -10 °C and the resultant mixture was stirred
(0 °C) for 30 min. The reaction mixture was allowed to warm to room temperature,
quenched with 0.1 M aqueous acetic acid (40.5 mL) and stirred until the deep yellow
36
color of diazomethane was no longer present. The biphasic mixture was separated and
the organic phase was washed with saturated aqueous NaHCO3 (2 X 81 mL). The
aqueous washings were extracted with CH2Cl2 (81 mL) and the combined organic phases
were dried over MgSO4, filtered and concentrated in vacuo. The resultant yellow oil was
chromatographed on silica employing 4:1 hexanes:EtOAc as eluant to furnish (+)-12
(2.958 g, 70% yield) as a yellow oil An analytical sample (yellow oil) was obtained by
HPLC employing 9:1 hexanes:EtOAc as eluant: [α]D20 +19° (c 1.01, CHCl3); FTIR
(thin film/NaCl) 3129 (m), 2992 (m), 2957 (s), 2934 (s), 2856 (s), 2114 (m), 1622 (m),
1471 (w), 1460 (m), 1454 (m), 1381 (s), 1361 (s), 1254 (s), 1078 (s), 840 (s) cm-1; 1H
NMR (500 MHz, CDCl3) δ 5.81 (s, 1H), 4.34 (d, J=7.6 Hz, 1H), 4.08-4.05 (m, 1H), 3.93
(dd, J=11.5, 2.4 Hz, 1H), 3.77 (dd, J=11.5, 4.1 Hz, 1H), 1.43 (s, 3H), 1.40 (s, 3H), 0.89
(s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 194.4, 110.9, 80.3,
79.3, 62.9, 52.8, 27.0, 26.4, 26.0, 18.5, -5.2, -5.3; HRMS (CI, isobutane) m/z 315.1753
[calcd for C14H27N2O4Si (M+H) 315.1740].
Preparation of α-Bromoketone (-)-13.
OTBS
O
O
O
(-)-13
Br
α-Bromoketone (-)-13. This compound was prepared in the same manner as its
enantiomer (+)-13 [29% overall yield from (-)-11]. An analytical sample (colorless oil)
was prepared by flash column chromatography employing 9:1 hexanes:EtOAc as eluant:
37
[α]D20 -17° (c 0.95, CHCl3); FTIR (thin film/NaCl) 2988 (w), 2954 (s), 2930 (s), 2885
(m), 2858 (m), 1733 (m), 1472 (w), 1463 (w), 1383 (m), 1374 (m), 1254 (s), 1216 (m),
1146 (s), 1096 (s), 838 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 4.57 (d, J=7.5 Hz, 1H),
4.28 (d, J=13.7 Hz, 1H), 4.24 (d, J=13.7 Hz, 1H), 4.14 (app. dt, J=7.4, 3.7 Hz, 1H), 3.89
(dd, J=11.3, 3.4 Hz, 1H), 3.79 (dd, J=11.3, 3.6 Hz, 1H), 1.46 (s, 3H), 1.43 (s, 3H), 0.90
(s, 9H), 0.08 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 201.1, 111.3, 79.9, 79.4, 62.7, 32.5,
27.0, 26.5, 26.1, 18.6, -5.1, -5.3; HRMS (CI, isobutane) m/z 369.0910 [calcd for
C14H2181BrO4Si (M+H) 369.0920].
Preparation of α-Bromoketone (+)-13.
TBSO
O
O
O
(+)-13
Br
α-Bromoketone (+)-13. A ca. 1 M soln of HBr in MeOH was prepared by
adding MeOH (0.85 mL, 20.98 mmol, 2.90 equiv) to a stirred (0 °C) solution of acetyl
bromide (1.04 mL, 14.07 mmol, 1.95 equiv) in Et2O (14 mL). The HBr solution was
added dropwise to a stirred (-78 °C) solution of (+)-12 (2.272 g, 7.23 mol, 1 equiv) in
Et2O (12 mL). Gas evolution was immediately noted upon addition of the HBr solution.
After stirring at -78 °C for 30 min, saturated aqueous NaHCO3 (48 mL) was added. After
allowing to warm to room temperature, the biphasic mixture was separated and the
organic phase was washed with saturated aqueous NaHCO3 (2 X 48 mL) and brine (60
mL). The aqueous washings were extracted with CH2Cl2 (48 mL) and then the combined
38
organic phases were dried over MgSO4, filtered and concentrated in vacuo. The resultant
yellow oil was chromatographed on silica employing 9:1 hexanes:EtOAc as eluant to
furnish (+)-13 (1.955 g, 74% yield) as a yellowish oil. An analytical sample (colorless
oil) was obtained by a second flash chromatography employing 9:1 hexanes:EtOAc as
eluant: [α]D20 +16° (c 1.33, CHCl3); FTIR (thin film/NaCl) 2989 (w), 2954 (s), 2930 (s),
2885 (m), 2858 (m), 1733 (m), 1472 (w), 1463 (w), 1383 (m), 1374 (m), 1254 (s), 1216
(m), 1146 (s), 1096 (s), 838 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 4.57 (d, J=7.5 Hz,
1H), 4.28 (d, J=13.7 Hz, 1H), 4.24 (d, J=13.7 Hz, 1H), 4.14 (app. dt, J=7.4, 3.7 Hz, 1H),
3.89 (dd, J=11.3, 3.4 Hz, 1H), 3.79 (dd, J=11.3, 3.6 Hz, 1H), 1.46 (s, 3H), 1.43 (s, 3H),
0.90 (s, 9H), 0.08 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 200.6, 110.9, 79.5, 79.1, 62.4,
32.3, 26.7, 26.3, 25.8, 18.2, -5.4, -5.5; HRMS (CI, isobutane) m/z 369.0910 [calcd for
C14H2181BrO4Si (M+H) 369.0920].
Preparation of Butenolide (-)-16a.
OTBS
O
O
O
OO
(-)-16a
Butenolide (-)-16a. This compound was prepared in the same manner as its
enantiomer (+)-16a (50% yield). An analytical sample (yellow oil) was prepared by flash
column chromatography employing 9:1 hexanes:EtOAc as eluant: [α]D20 -38° (c 0.97,
CHCl3); FTIR (thin film/NaCl) 2987 (m), 2956 (s), 2931 (s), 2858 (m), 1769 (s), 1694
39
(m), 1632 (m), 1471 (m), 1463 (m), 1381 (m), 1373 (m), 1252 (m), 1090 (s), 838 (s) cm-
1; 1H NMR (500 MHz, CDCl3) δ 5.48 (d, J=7.4 Hz, 1H), 5.05 (d, J=19.4 Hz, 1H), 4.88
(dd, J=19.8, 0.9 Hz, 1H), 3.93-3.84 (m, 3H), 2.96 (dt, J=18.4, 7.5 Hz, 1H), 2.91 (dt,
J=18.2, 7.4 Hz, 1H), 1.60 (quint., J=7.2 Hz, 2H), 1.44 (s, 6H), 1.36-1.25 (m, 4H), 0.91-
0.86 (m, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
196.6, 173.3, 170.5, 126.9, 111.2, 83.0, 73.5, 69.3, 63.6, 42.1, 31.4, 27.1, 27.0, 26.1, 23.0,
22.7, 18.6, 14.1, -5.1, -5.2; HRMS (CI, isobutane) m/z 427.2499 [calcd for C22H39SiO6
(M+H) 427.2516].
Preparation of Butenolide (+)-16a.
TBSO
O
O
O
O O
(+)-16a
Butenolide (+)-16a. To a stirred solution of β-ketoacid 14a (548 mg, 3.58 mmol,
1.26 equiv) and α-bromoketone (+)-13 (1.010 g, 2.75 mmol, 1 equiv) in DMF (3 mL)
was added in small portions over a 10 min period solid Cs2CO3 (1.167 g, 3.58 mmol, 1.30
equiv). The reaction mixture was stirred at room temperature for 30 min and then diluted
with water and EtOAc (10 mL ea.). The aqueous layer was acidified to pH 1 with 1 N
HCl and extracted with EtOAc (3 X 20 mL). The combined organic layers were dried
over MgSO4, filtered and concentrated in vacuo to a brown oil. Silica gel
chromatography employing 9:1 hexanes:EtOAc as eluant furnished (+)-16a (546 mg,
40
47% yield) as a yellow oil. An analytical sample (yellow oil) was obtained by a second
flash chromatography using 9:1 hexanes:EtOAc as eluant: [α]D20 +37° (c 1.03, CHCl3);
FTIR (thin film/NaCl) 2987 (m), 2956 (s), 2931 (s), 2858 (m), 1769 (s), 1693 (m), 1632
(m), 1471 (m), 1463 (m), 1381 (m), 1373 (m), 1252 (m), 1090 (s), 838 (s) cm-1; 1H
NMR (500 MHz, CDCl3) δ 5.48 (d, J=7.4 Hz, 1H), 5.05 (d, J=19.6 Hz, 1H), 4.88 (dd,
J=19.6, 0.5 Hz, 1H), 3.928-3.847 (m, 3H), 2.96 (dt, J=18.3, 7.5 Hz, 1H), 2.91 (dt, J=18.6,
7.3 Hz, 1H), 1.60 (quint., J=7.3 Hz, 2H), 1.44 (s, 6H), 1.35-1.25 (m, 4H), 0.91-0.86 (m,
3H), 0.88 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 196.6,
173.2, 170.5, 126.8, 111.2, 83.0, 73.5, 69.3, 63.6, 42.1, 31.4, 27.1, 26.9, 26.1, 23.0, 22.7,
18.6, 14.1, -5.2 (2); HRMS (CI, isobutane) m/z 427.2512 [calcd for C22H39SiO6 (M+H)
427.2516].
Preparation of Butenolide (-)-16b.
OTBS
O
O
O
OO
(-)-16b
Butenolide (-)-16b. To a stirred solution of β-ketoacid 14b (956 mg, 5.13 mmol,
1.27 equiv) and α-bromoketone (-)-13 (1.487 g, 4.05 mmol, 1 equiv) in DMF (4.5 mL)
was added in small portions over a 10 min period solid Cs2CO3 (1.723 g, 5.29 mmol, 1.31
equiv). The reaction mixture was stirred at room temperature for 30 min and then diluted
with water and EtOAc (15 mL ea.). The aqueous layer was acidified to pH 1 with 1 N
41
HCl and extracted with EtOAc (3 X 30 mL). The combined organic layers were dried
over MgSO4, filtered and concentrated in vacuo to a brown oil. Silica gel
chromatography employing 9:1 hexanes:EtOAc as eluant furnished (-)-16b (863 mg,
47% yield) as a yellow oil. An analytical sample (yellow oil) was obtained by a second
flash chromatography using 9:1 hexanes:EtOAc as eluant: [α]D20 -36° (c 0.57, CHCl3);
FTIR (thin film/NaCl) 2986 (w), 2955 (m), 2930 (s), 2857 (m), 1769 (s), 1693 (m), 1632
(w), 1463 (w), 1381 (m), 1373 (m), 1252 (m), 1089 (m), 838 (s) cm-1; 1H NMR (500
MHz, CDCl3) δ 5.48 (d, J=6.9 Hz, 1H), 5.05 (d, J=19.4 Hz, 1H), 4.88 (dd, J=19.7, 0.9
Hz, 1H), 3.93-3.85 (m, 3H), 2.96 (dt, J=17.8, 7.4 Hz, 1H), 2.91 (dt, J=18.0, 7.4 Hz, 1H),
1.59 (quint., J=7.1 Hz, 2H), 1.44 (s, 6H), 1.31-1.27 (m, 8H), 0.95-0.86 (m, 3H), 0.89 (s,
9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 196.6, 173.2, 170.5,
126.9, 111.2, 83.0, 73.5, 69.3, 63.6, 42.2, 31.9, 29.3, 29.2, 27.1, 27.0, 26.1, 23.3, 22.8,
18.6, 14.3, -5.1, -5.2; HRMS (CI, isobutane) m/z 455.2820 [calcd for C24H43SiO6
(M+H) 455.2829].
Preparation of Butenolide (+)-16b.
TBSO
O
O
O
O O
(+)-16b
Butenolide (+)-16b. This compound was prepared in the same manner as its
enantiomer (-)-16b (42% yield). An analytical sample (yellow oil) was prepared by flash
42
column chromatography employing 9:1 hexanes:EtOAc as eluant: [α]D20 +35° (c 0.86,
CHCl3); FTIR (thin film/NaCl) 2986 (w), 2955 (m), 2930 (s), 2857 (m), 1769 (s), 1693
(s), 1693 (m), 1632 (m), 1463 (w), 1381 (m), 1373 (m), 1252 (m), 1089 (m), 838 (s) cm-
1; 1H NMR (500 MHz, CDCl3) δ 5.49 (d, J=7.2 Hz, 1H), 5.05 (dd, J=19.5 Hz, 1H), 4.89
(dd, J=19.7, 0.9 Hz, 1H), 3.93-3.85 (m, 3H), 2.97 (dt, J=18.1, 7.5 Hz, 1H), 2.93 (dt,
J=18.3, 7.5 Hz, 1H), 1.59 (quint., J=7.0 Hz, 2H), 1.44 (s, 6H), 1.31-1.25 (m, 8H), 0.95-
0.86 (m, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
196.6, 173.2, 170.5, 126.9, 111.2, 83.0, 73.5, 69.3, 63.6, 42.2, 31.8, 29.2, 29.1, 27.1, 27.0,
26.0, 23.3, 22.8, 18.6, 14.2, -5.1, -5.2; HRMS (CI, isobutane) m/z 455.2818 [calcd for
C24H43SiO6 (M+H) 455.2829].
Preparation of Butenolide (-)-16c.
OTBS
O
O
O
OO
(-)-16c
Butenolide (-)-16c. This compound was prepared in the same manner as its
enantiomer (+)-16c (53% yield). An analytical sample (yellow oil) was prepared by flash
column chromatography followed by HPLC employing 9:1 hexanes:EtOAc as eluant in
both cases: [α]D20 -36.74° (c 0.89, CHCl3); FTIR (thin film/NaCl) 2959 (m), 2932 (m),
2881 (m), 2858 (m), 1769 (s), 1694 (m), 1633 (w), 1472 (w), 1463 (w), 1381 (m), 1373
(m), 1252 (m), 1090 (m), 838 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.50 (d, J=7.9 Hz,
43
1H), 5.06 (d, J=19.9 Hz, 1H), 4.87 (d, J=19.0 Hz, 1H), 3.93-3.85 (m, 3H), 2.96 (dt,
J=18.2, 7.3 Hz, 1H), 2.91 (dt, J=18.2, 7.4 Hz, 1H), 1.64 (sext., J=7.4 Hz, 2H), 1.45 (s,
6H), 0.95 (t, J=7.4 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 196.4, 173.2, 170.5, 126.8, 111.1, 83.0, 73.5, 69.3, 63.6, 44.0, 27.1, 27.0, 26.0,
18.5, 16.7, 13.7, -5.2, -5.3; HRMS (CI, isobutane) m/z 399.2192 [calcd for C20H35SiO6
(M+H) 399.2203].
Preparation of Butenolide (+)-16c.
TBSO
O
O
O
O O
(+)-16c
Butenolide (+)-16c. To a stirred solution of β-ketoacid 14c (598 mg, 4.59 mmol,
1.11 equiv) and α-bromoketone (+)-13 (1.517 g, 4.13 mmol, 1 equiv) in DMF (4.8 mL)
was added in small portions over a 10 min period solid Cs2CO3 (1.723 g, 5.29 mmol, 1.28
equiv). The reaction mixture was stirred at room temperature for 30 min and then diluted
with water and EtOAc (16 mL ea.). The aqueous layer was acidified to pH 1 with 1 N
HCl and extracted with EtOAc (3 X 32 mL). The combined organic layers were dried
over MgSO4, filtered and concentrated in vacuo to a brown oil. Silica gel
chromatography employing 9:1 hexanes:EtOAc as eluant furnished (+)-16c (836 mg,
51% yield) as a yellow oil. An analytical sample (yellow oil) was prepared by flash
column chromatography followed by HPLC employing 9:1 hexanes:EtOAc as eluant in
both cases: [α]D20 +39.74° (c 1.16, CHCl3); FTIR (thin film/NaCl) 2958 (m), 2932 (m),
44
2881 (w), 2858 (m), 1769 (s), 1694 (m), 1633 (w), 1472 (w), 1463 (w), 1381 (m), 1373
(m), 1252 (m), 1090 (m), 838 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.50 (d, J=7.5 Hz,
1H), 5.05 (d, J=19.4 Hz, 1H), 4.88 (d, J=20.0 Hz, 1H), 3.94-3.86 (m, 3H), 2.96 (dt,
J=18.2, 7.3 Hz, 1H), 2.91 (dt, J=18.2, 7.4 Hz, 1H), 1.64 (sext., J=7.4 Hz, 2H), 1.45 (s,
6H), 0.96 (t, J=7.3 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 196.4, 173.1, 170.5, 126.9, 111.1, 83.0, 73.5, 69.3, 63.6, 44.0, 27.1, 27.0, 26.0,
18.5, 16.8, 13.7, -5.1, -5.2; HRMS (CI, isobutane) m/z 399.2192 [calcd for C20H35SiO6
(M+H) 399.2203].
Preparation of (-)-Syringolide 1 and Acetal (-)-51a.
OO
O
HO
OHO H
(-)-Syringolide 1(-)-1
OO
O
OH
O
(-)-51a
(-)-Syringolide 1 and Acetal (-)-51a. These compounds were prepared in the
same manner as their enantiomers (+)-1 and (+)-51a (12% and 8% yields respectively).
An analytical sample of (-)-syringolide 1 [(-)-1, white solid] was prepared by
HPLC employing 1:1 CH2Cl2:EtOAc as eluant: mp 113-114 °C; [α]D20 -73.64° (c 0.11,
CHCl3); FTIR (thin film/NaCl) 3400 (br w), 2955 (m), 2933 (m), 2870 (w), 2861 (w),
1759 (s), 1467 (m), 1380 (m), 1192 (m), 1153 (m), 1076 (s), 1031 (s), 977 (m), 915 (m)
cm-1; 1H NMR (500 MHz, acetone-d6) δ 5.36 (d, J=1.0 Hz, 1H), 4.67 (d, J=10.2 Hz,
1H), 4.49 (s, 1H), 4.32 (d, J=9.9 Hz, 1H), 4.16-4.14 (m, 1H), 3.95 (dd, J=9.5, 0.9 Hz,
45
1H), 3.83 (dd, J=10.4, 2.6 Hz, 1H), 3.09 (s, 1H), 1.89 (m, 2H), 1.67-1.54 (m, 1H), 1.53-
1.42 (m, 1H), 1.32-1.29 (m, 4H), 0.88 (t, J=7.1 Hz, 3H); 1H NMR (500 MHz, CDCl3) δ
4.72 (d, J=10.2 Hz, 1H), 4.55 (s, 1H), 4.41 (d, J=10.3 Hz, 1H), 4.31 (d, J=3.0 Hz, 1H),
4.04 (dd, J=10.3, 1.2 Hz, 1H), 3.85 (dd, J=10.5, 2.7 Hz, 1H), 3.07 (s, 1H), 2.47 (br s,
1H), 1.93 (dd, J=6.9, 2.4 Hz, 1H), 1.91 (dd, J=7.1, 2.2 Hz, 1H), 1.65-1.42 (m, 2H), 1.34-
1.32 (m, 4H), 1.26 (s, 1H), 0.90 (t, J=6.8 Hz, 3H); 13C NMR (125 MHz, acetone-d6) δ
172.7, 108.8, 98.9, 92.2, 75.6, 75.4, 74.9, 59.7, 39.4, 32.6, 24.0, 23.1, 14.2; HRMS (CI,
isobutane) m/z 273.1343 [calcd for C13H21O6 (M+H) 273.1338].
An analytical sample of (-)-51a (colorless oil) was prepared by HPLC employing
1:1 CH2Cl2:EtOAc as eluant: [α]D20 -33.23° (c 0.99, CHCl3); FTIR (thin film/NaCl)
3426 (br m), 2956 (s), 2931 (s), 2871 (m), 2861 (m), 1736 (s), 1657 (m), 1440 (m), 1378
(m), 1338 (s), 1247 (m), 1173 (m), 1088 (s), 1027 (s), 1018 (s), 991 (s) cm-1; 1H NMR
(500 MHz, CDCl3) δ 5.09 (d, J=3.8 Hz, 1H), 4.99 (d, J=18.0 Hz, 1H), 4.77 (dd, J=18.2,
1.2 Hz, 1H), 4.64 (ddd, J=6.0, 4.4, 2.0 Hz, 1H), 4.10 (dd, J=8.8, 2.0 Hz, 1H), 4.05-4.02
(m, 1H), 3.07 (br s, 1H), 2.27 (ddd, J=14.8, 10.8, 4.0 Hz, 1H), 2.05 (ddd, J=14.7, 10.5,
4.6 Hz, 1H), 1.50-1.27 (m, 6H), 0.88 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
170.2, 163.4, 129.0, 104.4, 75.6, 69.3, 66.8, 64.1, 32.0, 31.3, 22.7, 22.6, 14.1; HRMS (CI,
isobutane) m/z 255.1231 [calcd for C13H19O5 (M+H) 255.1232]. Spectroscopic data for
this material was identical to that reported in the literature.21-23
46
Preparation of (+)-Syringolide 1 and Acetal (+)-51a.
O O
O
OH
O OHH
(+)-Syringolide 1(+)-1
OO
O
OH
O
(+)-51a
(+)-Syringolide 1 and Acetal (+)-51a. To a stirred solution of butenolide (+)-
16a (546 mg, 1.28 mmol, 1 equiv) in CH3CN (50 mL) was added 10% aq HF (50 mL).
The reaction mixture was stirred at room temperature for 36 h and then neutralized to pH
7 with saturated aqueous NaHCO3 and extracted with EtOAc (4 X 100 mL). The organic
phases were washed with brine (100 mL) and then they were combined, dried over
MgSO4, filtered and concentrated in vacuo to a beige solid. Silica gel chromatography
employing 1:1 CH2Cl2:EtOAc as eluant furnished two products: (+)-syringolide 1 [(+)-1]
(59 mg, 17% yield, eluted second) as a white solid and (+)-51a (22 mg, 7% yield, eluted
first) as a yellowish oil.
An analytical sample of (+)-1 (white solid) was prepared by HPLC employing 1:1
hexanes:EtOAc as eluant: mp 118-119 °C; [α]D20 +77.42° (c 0.16, CHCl3); FTIR (thin
film/NaCl) 3401 (br m), 2955 (s), 2937 (s), 2924 (s), 2878 (m), 2853 (m), 1755 (s), 1467
(w), 1385 (w), 1198 (w), 1151 (w), 1131 (w), 1071 (m), 1044 (m), 973 (w), 913 (w) cm-
1; 1H NMR (500 MHz, acetone-d6) δ 5.36 (s, 1H), 4.67 (d, J=10.3 Hz, 1H), 4.49 (s, 1H),
4.33 (s, 1H), 4.32 (d, J=10.5 Hz, 1H), 4.15 (m, 1H), 3.95 (d, J=10.7 Hz, 1H), 3.83 (dd,
J=9.6, 3.1 Hz, 1H), 3.09 (s, 1H), 1.89 (m, 2H), 1.66-1.57 (m, 1H), 1.53-1.44 (m, 1H),
1.34-1.29 (m, 4H), 0.89 (t, J=6.9 Hz, 3H); 1H NMR (500 MHz, CDCl3) δ 4.72 (d, J=10.5
47
Hz, 1H), 4.55 (s, 1H), 4.46 (d, J=10.2 Hz, 1H), 4.31 (d, J=2.9 Hz, 1H), 4.04 (dd, J=10.3,
1.5 Hz, 1H), 3.85 (dd, J=10.5, 2.7 Hz, 1H), 3.08 (s, 1H), 2.53 (br s, 1H), 1.93 (dd, J=6.6,
2.4 Hz, 1H), 1.91 (dd, J=7.0, 2.4 Hz, 1H), 1.65-1.44 (m, 2H), 1.34-1.32 (m, 4H), 1.25 (s,
1H), 0.90 (m, 3H); 13C NMR (125 MHz, acetone-d6) δ 172.7, 108.8, 99.0, 92.2, 75.6,
75.4, 74.9, 59.7, 39.4, 32.6, 24.0, 23.1, 14.2; HRMS (CI, isobutane) m/z 273.1343 [calcd
for C13H21O6 (M+H) 273.1338];
An analytical sample of (+)-51a (colorless oil) was prepared by HPLC employing
1:1 hexanes:EtOAc as eluant: [α]D20 +24.67° (c 0.15, CHCl3); FTIR (thin film/NaCl)
3424 (w), 2957 (m), 2930 (m), 2870 (w), 2860 (w), 1740 (s), 1659 (w), 1443 (w), 1378
(w), 1339 (m), 1246 (w), 1173 (m), 1087 (m), 1018 (m), 991 (m) cm-1; 1H NMR (500
MHz, CDCl3) δ 5.11 (d, J=4.3 Hz, 1H), 4.98 (d, J=18.0 Hz, 1H), 4.76 (dd, J=18.1, 0.9
Hz, 1H), 4.64 (m, 1H), 4.10 (dd, J=8.5, 2.3 Hz, 1H), 4.07-4.04 (m, 1H), 2.54 (br s, 1H),
2.29 (ddd, J=14.4, 11.2, 4.3 Hz, 1H), 2.06 (ddd, J=14.4, 11.0, 4.7 Hz, 1H), 1.48-1.27 (m,
6H), 0.88 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.5, 162.0, 129.6, 104.7,
75.7, 68.8, 67.2, 64.0, 32.1, 31.3, 22.7 (2), 14.1; HRMS (CI, isobutane) m/z 255.1233
[calcd for C13H19O5 (M+H) 255.1232].
48
Preparation of (-)-Syringolide 2 and Acetal (-)-51b.
OO
O
HO
OHO H
(-)-Syringolide 2(-)-2
OO
O
OH
O
(-)-51b
(-)-Syringolide 2 and Acetal (-)-51b. These compounds were prepared in the
same manner as their enantiomers (-)-2 and (-)-51b (8% and 10% yields respectively).
An analytical sample of (-)-syringolide 2 [(-)-2, white solid] was prepared by
HPLC employing 5:6 CH2Cl2:EtOAc as eluant: mp 108-109 °C; [α]D20 -71.57° (c 0.10,
CHCl3); FTIR (thin film/NaCl) 3404 (br m), 2955 (m), 2939 (m), 2918 (m), 2873 (w),
2848 (m), 1754 (s), 1467 (w), 1386 (w), 1198 (w), 1151 (w), 1046 (m), 1025 (m), 971
(w) cm-1; 1H NMR (500 MHz, acetone-d6) δ 5.36 (d, J=1.6 Hz, 1H), 4.67 (d, J=10.2 Hz,
1H), 4.49 (s, 1H), 4.32 (d, J=10.2 Hz, 1H), 4.23 (br s, 1H), 4.14 (m, 1H), 3.95 (d, J=10.0
Hz, 1H), 3.83 (dd, J=10.1, 2.8 Hz, 1H), 3.09 (s, 1H), 1.89 (m, 2H), 1.65-1.59 (m, 1H),
1.53-1.43 (m, 1H), 1.32-1.29 (m, 8H), 0.88 (m, 3H); 1H NMR (500 MHz, CDCl3) δ 4.72
(d, J=10.6 Hz, 1H), 4.55 (s, 1H), 4.46 (d, J=10.6 Hz, 1H), 4.31 (d, J=2.5 Hz, 1H), 4.05
(dd, J=10.4, 1.1 Hz, 1H), 3.85 (dd, J=10.4, 2.8 Hz, 1H), 3.07 (s, 1H), 2.48 (br s, 1H),
1.93 (dd, J=6.7, 2.4 Hz, 1H), 1.91 (dd, J=6.9, 2.0 Hz, 1H), 1.65-1.42 (m, 2H), 1.35-1.26
(m, 8H), 1.26 (s, 1H), 0.88 (t, J=6.5 Hz, 3H); 13C NMR (125 MHz, acetone-d6) δ 172.6,
108.8, 99.0, 92.2, 75.6, 75.4, 74.9, 59.7, 39.5, 32.5, 30.4, 29.9, 24.4, 23.3, 14.3; HRMS
(CI, isobutane) m/z 301.1650 [calcd for C15H25O6 (M+H) 301.1651].
49
An analytical sample of (-)-51b (colorless oil) was prepared by HPLC employing
5:6 CH2Cl2:EtOAc as eluant: [α]D20 -30.77° (c 0.46, CHCl3); FTIR (thin film/NaCl)
3436 (br m), 2956 (s), 2929 (s), 2870 (m), 2857 (s), 1737 (s), 1659 (m), 1467 (m), 1378
(m), 1339 (s), 1246 (m), 1089 (s), 1028 (s), 991 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ
5.10 (d, J=3.3 Hz, 1H), 4.98 (d, J=17.7 Hz, 1H), 4.76 (dd, J=18.1, 0.9 Hz, 1H), 4.64 (m,
1H), 4.10 (dd, J=8.9, 2.0 Hz, 1H), 4.05 (dd, J=8.6, 6.1 Hz, 1H), 2.63 (br s, 1H), 2.28
(ddd, J=14.4, 10.7, 4.6 Hz, 1H), 2.06 (ddd, J=14.8, 10.4, 4.6 Hz, 1H), 1.50-1.21 (m,
10H), 0.87 (t, J=6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.9, 162.8, 129.2, 104.5,
75.6, 69.1, 66.9, 64.0, 31.9, 31.3, 29.8, 29.3, 23.0, 22.8, 14.3; HRMS (CI, isobutane) m/z
283.1550 [calcd for C15H23O5 (M+H) 283.1545].
Preparation of (+)-Syringolide 2 and Acetal (+)-51b.
O O
O
OH
O OHH
(+)-Syringolide 2(+)-2
OO
O
OH
O
(+)-51b
(+)-Syringolide 2 and Acetal (+)-51b. To a stirred solution of butenolide (+)-
16b (524 mg, 1.15 mmol, 1 equiv) in CH3CN (48 mL) was added 10% aq HF (48 mL).
The reaction mixture was stirred at room temperature for 36 h and then neutralized to pH
7 with saturated aqueous NaHCO3 and extracted with EtOAc (4 X 96 mL). The organic
phases were washed with brine (96 mL) and then they were combined, dried over
MgSO4, filtered and concentrated in vacuo to a beige oil. Silica gel chromatography
50
employing 6:5 CH2Cl2:EtOAc as eluant furnished two products: (+)-syringolide 2 [(+)-2]
(49 mg, 14% yield eluted second) as a yellowish solid and (+)-51b (21 mg, 6% yield,
eluted first) as a yellowish oil.
An analytical sample of (+)-2 (white solid) was prepared by HPLC employing 5:6
CH2Cl2:EtOAc as eluant: mp 113 °C; [α]D20 +84.12° (c 0.17, CHCl3); FTIR (thin
film/NaCl) 3404 (br m), 2954 (m), 2939 (m), 2873 (m), 2848 (m), 1754 (s), 1466 (w),
1385 (m), 1197 (m), 1151 (w), 1047 (m), 1024 (m), 971 (m) cm-1; 1H NMR (500 MHz,
acetone-d6) δ 5.36 (s, 1H), 4.67 (d, J=10.3 Hz, 1H), 4.49 (s, 1H), 4.32 (d, J=10.3 Hz,
1H), 4.30 (s, 1H), 4.14 (m, 1H), 3.95 (d, J=10.2 Hz, 1H), 3.83 (dd, J=10.4, 2.5 Hz, 1H),
3.09 (s, 1H), 1.89 (m, 2H), 1.65-1.57 (m, 1H), 1.53-1.44 (m, 1H), 1.32-1.29 (m, 8H), 0.88
(t, J=6.7 Hz, 3H); 1H NMR (500 MHz, CDCl3) δ 4.72 (d, J=10.6 Hz, 1H), 4.55 (s, 1H),
4.46 (d, J=10.2 Hz, 1H), 4.30 (d, J=2.4 Hz, 1H), 4.05 (dd, J=10.3, 1.4 Hz, 1H), 3.85 (dd,
J=10.3, 2.9 Hz, 1H), 3.07 (s, 1H), 2.52 (br s, 1H), 1.93 (dd, J=7.1, 2.6 Hz, 1H), 1.91 (dd,
J=6.7, 2.0 Hz, 1H), 1.67-1.40 (m, 2H), 1.35-1.12 (m, 8H), 0.88 (t, J=7.03 Hz, 1H); 13C
NMR (125 MHz, acetone-d6) δ 172.7, 108.9, 99.0, 92.3, 75.6, 75.5, 75.0, 59.8, 39.5,
32.5, 30.4, 29.9, 24.4, 23.3, 14.3; HRMS (CI, isobutane) m/z 301.1646 [calcd for
C15H25O6 (M+H) 301.1651].
An analytical sample of (+)-51b (colorless oil) was prepared by HPLC employing
5:6 CH2Cl2:EtOAc as eluant: [α]D20 +26.67° (c 0.16, CHCl3); FTIR (thin film/NaCl)
3435 (m), 2954 (m), 2925 (s), 2869 (m), 2855 (m), 1737 (s), 1659 (m), 1467 (m), 1378
(m), 1339 (m), 1245 (m), 1088 (m), 1018 (s), 991 (s) cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.10 (d, J=3.9 Hz, 1H), 4.98 (d, J=18.4 Hz, 1H), 4.76 (d, J=18.4 Hz, 1H), 4.64 (m, 1H),
4.10 (dd, J=8.8, 2.1 Hz, 1H), 4.06-4.03 (m, 1H), 2.72 (br s, 1H), 2.28 (ddd, J=14.5, 10.9,
51
4.0 Hz, 1H), 2.06 (ddd, J=14.4, 10.3, 4.7 Hz, 1H), 1.48-1.21 (m, 10H), 0.87 (t, J=6.8 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 169.6, 162.3, 129.5, 104.6, 75.7, 68.9, 67.1, 64.0,
31.9, 31.3, 29.8, 29.3, 23.0, 22.8, 14.2; HRMS (CI, isobutane) m/z 283.1548 [calcd for
C15H23O5 (M+H) 283.1545].
Preparation of (-)-Syringolide 3 and Acetal (-)-51c.
OO
O
HO
OHO H
(-)-Syringolide 3(-)-3
OO
O
OH
O
(-)-51c
(-)-Syringolide 3 and Acetal (-)-51c. These compounds were prepared in the
same manner as their enantiomers (+)-3 and (+)-51c (7% and 7% yields respectively).
Recrystallization of (-)-syringolide 3 [(-)-3] from heptane produced crystals suitable for a
single-crystal X-ray analysis which established the illustrated relative stereochemical
configuration.24
An analytical sample of (-)-3 (white solid) was prepared by HPLC employing 5:6
CH2Cl2:EtOAc as eluant: mp 120-122 °C; [α]D20 -97.74° (c 0.09, CHCl3); FTIR (thin
film/NaCl) 3358 (br m), 2961 (m), 2933 (m), 2917 (m), 2874 (w), 2848 (w), 1759 (s),
1466 (w), 1380 (m), 1191 (m), 1151 (m), 1077 (m), 1025 (s), 975 (m) cm-1; 1H NMR
(500 MHz, acetone-d6) δ 5.35 (s, 1H), 4.67 (d, J=10.2 Hz, 1H), 4.49 (s, 1H), 4.32 (d,
J=10.5 Hz, 1H), 4.31 (br s, 1H), 4.15 (s, 1H), 3.95 (d, J=9.6 Hz, 1H), 3.82 (d, J=10.3 Hz,
1H), 3.08 (s, 1H), 1.87 (t, J=8.1 Hz, 2H), 1.66-1.57 (m, 1H), 1.55-1.46 (m, 1H), 0.92 (t,
52
J=7.4 Hz, 3H); 13C NMR (125 MHz, acetone-d6) δ 172.7, 108.7, 99.0, 92.3, 75.6, 75.4,
74.9, 59.7, 41.7, 17.8, 14.4; HRMS (CI, isobutane) m/z 245.1031 [calcd for C11H16O6
(M+H) 245.1025].
An analytical sample of (-)-51c (colorless oil) was prepared by HPLC employing
5:6 CH2Cl2:EtOAc as eluant: [α]D20 -33.40° (c 0.94, CHCl3); FTIR (thin film/NaCl)
3418 (br m), 2965 (m), 2933 (w), 2879 (w), 1736 (s), 1658 (w), 1434 (w), 1377 (w), 1339
(m), 1245 (w), 1179 (m), 1086 (m), 1023 (m), 990 (m) cm-1; 1H NMR (500 MHz,
CDCl3) δ 5.10 (d, J=3.1 Hz, 1H), 4.99 (d, J=18.3 Hz, 1H), 4.76 (dd, J=18.0, 1.0 Hz, 1H),
4.64 (m, 1H), 4.10 (dd, J=8.6, 2.3 Hz, 1H), 4.05-4.02 (m, 1H), 2.99 (br s, 1H), 2.26 (ddd,
J=14.4, 10.9, 5.5 Hz, 1H), 2.05 (ddd, J=14.1, 10.7, 5.2 Hz, 1H), 1.53-1.38 (m, 2H), 0.98
(t, J=7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.4, 163.5, 129.0, 104.3, 75.5, 69.4,
66.8, 64.0, 33.3, 16.5, 14.4; HRMS (CI, isobutane) m/z 227.0914 [calcd for C11H15O5
(M+H) 227.0919].
Preparation of (+)-Syringolide 3 and Acetal (+)-51c.
O O
O
OH
O OHH
(+)-Syringolide 3(+)-3
OO
O
OH
O
(+)-51c
(+)-Syringolide 3 and Acetal (+)-51c. To a stirred solution of butenolide (+)-16c
(836 mg, 2.10 mmol, 1 equiv) in CH3CN (85 mL) was added 10% aq HF (85 mL). The
reaction mixture was stirred at room temperature for 36 h and then neutralized to pH 7
53
with saturated aqueous NaHCO3 and extracted with EtOAc (4 X 170 mL). The organic
phases were washed with brine (170 mL) and then they were combined, dried over
MgSO4, filtered and concentrated in vacuo to a brown syrup. Silica gel chromatography
employing 1:1 CH2Cl2:EtOAc as eluant furnished two products: (+)-syringolide 3 [(+)-3]
(50 mg, 10% yield, eluted second) as a white solid and (+)-51c (47 mg, 10% yield, eluted
first) as a yellowish oil.
An analytical sample of (+)-3 (white solid) was prepared by HPLC employing 5:6
CH2Cl2:EtOAc as eluant: mp 118-120 °C; [α]D20 +98.46° (c 0.13, CHCl3); FTIR (thin
film/NaCl) 3396 (br m), 2963 (m), 2937 (m), 2922 (w), 2876 (m), 1755 (s), 1467 (w),
1385 (m), 1198 (m), 1053 (m), 1029 (s), 973 (m) cm-1; 1H NMR (500 MHz, acetone-d6)
δ 5.35 (s, 1H), 4.67 (d, J=10.2 Hz, 1H), 4.48 (s, 1H), 4.32 (d, J=10.4 Hz, 1H), 4.31 (s,
1H), 4.14 (s, 1H), 3.95 (d, J=10.2 Hz, 1H), 3.82 (d, J=9.8 Hz, 1H), 3.08 (s, 1H), 1.87 (t,
J=7.9 Hz, 2H), 1.66-1.57 (m, 1H), 1.55-1.47 (m, 1H), 0.87 (t, 3H); 13C NMR (125 MHz,
acetone-d6) δ 172.7, 108.7, 99.0, 92.2, 75.6, 75.4, 74.9, 59.7, 41.6, 17.8, 14.4; HRMS
(CI, isobutane) m/z 245.1028 [calcd for C11H16O6 (M+H) 245.1025].
An analytical sample of (+)-51c (colorless oil) was prepared by HPLC employing
5:6 CH2Cl2:EtOAc as eluant: [α]D20 +33.5° (c 0.83, CHCl3); FTIR (thin film/NaCl)
3416 (m), 2965 (m), 2933 (w), 1737 (s), 1657 (w), 1433 (w), 1376 (w), 1339 (m), 1246
(w), 1180 (m), 1025 (m), 990 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.09 (d, J=4.4
Hz, 1H), 4.99 (d, J=18.2 Hz, 1H), 4.77 (d, J=18.2 Hz, 1H), 4.64 (ddd, J=6.3, 4.5, 1.9 Hz,
1H), 4.10 (dd, J=8.8, 2.0 Hz, 1H), 4.05-4.02 (m, 1H), 3.14 (br s, 1H), 2.25 (ddd, J=14.3,
11.0, 4.9 Hz, 1H), 2.04 (ddd, J=14.2, 10.9, 5.3 Hz, 1H), 1.52-1.38 (m, 2H), 0.97 (t, J=7.6
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.1, 163.0, 129.2, 104.3, 75.7, 69.2, 66.9,
54
64.0, 33.3, 16.4, 14.4; HRMS (CI, isobutane) m/z 227.0912 [calcd for C11H15O5 (M+H)
227.0919].
Preparation of Butenolide (-)-91.
4
OTBS
O
O
O
ONH
O
(-)-91
O
O
Butenolide (-)-91. To a stirred solution of β-ketoacid 90 (1.668 g, 5.43 mmol,
1.25 equiv) and α-bromoketone (-)-13 (1.591 g, 4.33 mmol, 1 equiv) in DMF (5 mL) was
added in small portions over a 10 min period solid Cs2CO3 (1.843 g, 5.66 mmol, 1.31
equiv). The reaction mixture was stirred at room temperature for 4 h and then diluted
with water and EtOAc (50 mL ea.). The aqueous layer was acidified to pH 1 with 1 N
HCl and extracted with EtOAc (3 X 100 mL). The combined organic layers were dried
over MgSO4, filtered and concentrated in vacuo to a brown oil. Silica gel
chromatography employing 9:1 hexanes:EtOAc as eluant furnished (-)-91 (1.114 g, 45%
yield) as a yellow oil. An analytical sample (yellow oil) was prepared by HPLC
employing 9:1 hexanes:EtOAc as eluant: [α]D20 -28.97° (c 1.37, CHCl3); FTIR (thin
film/NaCl) 3352 (br w), 2985 (w), 2932 (w), 2884 (w), 2857 (m), 1766 (s), 1714 (s),
1631 (w), 1527 (m), 1381 (m), 1373 (m), 1250 (s), 1138 (m), 1088 (m), 1050 (m), 838 (s)
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.34 (s, 2H), 7.33 (s, 2H), 7.30 (m, 1H), 5.47 (d,
J=7.1 Hz, 1H), 5.07 (s, 2H), 5.04 (d, J=18.6 Hz, 1H), 4.87 (d, J=19.6 Hz, 1H), 4.83 (br s,
55
1H), 3.92-3.89 (m, 2H), 3.85 (dd, J=12.0, 5.8 Hz, 1H), 3.18 (m, 2H), 2.93 (m, 2H), 1.61
(m, 2H), 1.51 (m, 2H), 1.43 (s, 6H), 1.34 (m, 2H), 0.88 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 196.1, 173.4, 170.5, 156.5, 136.8, 128.6, 128.2, 126.7,
111.2, 82.9, 73.5, 69.3, 66.7, 63.6, 41.9, 41.0, 29.9, 27.1, 26.9, 26.3, 26.0, 22.9, 18.5, -
5.2, -5.3; HRMS (CI, isobutane) m/z 576.2981 [calcd for C30H46NO8Si (M+H)
576.2992].
Preparation of (-)-N-(Carbobenzyloxy)-8-aminosyringolide 1 and Acetal (-)-93.
OO
O
HO
OHN
4
HO H
OO
O
OH
O
HN
(-)-93
4
O
O
O
O
(-)-N-(Carbobenzyloxy)-aminosyringolide 1(-)-92
(-)-N-(Carbobenzyloxy)-8-aminosyringolide 1 and Acetal (-)-93. To a stirred
solution of butenolide (-)-91 (1.197 g, 2.08 mmol, 1 equiv) in CH3CN (84 mL) was added
16% aq HF (84 mL). The reaction mixture was stirred at room temperature for 24 h and
then neutralized to pH 7 with saturated aqueous NaHCO3 and extracted with EtOAc (4 X
168 mL). The organic phases were washed with brine (168 mL) and then they were
combined, dried over MgSO4, filtered and concentrated in vacuo to a brownish oil. Silica
gel chromatography employing 1:3 hexanes:EtOAc as eluant furnished two products: (-)-
N-(carbobenzyloxy)-8-aminosyringolide 1 [(-)-92] (100 mg, 11% yield, eluted second) as
a yellowish oil and (-)-93 (39 mg, 5% yield, eluted first) as a yellowish oil.
56
An analytical sample of (-)-92 (colorless oil) was prepared by flash column
chromatography employing 1:3 hexanes:EtOAc as eluant followed by HPLC using 1:2
hexanes:EtOAc as eluant: [α]D20 -46.4° (c 0.13, CHCl3); FTIR (thin film/NaCl) 3347
(br m), 2935 (m), 2862 (w), 1736 (s), 1693 (s), 1529 (m), 1455 (w), 1376 (w), 1253 (s),
1185 (m), 1148 (m), 1076 (m), 1028 (s), 977 (m), 912 (w) cm-1; 1H NMR (500 MHz,
acetone-d6) δ 7.36 (s, 2H), 7.35 (s, 2H), 7.30 (m, 1H), 6.33 (br s, 1H), 5.41 (s, 1H), 5.05
(s, 2H), 4.68 (d, J=10.3 Hz, 1H), 4.49 (s, 1H), 4.35 (br s, 1H), 4.33 (d, J=10.4 Hz, 1H),
4.16 (s, 1H), 3.93 (d, J=9.9 Hz, 1H), 3.83 (d, J=9.9 Hz, 1H), 3.14 (q, J=6.5 Hz, 2H), 3.11
(s, 1H), 1.90 (t, J=7.9 Hz, 2H), 1.63 (m, 1H), 1.53 (m, 3H), 1.37 (m, 2H); 1H NMR (500
MHz, CDCl3) δ 7.36-7.28 (m, 5H), 5.06 (s, 3H), 5.02 (br s, 1H), 4.71 (d, J=10.2 Hz, 1H),
4.53 (s, 1H), 4.44 (d, J=10.4 Hz, 1H), 4.24 (d, J=1.7 Hz, 1H), 4.01 (d, J=10.0 Hz, 1H),
3.78 (d, J=8.6 Hz, 1H), 3.15 (m, 3H), 3.03 (s, 1H), 1.81 (t, J=7.8 Hz, 2H), 1.50 (m, 5H),
1.35 (m, 3H); 13C NMR (125 MHz, acetone-d6) δ 172.7, 157.2, 138.5, 129.1, 128.6,
128.5, 108.8, 98.9, 92.3, 75.7, 75.4, 74.9, 66.3, 59.7, 41.4, 39.3, 30.5, 27.5, 24.0; HRMS
(CI, isobutane) m/z 422.1809 [calcd for C21H28NO8 (M+H) 422.1815].
An analytical sample of (-)-93 (colorless oil) was prepared by flash column
chromatography employing 1:3 hexanes:EtOAc as eluant followed by HPLC using 2:3
hexanes:EtOAc as eluant: [α]D20 -29.91° (c 0.56, CHCl3); FTIR (thin film/NaCl) 3368
(br s), 2935 (m), 2862 (w), 1754 (s), 1695 (s), 1533 (m), 1455 (m), 1338 (m), 1258 (s),
1094 (m), 1020 (m), 990 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.37-7.30 (m, 5H),
5.07 (s, 2H), 5.03 (d, J=3.7 Hz, 1H), 4.96 (d, J=18.3 Hz, 1H), 4.87 (br s, 1H), 4.73 (dd,
J=18.2, 1.5 Hz, 1H), 4.61 (m, 1H), 4.09 (dd, J=8.8, 2.2 Hz, 1H), 4.02-3.99 (m, 1H), 3.16
(m, 2H), 3.07 (br s, 1H), 2.28 (m, 1H), 2.06 (ddd, J=14.4, 10.1, 4.7 Hz, 1H), 1.54-1.45
57
(m, 3H), 1.42-1.37 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 169.8, 163.1, 156.8, 136.7,
129.0, 128.7, 128.3, 128.2, 104.3, 75.7, 69.1, 66.9, 64.1, 41.1, 31.1, 29.7, 26.8, 22.5;
HRMS (CI, isobutane) m/z 404.1704 [calcd for C21H26NO7 (M+H) 404.1709].
2.7 Notes and references.
(1) Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1987, 52, 3337-3342.
(2) Preparation of (+)-11 in a 30.5 mmol scale: Taunton, J.; Collins, J. L.;
Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 10412-10422.
(3) McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org. Chem. 1986,
51, 3388-3390.
(4) Preparation of (+)-10 in a 0.37 mol scale: Mash, E. A.; Nelson, K. A.; Van
Deusen, S.; Hemperly, S. B. Org. Synth. 1990, 68, 92-103.
(5) (a) Carlsen, P. H. J; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem.
1981, 46, 3936-3938. (b) Calculations based on n = 1 [RuCl3(H2O)n)]
(6) (a) Birch, P. L.; El-Obeid, H. A.; Akhtar, M. Arch. Biochem. Biophys. 1972,
148, 447-451. (b) Coggins, J. R.; Kray, W.; Shaw, E. Biochem. J. 1974, 137, 579-585.
58
(7) β-Ketoacids are readily available by saponification of their corresponding
ethyl esters.8,10,11
(8) For an easy preparation of β-ketoesters see: Wang, X.; Monte, W. T.; Naiper,
J. J.; Ghannam, A. Tetrahedron Lett. 1994, 35, 9323-9326.
(9) For acylation (macrolactonization) of alkyl halides using cesium carboxylates
in DMF see: (a) Kruizinga, W. H.; Kellogg, R. M. J. Chem. Soc., Chem. Commun. 1979,
286-288. (b) Kruizinga, W. H.; Kellogg, R. M. J. Am. Chem. Soc. 1981, 103, 5183-5189.
(10) Cook, L.; Ternai, B.; Ghosh, P. J. Med. Chem. 1987, 30, 1017-1023.
(11) (a) Bloodworth, A. J.; Bothwell, B. D.; Collins, A. N.; Maidwell, N. L.
Tetrahedron Lett. 1996, 37, 1885-1888. (b) The corresponding ethyl ester of 14c is
commercially available.
(12) For butenolide formation employing a dihydroxyacetone derivative see:
Sakuda, S.; Tanaka, S.; Mizuno, K.; Sukcharoen, O.; Nihira, T.; Yamada, Y. J. Chem.
Soc., Perkin Trans. 1 1993, 2309-2315.
(13) Yu, P.; Yang, Y.; Zhang, Z. Y.; Mak, T. C. W.; Wong, H. N. C. J. Org
Chem. 1997, 62, 6359-6366.
59
(14) (a) Smith, M. J., Mazzola, E. P.; Sims, J. J.; Midland, S. L.; Keen, N. T.;
Burton, V.; Stayton, M. M. Tetrahedron Lett. 1993, 34, 223-226. (b) Midland, S. L.;
Keen, N. T.; Sims, J. J.; Midland, M. M.; Stayton, M. M.; Burton, V.; Smith, M. J.,
Mazzola, E. P.; Graham, K. J.; Clardy, J. J. Org. Chem. 1993, 58, 2940-2945.
(15) Chênevert, R.; Dasser, M. Can. J. Chem. 2000, 78, 275-279.
(16) Sample of natural (-)-syringolide 2 kindly provided by Mitchell J. Smith
(U.S. Food and Drug Administration)
(17) Readily available by saponification10,11 of the corresponding ethyl ester.8
(18) Noel T. Keen, personal communication (University of California, Riverside;
Dept. of Plant Pathology).
(19) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-2925.
(20) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512-
7515.
(21) Ishihara, I.; Sugimoto, T.; Murai, A.; Tetrahedron 1997, 53, 16029-16040.
60
(22) Zeng, C.-M.; Midland, S. L.; Keen, N. T.; Sims, J. J. J. Org. Chem. 1997, 62,
4780-4784.
(23) Yu, P.; Wang, Q.-G.; Mak, T. C. W.; Wong, H. N. C. Tetrahedron, 1998, 54,
1783-1788.
(24) The atomic coordinates for this structure have been deposited with the
Cambridge Crystallographic Data Centre.
61
Appendix 1
Spectra Relevant to Chapter 2.
62 62
8 6 4 2 0 ppm
Figure A.1.1 1H NMR (500 MHz, CDCl3) of Compound (-)-12.
OTBS
ON2
(-)-12
O
O
63 63
200
150
100
50PP
M
20406080
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.1.2
FTI
R S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
12.
Figu
re A
.1.3
13C
NM
R (1
25 M
Hz,
CD
Cl 3)
of C
ompo
und
(-)-
12.
64 64
8 6 4 2 0 ppm
Figure A.1.4 1H NMR (500 MHz, CDCl3) of Compound (+)-12.
TBSO
ON2
(+)-12
O
O
65 65
200
150
100
50PP
M
Figu
re A
.1.6
13C
NM
R (1
25 M
Hz,
CD
Cl 3)
of C
ompo
und
(+)-
12.
020406080
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.1.5
FTI
R S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
12.
66 66
8 6 4 2 0 ppm
OTBS
O
O
O
(-)-13
Br
Figure A.1.7 1H NMR (500 MHz, CDCl3) of Compound (-)-13.
67 67
200
150
100
50PP
M
Figu
re A
.1.9
13C
NM
R (1
25 M
Hz,
CD
Cl 3)
of C
ompo
und
(-)-
13.
Figu
re A
.1.8
FTI
R S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
13.
406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
68 68
8 6 4 2 0 ppm
TBSO
O
O
O
(+)-13
Br
Figure A.1.10 1H NMR (500 MHz, CDCl3) of Compound (+)-13.
69 69
200
150
100
50PP
M
Figu
re A
.1.1
2 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (+
)-13
.
Figu
re A
.1.1
1 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
13.
20406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
70 70
8 6 4 2 0 ppm
OTBS
O
O
O
OO
(-)-16a
Figure A.1.13 1H NMR (500 MHz, CDCl3) of Compound (-)-16a.
71 71
200
150
100
50PP
M
Figu
re A
.1.1
5 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-16
a.
Figu
re A
.1.1
4 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
16a.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
72 72
8 6 4 2 0 ppm
Figure A.1.16 1H NMR (500 MHz, CDCl3) of Compound (+)-16a.
TBSO
O
O
O
O O
(+)-16a
73 73
200
150
100
50PP
M
Figu
re A
.1.1
8 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (+
)-16
a.
Figu
re A
.1.1
7 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
16a.
20406080100
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
74 74
8 6 4 2 0 ppm
Figure A.1.19 1H NMR (500 MHz, CDCl3) of Compound (-)-16b.
OTBS
O
O
O
OO
(-)-16b
75 75
200
150
100
50PP
M
Figu
re A
.1.2
1 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-16
b.
Figu
re A
.1.2
0 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
16b.
406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
76 76
8 6 4 2 0 ppm
Figure A.1.22 1H NMR (500 MHz, CDCl3) of Compound (+)-16b.
TBSO
O
O
O
O O
(+)-16b
77 77
200
150
100
50PP
M
Figu
re A
.1.2
4 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (+
)-16
b.
Figu
re A
.1.2
3 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
16b.
406080100
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
78 78
8 6 4 2 0 ppm
OTBS
O
O
O
OO
(-)-16c
Figure A.1.25 1H NMR (500 MHz, CDCl3) of Compound (-)-16c.
79 79
200
150
100
50PP
M
Figu
re A
.1.2
7 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-16
c.
Figu
re A
.1.2
6 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
16c.
406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
80 80
8 6 4 2 0 ppm
Figure A.1.28 1H NMR (500 MHz, CDCl3) of Compound (+)-16c.
TBSO
O
O
O
O O
(+)-16c
81 81
200
150
100
50PP
M
Figu
re A
.1.3
0 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (+
)-16
c.
Figu
re A
.1.2
9 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
16c.
5060708090100
110
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
82 82
8 6 4 2 0 ppm
OO
OHO
OHO H
(-)-Syringolide 1(-)-1
Figure A.1.31 1H NMR (500 MHz, acetone-d6) of Compound (-)-1.
83 83
8 6 4 2 0 ppm
Figure A.1.32 1H NMR (500 MHz, CDCl3) of Compound (-)-1.
OO
OHO
OHO H
(-)-Syringolide 1(-)-1
84 84
200
150
100
50PP
M
Figu
re A
.1.3
4 13
C N
MR
(125
MH
z, a
ceto
ne-d
6) o
f Com
poun
d (-
)-1.
Figu
re A
.1.3
3 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
1.
9092949698
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
85 85
8 6 4 2 0 ppm
OO
O
OH
O
(-)-51a
Figure A.1.35 1H NMR (500 MHz, CDCl3) of Compound (-)-51a.
86 86
200
150
100
50PP
M
Figu
re A
.1.3
7 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-51
a.
Figu
re A
.1.3
6 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
51a.
60708090100
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
87 87
8 6 4 2 0 ppm
O O
OOH
O OHH
(+)-Syringolide 1(+)-1
Figure A.1.38 1H NMR (500 MHz, acetone-d6) of Compound (+)-1.
88 88
8 6 4 2 0 ppm
O O
OOH
O OHH
(+)-Syringolide 1(+)-1
Figure A.1.39 1H NMR (500 MHz, CDCl3) of Compound (+)-1.
89 89
200
150
100
50PP
M
Figu
re A
.1.4
1 13
C N
MR
(125
MH
z, a
ceto
ne-d
6) o
f Com
poun
d (+
)-1.
Figu
re A
.1.4
0 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
1.
979899100
101
102
103
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
90 90
8 6 4 2 0 ppm
OO
O
OH
O
(+)-51a
Figure A.1.42 1H NMR (500 MHz, CDCl3) of Compound (+)-51a.
91 91
200
150
100
50PP
M
Figu
re A
.1.4
4 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (+
)-51
a.
Figu
re A
.1.4
3 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
51a.
65707580859095100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
92 92
8 6 4 2 0 ppm
Figure A.1.45 1H NMR (500 MHz, acetone-d6) of Compound (-)-2.
OOO
HO
OHO H
(-)-Syringolide 2(-)-2
93 93
8 6 4 2 0 ppm
OOO
HO
OHO H
(-)-Syringolide 2(-)-2
Figure A.1.46 1H NMR (500 MHz, CDCl3) of Compound (-)-2.
94 94
200
150
100
50PP
M
Figu
re A
.1.4
8 13
C N
MR
(125
MH
z, a
ceto
ne-d
6) o
f Com
poun
d (-
)-2.
Figu
re A
.1.4
7 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
2.
7580859095
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
95 95
8 6 4 2 0 ppm
Figure A.1.49 1H NMR (500 MHz, CDCl3) of Compound (-)-51b.
OO
O
OH
O
(-)-51b
96 96
200
150
100
50PP
M
Figu
re A
.1.5
1 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-51
b.
Figu
re A
.1.5
0 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
51b.
65707580859095100
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
97 97
8 6 4 2 0 ppm
Figure A.1.52 1H NMR (500 MHz, acetone-d6) of Compound (+)-2.
O O
O
OH
O OHH
(+)-Syringolide 2(+)-2
98 98
O O
O
OH
O OHH
(+)-Syringolide 2(+)-2
8 6 4 2 0 ppm
Figure A.1.53 1H NMR (500 MHz, CDCl3) of Compound (+)-2.
99 99
200
150
100
50PP
M
Figu
re A
.1.5
5 13
C N
MR
(125
MH
z, a
ceto
ne-d
6) o
f Com
poun
d (+
)-2.
Figu
re A
.1.5
4 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
2.
9698100
102
104
106
108
110
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
100 10
0
8 6 4 2 0 ppm
Figure A.1.56 1H NMR (500 MHz, CDCl3) of Compound (+)-51b.
OO
O
OH
O
(+)-51b
101 10
1
200
150
100
50PP
M
Figu
re A
.1.5
8 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (+
)-51
b.
Figu
re A
.1.5
7 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
51b.
80859095100
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
102 10
2
8 6 4 2 0 ppm
OOO
HO
OHO H
(-)-Syringolide 3(-)-3
Figure A.1.59 1H NMR (500 MHz, acetone-d6) of Compound (-)-3.
103 10
3
200
150
100
50PP
M
Figu
re A
.1.6
1 13
C N
MR
(125
MH
z, a
ceto
ne-d
6) o
f Com
poun
d (-
)-3.
Figu
re A
.1.6
0 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
3.
859095
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
104 10
4
8 6 4 2 0 ppm
Figure A.1.62 1H NMR (500 MHz, CDCl3) of Compound (-)-51c.
OO
O
OH
O
(-)-51c
105 10
5
200
150
100
50PP
M
Figu
re A
.1.6
4 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-51
c.
Figu
re A
.1.6
3 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
51c.
707580859095100
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
106 10
6
8 6 4 2 0 ppm
O O
O
OH
O OHH
(+)-Syringolide 3(+)-3
Figure A.1.65 1H NMR (500 MHz, acetone-d6) of Compound (+)-3.
107 10
7
200
150
100
50PP
M
Figu
re A
.1.6
7 13
C N
MR
(125
MH
z, a
ceto
ne-d
6) o
f Com
poun
d (+
)-3.
Figu
re A
.1.6
6 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
3.
5060708090
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
108 10
8
8 6 4 2 0 ppm
OO
O
OH
O
(+)-51c
Figure A.1.68 1H NMR (500 MHz, CDCl3) of Compound (+)-51c.
109 10
9
200
150
100
50PP
M
Figu
re A
.1.7
0 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (+
)-51
c.
Figu
re A
.1.6
9 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
51c.
708090100
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
110 11
0
8 6 4 2 0 ppm
4
OTBS
O
O
O
ONH
O
(-)-91
O
O
Figure A.1.71 1H NMR (500 MHz, CDCl3) of Compound (-)-91.
111 11
1
200
150
100
50PP
M
Figu
re A
.1.7
3 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-91
.
Figu
re A
.1.7
2 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
91.
707580859095100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
112 11
2
8 6 4 2 0 ppm
Figure A.1.74 1H NMR (500 MHz, acetone-d6) of Compound (-)-92.
OOO
HO
OHN
4
HO HO
O
(-)-N-(Carbobenzyloxy)-aminosyringolide 1(-)-92
113 11
3
8 6 4 2 0 ppm
Figure A.1.75 1H NMR (500 MHz, CDCl3) of Compound (-)-92.
OOO
HO
OHN
4
HO HO
O
(-)-N-(Carbobenzyloxy)-aminosyringolide 1(-)-92
114 11
4
200
150
100
50PP
M
Figu
re A
.1.7
7 13
C N
MR
(125
MH
z, a
ceto
ne-d
6) o
f Com
poun
d (-
)-92
.
Figu
re A
.1.7
6 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
92.
8486889092949698
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
115 11
5
8 6 4 2 0 ppm
Figure A.1.78 1H NMR (500 MHz, CDCl3) of Compound (-)-93.
OO
O
OH
O
HN
(-)-93
4
O
O
116 11
6
200
150
100
50PP
M
Figu
re A
.1.8
0 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-93
.
Figu
re A
.1.7
9 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
93.
405060708090
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
117
Appendix 2
X-ray Structure Reports Relevant to Chapter 2.
A.2.1 X-ray Structure Report for (-)-Syringolide 3.
OO
O
HO
OHO H
(-)-Syringolide 3(-)-3
O1
O2
O3
O4
O5
O6
C1
C2 C3
C4
C5
C6
C7 C8
C9
C10
C11
H1
H2
H3
H8
H9
Figure A.2.1 ORTEP plot of Syringolide 3.
A.2.1.1 Crystal Data.
Empirical Formula C11H16O6 Formula Weight 244.24 Crystal Color, Habit colorless, plate Crystal Dimensions 0.07 X 0.12 X 0.23 mm Crystal System monoclinic Lattice Type Primitive Lattice Parameters a = 8.0462(4)Å b = 5.7570(3) Å c = 12.680(1) Å β = 102.094(3)o V = 574.34(6) Å3 Space Group P21 (#4) Z value 2 Dcalc 1.412 g/cm3 F000 260.00 µ(MoKα) 1.15 cm-1
118
A.2.1.2 Intensity Measurements.
Diffractometer Nonius KappaCCD Radiation MoKα (λ = 0.71069 Å) Graphite monochromated Take-off Angle 2.8o Crystal to Detector Distance 33 mm Temperature -90.0oC Scan Rate 120s/frame Scan Width 2.0o/frame 2θmax 54.9o No. of Reflections Measured Total: 2478 Unique: 1453 (Rint = 0.040) Corrections Lorentz-polarization A.2.1.3 Structure Solution and Refinement.
Structure Solution Direct Methods (SIR92) Refinement Full-matrix least-squares Function Minimized Σ w (|Fo| - |Fc|)2 Least Squares Weights 1/σ 2(Fo) p-factor 0.0100 Anomalous Dispersion All non-hydrogen atoms No. Observations (I>3.00σ(I)) 959 No. Variables 217 Reflection/Parameter Ratio 4.42 Residuals: R; Rw 0.041 ; 0.041 Goodness of Fit Indicator 1.80 Max Shift/Error in Final Cycle 0.00 Maximum peak in Final Diff. Map 0.21 e-/Å3 Minimum peak in Final Diff. Map -0.25 e-/Å3
119
A.2.1.4 Atomic coordinates and Biso/Beq.
Table A.2.1 Atomic coordinates and Biso/Beq for Syringolide 3.
atom x y z Beq O(1) 0.9081(3) 0.5000 0.2473(2) 2.24(6) O(2) 0.5268(3) 0.5908(8) 0.0401(2) 3.31(7) O(3) 0.6705(3) 0.9421(6) 0.1840(2) 2.22(6) O(4) 1.0367(3) 1.0865(7) 0.1006(2) 2.75(6) O(5) 1.2308(3) 1.1354(6) 0.2511(2) 3.04(6) O(6) 1.1715(3) 0.6108(7) 0.2155(2) 2.20(6) C(1) 0.8067(5) 0.5921(9) 0.1494(3) 2.09(8) C(2) 0.6193(5) 0.5508(8) 0.1471(3) 2.46(9) C(3) 0.5799(6) 0.7477(9) 0.2158(3) 2.39(10) C(4) 0.8274(5) 0.8586(8) 0.1617(3) 1.89(8) C(5) 0.8683(5) 0.9920(9) 0.0657(3) 2.14(9) C(6) 1.0994(5) 1.0492(7) 0.2073(3) 2.14(9) C(7) 0.9812(5) 0.8958(8) 0.2527(3) 2.03(9) C(8) 1.0527(5) 0.6469(8) 0.2812(3) 2.08(8) C(9) 1.1233(6) 0.6008(10) 0.3985(3) 2.53(9) C(10) 1.2800(6) 0.746(1) 0.4486(4) 3.3(1) C(11) 1.3484(8) 0.693(1) 0.5660(4) 4.3(1) H(1) 0.849(4) 0.536(5) 0.081(2) 0.3(6) H(2) 0.603(5) 0.397(10) 0.178(3) 3.2(9) H(3) 0.512(9) 0.46(2) -0.012(7) 10(1) H(4) 0.628(5) 0.717(8) 0.292(3) 3.4(9) H(5) 0.457(5) 0.796(6) 0.206(2) 0.7(7) H(6) 0.793(4) 1.131(7) 0.049(2) 1.7(7) H(7) 0.870(6) 0.89(1) -0.013(4) 7(1) H(8) 0.953(4) 0.976(8) 0.330(3) 3.3(8) H(9) 1.202(5) 0.480(8) 0.221(3) 1.3(8) H(10) 1.036(5) 0.625(9) 0.449(3) 4.2(9) H(11) 1.146(5) 0.437(9) 0.401(3) 3.6(10) H(12) 1.364(6) 0.712(9) 0.387(4) 5(1) H(13) 1.251(8) 0.90(1) 0.432(5) 8(1) H(14) 1.457(7) 0.78(1) 0.617(4) 6(1) H(15) 1.357(8) 0.52(1) 0.564(5) 8(1) H(16) 1.271(5) 0.728(9) 0.622(3) 3.9(9)
Beq = 8/3 π2(U11(aa*)2 + U22(bb*)2 + U33(cc*)2 + 2U12(aa*bb*)cos γ + 2U13(aa*cc*)cos β + 2U23(bb*cc*)cos α)
120
Chapter 3
Syringolides: C-H Insertion Synthetic Studies.
3.1 Retrosynthetic analysis.
In 1995 Doyle and Dyatkin1 reported that diazoacetate 94 underwent a
regioselective carbon-hydrogen insertion to furnish spirolactone 95 upon exposure to
Rh2(cap)4 (Scheme 3.1).
Rh2(cap)4, CH2Cl2
reflux (76%)
Scheme 3.1 Doyle and Dyatkin: Spirolactone Synthesis.
95
OO
O
94
OO
H
OH
N2 H H
Based on this report and with an interest in improving the syringolide synthesis, a
new approach using a C-H insertion as the key step was devised. Accordingly the
retrosynthetic analysis shown on Scheme 3.2 was conceived. As illustrated, the
hemiacetals of syringolides (1-3) were envisioned to arise via an intramolecular ring
closure in ketones 96a-c. The spirolactone rings in 96a-c would, in time, arise from an
intramolecular C-H insertion reaction applied to the α-diazoesters 97a-c. The requisite
α-diazoesters 97a-c would be synthesized by acylation of a primary alcohol such as 98
and the corresponding β-ketoacids 14a-c, followed by the required diazo transfer
reaction.
121
OO
O
HO
O
n
Syringolide 1 (1, n = 3)Syringolide 2 (2, n = 5)Syringolide 3 (3, n = 1)
HHO
O
O
O
n
96a, n = 396b, n = 596c, n = 1
O
HO
HO
H
O
n
97a, n = 397b, n = 597c, n = 1
HO
HO
HO
ON2
O
OHO
HO
HOH
OH
OO
14a, n = 314b, n = 514c, n = 1
+
98
n
Scheme 3.2 Syringolides: Retrosynthetic Analysis.
3.2 General Strategy.
Rather than synthesizing the highly advanced intermediates 97a-c, it was decided
to first try the C-H insertion key step with a series of model systems such as 101 where
the lateral chain and the trans diol would be masked with suitable precursors. Such
precursors would be synthesized as described on Scheme 3.3. First, a masked diol such
as 99 (R-R’ = masked diol) would be acylated with an acid2 or diketene3 to give ester
100. Exposure of 100 to diazo transfer conditons4,5 would furnish the α-diazoester 101
which, when treated with a rhodium(II) catalyst such as Rh2(OAc)4, would undergo the
122
desired intramolecular C-H insertion6 producing the spirolactones 102, the proposed
precursors to syringolides 1-3.
O
O
O
OH
O
Syringolide 1 (1, n = 3)Syringolide 2 (2, n = 5)Syringolide 3 (3, n = 1)
HHO
99
Scheme 3.3 C-H Insertion: General Strategy.
R R'
OHO
Diazo transferAcylation
100
R R'
OO
OR"
101
R R'
OO
OR"
N2
Rh2(L)4R R'
OO
OR"
102
n
O
OO
N2
RO
O
N2
RO
OTBSO
N2
RO
O
N2
R
O
O
N2
RO
O
N2
RO
O
N2
RMeO
MeOO
HO OH
R =
103 104 105 107
108 109 110
O
O
MeO
O
N2
R
106
H
Figure 3.1 Side Chains for Model Studies.
In model studies, the α-diazo-β-ketoester side chain of 97 was masked as a
diazoacetoacetate (103), a diazoacetate7 (104), a 2-diazo-3-[(t-butyldimethylsilyl)oxy]-3-
123
butenoate8 (105), a diazomalonate (106), a vinyldiazoacetate (107-108) or a
methoxyphenyldiazoacetate (109-110) (Figure 3.1). Additionally, the diol coupling
partner was masked as a protected trans diol (111), and an olefin (112) (Figure 3.2). To
assess reactivity of the various side chains (i.e.: 103-110) towards C-H insertion
chemistry, the parent tetrahydrofuran (113) was also included in our model studies.
ORO O O
N2
R =OROO
PO OP
RO
111P = Bn, Me or TBS
112 113
Figure 3.2 Masked Trans Diol for Model Studies.
3.3 C-H Insertion: Tetrahydrofurfuryl Esters.
3.3.1 Initial Studies with Tetrahydrofurfuryl Esters of 113.
3.3.1.1 Diazoacetoacetate.
Given that the diazoacetoacetate side chain (103) most closely resembles that
required for the synthesis of 97, known acetoacetate 1149 was exposed to diazo transfer
conditions (Scheme 3.4). The derived diazoacetoacetate 1151 was treated with several
rhodium(II) catalysts [i.e.: Rh2(OAc)4, Rh2(cap)4, Rh2(tfa)4 and Rh2(NHCOC3F7)4], all of
which failed to promote the formation of the desired spirolactone 116 and produced
instead an intractable mixture of compounds.
124
Scheme 3.4
114
OO
OO
N2
O
OO
O
O
115
116
p-ABSA, Et3N
CH3CN (88%)
Rh2(L)4
CH2Cl2X
O O O
3.3.1.2 2-Diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate.
Knowing that methyl 2-diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate
undergoes O-H insertion when treated with Rh2(OAc)4,10 the reactivity of the 2-diazo-3-
[(t-butyldimethylsilyl)oxy]-3-butenoate side chain (105) was explored as an alternative to
the diazoacetoacetate chain (103). To this end, 115 was treated with TBSOTf and Et3N
to furnish 117 quantitatively (Scheme 3.5). Diazo decomposition of 117 furnished the
desired spirolactone 118, but unfortunately it is unstable and decomposed to an
intractable mixture of compounds before it could be fully characterized.
Scheme 3.5
TBSOTf, Et3N
CH2Cl2 (100%)
OO
N2
O
115
OO
ON2
OTBS
117
O
OO
O
TBSO
118
Rh2(OAc)4
CH2Cl2 (18%)
125
3.3.1.3 Diazomalonate.
Having failed with 103, we turned to the diazomalonate side chain (106) (Scheme
3.6). Thus, acylation of tetrahydrofurfuryl alcohol (119) with methyl malonyl chloride11
(120) followed by exposure of the derived malonate 121 to diazo transfer conditions
provided diazomalonate 122. Treatment of 122 with Rh2(OAc)4 failed to furnish any of
the desired spirolactone 123 and resulted in an intractable mixture of products.
Cl
O
MeO
OOOH +
Pyridine, CH2Cl2
(96%)
121
OO OMe
OO
N2
OMe
O
122
p-ABSA, Et3N
CH3CN (68%)
119 120
OO
O
O OMe123
Rh2(OAc)4
CH2Cl2X
Scheme 3.6
O O
O
3.3.1.4 3-Methoxyphenyldiazoacetate.
Concerned over the stabilizing effects of the β-dicarbonyl moieties in 115 and 122
we next turned to the 3-methoxyphenylacetate side chain (109) since it could produce a
less stable and thus more reactive carbenoid (Scheme 3.7). To this end, 119 was acylated
with 3-methoxyphenylacetic acid (124) to furnish ester 125. Diazo transfer reaction on
125 provided 3-methoxyphenyldiazoacetate 126 which when treated with Rh2(OAc)4
produced the desired spirolactone 127 in very good yield (85%). Only one of the two
possible C-H insertion isomers was observed and single-crystal X-ray analysis
established the illustrated anti orientation of the tetrahydrofurfuryl oxygen and the proton
126
α to the carbonyl. As described later in this chapter, the same relative stereochemical
configuration was observed in all the other spirolactones analyzed by X-ray
crystallography. Although transformation of the aromatic side chain in 127 to the
required β-ketoester for the actual synthesis of syringolides would be difficult, the high
yield obtained with the 3-methoxyphenyldiazoacetate side chain led us to continue its use
in other model systems.
OH
O+
DCC, DMAP
CH2Cl2 (96%)
125
OO
OO
N2
126
p-ABSA, DBU
CH3CN (81%)
119 124
Rh2(OAc)4
CH2Cl2 (85%)
Scheme 3.7
MeO
OO
O
127
H
OMe
OOH
O
O
OMe
OMe
3.3.1.5 Vinyldiazoacetate.
Since an olefin could serve as a precursor to the β-ketoester functionality of the
side chain, it was decided to test the reactivity of the vinyldiazoacetate side chain (107)
(Scheme 3.8). Accordingly, 119 was acylated with vinylacetic acid (128) to furnish ester
129. Diazo transfer reaction on 129 provided vinyldiazoacetate 130 which, upon
127
treatment with Rh2(OAc)4, produced the desired spirolactone 131. Again only one of the
two possible diastereomeric C-H insertion products was observed by 1H NMR. Based on
analogy to 127, it is believed that 131 possesses a relative stereochemical configuration
wherein the tetrahydrofuranyl oxygen and the proton α to the carbonyl group are anti.
OH
OOOH +
129
OO
OO
N2
130
119 128
OO
O
131
Scheme 3.8
DCC, DMAP
CH2Cl2 (100%)
p-ABSA, DBU
CH3CN (34%)
Rh2(OAc)4
CH2Cl2 (36%)
O
O
3.3.1.6 Cyclohexenyldiazoacetate.
Based on successes with 130 and recognizing that a cyclic olefin would be a
preferred substrate we next prepared 134 (Scheme 3.9). To this end, the
vinyldiazocarboxylate functionality was prepared via the two step procedure developed
by Padwa and co-workers.11 Thus, treatment of diazoacetate 941 with LDA and
cyclohexene furnished alcohol 133 which could, in turn, be dehydrated to 134 upon
exposure to POCl3. Intramolecular C-H insertion of 134 in the presence of Rh2(OAc)4
furnished the desired spirolactone 135. As with 127 and 131, only one of the two
possible C-H insertion isomers was observed by 1H NMR and again by analogy to 127
128
we have assigned the relative stereochemistry such that the tetrahydrofuranyl oxygen and
the proton α to the carbonyl group are anti.
OO
N2
133
OO
O
134
Scheme 3.9
LDA, THF
(87%)
Rh2(OAc)4
CH2Cl2 (51%)
94
OO
N2
OO
N2
132
O
+
135
POCl3, pyridine
(81%)
O
O
O
OH
As mentioned in Chapters 1 and 2, it was supposed that syringolide-like
molecules with an amino functionality at the terminus of the side chain could be used as
molecular probes in affinity chromatography for the isolation of the receptor protein in
soybean provided these derivatives retained their biological activity and could bind to
their receptor. Of particular interest with regard to 135 was the possibility of unmasking
the requisite ketone via ozonolysis since an aldehyde functionality would be obtained at
the end of the side chain. This aldehyde could be oxidized to the corresponding
carboxylic acid or used to incorporate an amino group, both of which would be useful in
the synthesis of a syringolide analog suitable for affinity chromatography. Unfortunately,
attempts to produce the desired β-keto-η-aldo side chain via oxidative cleavage13 did not
furnish the expected spirolactone 136 but its corresponding β-elimination derivative 137
which could not be characterized since it was labile and did not survive purification (flash
129
chromatography, HPLC) (Scheme 3.10). These results indicated that the cyclohexenyl
side chain would be difficult to derivatize to the required β-keto-η-aldo side chain and
the approach was abandoned.
OO
O
O
136
H
O
1. O3, CH2Cl2
2. Me2S
OO
O
135
OO
OOH
OH
137
Scheme 3.10
3.4 C-H Insertion: 2,5-Dihydrofurfuryl Esters.
3.4.1 Studies with 2,5-Dihydrofurfuryl Esters.
Dihydrofurfuryl esters (112) were chosen for the second set of model studies
since dihydroxylation of the resident olefin could furnish the requisite trans diol. The
diazoacetoacetate, diazoacetate, 3-methoxyphenyldiazoacetate and 4-methoxyphenyl-
diazoacetate side chains were chosen for these experiments.
3.4.1.1 Diazoacetoacetate.
Once again the diazoacetoacetate side chain (103) was tried first (Scheme 3.11)
since it most closely resembled that required for the synthesis of 97. Thus, 2,5-
dihydrofurfuryl alcohol (138)14 was treated with diketene (139) to furnish acetoacetate
140. Diazo transfer reaction on acetoacetate 140 produced diazoacetoacetate 141 which
130
was treated with two different rhodium(II) catalysts: Rh2(OAc)4 and Rh2(tfa)4. The
experiments were unsuccessful and the desired spirolactone 142 was not obtained, instead
an intractable mixture of compounds was produced.
Scheme 3.11
140
OO
OO
N2
O OO
O
O
141 142
MsN3, Et3N
CH3CN (82%)
Rh2(L)4
CH2Cl2X
138
OOH
O O
O
OO
139
DMAP, THF
(93%)+
3.4.1.2 2-Diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate.
The reactivity of the 2-diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate side chain
(105) was explored again as an alternative to the diazoacetoacetate chain (103). To this
end, 141 was treated with TBSOTf and Et3N to furnish 143 (Scheme 3.12). Diazo
decomposition of 143 furnished the desired spirolactone 144 but unfortunately, just as
118, it is unstable and decomposed to an intractable mixture of compounds before it
could be fully characterized.
131
Scheme 3.12
TBSOTf, Et3N
CH2Cl2 (98%)
OO
N2
O
141
OO
ON2
OTBS
143
O
OO
O
TBSO
144
Rh2(OAc)4
CH2Cl2 (13%)
3.4.1.3 Diazoacetate.
The diazoacetate side chain (104) was tested (Scheme 3.13) since Doyle and
Dyatkin1 had shown that the corresponding tetrahydrofurfuryl ester (94) undergoes the
desired C-H insertion reaction to furnish spirolactone 95 (Scheme 3.1). Deacylation of
diazoacetoacetate 141 under basic conditions produced diazoacetate 145 which was
treated with two different rhodium(II) catalysts: Rh2(OAc)4 and Rh2(cap)4. The
experiments were unsuccessful and the desired spirolactone 146 was not obtained, instead
an intractable mixture of compounds was produced.
OO
N2
OO
O
145 146
Rh2(L)4
CH2Cl2X
O
Scheme 3.13
OO
N2
O
141
O LiOH, H2O
CH3CN (52%)
132
3.4.1.4 3-Methoxyphenyldiazoacetate.
After the previous unsuccessful experiments, the 3-methoxyphenylacetate chain
(109) was tested (Scheme 3.14) since, as discussed in section 3.3.1.4, this had proven to
be a good side chain. To this end, 138 was acylated with 124 to furnish ester 147. Diazo
transfer reaction on 147 provided 3-methoxyphenyldiazoacetate 148 which, upon
treatment with Rh2(OAc)4, produced the desired spirolactone 149 in very good yield.
Only one of the two possible C-H insertion isomers was observed and single-crystal X-
ray analysis established the illustrated the relative stereochemical configuration where the
2,5-dihydrofuranyl oxygen and the proton α to the carbonyl group are anti to each other.
OH
O+
DCC, DMAP
CH2Cl2 (87%)
147
OO
OO
N2
148
p-ABSA, DBU
CH3CN (78%)
124
Rh2(OAc)4
CH2Cl2 (73%)
Scheme 3.14
MeO
OO
O
149
H
OMe
O
O
OMe
OMe
138
OOH
133
3.4.1.5 4-Methoxyphenyldiazoacetate.
The 4-methoxyphenylacetate side chain (110) was tested as an alternative to the
3-methoxyphenylacetate (Scheme 3.15). To this end, 138 was acylated with 150 to
furnish ester 151. Diazo transfer reaction on 151 provided 4-methoxyphenyldiazoacetate
152. In contrast to 147, diazo transfer produced only 43% of the desired product (60%
based on recovered 151). Diazo decomposition of 152 with Rh2(OAc)4 furnished the
desired spirolactone 153 in good yield and again as a single diastereomeric product.
Single-crystal X-ray analysis established the illustrated relative stereochemical
configuration wherein the 2,5-dihydrofuranyl oxygen and the proton α to the carbonyl
group are anti.
OH
O+
DCC, DMAP
CH2Cl2 (95%)
151
OO
OO
N2
152
p-ABSA, DBU
CH3CN (43%)
150
Rh2(OAc)4
CH2Cl2 (63%)
Scheme 3.15
OO
O
153
H
O
O
138
OOH
MeO
OMe
OMe
MeO
134
3.5 C-H Insertion: 1,4-Anhydroarabinityl Esters.
3.5.1 Studies with 2,3-di-O-Protected 1,4-Anhydroarabinityl Esters.
Model systems based on 1,4-anhydroarabinitol (98) (Figure 3.3) highly resemble
the trans diol required for the real system (97). Thus, a series of 2,3-di-O-protected 1,4-
arabinitol ethers were used for model studies. These include the TBS-diprotected 154,
benzyl-diprotected 155 and methyl-diprotected 156. All the experiments are outlined
below.
OHO
98
HO OH
OHO
154
TBSO OTBS
OHO
155
BnO OBn
OHO
156
MeO OMe
OO
97cHO OH
O
N2
O
Figure 3.3 2,3-di-O-1,4-Arabinitol (98) and Derivatives.
3.5.1.1 Masked Diols: 2,3-di-O-(t-Butyldimethylsilyl)-1,4-anhydro-DL-arabinityl
Esters.
The TBS-diprotected model system was selected since the TBS protecting group
is generally easy to install and remove. Preparation of the several TBS-diprotected
substrates commenced with 2,3-di-O-(t-butyldimethylsilyl)-1,4-anhydro-DL-arabinitol
(154) which is readily available from 5-O-benzoyl-1,4-anhydro-DL-arabinitol (157)15 via
135
treatment with TBSCl and imidazole16 followed by debenzoylation to 154 under basic
conditions (Scheme 3.16).
Scheme 3.16
157
OHO
OO
O
OO
O
Imidazole, TBSCl
DMF
NaOMe, MeOH
(59%, two steps)
158
154
OTBSOH
OTBS
TBSOHO
TBSO
3.5.1.1.1 Diazoacetoacetate.
As in previous studies, the diazoacetoacetate side chain (103) was tried first
(Scheme 3.17) since it most resembled that required one for the preparation of 97. Thus,
alcohol 154 was treated with diketene (139) to furnish acetoacetate 159. Diazo transfer
reaction on acetoacetate 159 produced diazoacetoacetate 160 which was treated with
Rh2(OAc)4. The reaction was unsuccessful and the desired spirolactone 161 was not
obtained, instead an intractable mixture of compounds was produced.
136
OHO
154
OTBSTBSO
Scheme 3.17
OO
O
161
Rh2(OAc)4
CH2Cl2X
OO
139
DMAP, THF
(84%)+ OO
O
159
OTBSTBSO
O
OO
O
160
OTBSTBSO
O
N2
p-ABSA, Et3N
CH3CN (90%) OTBSOTBS
O
3.5.1.1.2 2-Diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate.
Based on previous successes with α,β-unsaturated diazo substrates (i.e.: 130 and
134) and knowing that methyl 2-diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate
undergoes O-H insertion when treated with Rh2(OAc)4,10 the reactivity of the 2-diazo-3-
[(t-butyldimethylsilyl)oxy]-3-butenoate side chain (105) was explored as an alternative to
the diazoacetoacetate chain (103). To this end, 160 was treated with TBSOTf and Et3N
to furnish 162 quantitatively (Scheme 3.18). Diazo decomposition of 162 did not
produce the desired spirolactone 163, instead an intractable mixture of compounds was
produced.
137
Scheme 3.18
OO
O
163
Rh2(OAc)4
CH2Cl2X
OO
O
162
OTBSTBSO
TBSO
N2
OTBSOTBS
TBSO
OO
O
160
OTBSTBSO
O
N2
TBSOTf, Et3N
CH2Cl2 (100%)
3.5.1.1.3 Diazoacetate.
Again based the work by Doyle and Dyatkin1 we explored the reactivity of the
diazoacetate side chain (104). Thus, deacylation of diazoacetoacetate 160 with LiOH
produced diazoacetate 164 which was treated with two different rhodium(II) catalysts:
Rh2(OAc)4 and Rh2(cap)4 (Scheme 3.19). The desired spirolactone 165 was obtained only
in the presence of the Rh2(OAc)4 catalyst.
OO
O
165
OO
O
164
OTBSTBSO
N2
OO
O
160
OTBSTBSO
O
N2
LiOH, H2O
CH3CN (82%)
OTBSTBSO
Scheme 3.19
Rh2(OAc)4
CH2Cl2 (69%)
138
3.5.1.1.4 3-Methoxyphenyldiazoacetate.
To explore the effects of a less stabilized carbenoid, we turned again to the 3-
methoxyphenylacetate side chain (109). To this end, 154 was acylated with 124 to
furnish ester 166 (Scheme 3.20). Diazo transfer reaction on 166 provided 3-
methoxyphenyldiazoacetate 167 which, upon treatment with Rh2(OAc)4 and produced the
desired spirolactone 168. Only one of the two possible C-H insertion isomers was
observed and single-crystal X-ray analysis established the illustrated relative
stereochemical configuration wherein the tetrahydrofuranyl oxygen and the proton α to
the carbonyl group are anti.
OH
O+
DCC, DMAP
CH2Cl2 (100%)
p-ABSA, DBU
CH3CN (67%)
124
Rh2(OAc)4
CH2Cl2 (36%)
Scheme 3.20
MeO
168
OHO
154
OTBSTBSO
OO
166
OTBSTBSO
O
MeO
OO
167
OTBSTBSO
O
MeON2
OO
O
HMeO OTBSOTBS
139
3.5.1.2 Masked Diols: 1,4-Anhydro-2,3-di-O-benzyl-D-arabinityl Esters.
The benzyl-diprotected model system was selected since the benzyl protecting
group is easy to remove and the required common intermediate 1,4-anhydro-2,3-di-O-
benzyl-D-arabinitol (155) is readily available on multigram scale.17
3.5.1.2.1 Diazoacetoacetate.
Based on its resemblance to 97, the diazoacetoacetate derived substrate was
explored first (Scheme 3.21). Thus, alcohol 155 was treated with diketene (139) to
furnish acetoacetate 169. Diazo transfer reaction on acetoacetate 169 produced
diazoacetoacetate 170 which was treated with Rh2(OAc)4. The reaction was unsuccessful
and the desired spirolactone 171 was not obtained. An intractable mixture of compounds
was produced instead.
OHO
155
OBnBnO
Scheme 3.21
OO
O
171
Rh2(OAc)4
CH2Cl2X
OO
139
DMAP, THF
(94%)+ OO
O
169
OBnBnO
O
OO
O
170
OBnBnO
O
N2
p-ABSA, Et3N
CH3CN (89%)O OBn OBn
140
Scheme 3.22
Rh2(OAc)4
CH2Cl2X
OO
O
172
OBnBnO
TBSO
N2
OO
O
170
OBnBnO
O
N2
TBSOTf, Et3N
CH2Cl2 (93%)
OO
O
173
TBSO OBn OBn
3.5.1.2.2 2-Diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate.
As before, the 2-diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate side chain (105)
was explored as an alternative to the diazoacetoacetate. To this end, 170 was treated with
TBSOTf and Et3N to furnish 172 (Scheme 3.22). Diazo decomposition of 170 did not
produce the desired spirolactone 173 and resulted in an intractable mixture of products.
OO
O
175
OO
O
174
OBnBnO
N2
OO
O
170
OBnBnO
O
N2
LiOH, H2O
CH3CN (84%)
OBnBnO
Scheme 3.23
Rh2(OAc)4
CH2Cl2 (7%)
141
3.5.1.2.3 Diazoacetate.
Turning to a potentially more promising substrate, diazoacetoacetate 170 was
exposed to deacylation conditions to produce diazoacetate 174 (Scheme 3.23). Although
treatment of 174 with Rh2(OAc)4 furnished the desired spirolactone 175,18 the yield was
quite low (7%).
OH
O+
DCC, DMAP
CH2Cl2 (100%)
p-ABSA, DBU
CH3CN (79%)
124
Rh2(OAc)4
CH2Cl2 (15%)
Scheme 3.24
MeO
178
OHO
155
OBnBnO
OO
176
OBnBnO
O
MeO
OO
177
OBnBnO
O
MeON2
OO
O
HMeO OBnOBn
3.5.1.2.4 3-Methoxyphenyldiazoacetate.
In accord with previous studies, the 3-methoxyphenylacetate side chain (109) was
explored next (Scheme 3.24). To this end, 155 was acylated with 124 to furnish ester
176. Diazo transfer reaction on 176 provided 3-methoxyphenyldiazoacetate 177 which,
upon treatment with Rh2(OAc)4, produced the desired spirolactone 178. Only one of the
two possible C-H insertion isomers was observed by 1H NMR. Based on analogy to 127,
142
149, 153 and 168 (structures secured by X-ray analysis) we have tentatively assigned 178
as possessing an anti relationship between the tetrahydrofuranyl oxygen and the proton α
to the lactone carbonyl.
Scheme 3.25
157
OO
O
OO
O48% wt aq HBF4, TMSCHN2
CH2Cl2, hexanes
NaOMe, MeOH
(29%, two steps)
179
OHO
156
MeO OMeOMe
OH
MeO
HO
3.5.1.3 Masked Diols: 1,4-Anhydro-2,3-di-O-methyl-DL-arabinityl Esters.
The methyl-diprotected model system was selected to see if the bulk of the TBS
and benzyl protecting groups of the previous model systems was interfering with the C-H
insertion reaction. However, it was not considered as a precursor for the real system
since the methyl ethers would be difficult to remove. In order to obtain the common
intermediate 1,4-anhydro-2,3-di-O-methyl-DL-arabinitol (156), 5-O-benzoyl-1,4-
anhydro-DL-arabinitol (157)15 was treated with TMSCHN2 and HBF419 to produce 179
which was debenzoylated under basic conditions to furnish 156 (Scheme 3.25).
143
3.5.1.3.1 Diazoacetoacetate.
The diazoacetoacetate side chain (103) was tried first (Scheme 3.26) since it most
closely resembled that required for the synthesis of 97. Thus, alcohol 156 was treated
with diketene (139) to furnish acetoacetate 180. Diazo transfer reaction on acetoacetate
180 produced diazoacetoacetate 181 which was treated with Rh2(OAc)4. The reaction
was unsuccessful and the desired spirolactone 182 was not obtained, an intractable
mixture of compounds was produced instead.
OHO
156
OMeMeO
Scheme 3.26
OO
O
182
Rh2(OAc)4
CH2Cl2X
OO
139
DMAP, THF
(95%)+ OO
O
180
OMeMeO
O
OO
O
181
OMeMeO
O
N2
p-ABSA, Et3N
CH3CN (78%) OMeOOMe
3.5.1.3.2 2-Diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate.
As before, the 2-diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate side chain (105)
was explored next. Thus, 181 was treated with TBSOTf and Et3N to furnish 183
(Scheme 3.27). Diazo decomposition of 183 did not produce the desired spirolactone 184
and resulted instead in an intractable mixture of compounds.
144
Scheme 3.27
OO
O
184
Rh2(OAc)4
CH2Cl2X
OO
O
183
OMeMeO
TBSO
N2
OMeTBSO
OO
O
181
OMeMeO
O
N2
TBSOTf, Et3N
CH2Cl2 (87%)
OMe
3.5.1.3.3 Diazoacetate.
Turning again to a potentially more promising diazo substrate, diazoacetoacetate
181 was deacylated under basic conditions to produce diazoacetate 185. Treatment of
185 with two different rhodium(II) catalysts: Rh2(OAc)4 and Rh2(cap)4 furnished the
desired spirolactone 186 only in the presence of the former (Scheme 3.28).
OO
O
186
OO
O
185
OMeMeO
N2
OO
O
181
OMeMeO
O
N2
LiOH, H2O
CH3CN (68%)
OMeMeO
Scheme 3.28
Rh2(OAc)4
CH2Cl2 (54%)
145
3.5.1.3.4 3-Methoxyphenyldiazoacetate.
The final substrate in this series was the 3-methoxyphenyldiazoacetate derivative
188 (Scheme 3.29). This material was prepared by acylation of 156 with 124 to furnish
ester 187. Diazo transfer reaction on 187 provided 3-methoxyphenyldiazoacetate 188
which was treated with Rh2(OAc)4. Unlike its TBS (167) and benzyl (177) counterparts,
188 did not furnish the desired spirolactone 189. Instead, an intractable mixture of
compounds was produced.
OH
O+
DCC, DMAP
CH2Cl2 (75%)
p-ABSA, DBU
CH3CN (32%)
124
Scheme 3.29
MeO
189
OHO
156
OMeMeO
OO
187
OMeMeO
O
MeO
OO
188
OMeMeO
O
MeON2
OO
O
HMeO OMeOMe
Rh2(OAc)4
CH2Cl2X
146
3.5.2 Unmasked Diols: 1,4-Anhydroarabinityl Esters.
The final set of model systems were based on unprotected 1,4-anhydroarabinitol
(98) and highly resemble the trans diol required for the real system (97). Only the
diazoacetoacetate and the 3-methoxyphenyldiazoacetate side chains were tested since
other model systems were difficult to prepare. The experiments are outlined below.
3.5.2.1 Diazoacetoacetate.
The diazoacetoacetate side chain (103) was tried first (Scheme 3.30) since it most
closely resembled that required for the synthesis of 97. Thus, 1,4-anhydro-D-arabinitol
(98)20 was treated with diketene (139) to furnish acetoacetate 190. Diazoacetoacetate 194
was obtained via a three step procedure that involved diol protection to produce 192,
diazo transfer reaction to give diazoacetoacetate 193 and diol deprotection to furnish 194.
Diazo decomposition of 194 with Rh2(OAc)4 did not yield the desired spirolactone 195,
instead an intractable mixture of compounds was produced.
147
OHO
98
OHHO
Scheme 3.30
OO
O
195
Rh2(OAc)4
CH2Cl2X
OO
139
DMAP, THF
(34%)+ OO
O
190
OHHO
O
OO
O
194
OHHO
O
N2
p-ABSA, Et3N
CH3CN
OHO OH
OO
O
192
OO
O
MeO OMe
OO
O
193
OO
O
MeO OMe
N2
OMe
191
POCl3, THF
p-TsOH, MeOH
(91%, three steps)
3.5.2.2 3-Methoxyphenyldiazoacetate.
Given that the 3-methoxyphenylacetate derivatives were among the best model
systems examined, we explored the analogous 1,4-anhydroarabinityl substrate (Scheme
3.31). To this end, 166 was treated with 48% wt aq HBF416 to furnish diol 196.
3-Methoxyphenyldiazoacetate 199 was obtained via a three step procedure that involved
diol protection to produce 197, diazo transfer reaction to give 3-methoxyphenyl-
148
diazoacetate 198 and diol deprotection to furnish 199. Diazo decomposition of 199 with
either Rh2(OAc)4 or Rh2(tfa)4 did not yield the desired spirolactone 200, instead an
intractable mixture of compounds was produced.
Scheme 3.31
OO
O
200
Rh2(L)4
CH2Cl2X OH OH
OO
O
197
OOMeO OMe
OMe
191
POCl3, THF
p-TsOH, MeOH
(44%, three steps)
p-ABSA, DBU
CH3CN
OO
166
OTBSTBSO
O 48% wt aq HBF4
CH3CN (93%) OO
196
OHHO
O
OMe OMe
OMe
OO
O
198
OOMeO OMe
OMe
N2OO
O
199
HO
OMe
N2
OH
MeO
149
3.6 C-H Insertion: Stereochemistry.
All of the C-H insertion products analyzed by X-ray crystallography were shown
to possess the same relative stereochemistry (i.e. the polihydrofuranyl oxygen and the
proton α to the lactone carbonyl were always oriented anti about the lactone ring) (Figure
3.4). Although this relative configuration is opposite to that needed for the synthesis of
the syringolides (cf. 3 to 168), the potential epimerizability of the α-center renders the
stereochemical outcome secondary in importance compared to the formation of the C-C
bond.
OO
O
127
H
OMe
OO
O
149
H
OMe
OO
O
153
H
MeO
168
OO
O
HMeO OTBSOTBS
O
O
OO
H
OHHO
Syringolide 3 (3)
Figure 3.4 Spirolactones Analyzed by X-ray Crystallography.
Based on the observed relative stereochemical configuration of all the C-H
insertion products analyzed by X-ray crystallography and in the fact that whenever two
diastereomers could be formed in the C-H insertion reaction only was observed, it is
believed that 131, 135 and 178 have the same relative stereochemical configuration as the
150
C-H insertion products analyzed by X-ray crystallography: with the tetrahydrofuranyl
oxygen and the proton α to the carbonyl group anti to each other (Figure 3.5).
OO
O
131
H
OO
O
135
H
178
OO
O
HMeO OBn OBn
Figure 3.5 Proposed Relative Stereochemical Configuration for C-H Insertion Products
131, 135 and 178
It is unclear wether the observed stereochemistry of the C-H insertion products
arises trough a kinetic or thermodynamic process. The C-H insertion mechanism
described by Taber et al.20 is highly speculative21 and more information regarding this
mechanism is needed before it can be used to explain the experimental outcome.
3.7 Conclusions.
The desired C-H insertion products could not be isolated in any of the model
systems where the side chain could be readily modified to that required for the synthesis
of syringolides. These model side chains include the diazoacetoacetate and the 2-diazo-
3-[(t-butyldimethylsilyl)oxy]-3-butenoate. As discussed in section 3.3.1.6, ozonolysis of
135 did not furnish spirolactone 136 but its corresponding β-elimination derivative 137
(Scheme 3.32). This β-elimination could be favored by two factors:
a) The anti relationship between the proton α to the carbonyl group and the
tetrahydrofuranyl oxygen.
151
b) The increased acidity of this proton due to the 3-oxo functionality.
OO
OHO
OO
O
135
H
136
1. O3, CH2Cl2
2. Me2S
OO
OO
H
137
Scheme 3.33
HO
HO
Thus, the β-elimination process could limit the utility of the C-H insertion route
for the syringolide synthesis since formation or unmasking the β-keto functionality could
make the α proton acidic enough to eliminate and, as described in Chapter 2, the
formation of syringolides from their butenolide precursors is usually problematic and
low-yielding.
The diazoacetate model systems are also limited by the fact that attempts of
derivatization of the corresponding spirolactones to the side chain required for the real
system could easily result in decomposition of the spirolactone system by β-elimination.
The 3- and 4-methoxyphenylacetate side chains proved to be excellent moieties
for the C-H insertion reaction working in most of the experiments where they were used.
Unfortunately derivatization to the real system would be difficult.
A model system where the C-H insertion reaction worked and the product could
be easily derivatized to the real system was never found. However, a highly
stereospecific synthesis of spirolactones was achieved and this methodology could
potentially be employed in the assembly of other synthetically useful compounds.
152
3.8 Experimental Section.
3.8.1 Materials and Methods.
Unless stated otherwise, reactions were performed in flame dried glassware under
a nitrogen atmosphere, using freshly distilled solvents. Diethyl ether (Et2O) and
tetrahydrofuran (THF) were distilled from sodium/benzophenone ketyl. Methylene
chloride (CH2Cl2) and triethylamine (Et3N) were distilled from calcium hydride. All
other commercially obtained reagents were used as received.
Unless stated otherwise, all reactions were magnetically stirred and monitored by
thin-layer chromatography (TLC) using E. Merck silica gel 60 F254 precoated plates (0.25
mm). Column or flash chromatography was performed with the indicated solvents using
silica gel (230-400 mesh) purchased from Bodman. In general, the chromatography
guidelines reported by Still et al.23 were followed. When reactions were adsorbed onto
silica gel, the amount of silica gel used was equal to two times the weight of the reagents.
All melting points were obtained on a Thomas Hoover capillary melting point
apparatus and are uncorrected. Infrared spectra were recorded on a Midac M1200 FTIR.
1H and 13C NMR spectra were recorded on a Bruker AM-500, Bruker Avance DPX-500
or Bruker Avance DPX-400 spectrometer. Chemical shifts are reported relative to
internal chloroform (1H, δ 7.26 ppm; 13C, δ 77.2 ppm),24 Me4Si (1H, δ 0.00 ppm) or
acetone (1H, δ 2.05 ppm; 13C, δ 29.8 ppm).24 High resolution mass spectra were
performed at the University of Illinois Mass Spectrometry Center. High performance
liquid chromatography (HPLC) was performed on a Waters 510 solvent delivery system
using a Rainin Microsorb 80-199-C5 column, or a Rainin Dynamax SD-200 solvent
153
delivery system with a Rainin Microsorb 80-120-C5 column. Optical rotations were
measured on a Perkin Elmer 341 polarimeter. Single-crystal X-ray analyses were
performed by Susan DeGala of Yale University.
For purposes of this work, in any given reaction the number of equivalents of a
reactant A is equal to the number of mmol of A used per mmol of the limiting reagent B
employed. The phrase: “was allowed to warm to room temperature” should be taken to
mean that no more cooling agent (ice or dry-ice) was added to the insulating cooling bath.
3.8.2 Preparative Procedures.
Preparation of Diazoacetoacetate 115.
OO
N2
O
115
O
Diazoacetoacetate 115. Triethylamine (8.8 mL, 63.14 mmol, 3.04 equiv) was
added dropwise to a stirred (0 °C) solution of acetoacetate 114 (3.862 g, 20.74 mmol, 1
equiv) and p-ABSA (5.532 g, 23.03 mmol, 1.11 equiv) in CH3CN (52 mL). After
allowing to warm to room temperature and stirring overnight, the reaction mixture was
concentrated in vacuo, triturated with 1:1 Et2O:petroleum ether (104 mL), filtered and
reconcentrated to a yellow oil. Silica gel chromatography employing 6:4 hexanes:EtOAc
as eluant furnished 115 (3.857 g, 88% yield) as a yellow oil. An analytical sample
(yellow oil) was obtained by selecting fractions from the flash chromatography: FTIR
(thin film/NaCl) 2976 (m), 2955 (m), 2874 (m), 2142 (s), 1717 (s), 1658 (s), 1451 (w),
154
1386 (m), 1366 (s), 1341 (s), 1313 (s), 1250 (s), 1158 (s), 1073 (s) cm-1; 1H NMR (500
MHz, CDCl3) δ 4.20 (dd, J=10.7, 2.8 Hz, 1H), 4.14-4.08 (m, 2H), 3.79 (dd, J=14.6, 7.3
Hz, 1H), 3.72 (dd, J=14.7, 7.0 Hz, 1H), 2.40 (s, 3H), 1.96 (m, 1H), 1.88 (m, 2H), 1.56
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 189.9, 161.3, 76.3, 68.5, 67.0, 28.2, 27.9, 25.7;
HRMS (FAB) m/z 213.0876 [calcd for C9H13N2O4 (M+H) 213.0875].
Preparation of TBS-enol ether 117.
OO
N2
OTBS
117
O
TBS-enol ether 117. TBSOTf (860 µL, 3.74 mmol, 1.12 equiv) was added dropwise to a
stirred (0 °C) solution of diazoacetoacetate 115 (663 mg, 3.12 mmol, 1 equiv) and
triethylamine (660 µL, 4.74 mmol, 1.52 equiv) in CH2Cl2 (8 mL). After allowing to
warm to room temperature and stirring for 2.5 h, the reaction mixture was diluted with
petroleum ether (32 mL) and washed with 1:1 saturated aqueous NaHCO3:water (2 X 32
mL) and brine (32 mL). The aqueous washings were extracted with petroleum ether (32
mL) and the combined organic phases were dried over MgSO4, filtered and concentrated
in vacuo to furnish 117 (1.020 g, 100% yield) as an orange oil. Typically this material
was used without purification due to its instability. However, an analytical sample
(orange oil) was prepared by flash column chromatography employing 90:10:1
hexanes:EtOAc:Et3N as eluant: FTIR (thin film/NaCl) 2656 (s), 2932 (s), 2884 (m),
2859 (s), 2103 (s), 1713 (s), 1636 (w), 1609 (m), 1472 (m), 1463 (m), 1389 (s), 1364 (s),
1348 (s), 1259 (s), 1080 (s), 1013 (s), 1003 (s), 840 (s), 830 (s), 813 (s), 784 (s) cm-1; 1H
155
NMR (500 MHz, CDCl3) δ 5.00 (d, J=2.1 Hz, 1H), 4.24 (d, J=2.1 Hz, 1H), 4.24-4.21 (m,
1H), 4.19-4.14 (m, 2H), 3.86 (m, 1H), 3.79 (m, 1H), 2.04-1.98 (m, 1H), 1.93-1.89 (m,
2H), 1.68-1.61 (m, 1H), 0.91 (s, 9H), 0.22 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 164.1,
140.7, 90.6, 76.5, 68.5, 66.6, 28.0, 25.8, 25.6, 18.1, -4.7; HRMS (EI) m/z 326.1662
[calcd for C15H26N2O4Si (M+) 326.1662].
Preparation of Malonate 121.
121
OO OMe
O O
Malonate 121. To a stirred (0 °C) solution of tetrahydrofurfuryl alcohol (1 ml,
10.32 mmol, 1 equiv) and pyridine (1.25 mL, 15.46 mmol, 1.5 equiv) in CH2Cl2 (55 mL)
was added dropwise over a 1 h period (syringe pump) a solution of methyl malonyl
chloride (1.2 mL, 11.19 mmol, 1.08 equiv) in CH2Cl2 (20 mL). The reaction mixture was
stirred at 0 °C for 30 min and then washed with water (20 mL) and brine (20 mL). The
aqueous washings were extracted with CH2Cl2 (20 mL) and the combined organic phases
were dried over MgSO4, filtered and concentrated in vacuo to furnish 121 (2.004 g, 96%
yield) as a yellow oil. Typically this material was used without purification. However,
an analytically pure sample (colorless oil) was prepared by flash column chromatography
employing 6:4 hexanes:EtOAc as eluant: FTIR (thin film/NaCl) 2955 (m), 2876 (m),
1753 (s), 1737 (s), 1438 (m), 1412 (m), 1333 (m), 1276 (m), 1200 (m), 1154 (s), 1088
(m), 1026 (s), 921 (w) cm-1; 1H NMR (500 MHz, CDCl3) δ 4.17 (dd, J=11.0, 3.4 Hz,
1H), 4.07 (ddd, J=13.5, 6.7, 3.0 Hz, 1H), 4.03 (dd, J=11.0, 6.4 Hz, 1H), 3.84-3.80 (m,
156
1H), 3.76-3.71 (m, 1H), 3.69 (s, 3H), 3.38 (s, 2H), 1.99-1.91 (m, 1H), 1.90-1.81 (m, 2H),
1.60-1.53 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 166.9, 166.5, 76.2, 68.5, 67.4, 52.5,
41.2, 27.9, 25.7; HRMS (EI) m/z 203.0920 [calcd for C9H15O5 (M+H) 203.0919].
Preparation of Diazomalonate 122.
OO
N2
OMe
O
122
O
Diazomalonate 122. Triethylamine (3.8 mL, 27.26 mmol, 2.99 equiv) was added
dropwise to a stirred (0 °C) solution of malonate 121(1.843 g, 9.11 mmol, 1 equiv) and p-
ABSA (2.411 g, 10.04 mmol, 1.10 equiv) in CH3CN (25 mL). After allowing to warm to
room temperature and stirring overnight, the reaction mixture was concentrated in vacuo,
triturated with 1:1 Et2O:petroleum ether (50 mL), filtered and reconcentrated to a yellow
oil. Silica gel chromatography employing 6:4 hexanes:EtOAc as eluant furnished 122
(1.406 g, 68% yield) as a yellow oil. An analytical sample (yellow oil) was obtained by
selecting fractions from the flash chromatography: FTIR (thin film/NaCl) 2965 (s), 2875
(m), 2137 (s), 1761 (s), 1738 (s), 1694 (s), 1438 (s), 1387 (s), 1325 (s), 1237 (s), 1183 (s),
1081 (s), 1019 (m), 992 (m), 923 (w), 761 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 4.27
(dd, J=11.0, 3.4 Hz, 1H), 4.21-4.14 (m, 2H), 3.87 (dd, J=15.1, 7.0 Hz, 1H), 3.83 (s, 3H),
3.79 (dd, J=14.3, 7.3 Hz, 1H), 2.01 (m, 1H), 1.90 (m, 2H), 1.65 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 161.3, 160.7, 76.2, 68.4, 67.1, 52.4, 27.8, 25.6; HRMS (EI) m/z
229.0825 [calcd for C9H13N2O5 (M+H) 229.0824].
157
Preparation of 3-Methoxyphenylacetate 125.
125
OO
O
OMe
3-Methoxyphenylacetate 125. To a stirred (0 °C) solution of tetrahydrofurfuryl
alcohol (1 mL, 10.32 mmol, 1 equiv), 3-methoxyphenylacetic acid (1.927 g, 11.60 mmol,
1.12 equiv) and DMAP (14 mg, 0.11 mmol, 1.1% equiv) in CH2Cl2 (10 mL) was added
DCC (2.466 g, 11.95 mmol, 1.15 equiv). After allowing to warm to room temperature
and stirring for 4 h, the resulting white precipitate was removed by filtration through a
cotton plug. The filtrate was concentrated in vacuo and the residue taken in CH3CN (10
mL), filtered through a cotton plug and reconcentrated; this procedure was repeated using
acetone (10 mL) and a reddish oil was recovered. Silica gel chromatography employing
3:1 hexanes:EtOAc as eluant furnished 125 (2.479 g, 96% yield) as a yellow oil. An
analytical sample (yellowish oil) was obtained by selecting fractions from the flash
chromatography: FTIR (thin film/NaCl) 3053 (w), 2949 (s), 2874 (s), 2837 (s), 1737 (s),
1662 (w), 1601 (s), 1586 (s), 1491 (s), 1455 (s), 1437 (s), 1262 (s), 1151 (s) cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.19 (t, J=7.6 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.82 (d, J=2.2
Hz, 1H), 6.77 (dd, J=8.4, 2.0 Hz, 1H), 4.14 (dd, J=11.5, 3.4 Hz, 1H), 4.07 (ddd, J=13.5,
7.1, 3.1 Hz, 1H), 3.82-3.78 (m, 1H), 3.74 (s, 3H), 3.76-3.71 (m, 1H), 3.60 (s, 2H), 1.95-
1.88 (m, 1H), 1.85-1.79 (m, 2H), 1.56-1.49 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
171.3, 159.8, 135.4, 129.5, 121.6, 114.9, 112.8, 76.5, 68.4, 66.8, 55.2, 41.3, 28.0, 25.7;
HRMS (EI) m/z 250.1222 [calcd for C14H18O4 (M+) 250.1205].
158
Preparation of 3-Methoxyphenyldiazoacetate 126.
OO
N2
126
O
OMe
3-Methoxyphenyldiazoacetate 126. DBU (0.9 mL, 6.02 mmol, 1.98 equiv) was
added dropwise to a stirred (0 °C) solution of 3-methoxyphenylacetate 125 (760 mg, 3.04
mmol, 1 equiv) and p-ABSA (1.103 g, 4.59 mmol, 1.51 equiv) in CH3CN (9 mL). After
allowing to warm to room temperature and stirring overnight, the reaction mixture was
treated with saturated aqueous NH4Cl (9 mL) and extracted with CH2Cl2 (2 X 18 mL).
The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo
to furnish an orange oil. Silica gel chromatography employing 6:4 hexanes:EtOAc as
eluant furnished 126 (681 mg, 81% yield) as an orange oil. An analytical sample (orange
oil) was obtained by a second flash chromatography using 9:1 hexanes:EtOAc as eluant:
FTIR (thin film/NaCl) 3086 (w), 2951 (s), 2872 (s), 2838 (m), 2091 (s), 1704 (s), 1599
(s), 1578 (s), 1494 (s), 1294 (s), 1251 (s), 1180 (s), 1152 (s), 1035 (s) cm-1; 1H NMR
(500 MHz, CDCl3, Me4Si) δ 7.27 (t, J=7.8 Hz, 1H), 7.16 (s, 1H), 6.97 (d, J=7.8 Hz, 1H),
6.72 (d, J=8.6 Hz, 1H), 4.30 (dd, J=10.7, 3.5 Hz, 1H), 4.25-4.16 (m, 2H), 3.88 (dd,
J=14.9, 7.6 Hz, 1H), 3.82-3.77 (m, 1H), 3.80 (s, 3H), 2.02 (m, 1H), 1.95-1.88 (m, 2H),
1.67 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 165.1, 160.2, 130.0, 127.1, 116.1, 111.7,
109.9, 76.6, 68.7, 66.9, 55.4, 28.1, 25.9; HRMS (EI) m/z 276.1110 [calcd for
C14H16N2O4 (M+) 276.1110].
159
Preparation of Spirolactone 127.
OO
O
127
H
OMe
Spirolactone 127. To a suspension of Rh2(OAc)4 (9.7 mg, 0.02 mmol, 0.9%
equiv) in CH2Cl2 (45 mL) at reflux was added dropwise (over a 10 h period via syringe
pump) a solution of 3-methoxyphenyldiazoacetate 126 (680 mg, 2.46 mmol, 1 equiv) in
CH2Cl2 (12 mL). After allowing to cool to room temperature and concentrating in vacuo,
the resultant green oil was chromatographed on silica employing 2:3 hexanes:EtOAc as
eluant to furnish 127 (522 mg, 85% yield) as a white solid. Recrystallization of 127 from
heptane produced crystals suitable for a single-crystal X-ray analysis which established
the illustrated relative stereochemical configuration.25 An analytical sample (white solid)
was obtained by a second flash chromatography using 6:4 hexanes:EtOAc as eluant: mp
118-119 °C; FTIR (thin film/NaCl) 2972 (m), 2950 (m), 2884 (m), 2839 (w), 1777 (s),
1610 (m), 1585 (m), 1490 (m), 1457 (m), 1441 (m), 1372 (m), 1293 (m), 1266 (m), 1233
(m), 1161 (m), 1117 (s), 1034 (s), 1051 (s), 959 (m), 785 (m), 701 (m) cm-1; 1H NMR
(500 MHz, CDCl3, Me4Si) δ 7.26 (t, J=8.0 Hz, 1H), 6.89-6.84 (m, 3H), 4.33 (d, J=10.1
Hz, 1H), 4.26 (d, J=10.2 Hz, 1H), 3.80 (s, 3H), 3.72 (app. dt, J=8.5, 6.9 Hz, 1H), 3.67 (s,
1H), 3.33 (app. td, J=7.9, 6.3 Hz, 1H), 2.09 (ddd, J=13.0, 8.1, 6.2 Hz, 1H), 1.98 (ddd,
J=13.0, 8.0, 7.6 Hz, 1H), 1.75 (m, 1H), 1.50 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
160
175.7, 159.5, 133.3, 129.2, 123.4, 116.6, 113.6, 87.7, 76.3, 69.1, 55.8, 55.4, 31.8, 25.6;
HRMS (EI) m/z 248.1045 [calcd for C4H16O4 (M+) 248.1048].
Preparation of Vinylacetate 129.
129
OO
O
Vinylacetate 129. To a stirred (0 °C) solution of tetrahydrofurfuryl alcohol (1
mL, 10.32 mmol, 1 equiv), vinylacetic acid (0.98 mL, 11.53 mmol, 1.12 equiv) and
DMAP (14 mg, 0.12 mmol, 0.01 equiv) in CH2Cl2 (10 mL) was added DCC (2.494 g,
12.09 mmol, 1.17 equiv). After allowing to warm to room temperature and stirring for 4
h, the resulting white precipitate was removed by filtration through a cotton plug. The
filtrate was concentrated in vacuo and the residue taken in CH3CN (10 mL), filtered
through a cotton plug and reconcentrated; this procedure was repeated using acetone (10
mL) and a yellowish oil was recovered. Silica gel chromatography employing 3:1
hexanes:EtOAc as eluant furnished 129 (1.767 g, 100% yield) as a colorless oil. An
analytical sample (colorless oil) was obtained by selecting fractions from the flash
chromatography: FTIR (thin film/NaCl) 2976 (m), 2953 (m), 2874 (m), 1739 (s), 1641
(w), 1451 (w), 1426 (w), 1405 (w), 1340 (m), 1324 (m), 1291 (m), 1254 (m), 1173 (s),
1089 (m), 1023 (m), 994 (m), 922 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.91-5.83
(m, 1H), 5.12 (m, 1H), 5.09 (m, 1H), 4.14 (dd, J=11.0, 3.5 Hz, 1H), 4.06 (ddd, J=13.8,
7.0, 3.5 Hz, 1H), 3.95 (dd, J=11.1, 6.5 Hz, 1H), 3.82 (m, 1H), 3.73 (dd, J=11.0, 7.8 Hz,
1H), 3.08 (dt, J=10.5, 1.2 Hz, 2H), 1.97-1.89 (m, 1H), 1.89-1.79 (m, 2H), 1.58-1.51 (m,
161
1H); 13C NMR (125 MHz, CDCl3) δ 171.4, 130.2, 118.5, 76.4, 68.4, 66.6, 38.9, 28.0,
25.6; HRMS (EI) m/z 171.1024 [calcd for C9H15O3 (M+H) 171.1021].
Preparation of Vinyldiazoacetate 130.
OO
N2
130
O
Vinyldiazoacetate 130. DBU (1 mL, 6.69 mmol, 1.74 equiv) was added
dropwise to a stirred (0 °C) solution of vinylacetate 129 (654 mg, 3.84 mmol, 1 equiv)
and p-ABSA (1.154 g, 4.80 mmol, 1.25 equiv) in CH3CN (10 mL). After allowing to
warm to room temperature and stirring for 4.5 h, the reaction mixture was treated with
saturated aqueous NH4Cl (10 mL) and extracted with CH2Cl2 (2 X 20 mL). The
combined organic phases were dried over MgSO4, filtered and concentrated in vacuo to
furnish a red oil. Silica gel chromatography employing 4:1 hexanes:EtOAc as eluant
furnished 130 (257 mg, 34% yield) as a red oil which was used without further
purification.
162
Preparation of Spirolactone 131.
OO
O
131
Spirolactone 131. To a suspension of Rh2(OAc)4 (5.5 mg, 0.01 mmol, 1.0%
equiv) in CH2Cl2 (25 mL) at reflux was added dropwise (over a 10 h period via syringe
pump) a solution of vinyldiazoacetate 130 (253 mg, 1.29 mmol, 1 equiv) in CH2Cl2 (5
mL). After allowing to cool to room temperature and concentrating in vacuo, the
resultant brown oil was chromatographed on silica employing 6:4 hexanes:EtOAc as
eluant to furnish 131 (79 mg, 36% yield) as a colorless oil. An analytical sample
(colorless oil) was obtained by a second flash chromatography using 7:3 hexanes:EtOAc
as eluant: FTIR (thin film/NaCl) 3081 (w), 2980 (m), 2955 (m), 2875 (m), 1773 (s),
1642 (w), 1461 (m), 1370 (m), 1256 (m), 1147 (m), 1111 (m), 1092 (m), 1021 (s), 992
(m), 928 (m), 909 (m), 887 (m), 809 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.79 (ddd,
J=17.3, 10.1, 8.5 Hz, 1H), 5.38 (dd, J=10.5, 1.7 Hz, 1H), 5.30 (d, J=17.2 Hz, 1H), 4.22
(d, J=9.1 Hz, 1H), 4.08 (d, J=9.1 Hz, 1H), 3.87-3.79 (m, 2H), 3.06 (d, J=9.3 Hz, 1H),
2.03-1.85 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 175.7, 128.5, 122.5, 87.5, 76.3, 69.0,
53.7, 31.7, 25.9; HRMS (EI) m/z 168.0790 [calcd for C9H12O3 (M+) 168.0786].
163
Preparation of Alcohol 133.
133
OO
N2
O
OH
Alcohol 133. A solution of LDA was prepared in a jacketed addition funnel by
adding 2.5 M n-BuLi in hexanes (7.8 mL, 19.50 mmol, 1.20 equiv) to a (-78 °C) solution
of diisopropylamine (2.6 mL, 18.55 mmol, 1.14 equiv) in THF (20 mL). This cold
solution was added dropwise over a 20 min period to a stirred (-78 °C) solution of
diazoacetate 94 (2.769 g, 16.27 mmol, 1 equiv) and cyclohexanone (1.7 mL, 16.40 mmol,
1.01 equiv) in THF (15 mL). The reaction mixture was stirred at -78 °C for 70 min and
then quenched by adding NH4Cl (10 mL, sat. aqueous). The mixture was allowed to
warm to room temperature and partitioned between NH4Cl (30 mL, sat. aqueous) and
Et2O (3 X 30 mL). The organic extracts were washed with NH4Cl (30 mL, sat. aqueous)
and brine (30 mL) and then they were combined, dried over MgSO4, filtered and
concentrated in vacuo. The resultant red oil was chromatographed on silica employing
6:4 hexanes:EtOAc as eluant to furnish 133 (3.814 g, 87% yield) as a yellow oil which
solidified upon refrigeration and was used without further purification.
164
Preparation of Cyclohexenyldiazoacetate 134.
OO
N2
134
O
Cyclohexenyldiazoacetate 134. POCl3 (0.9 mL, 9.66 mmol, 4.35 equiv) was
added dropwise to a stirred (-5 °C) solution of alcohol 133 (596 mg, 2.22 mmol, 1 equiv)
in pyridine (9 mL). The reaction mixture was stirred at -5 °C for 3 h, filtered and diluted
with pentane (10 mL). Ice-cold water (10 mL) was added (this was done carefully since
an exothermic reaction occurs upon addition), the phases were separated and the aqueous
one was extracted with pentane (10 mL). The organic extracts were washed with water
(10 mL) and then combined, dried over MgSO4, filtered and concentrated in vacuo. In
order to remove remaining pyridine, the residue was taken in heptane (4 X 100 mL) and
concentrated in vacuo furnishing 134 (449 mg, 81% yield) as a red oil which was used
without purification. An analytical sample (red oil) was obtained by flash
chromatography employing 9:1 hexanes:EtOAc as eluant: FTIR (thin film/NaCl) 2937
(m), 2862 (m), 2078 (s), 1706 (s), 1604 (w), 1448 (m), 1320 (m), 1310 (m), 1270 (m),
1249 (m), 1160 (s), 1083 (m), 1024 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 6.06 (m,
1H), 4.23-4.12 (m, 3H), 3.89-3.84 (m, 1H), 3.81-3.76 (m, 1H), 2.17-1.57 (m, 12H); 13C
NMR (125 MHz, CDCl3) δ 166.0, 124.0, 120.0, 76.7, 68.7, 66.5, 46.3, 28.1, 26.4, 25.9,
22.7, 22.0; HRMS (EI) m/z 250.1315 [calcd for C13H18N2O3 (M+) 250.1317].
165
Preparation of Spirolactone 135.
OO
O
135
Spirolactone 135. To a suspension of Rh2(OAc)4 (23.6 mg, 0.05 mmol, 1.0%
equiv) in CH2Cl2 (110 mL) at reflux was added dropwise (over a 10 h period via syringe
pump) a solution of cyclohexenyldiazoacetate 134 (1.354 g, 5.41 mmol, 1 equiv) in
CH2Cl2 (30 mL). After allowing to cool to room temperature and concentrating in vacuo,
the resultant purple oil was chromatographed on silica employing 6:4 hexanes:EtOAc as
eluant to furnish 135 (612 mg, 51% yield) as a colorless oil. An analytical sample
(colorless oil) was obtained by a second flash chromatography using 3:1 hexanes:EtOAc
as eluant: FTIR (thin film/NaCl) 2930 (m), 2885 (m), 2857 (m), 1773 (s), 1459 (w),
1447 (w), 1368 (w), 1268 (w), 1146 (m), 1110 (m), 1032 (m), 977 (w) cm-1; 1H NMR
(500 MHz, CDCl3) δ 5.60 (m, 1H), 4.23 (d, J=9.5 Hz, 1H), 4.07 (d, J=9.2 Hz, 1H), 3.83
(m, 2H), 3.01 (s, 1H), 2.19-2.02 (m, 5H), 1.98-1.86 (m, 3H), 1.68-1.53 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 175.7, 130.5, 129.9, 88.1, 76.6, 68.9, 57.1, 33.0, 27.4, 25.8,
25.7, 23.1, 22.1; HRMS (EI) m/z 222.1251 [calcd for C13H18O3 (M+) 222.1256].
166
Preparation of Acetoacetate 140.
140
OO
O O
Acetoacetate 140. Diketene (0.8 mL, 10.37 mmol, 1.34 equiv) was added
dropwise to a stirred (0 °C) solution of 2,5-dihydrofurfuryl alcohol (774 mg, 7.73 mmol,
1 equiv) and DMAP (93 mg, 0.76 mmol, 0.1 equiv) in THF (5 mL). After removing the
cooling bath and stirring at room temperature for 1 h, the reaction mixture was
concentrated in vacuo. The resultant red oil was chromatographed on silica employing
1:1 hexanes:EtOAc as eluant to furnish 140 (1.323 g, 93% yield) as a yellow oil. An
analytical sample (yellow oil) was prepared by a second flash column chromatography
followed by HPLC employing 6:4 hexanes:EtOAc as eluant in both cases: FTIR (thin
film/NaCl) 2954 (w), 2856 (m), 1744 (s), 1717 (s), 1649 (w), 1412 (m), 1359 (m), 1315
(m), 1264 (m), 1175 (m), 1152 (m), 1087 (m), 1035 (m) cm-1; 1H NMR (500 MHz,
CDCl3, Me4Si) δ 6.03 (m, 1H), 5.75 (m, 1H), 5.03 (m, 1H), 4.73-4.68 (m, 1H), 4.67-4.63
(m, 1H), 4.24 (dd, J=10.9, 3.4 Hz, 1H), 4.17 (dd, J=11.1, 6.0 Hz, 1H), 3.49 (s, 1H), 2.27
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 200.4, 167.1, 129.4, 125.6, 84.1, 75.8, 67.1,
50.1, 30.3; HRMS (EI) m/z 185.0814 [calcd for C9H13O4 (M+H) 185.0814].
167
Preparation of Diazoacetoacetate 141.
OO
N2
O
141
O
Diazoacetoacetate 141. Triethylamine (1.5 mL, 10.76 mmol, 1.50 equiv) was
added dropwise to a stirred (0 °C) solution of acetoacetate 140 (1.320 g, 7.17 mmol, 1
equiv) and methanesulfonyl azide (1.082 g, 8.93 mmol, 1.25 equiv) in CH3CN (14 mL).
After allowing to warm to room temperature and stirring overnight, the reaction mixture
was diluted with 10% aq NaOH (14 mL) and extracted with Et2O (3 X 28 mL). The
combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo.
The resultant orange oil was chromatographed on silica employing 6:4 hexanes:EtOAc as
eluant to furnish 141 (1.241 g, 82% yield) as a yellow oil. An analytical sample (yellow
oil) was prepared by HPLC employing 3:1 hexanes:EtOAc as eluant: FTIR (thin
film/NaCl) 2954 (w), 2855 (m), 2142 (s), 1717 (s), 1656 (s), 1384 (s), 1366 (s), 1312 (s),
1249 (s), 1157 (s), 1073 (s), 966 (m), 742 (m) cm-1; 1H NMR (500 MHz, CDCl3, Me4Si)
δ 6.07 (m, 1H), 5.77 (m, 1H), 5.07 (m, 1H), 4.67 (m, 2H), 4.33 (dd, J=11.7, 3.2 Hz, 1H),
4.29 (dd, J=12.0, 4.9 Hz, 1H), 2.47 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 189.8, 161.2,
129.3, 125.3, 84.0, 75.7, 66.6, 28.1; HRMS (EI) m/z 211.0714 [calcd for C9H11N2O4
(M+H) 211.0719].
168
Preparation of TBS-enol ether 143.
OO
N2
OTBS
143
O
TBS-enol ether 143. TBSOTf (850 µL, 3.70 mmol, 1.21 equiv) was added
dropwise to a stirred (0 °C) solution of diazoacetoacetate 141 (645 mg, 3.07 mmol, 1
equiv) and triethylamine (650 µL, 4.66 mmol, 1.52 equiv) in CH2Cl2 (8 mL). After
allowing to warm to room temperature and stirring for 2.5 h, the reaction mixture was
diluted with petroleum ether (32 mL) and washed with 1:1 saturated aqueous
NaHCO3:water (2 X 32 mL) and brine (32 mL). The aqueous washings were extracted
with petroleum ether (32 mL) and the combined organic phases were dried over MgSO4,
filtered and concentrated in vacuo to furnish 143 (974 mg, 98% yield) as an orange oil.
Typically this material was used without purification due to its instability. However, an
analytical sample (orange oil) was prepared by flash column chromatography employing
90:10:1 hexanes:EtOAc:Et3N as eluant (HRMS could not be obtained due to the lability
of the compound): FTIR (thin film/NaCl) 2956 (s), 2932 (s), 2886 (m), 2858 (s), 2104
(s), 1713 (s), 1609 (m), 1472 (m), 1464 (m), 1387 (s), 1347 (s), 1258 (s), 1220 (m), 1123
(s), 1097 (s), 1080 (s), 1013 (s), 1003 (s), 847 (s), 831 (s), 811 (s), 784 (s) cm-1; 1H
NMR (400 MHz, CDCl3, TMS) δ 6.03 (m, 1H), 5.75 (m, 1H), 5.04 (m, 1H), 4.99 (d,
J=1.8 Hz, 1H), 4.67 (m, 2H), 4.27 (d, J=4.1 Hz, 2H), 4.24 (d, J=1.9 Hz, 1H), 0.91 (s,
9H), 0.22 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 164.2, 140.8, 129.2, 125.7, 90.5, 84.3,
75.9, 66.3, 25.7, 18.2, -4.6, -4.7.
169
Preparation of Diazoacetate 145.
OO
N2
145
O
Diazoacetate 145. To a stirred solution of diazoacetoacetate 141 (409 mg, 1.95
mmol, 1 equiv) in CH3CN (30 mL) was added a solution of LiOH monohydrate (253 mg,
6.02 mmol, 3.10 equiv) in water (10 mL). The reaction mixture was stirred at room
temperature for 7 h, diluted with water (40 mL) and extracted with Et2O (4 X 10 mL).
The combined organic extracts were dried over MgSO4, filtered and concentrated in
vacuo. The residue contained water, so it was taken in CH2Cl2 (20 mL), dried over
MgSO4, filtered and reconcentrated. The resultant yellow oil was chromatographed on
silica employing 3:1 hexanes:EtOAc as eluant to furnish 145 (187 mg, 57% yield) as a
yellow oil. An analytical sample (yellow oil) was prepared by flash column
chromatography employing 4:1 hexanes:EtOAc as eluant followed by HPLC using 3:1
hexanes:EtOAc as eluant: FTIR (thin film/NaCl) 3096 (w), 2952 (w), 2855 (m), 2114
(s), 1694 (s), 1621 (w), 1437 (w), 1394 (s), 1360 (s), 1239 (s), 1187 (s), 1117 (m), 1087
(s), 1036 (m), 1001 (m), 739 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.96 (m, 1H),
5.67 (m, 1H), 4.94 (m, 1H), 4.75 (br s, 1H), 4.65-4.60 (m, 1H), 4.59-4.55 (m, 1H), 4.17
(dd, J=11.5, 3.5 Hz, 1H), 4.11 (dd, J=11.4, 5.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
129.1, 125.6, 84.3, 75.7, 66.4, 46.2; HRMS (EI) m/z 169.0615 [calcd for C7H9N2O3
(M+H) 169.0613].
170
Preparation of 3-Methoxyphenylacetate 147.
147
OO
O
OMe
3-Methoxyphenylacetate 147. To a stirred (0 °C) solution of 2,5-dihydrofurfuryl
alcohol (651 mg, 6.50 mmol, 1 equiv), 3-methoxyphenylacetic acid (1.189 g, 7.15 mmol,
1.10 equiv) and DMAP (11 mg, 0.09 mmol, 1.4% equiv) in CH2Cl2 (7 mL) was added
DCC (1.447 g, 7.01 mmol, 1.08 equiv). After allowing to warm to room temperature and
stirring for 3 h, the resulting white precipitate was removed by filtration through a cotton
plug. The filtrate was concentrated in vacuo and the residue taken in CH3CN (7 mL),
filtered through a cotton plug and reconcentrated; this procedure was repeated using
acetone (7 mL) and a yellow oil was recovered. Silica gel chromatography employing
3:1 hexanes:EtOAc as eluant furnished 147 (1.403 g, 87% yield) as a yellowish oil. An
analytical sample (colorless oil) was obtained by HPLC employing 8:3 hexanes:EtOAc as
eluant: FTIR (thin film/NaCl) 2999 (w), 2950 (s), 2852 (s), 1736 (s), 1601 (s), 1586 (s),
1491 (s), 1455 (s), 1437 (s), 1263 (s), 1151 (s), 1087 (s), 1050 (s), 1014 (s) cm-1; 1H
NMR (500 MHz, CDCl3, Me4Si) δ 7.21 (t, J=7.9 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 6.83
(s, 1H), 6.80 (dd, J=8.3, 2.0 Hz, 1H), 5.93 (m, 1H), 5.68 (m, 1H), 4.98 (m, 1H), 4.59 (m,
2H), 4.16 (s, 1H), 4.15 (d, J=1.6 Hz, 1H), 3.78 (s, 3H), 3.61 (s, 2H); 13C NMR (125
MHz, CDCl3) δ 171.3, 159.8, 135.5, 129.5, 129.0, 125.7, 121.8, 115.1, 112.8, 84.3, 75.6,
66.5, 55.2, 41.4; HRMS (EI) m/z 249.1123 [calcd for C9H15O5 (M+H) 249.1127].
171
Preparation of 3-Methoxyphenyldiazoacetate 148.
OO
N2
148
O
OMe
3-Methoxyphenyldiazoacetate 148. DBU (800 µL, 5.35 mmol, 1.12 equiv) was
added dropwise to a stirred (0 °C) solution of 3-methoxyphenylacetate 147 (1.190 g, 4.79
mmol, 1 equiv) and p-ABSA (1.444 g, 6.01 mmol, 1.25 equiv) in CH3CN (12.5 mL).
After allowing to warm to room temperature and stirring overnight, the reaction mixture
was treated with saturated aqueous NH4Cl (25 mL) and extracted with CH2Cl2 (2 X 25
mL). The combined organic phases were dried over MgSO4, filtered and concentrated in
vacuo to furnish a red semisolid. Silica gel chromatography employing 4:1
hexanes:EtOAc as eluant furnished 148 (1.023 g, 78% yield) as an orange oil. An
analytical sample (orange oil) was obtained by HPLC using 4:1 hexanes:EtOAc as eluant:
FTIR (thin film/NaCl) 3000 (w), 2951 (m), 2852 (m), 2088 (s), 1704 (s), 1600 (s), 1578
(s), 1494 (s), 1465 (m), 1453 (m), 1253 (s), 1180 (m), 1152 (s), 1087 (s), 1035 (s) cm-1;
1H NMR (500 MHz, CDCl3, Me4Si) δ 7.27 (t, J=7.5 Hz, 1H), 7.15 (t, J=1.9 Hz, 1H),
6.97 (ddd, J=7.9, 2.0, 1.1 Hz, 1H), 6.72 (dd, J=8.4, 2.3 Hz, 1H), 6.04 (m, 1H), 5.78 (m,
1H), 5.08 (m, 1H), 4.73-4.63 (m, 2H), 4.33 (d, J=4.1 Hz, 2H), 3.81 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 165.0, 160.2, 129.9, 129.3, 127.0, 125.7, 116.1, 111.6, 109.9, 84.4,
75.9, 66.5, 55.4; HRMS (EI) m/z 274.0957 [calcd for C14H14N2O4 (M+) 274.0954].
172
Preparation of Spirolactone 149.
OO
O
149
H
OMe
Spirolactone 149. To a suspension of Rh2(OAc)4 (26.1 mg, 0.06 mmol, 1.0%
equiv) in CH2Cl2 (115 mL) at reflux was added dropwise (over a 11 h period via syringe
pump) a solution of 3-methoxyphenyldiazoacetate 148 (1.579 g, 5.76 mmol, 1 equiv) in
CH2Cl2 (30 mL). After allowing to cool to room temperature and concentrating in vacuo,
the resultant green solid was chromatographed on silica employing 1:1 hexanes:EtOAc as
eluant to furnish 149 (1.031 g, 73% yield) as a white solid. Recrystallization of 149 from
heptane produced crystals suitable for a single-crystal X-ray analysis which established
the illustrated relative stereochemical configuration.25 An analytical sample (white solid)
was obtained by a second flash chromatography using 6:4 hexanes:EtOAc as eluant: mp
109-110 °C; FTIR (thin film/NaCl) 3097 (w), 3057 (w), 3004 (m), 2947 (m), 2896 (m),
2857 (m), 1778 (s), 1610 (m), 1602 (m), 1585 (m), 1491 (m), 1457 (m), 1438 (m), 1371
(m), 1293 (m), 1254 (s), 1232 (m), 1120 (m), 1085 (m), 1015 (s), 959 (m), 824 (m), 784
(m), 740 (m), 721 (m), 699 (m) cm-1; 1H NMR (500 MHz, CDCl3, Me4Si) δ 7.23 (t,
J=7.9 Hz, 1H), 6.85 (dd, J=8.2, 2.4 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 6.80 (d, J=1.7 Hz,
1H), 6.02 (d, J=6.0 Hz, 1H), 5.76 (m, 1H), 4.46 (d, J=14.2 Hz, 1H), 4.42 (d, J=9.7 Hz,
1H), 4.39 (d, J=10.0 Hz, 1H), 3.87 (dd, J=14.5, 2.8 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 1H);
13C NMR (125 MHz, CDCl3) δ 175.0, 159.3, 132.7, 132.5, 129.0, 125.3, 123.3, 116.5,
173
113.5, 95.4, 76.1, 75.1, 55.4, 55.2; HRMS (EI) m/z 246.0893 [calcd for C14H14O4 (M+)
246.0892].
Preparation of 4-Methoxyphenylacetate 151.
151
OO
OOMe
4-Methoxyphenylacetate 151. To a stirred (0 °C) solution of 2,5-dihydrofurfuryl
alcohol (636 mg, 6.35 mmol, 1 equiv), 4-methoxyphenylacetic acid (1.163 g, 7.00 mmol,
1.10 equiv) and DMAP (9 mg, 0.07 mmol, 1.2% equiv) in CH2Cl2 (7 mL) was added
DCC (1.457 g, 7.06 mmol, 1.11 equiv). After allowing to warm to room temperature and
stirring for 3 h, the resulting white precipitate was removed by filtration through a cotton
plug. The filtrate was concentrated in vacuo and the residue taken in CH3CN (7 mL),
filtered through a cotton plug and reconcentrated; this procedure was repeated using
acetone (7 mL) and a yellow oil was recovered. Silica gel chromatography employing
3:1 hexanes:EtOAc as eluant furnished 151 (1.498 g, 95% yield) as a colorless oil. An
analytical sample (colorless oil) was obtained by HPLC employing 3:1 hexanes:EtOAc as
eluant: FTIR (thin film/NaCl) 3035 (w), 2998 (w), 2952 (m), 2903 (m), 2852 (m), 1736
(s), 1613 (m), 1585 (m), 1513 (s), 1464 (m), 1442 (m), 1301 (s), 1248 (s), 1156 (s), 1087
(s), 1033 (s), 821 (m) cm-1; 1H NMR (500 MHz, CDCl3, Me4Si) δ 7.19 (d, J=8.8 Hz,
2H), 6.84 (d, J=8.5 Hz, 2H), 5.93 (m, 1H), 5.68 (m, 1H), 4.99 (m, 1H), 4.60 (m, 2H),
4.15 (d, J=3.7 Hz, 1H), 4.14 (d, J=4.9 Hz, 1H), 3.77 (s, 3H), 3.58 (s, 2H); 13C NMR (125
174
MHz, CDCl3) δ 171.7, 158.8, 130.4, 129.0, 126.1, 125.8, 114.0, 84.2, 75.6, 66.4, 55.3,
40.4; HRMS (EI) m/z 248.1054 [calcd for C14H16O4 (M+) 248.1049].
Preparation of 4-Methoxyphenyldiazoacetate 152.
OO
N2
152
OOMe
4-Methoxyphenyldiazoacetate 152. DBU (850 µL, 5.68 mmol, 1.12 equiv) was
added dropwise to a stirred (0 °C) solution of 4-methoxyphenylacetate 151 (1.264 g, 5.09
mmol, 1 equiv) and p-ABSA (1.527 g, 6.36 mmol, 1.25 equiv) in CH3CN (12.5 mL).
After allowing to warm to room temperature and stirring for 5 days, the reaction mixture
was treated with saturated aqueous NH4Cl (25 mL) and extracted with CH2Cl2 (2 X 25
mL). The combined organic phases were dried over MgSO4, filtered and concentrated in
vacuo to furnish a red semisolid. Silica gel chromatography employing 4:1
hexanes:EtOAc as eluant furnished two compounds: 152 (597 mg, 43% yield, eluted
first) as an orange solid and the starting material, 151, (365 mg, 29% yield, eluted
second) as a red oil (colored due to the presence of 152 in the sample). An analytical
sample of 152 (orange solid) was obtained by HPLC using 4:1 hexanes:EtOAc as eluant:
mp 64-65 °C; FTIR (thin film/NaCl) 2999 (w), 2953 (m), 2895 (m), 2851 (m), 2085 (s),
1707 (s), 1608 (m), 1575 (m), 1513 (s), 1463 (m), 1443 (m), 1296 (s), 1254 (s), 1162 (s),
1087 (s), 1027 (s), 831 (s) cm-1; 1H NMR (500 MHz, CDCl3, Me4Si) δ 7.37 (d, J=8.9
Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 6.03 (m, 1H), 5.78 (m, 1H), 5.07 (m, 1H), 4.72-4.63 (m,
2H), 4.33 (d, J=4.3 Hz, 1H), 4.32 (d, J=4.1 Hz, 1H), 3.80 (s, 3H); 13C NMR (125 MHz,
175
CDCl3) δ 165.7, 158.2, 129.2, 126.1, 125.8, 117.0, 114.8, 84.4, 75.9, 66.5, 55.5; HRMS
(EI) m/z 274.0949 [calcd for C14H14N2O5 (M+) 274.0954].
Preparation of Spirolactone 153.
OO
O
153
H
MeO
Spirolactone 153. To a suspension of Rh2(OAc)4 (7.8 mg, 0.02 mmol, 1.0%
equiv) in CH2Cl2 (15 mL) at reflux was added dropwise (over a 10 h period via syringe
pump) a solution of 4-methoxyphenyldiazoacetate 152 (471 mg, 1.72 mmol, 1 equiv) in
CH2Cl2 (30 mL). After allowing to cool to room temperature and concentrating in vacuo,
the resultant green solid was chromatographed on silica employing 6:4 hexanes:EtOAc as
eluant to furnish 153 (266 mg, 63% yield) as a white solid. Recrystallization of 153 from
heptane produced crystals suitable for a single-crystal X-ray analysis which established
the illustrated relative stereochemical configuration.25 An analytical sample (white solid)
was obtained by selecting fractions from the flash chromatography: mp 115-116 °C;
FTIR (thin film/NaCl) 3001 (w), 2953 (w), 2904 (w), 2859 (w), 2840 (w), 1775 (s), 1614
(m), 1585 (w), 1516 (s), 1463 (m), 1371 (w), 1291 (m), 1251 (s), 1182 (m), 1117 (m),
1084 (m), 1015 (s), 929 (w), 830 (m), 743 (m), 719 (m) cm-1; 1H NMR (500 MHz,
CDCl3, Me4Si) δ 7.15 (d, J=9.2 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 5.98 (dt, J=6.2, 1.6 Hz,
1H), 5.74 (dt, J=6.5, 2.5 Hz, 1H), 4.47 (dt, J=13.4, 2.1 Hz, 1H), 4.41 (d, J=9.5 Hz, 1H),
4.37 (d, J=9.5 Hz, 1H), 3.82 (ddd, J=13.3, 2.3, 1.8 Hz, 1H), 3.79 (s, 3H), 3.72 (s, 1H);
176
13C NMR (125 MHz, CDCl3) δ 175.5, 159.3, 132.6, 131.9, 125.3, 123.1, 113.7, 95.3,
76.0, 75.0, 55.3, 54.6; HRMS (EI) m/z 246.0896 [calcd for C14H14O4 (M+) 246.0892].
Preparation of Benzoate 158 and Alcohol 154.
OHO
154
TBSO OTBS
OO
O
158
OTBSTBSO
Benzoate 158 and Alcohol 154. To a stirred (0 °C) mixture of diol 157 (1.786 g,
7.50 mmol, 1 equiv) and imidazole (2.456 g, 36.08 mmol, 4.81 equiv) in DMF (15 mL)
was added TBSCl (3.026 g, 20.08 mmol, 2.68 equiv). After allowing to warm to room
temperature and stirring for 24 h, the reaction mixture was diluted with petroleum ether
(60 mL) and washed with saturated aqueous NaHCO3 (30 mL) and brine (30 mL). The
aqueous washings were extracted with petroleum ether (60 mL) and the organic phases
were combined, dried over MgSO4, filtered and concentrated in vacuo to furnish benzoate
158 as a colorless oil which was used without purification. However, an analytical
sample (colorless oil) was obtained by flash chromatography using 19:1 hexanes:EtOAc
as eluant: FTIR (thin film/NaCl) 2955 (s), 2930 (s), 2886 (m), 2858 (s), 1726 (s), 1603
(w), 1472 (m), 1463 (m), 1452 (m), 1272 (s), 1260 (s), 1114 (s), 1094 (s), 1027 (m), 1015
(m), 837 (s), 778 (s), 711 (s) cm-1; 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J=8.3, 1.3
Hz, 2H), 7.54 (tt, J=7.5, 1.3 Hz, 1H), 7.22 (t, J=7.5 Hz, 2H), 4.47 (dd, J=11.3, 5.7 Hz,
1H), 4.40 (dd, J=11.1, 6.9 Hz, 1H), 4.11-4.06 (m, 3H), 4.03 (dd, J=9.1, 3.5 Hz, 1H), 3.84
(d, J=9.0 Hz, 1H), 0.90 (s, 9H), 0.88 (s, 9H), 0.09 (s, 6H), 0.08 (s, 6H); 13C NMR (100
177
MHz, CDCl3) δ 166.4, 133.1, 130.2, 129.8, 128.4, 84.4, 80.2, 78.9, 74.6, 65.3, 25.9, 25.8,
18.1, 18.0, -4.4, -4.5, -4.6, -4.7; HRMS (FAB) m/z 467.2650 [calcd for C24H43O5Si2
(M+H) 467.2647].
To a stirred solution of the crude benzoate 158 in MeOH (38 mL) was added
NaOMe (632 mg, 11.70 mmol, 1.56 equiv). The reaction mixture was stirred at room
temperature overnight, neutralized with AcOH and concentrated in vacuo. The resultant
white semisolid was adsorbed on to silica gel and chromatographed employing 4:1
hexanes:EtOAc as eluant to furnish 154 (1.598 g, 59% yield, 2 steps) as a colorless oil.
An analytical sample (colorless oil) was obtained by a second flash chromatography
using 85:15 hexanes:EtOAc as eluant: FTIR (thin film/NaCl) 3465 (br w), 2954 (s), 2930
(s), 2887 (m), 2858 (s), 1472 (m), 1463 (m), 1257 (s), 1118 (s), 1102 (s), 1044 (m), 1015
(m), 837 (s), 777 (s) cm-1; 1H NMR (400 MHz, CDCl3) δ 3.98 (s, 2H), 3.91 (dd, J=9.0,
2.9 Hz, 1H), 3.83 (br s, 1H), 3.75 (d, J=9.2 Hz, 1H), 3.71 (dd, J=11.7, 3.1 Hz, 1H), 3.65
(dd, J=11.6, 4.6 Hz, 1H), 2.70 (br s, 1H), 0.86 (s, 9H), 0.84 (s, 9H), 0.06 (s, 3H), 0.05 (s,
6H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 87.5, 79.6, 79.0, 74.0, 62.8, 25.8, 18.0,
17.9, -4.5, -4.6, -4.7, -4.8; HRMS (FAB) m/z 363.2388 [calcd for C17H39O4Si2 (M+H)
363.2387].
178
Preparation of Acetoacetate 159.
OO
O
159
OTBSTBSO
O
Acetoacetate 159. Diketene (0.3 mL, 3.89 mmol, 1.04 equiv) was added
dropwise to a stirred (0 °C) solution of alcohol 154 (1.357 g, 3.74 mmol, 1 equiv) and
DMAP (7 mg, 0.06 mmol, 1.5% equiv) in THF (8 mL). After removing the cooling bath
and stirring at room temperature for 3 h, the reaction mixture was concentrated in vacuo.
The resultant orange oil was chromatographed on silica employing 9:1 hexanes:EtOAc as
eluant to furnish 159 (1.409 g, 84% yield) as a colorless oil. An analytical sample
(colorless oil) was obtained by selecting fractions from the flash chromatography: FTIR
(thin film/NaCl) 2955 (m), 2930 (m), 2886 (m), 2858 (m), 1748 (m), 1722 (m), 1656 (w),
1650 (w), 1632 (w), 1472 (m), 1464 (m), 1361 (m), 1316 (m), 1258 (s), 1151 (m), 1113
(s), 1086 (m), 1014 (m), 913 (m), 837 (s), 811 (m), 777 (s) cm-1; 1H NMR (500 MHz,
CDCl3) δ 4.29 (dd, J=11.0, 5.1 Hz, 1H), 4.21 (dd, J=11.3, 7.4 Hz, 1H), 4.04-4.03 (m,
1H), 3.99 (dd, J=9.4, 3.7 Hz, 1H), 3.96-3.92 (m, 2H), 3.79 (d, J=9.0 Hz, 1H), 3.49 (s,
2H), 2.27 (s, 3H), 0.88 (s, 18H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 200.4, 167.0, 84.0, 80.0, 78.7, 74.6, 65.7, 50.0, 30.3, 25.8,
25.7, 18.0, -4.5, -4.6, -4.7, -4.8; HRMS (EI) m/z 447.2599 [calcd for C21H43O6Si2
(M+H) 447.2598].
179
Preparation of Diazoacetoacetate 160.
OO
O
160
OTBSTBSO
O
N2
Diazoacetoacetate 160. Triethylamine (400 µL, 2.87 mmol, 3.05 equiv) was
added dropwise to a stirred (0 °C) solution of acetoacetate 159 (421 mg, 0.94 mmol, 1
equiv) and p-ABSA (275 mg, 1.14 mmol, 1.21 equiv) in CH3CN (5 mL). After allowing
to warm to room temperature and stirring overnight, the reaction mixture was
concentrated in vacuo, triturated with 1:1 Et2O:petroleum ether (10 mL), filtered and
reconcentrated to a yellow oil. Silica gel chromatography employing 9:1 hexanes:EtOAc
as eluant furnished 160 (401 mg, 90% yield) as a yellow oil. An analytical sample
(yellow oil) was obtained by selecting fractions from the flash chromatography: FTIR
(thin film/NaCl) 2953 (s), 2930 (s), 2886 (m), 2858 (m), 2138 (s), 1721 (s), 1663 (s),
1472 (m), 1463 (m), 1364 (m), 1314 (s), 1251 (s), 1156 (m), 1113 (s), 1078 (s), 1069 (s),
1013 (m), 915 (w), 837 (s), 811 (m), 777 (s) cm-1; 1H NMR (500 MHz, CDCl3, Me4Si)
δ 4.34 (dd, J=11.3, 5.6 Hz, 1H), 4.31 (dd, J=11.1, 6.7 Hz, 1H), 4.05-4.03 (m, 1H), 3.98
(dd, J=9.2, 3.7 Hz, 1H), 3.96-3.93 (m, 2H), 3.78 (d, J=9.1 Hz, 1H), 2.47 (s, 3H), 0.87 (s,
9H), 0.86 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 190.3, 161.2, 84.1, 80.0, 78.6, 74.7, 65.5, 28.5, 25.8, 25.7, 18.0, -4.5, -
4.6, -4.7, -4.8; HRMS (EI) m/z 473.2501 [calcd for C21H41N2O6Si2 (M+H) 473.2503].
180
Preparation of TBS-enol ether 162.
OO
O
162
OTBSTBSO
TBSO
N2
TBS-enol ether 162. TBSOTf (105 µL, 0.46 mmol, 2.06 equiv) was added
dropwise to a stirred (0 °C) solution of diazoacetoacetate 160 (105 mg, 0.22 mmol, 1
equiv) and triethylamine (100 µL, 0.72 mmol, 3.23 equiv) in CH2Cl2 (2.5 mL). After
allowing to warm to room temperature and stirring for 2.5 h, the reaction mixture was
diluted with petroleum ether (10 mL) and washed with 1:1 saturated aqueous
NaHCO3:water (2 X 10 mL) and brine (10 mL). The aqueous washings were extracted
with petroleum ether (10 mL) and the combined organic phases were dried over MgSO4,
filtered and concentrated in vacuo to furnish 162 (130 mg, 100% yield) as an orange oil.
Typically this material was used without purification due to its instability. However, an
analytical sample (orange oil) was prepared by flash column chromatography employing
95:5:1 hexanes:EtOAc:Et3N as eluant: FTIR (thin film/NaCl) 2955 (m), 2930 (m), 2886
(m), 2859 (m), 2103 (s), 1715 (s), 1609 (w), 1472 (m), 1463 (m), 1388 (m), 1362 (m),
1343 (m), 1257 (s), 1112 (s), 1079 (s), 1013 (m), 1005 (m), 913 (w), 837 (s), 811 (s), 778
(s), 745 (w) cm-1; 1H NMR (500 MHz, CDCl3, Me4Si) δ 5.01 (d, J=2.1 Hz, 1H), 4.29 (d,
J=6.3 Hz, 2H), 4.24 (d, J=2.1 Hz, 1H), 4.04 (m, 1H), 3.98 (dd, J=9.3, 3.7 Hz, 1H), 3.96-
3.94 (m, 2H), 3.78 (dd, J=9.1, 1.2 Hz, 1H), 0.91 (s, 9H), 0.88 (s, 9H), 0.87 (s, 9H), 0.21
(s, 6H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 164.0, 140.8, 90.8, 84.1, 79.9, 78.8, 74.6, 64.9, 25.9, 25.8, 25.7, 18.3, 18.1,
181
18.0, -4.5, -4.6, -4.7; HRMS (FAB) m/z 587.3370 [calcd for C27H55N2O6Si3 (M+H)
587.3368].
Preparation of Diazoacetate 164.
OO
O
164
OTBSTBSO
N2
Diazoacetate 164. To a stirred solution of diazoacetoacetate 160 (187 mg, 0.40
mmol, 1 equiv) in CH3CN (6 mL) was added a solution of LiOH monohydrate (50 mg,
1.19 mmol, 3.01 equiv) in water (2 mL). The reaction mixture was stirred at room
temperature for 6.5 h, diluted with water (8 mL) and extracted with Et2O (4 X 2.5 mL).
The combined organic extracts were dried over MgSO4, filtered and concentrated in
vacuo. The residue contained water, so it was taken in CH2Cl2 (10 mL), dried over
MgSO4, filtered and reconcentrated. The resultant yellow oil was chromatographed on
silica employing 9:1 hexanes:EtOAc as eluant to furnish 164 (139 mg, 82% yield) as a
yellow oil. An analytical sample (yellow oil) was obtained by selecting fractions from
the flash chromatography: FTIR (thin film/NaCl) 2955 (m), 2930 (m), 2887 (m), 2859
(m), 2111 (s), 1701 (s), 1472 (m), 1463 (m), 1389 (m), 1362 (m), 1339 (m), 1254 (m),
1183 (m), 1152 (w), 1113 (s), 1084 (m), 1027 (m), 1014 (m), 913 (w), 836 (s), 811 (m),
776 (s), 740 (m) cm-1; 1H NMR (500 MHz, CDCl3, Me4Si) δ 4.80 (br s, 1H), 4.31 (dd,
J=11.0, 5.6 Hz, 1H), 4.23 (dd, J=11.1, 7.4 Hz, 1H), 4.04-4.03 (m, 1H), 3.99 (dd, J=9.3,
3.6 Hz, 1H), 3.96-3.93 (m, 2H), 3.79 (d, J=9.6 Hz, 1H), 0.89 (s, 9H), 0.88 (s, 9H), 0.10
182
(s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 84.3,
80.0, 79.0, 74.6, 65.1, 46.4, 25.9, 25.8, 18.0, -4.5, -4.6, -4.7, -4.8; HRMS (FAB) m/z
431.2398 [calcd for C19H39N2O5Si2 (M+H) 431.2398].
Preparation of Spirolactone 165.
OO
O
165
OTBSTBSO
Spirolactone 165. To a suspension of Rh2(OAc)4 (1.5 mg, 0.003 mmol, 1.2%
equiv) in CH2Cl2 (5 mL) at reflux was added dropwise (over a 10 h period via syringe
pump) a solution of diazoacetate 164 (125 mg, 0.29 mmol, 1 equiv) in CH2Cl2 (5 mL).
After allowing to cool to room temperature and concentrating in vacuo, the resultant
green oil was chromatographed on silica employing 9:1 hexanes:EtOAc as eluant to
furnish 165 (81 mg, 69% yield) as a yellowish oil. An analytical sample (yellowish oil)
was obtained by selecting fractions from the flash chromatography: FTIR (thin
film/NaCl) 2954 (m), 2930 (m), 2886 (w), 2858 (m), 1788 (s), 1472 (w), 1463 (w), 1256
(m), 1201 (w), 1174 (w), 1112 (s), 1077 (m), 1013 (s), 911 (w), 854 (m), 837 (s), 777 (s)
cm-1; 1H NMR (500 MHz, CDCl3, Me4Si) δ 4.33 (s, 2H), 4.08 (m, 2H), 3.92 (d, J=1.1
Hz, 1H), 3.76 (m, 1H), 2.82 (d, J=18.4 Hz, 1H), 2.56 (d, J=18.3 Hz, 1H), 0.90 (s, 9H),
0.89 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 175.4, 88.7, 81.0, 78.3, 77.0, 74.6, 36.1, 25.8, 25.7, 18.0, 17.9, -4.3, -4.6, -4.7, -
4.8; HRMS (EI) m/z 403.2340 [calcd for C14H27N2O4Si (M+H) 403.2336].
183
Preparation of 3-Methoxyphenylacetate 166.
OO
166
OTBSTBSO
O
MeO
3-Methoxyphenylacetate 166. To a stirred (0 °C) solution of alcohol 154 (525
mg, 1.45 mmol, 1 equiv), 3-methoxyphenylacetic acid (265 mg, 1.59 mmol, 1.10 equiv)
and DMAP (2 mg, 0.02 mmol, 1.1% equiv) in CH2Cl2 (5 mL) was added DCC (350 mg,
1.70 mmol, 1.17 equiv). After allowing to warm to room temperature and stirring for 4 h,
the resulting white precipitate was removed by filtration through a cotton plug. The
filtrate was concentrated in vacuo and the residue taken in CH3CN (5 mL), filtered
through a cotton plug and reconcentrated; this procedure was repeated using acetone (5
mL) and a yellow oil was recovered. Silica gel chromatography employing 9:1
hexanes:EtOAc as eluant furnished 166 (739 mg, 100% yield) as a colorless oil. An
analytical sample (colorless oil) was obtained by selecting fractions from the flash
chromatography: FTIR (thin film/NaCl) 2954 (s), 2930 (s), 2886 (m), 2858 (s), 1742 (s),
1601 (m), 1586 (m), 1492 (m), 1471 (m), 1464 (m), 1260 (s), 1150 (s), 1112 (s), 1090 (s),
1014 (s), 837 (s), 777 (s) cm-1; 1H NMR (400 MHz, CDCl3, Me4Si) δ 7.23 (t, J=7.8 Hz,
1H), 6.87 (d, J=7.6 Hz, 1H), 6.84 (s, 1H), 6.80 (dd, J=8.3, 2.2 Hz, 1H), 4.25 (dd, J=11.2,
5.5 Hz, 1H), 4.17 (dd, J=11.0, 7.1 Hz, 1H), 4.04 (m, 1H), 3.99 (dd, J=9.1, 3.5 Hz, 1H),
3.96-3.91 (m, 2H), 3.79 (s, 3H), 3.79-3.78 (m, 1H), 3.64 (s, 2H), 0.88 (s, 18H), 0.08 (s,
3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3,
159.8, 135.4, 129.7, 121.8, 115.0, 112.9, 84.1, 79.9, 78.7, 75.5, 65.2, 55.3, 41.3, 25.9,
184
25.8, 18.0, 17.9, -4.5, -4.6, -4.7, -4.8; HRMS (FAB) m/z 511.2912 [calcd for
C26H47O6Si2 (M+H) 511.2911].
Preparation of 3-Methoxyphenyldiazoacetate 167.
OO
167
OTBSTBSO
O
MeON2
3-Methoxyphenyldiazoacetate 167. DBU (110 µL, 0.74 mmol, 1.24 equiv) was
added dropwise to a stirred (0 °C) solution of 3-methoxyphenylacetate 166 (303 mg, 0.59
mmol, 1 equiv) and p-ABSA (216 mg, 0.90 mmol, 1.52 equiv) in CH3CN (5 mL). After
allowing to warm to room temperature and stirring for 48 h, the reaction mixture was
treated with saturated aqueous NH4Cl (5 mL) and extracted with CH2Cl2 (2 X 5 mL).
The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo
to furnish an orange oil. Silica gel chromatography employing 95:5 hexanes:EtOAc as
eluant furnished 167 (213 mg, 67% yield) as an orange oil. An analytical sample (orange
oil) was obtained by a second flash chromatography using 95:5 hexanes:EtOAc as eluant:
FTIR (thin film/NaCl) 2955 (s), 2930 (s), 2886 (m), 2858 (m), 2087 (s), 1710 (s), 1600
(m), 1579 (m), 1495 (m), 1471 (m), 1464 (m), 1256 (s), 1150 (m), 1113 (s), 1088 (m),
1034 (m), 913 (w), 838 (s), 811 (m), 777 (s) cm-1; 1H NMR (500 MHz, CDCl3, Me4Si)
δ 7.28 (t, J=8.1 Hz, 1H), 7.16 (t, J=2.0 Hz, 1H), 6.99 (ddd, J=7.9, 1.8, 0.9 Hz, 1H), 6.73
(ddd, J=8.4, 2.5, 1.0 Hz, 1H), 4.39 (dd, J=11.0, 5.9 Hz, 1H), 4.36 (dd, J=11.1, 6.2 Hz,
1H), 4.07 (m, 1H), 4.03-4.00 (m, 3H), 3.81 (s, 3H), 3.80 (dd, J=9.5, 1.6 Hz, 1H), 0.90 (s,
185
9H), 0.88 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 164.7, 160.2, 130.0, 127.0, 116.2, 111.7, 109.8, 84.1, 79.9, 78.8, 74.6,
65.0, 55.4, 25.9, 25.8, 18.1, 18.0, -4.5, -4.6, -4.7; HRMS (FAB) m/z 537.2814 [calcd for
C26H45N2O6Si2 (M+H) 537.2816].
Preparation of Spirolactone 168.
168
OO
O
HMeO OTBSOTBS
Spirolactone 168. To a suspension of Rh2(OAc)4 (1.2 mg, 0.003 mmol, 0.9%
equiv) in CH2Cl2 (10 mL) at reflux was added dropwise (over a 10 h period via syringe
pump) a solution of 3-methoxyphenyldiazoacetate 167 (164 mg, 0.31 mmol, 1 equiv) in
CH2Cl2 (30 mL). After allowing to cool to room temperature and concentrating in vacuo,
the resultant brown oil was chromatographed on silica employing 9:1 hexanes:EtOAc as
eluant to furnish 168 (56 mg, 36% yield) as a yellowish oil. Recrystallization of 168
from heptane produced crystals suitable for a single-crystal X-ray analysis which
established the illustrated relative stereochemical configuration.25 An analytical sample
(white solid) was obtained by HPLC employing 9:1 hexanes:EtOAc as eluant: mp 75-76
°C; FTIR (thin film/NaCl) 2953 (m), 2930 (m), 2886 (m), 2857 (m), 1787 (s), 1602 (w),
1586 (w), 1490 (w), 1470 (m), 1464 (m), 1252 (m), 1158 (m), 1125 (m), 1031 (m), 906
(m), 838 (s), 778 (s), 697 (m) cm-1; 1H NMR (500 MHz, CDCl3, Me4Si) δ 7.26 (t, J=7.9
Hz, 1H), 6.90-6.85 (m, 3H), 4.35 (d, J=9.6 Hz, 1H), 4.31 (d, J=10.7 Hz, 1H), 4.16 (s,
186
1H), 4.01 (d, J=6.3 Hz, 1H), 3.79 (s, 3H), 3.77 (q, J=6.2 Hz, 1H), 3.42 (dd, J=8.6, 6.4 Hz,
1H), 3.39 (dd, J=8.7, 6.3 Hz, 1H), 0.98 (s, 9H), 0.79 (s, 9H), 0.18 (s, 3H), 0.16 (s, 3H), -
0.06 (s, 3H), -0.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.3, 159.6, 134.2, 129.4,
123.5, 116.4, 114.0, 89.4, 79.4, 76.1, 74.1, 71.6, 55.4, 50.4, 26.1, 25.9, 18.1, 18.0, -3.7, -
4.4, -4.5, -4.6; HRMS m/z 508.2686 [calcd for C26H44O6Si2 (M+) 508.2676].
Preparation of (+)-Acetoacetate 169.
OO
O
169
OBnBnO
O
(+)-Acetoacetate 169. Diketene (1 mL, 12.97 mmol, 1.52 equiv) was added
dropwise to a stirred (0 °C) solution of alcohol 155 (2.673 g, 8.50 mmol, 1 equiv) and
DMAP (12 mg, 0.10 mmol, 1.2% equiv) in THF (9 mL). After removing the cooling
bath and stirring at room temperature for 3 h, the reaction mixture was concentrated in
vacuo. The resultant yellow oil was chromatographed on silica employing 7:3
hexanes:EtOAc as eluant to furnish 169 (3.192 g, 94% yield) as a yellow oil. An
analytical sample (yellowish oil) was prepared by flash column chromatography followed
by HPLC employing 7:3 hexanes:EtOAc as eluant in both cases: [α]D20 +15.04° (c 1.35,
CHCl3); FTIR (thin film/NaCl) 3088 (w), 3063 (w), 3030 (m), 3005 (w), 2919 (m), 2866
(m), 1744 (s), 1716 (s), 1649 (m), 1631 (m), 1496 (m), 1453 (m), 1408 (m), 1359 (m),
1314 (m), 1260 (m), 1150 (s), 1091 (s), 1027 (s), 738 (s), 698 (s) cm-1; 1H NMR (500
MHz, CDCl3, Me4Si) δ 7.36-7.30 (m, 10H), 4.54 (s, 2H), 4.51 (d, J=12.0 Hz, 1H), 4.47
187
(d, J=12.2 Hz, 1H), 4.31 (dd, J=11.6, 4.8 Hz, 1H), 4.24 (dd, J=11.5, 6.7 Hz, 1H), 4.10-
4.07 (m, 2H), 4.04 (d, J=11.2 Hz, 1H), 3.94 (dd, J=10.1, 4.5 Hz, 1H), 3.91 (d, J=2.2 Hz,
1H), 3.42 (s, 2H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.2, 167.0, 137.7,
137.6, 128.6, 128.1, 128.0, 127.8, 84.4, 82.9, 81.4, 72.0, 71.8, 71.5, 65.1, 49.9, 30.1;
HRMS (FAB) m/z 399.1807 [calcd for C23H27O6 (M+H) 399.1808].
Preparation of (+)-Diazoacetoacetate 170.
OO
O
170
OBnBnO
O
N2
(+)-Diazoacetoacetate 170. Triethylamine (3.6 mL, 25.83 mmol, 3.15 equiv)
was added dropwise to a stirred (0 °C) solution of acetoacetate 169 (3.266 g, 8.20 mmol,
1 equiv) and p-ABSA (2.347 g, 9.77 mmol, 1.19 equiv) in CH3CN (25 mL). After
allowing to warm to room temperature and stirring overnight, the reaction mixture was
concentrated in vacuo, triturated with 1:1 Et2O:petroleum ether (50 mL), filtered and
reconcentrated to a yellow oil. Silica gel chromatography employing 7:3 hexanes:EtOAc
as eluant furnished 170 (3.103 g, 89% yield) as a yellow oil. An analytical sample
(yellowish oil) was obtained by selecting fractions from the flash chromatography:
[α]D20 +20.96° (c 1.04, CHCl3); FTIR (thin film/NaCl) 3088 (w), 3063 (w), 3030 (w),
3006 (w), 2922 (w), 2866 (w), 2141 (s), 1717 (s), 1657 (s), 1496 (w), 1454 (m), 1364
(m), 1312 (s), 1250 (m), 1208 (w), 1157 (m), 1076 (s), 1027 (m), 965 (m), 740 (m), 699
(m) cm-1; 1H NMR (500 MHz, CDCl3, Me4Si) δ 7.38-7.29 (m, 10H), 4.56 (d, J=11.8
188
Hz, 1H), 4.54 (d, J=11.9 Hz, 1H), 4.50 (d, J=11.8 Hz, 1H), 4.47 (d, J=12.2 Hz, 1H), 4.38
(dd, J=11.2, 4.4 Hz, 1H), 4.33 (dd, J=11.3, 6.4 Hz, 1H), 4.09 (m, 2H), 4.05 (d, J=10.3
Hz, 1H), 3.94 (dd, J=10.1, 4.3 Hz, 1H), 3.90 (d, J=3.1 Hz, 1H), 2.45 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 190.0, 161.2, 137.6, 137.4, 128.6, 128.1, 128.0, 127.8, 84.3, 82.6,
81.5, 72.0, 71.8, 71.5, 64.8, 28.4; HRMS (FAB) m/z 425.1712 [calcd for C23H25N2O6
(M+H) 425.1713].
Preparation of (+)-TBS-enol ether 172.
OO
O
172
OBnBnO
TBSO
N2
(+)-TBS-enol ether 172. TBSOTf (205 µL, 0.89 mmol, 1.21 equiv) was added
dropwise to a stirred (0 °C) solution of diazoacetoacetate 170 (314 mg, 0.74 mmol, 1
equiv) and triethylamine (160 µL, 1.15 mmol, 1.55 equiv) in CH2Cl2 (2 mL). After
allowing to warm to room temperature and stirring for 2.5 h, the reaction mixture was
diluted with petroleum ether (8 mL) and washed with 1:1 saturated aqueous
NaHCO3:water (2 X 8 mL) and brine (8 mL). The aqueous washings were extracted with
petroleum ether (8 mL) and the combined organic phases were dried over MgSO4,
filtered and concentrated in vacuo to furnish 172 (370 mg, 93% yield) as an orange oil.
Typically this material was used without purification due to its instability. However, an
analytical sample (orange oil) was prepared by flash column chromatography employing
85:15:1 hexanes:EtOAc:Et3N as eluant: [α]D20 +5.00° (c 0.98, CHCl3); FTIR (thin
189
film/NaCl) 3088 (w), 3064 (w), 3031 (w), 2955 (m), 2930 (m), 2885 (m), 2859 (m), 2104
(s), 1711 (s), 1607 (w), 1471 (m), 1463 (m), 1454 (m), 1389 (m), 1346 (m), 1258 (m),
1082 (s), 839 (m), 811 (m), 784 (m), 740 (m), 698 (m) cm-1; 1H NMR (400 MHz,
CDCl3, Me4Si) δ 7.36-7.29 (m, 10H), 5.01 (m, 1H), 4.52 (d, J=11.7 Hz, 1H), 4.51 (s,
2H), 4.47 (d, J=12.3 Hz, 1H), 4.31 (d, J=5.6 Hz, 2H), 4.24 (m, 1H), 4.12-4.07 (m, 2H),
4.03 (d, J=10.0 Hz, 1H), 3.97-3.91 (m, 2H), 0.91 (s, 9H), 0.22 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 163.9, 140.7, 137.7, 137.5, 128.6, 128.1, 128.0, 127.8, 127.7, 90.6, 84.4,
82.8, 81.5, 71.9, 71.8, 71.5, 64.5, 25.7, 18.2, -4.7; HRMS (FAB) m/z 539.2579 [calcd for
C29H39N2O6Si (M+) 539.2577].
Preparation of (+)-Diazoacetate 174.
OO
O
174
OBnBnO
N2
(+)-Diazoacetate 174. To a stirred solution of diazoacetoacetate 170 (556 mg,
1.31 mmol, 1 equiv) in CH3CN (21 mL) was added a solution of LiOH monohydrate (168
mg, 4.00 mmol, 3.06 equiv) in water (7 mL). The reaction mixture was stirred at room
temperature for 10 h, diluted with water (28 mL) and extracted with Et2O (4 X 10 mL).
The combined organic extracts were dried over MgSO4, filtered and concentrated in
vacuo. The residue contained water, so it was taken in CH2Cl2 (20 mL), dried over
MgSO4, filtered and reconcentrated. The resultant yellow oil was chromatographed on
silica employing 3:1 hexanes:EtOAc as eluant to furnish 174 (422 mg, 84% yield) as a
190
yellow oil. An analytical sample (yellow oil) was prepared by a second flash column
chromatography employing 3:1 hexanes:EtOAc as eluant: [α]D20 +12.45° (c 1.02,
CHCl3); FTIR (thin film/NaCl) 3109 (w), 3089 (w), 3064 (w), 3030 (w), 2918 (m), 2866
(m), 2111 (s), 1694 (s), 1496 (m), 1454 (m), 1393 (s), 1366 (s), 1241 (s), 1187 (s), 1094
(s), 1028 (s), 739 (s), 699 (s) cm-1; 1H NMR (400 MHz, CDCl3, Me4Si) δ 7.37-7.27 (m,
10H), 4.74 (br s, 1H), 4.53 (s, 2H), 4.51 (d, J=10.7 Hz, 1H), 4.46 (d, J=11.8 Hz, 1H),
4.32 (dd, J=11.6, 5.0 Hz, 1H), 4.26 (dd, J=11.4, 6.6 Hz, 1H), 4.10-4.06 (m, 2H), 4.04 (d,
J=10.1 Hz, 1H), 3.94 (dd, J=10.1, 4.3 Hz, 1H), 3.90 (d, J=3.2 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 137.6, 137.5, 128.6, 128.5, 128.0, 127.9, 127.8, 84.3, 82.7, 81.6, 71.9,
71.7, 71.4, 64.6, 46.4; HRMS (EI) m/z 382.1527 [calcd for C14H27N2O4Si (M+)
382.1529].
Preparation of (+)-Spirolactone 175.
OO
O
175
OBnBnO
(+)-Spirolactone 175. To a suspension of Rh2(OAc)4 (9.4 mg, 0.02 mmol, 0.6%
equiv) in CH2Cl2 (70 mL) at reflux was added dropwise (over a 10 h period via syringe
pump) a solution of diazoacetate 174 (1.340 g, 3.50 mmol, 1 equiv) in CH2Cl2 (18 mL).
After allowing to cool to room temperature and concentrating in vacuo, the resultant
green oil was purified by flash column chromatography followed by HPLC employing
3:1 hexanes:EtOAc as eluant in both cases. This furnished 175 (93 mg, 7% yield) as a
white solid. Spectroscopic data for this material was identical to that reported in the
191
literature,18 except for the δ 2.95, 2.56 AB-q in the 1H NMR; for this resonance we found
a coupling constant of 18.0 Hz (lit.: 8.5 Hz): [α]D20 +33.11° (c 0.97, CHCl3).
Preparation of (+)-3-Methoxyphenylacetate 176.
OO
176
OBnBnO
O
MeO
(+)-3-Methoxyphenylacetate 176. To a stirred (0 °C) solution of alcohol 155
(1.177 g, 3.74 mmol, 1 equiv), 3-methoxyphenylacetic acid (685 mg, 4.12 mmol, 1.10
equiv) and DMAP (46 mg, 0.38 mmol, 0.10 equiv) in CH2Cl2 (10 mL) was added DCC
(897 mg g, 4.35 mmol, 1.16 equiv). After allowing to warm to room temperature and
stirring for 4 h, the resulting white precipitate was removed by filtration through a cotton
plug. The filtrate was concentrated in vacuo and the residue taken in CH3CN (10 mL),
filtered through a cotton plug and reconcentrated; this procedure was repeated using
acetone (10 mL) and a reddish oil was recovered. Silica gel chromatography employing
3:1 hexanes:EtOAc as eluant furnished 176 (1.732 g, 100% yield) as a yellowish oil. An
analytical sample (yellowish oil) was obtained by selecting fractions from the flash
chromatography: [α]D20 +4.02° (c 1.37, CHCl3); FTIR (thin film/NaCl) 3087 (w), 3032
(m), 3030 (m), 3003 (m), 2940 (m), 2919 (m), 2868 (m), 2836 (m), 1739 (s), 1601 (s),
1589 (m), 1492 (s), 1454 (s), 1437 (m), 1261 (s), 1208 (m), 1150 (s), 1091s, 1050 (s),
1027 (s), 739 (s), 698 (s) cm-1; 1H NMR (500 MHz, CDCl3, Me4Si) δ 7.36-7.26 (m,
10H), 7.20 (t, J=7.9 Hz, 1H), 6.84 (d, J=7.9 Hz, 1H), 6.83 (s, 1H), 6.78 (dd, J=7.9, 2.7
192
Hz, 1H), 4.50 (d, J=12.0 Hz, 1H), 4.46 (d, J=11.9 Hz, 1H), 4.45 (s, 2H), 4.25 (dd, J=11.1,
5.2 Hz, 1H), 4.20 (dd, J=11.3, 6.4 Hz, 1H), 4.09-4.06 (m, 2H), 4.02 (d, J=10.6 Hz, 1H),
3.94 (dd, J=9.7, 4.5 Hz, 1H), 3.87 (d, J=3.1 Hz, 1H), 3.75 (s, 3H), 3.60 (s, 2H); 13C NMR
(125 MHz, CDCl3) δ 171.2, 159.9, 137.8, 137.7, 135.4, 129.6, 128.6, 128.1, 128.0, 127.8,
121.8, 115.1, 112.9, 84.6, 83.0, 81.5, 72.0, 71.7, 71.5, 64.8, 55.3, 41.3; HRMS (EI) m/z
462.2050 [calcd for C28H30O6 (M+) 462.2042].
Preparation of (+)-3-Methoxyphenyldiazoacetate 177.
OO
177
OBnBnO
O
MeON2
(+)-3-Methoxyphenyldiazoacetate 177. DBU (180 µL, 1.20 mmol, 2.04 equiv)
was added dropwise to a stirred (0 °C) solution of 3-methoxyphenylacetate 176 (273 mg,
0.59 mmol, 1 equiv) and p-ABSA (215 mg, 0.89 mmol, 1.52 equiv) in CH3CN (5 mL) .
After allowing to warm to room temperature and stirring for 7 h, the reaction mixture was
treated with saturated aqueous NH4Cl (5 mL) and extracted with CH2Cl2 (2 X 10 mL).
The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo
to furnish an orange oil. Silica gel chromatography employing 3:1 hexanes:EtOAc as
eluant furnished 177 (228 mg, 79% yield) as an orange oil. An analytical sample (orange
oil) was obtained by a second flash chromatography using 4:1 hexanes:EtOAc as eluant:
[α]D20 +4.39° (c 1.03, CHCl3); FTIR (thin film/NaCl) 3086 (w), 3062 (w), 3030 (w),
3003 (w), 2935 (m), 2865 (w), 2840 (w), 2089 (s), 1704 (s), 1599 (m), 1586 (m), 1578
193
(m), 1495 (m), 1453 (m), 1435 (m), 1254 (s), 1179 (m), 1151 (m), 1092 (m), 1034 (m),
737 (m), 698 (m) cm-1; 1H NMR (500 MHz, CDCl3, Me4Si) δ 7.36-7.25 (m, 11H), 7.14
(t, J=2.1 Hz, 1H), 6.96 (dd, J=7.9, 1.0 Hz, 1H), 6.73 (dd, J=8.5, 2.6 Hz, 1H), 4.54 (s, 2H),
4.53 (d, J=11.8 Hz, 1H), 4.49 (d, J=11.7 Hz, 1H), 4.39 (d, J=5.7 Hz, 2H), 4.14 (app. td,
J=5.6, 3.8 Hz, 1H), 4.10 (m, 1H), 4.05 (d, J=10.5 Hz, 1H), 3.97-3.94 (m, 2H), 3.81 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 164.8, 160.2, 137.8, 137.6, 130.0, 128.6, 128.1,
128.0, 127.8, 127.7, 127.0, 116.1, 111.7, 109.8, 84.5, 82.9, 81.6, 72.0, 71.8, 71.5, 64.6,
55.3; HRMS (FAB) m/z 489.2026 [calcd for C28H29N2O6 (M+H) 489.2026].
Preparation of (-)-Spirolactone 178.
178
OO
O
HMeO OBnOBn
(-)-Spirolactone 178. To a suspension of Rh2(OAc)4 (3.2 mg, 0.007 mmol, 0.5%
equiv) in CH2Cl2 (20 mL) at reflux was added dropwise (over a 10 h period via syringe
pump) a solution of 3-methoxyphenyldiazoacetate 177 (655 mg, 1.34 mmol, 1 equiv) in
CH2Cl2 (5 mL). After allowing to cool to room temperature and concentrating in vacuo,
the resultant brown oil was purified by flash column chromatography followed by HPLC
employing 3:1 hexanes:EtOAc as eluant in both cases. This furnished 178 (93 mg, 15%
yield) as a white oil: [α]D20 -47.11° (c 0.55, CHCl3); FTIR (thin film/NaCl) 3086 (w),
3062 (w), 3030 (m), 3003 (w), 2942 (m), 2916 (m), 2888 (m), 2836 (m), 1778 (s), 1601
(m), 1585 (m), 1491 (m), 1454 (m), 1436 (m), 1369 (m), 1248 (m), 1158 (m), 1124 (m),
194
1095 (m), 1025 (s), 914 (w), 780 (m), 739 (m), 698 (m) cm-1; 1H NMR (400 MHz,
CDCl3, Me4Si) δ 7.41-7.30 (m, 8H), 7.25-7.18 (m, 3H), 6.90-6.86 (m, 2H), 6.84 (d, J=1.5
Hz, 1H), 4.80 (d, J=11.8 Hz, 1H), 4.62 (d, J=11.7 Hz, 1H), 4.34 (d, J=11.7 Hz, 1H), 4.30
(d, J=9.9 Hz, 1H), 4.29 (d, J=11.5 Hz, 1H), 4.22 (s, 1H), 4.20 (d, J=10.1 Hz, 1H), 3.97
(d, J=4.9 Hz, 1H), 3.78 (q, J=5.6 Hz, 1H), 3.72 (s, 3H), 3.55 (dd, J=9.5, 4.9 Hz, 1H), 3.25
(dd, J=9.4, 6.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 176.2, 159.4, 137.3, 137.2,
133.7, 129.3, 128.8, 128.7, 128.4, 128.3, 128.1, 128.0, 123.8, 116.6, 114.0, 89.2, 83.6,
81.7, 74.4, 72.9, 72.4, 70.4, 55.3, 50.7; HRMS m/z 460.1895 [calcd for C28H28O6 (M+)
460.1886].
Preparation of Benzoate 179 and Alcohol 156.
OO
O
179
OHO
156
MeO OMeOMeMeO
Benzoate 179 and Alcohol 156. To a stirred (0 °C) mixture of diol 157 (5.009 g,
21.02 mmol, 1 equiv), 48% wt aq HBF4 (7.709 g, 42.14 mmol, 2.00 equiv) and CH2Cl2
(84 mL) was added dropwise in 4 portions separated by 20 min intervals 2 N TMSCHN2
in hexanes (2 X 21 mL and 2 X 11 mL, 128 mmol, 6.09 equiv). The reaction mixture
was stirred at 0 °C for 30 min, diluted with water (84 mL) and extracted with CH2Cl2 (2
X 84 mL). The organic phases were washed with water (84 mL) and then combined,
dried over MgSO4, filtered and concentrated in vacuo to furnish benzoate 179 as a yellow
oil (5.062 g) which was used without purification. However, an analytical sample
195
(colorless oil) was obtained by flash chromatography using 3:1 hexanes:EtOAc as eluant:
FTIR (thin film/NaCl) 2984 (m), 2934 (m), 2092 (m), 2826 (m), 1721 (s), 1602 (w), 1584
(w), 1452 (m), 1315 (m), 1274 (s), 1113 (s), 1071 (m), 1027 (m), 957 (w), 858 (w), 714
(s) cm-1; 1H NMR (400 MHz, CDCl3, Me4Si) δ 8.08 (d, J=7.2 Hz, 2H), 7.56 (t, J=7.4
Hz, 1H), 7.43 (t, J=7.6 Hz, 2H), 4.48 (dd, J=11.6, 5.0 Hz, 1H), 4.43 (dd, J=11.7, 6.3 Hz,
1H), 4.12 (m, 1H), 4.05 (d, J=10.1 Hz, 1H), 3.91 (dd, J=10.0, 4.0 Hz, 1H), 3.86 (d, J=4.2
Hz, 1H), 3.75 (d, J=3.5 Hz, 1H), 3.42 (s, 3H), 3.37 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 166.4, 133.1, 130.0, 129.8, 128.4, 86.5, 84.7, 81.5, 71.4, 64.9, 57.7, 56.9; HRMS (EI)
m/z 267.1227 [calcd for C14H19O5 (M+H) 267.1232].
To a stirred solution of benzoate 179 (5.062 g, 19.01 mmol, 1 equiv) in MeOH (5
mL) was added NaOMe (1.078 g, 19.96 mmol, 1.05 equiv). The reaction mixture was
stirred at room temperature for 8 h, neutralized with AcOH and concentrated in vacuo.
The resultant white semisolid was adsorbed on to silica gel and chromatographed
employing 1:3 hexanes:EtOAc as eluant to furnish 156 (985 mg, 29% yield, 2 steps) as a
yellowish oil. An analytical sample (colorless oil) was obtained by selecting fractions
from the flash chromatography: FTIR (thin film/NaCl) 3448 (br m), 2981 (m), 2932 (m),
2902 (m), 2826 (m), 1461 (m), 1389 (w), 1339 (w), 1194 (m), 1112 (s), 1056 (m), 978
(w), 953 (w), 852 (w) cm-1; 1H NMR (500 MHz, CDCl3) δ 3.96 (d, J=10.1 Hz, 1H),
3.85 (q, J=3.8 Hz, 1H), 3.81 (dd, J=9.9, 3.9 Hz, 1H), 3.78 (d, J=3.7 Hz, 1H), 3.75 (dd,
J=12.0, 3.6 Hz, 1H), 3.69 (d, J=2.9 Hz, 1H), 3.66 (dd, J=11.8, 5.0 Hz, 1H), 3.38 (s, 3H),
3.34 (s, 3H), 2.49 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 85.6, 84.6, 84.5, 71.3, 63.0,
57.7, 56.8; HRMS (EI) m/z 162.0891 [calcd for C14H14O4 (M+) 162.0892].
196
Preparation of Acetoacetate 180.
OO
O
180
OMeMeO
O
Acetoacetate 180. Diketene (1 mL, 12.97 mmol, 1.53 equiv) was added
dropwise to a stirred (0 °C) solution of alcohol 156 (1.375 g, 8.48 mmol, 1 equiv) and
DMAP (12 mg, 0.10 mmol, 1.2% equiv) in THF (17 mL). After removing the cooling
bath and stirring at room temperature for 1 h, the reaction mixture was concentrated in
vacuo. The resultant yellow oil was chromatographed on silica employing 1:1
hexanes:EtOAc as eluant to furnish 180 (1.984 g, 95% yield) as a yellow oil. An
analytical sample (yellowish oil) was prepared by a second flash column chromatography
employing 1:1 hexanes:EtOAc as eluant: FTIR (thin film/NaCl) 2984 (w), 2936 (m),
2905 (m), 2828 (w), 1746 (s), 1717 (s), 1650 (w), 1458 (m), 1412 (m), 1361 (m), 1316
(m), 1265 (m), 1191 (m), 1152 (m), 1112 (s), 1037 (m) cm-1; 1H NMR (400 MHz,
CDCl3) δ 4.33 (dd, J=11.5, 4.5 Hz, 1H), 4.23 (dd, J=11.6, 6.8 Hz, 1H), 4.01-3.96 (m,
2H), 3.87 (dd, J=10.1, 4.1 Hz, 1H), 3.82-3.81 (m, 1H), 3.62 (d, J=3.6 Hz, 1H), 3.50 (s,
2H), 3.40 (s, 3H), 3.35 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.5,
167.0, 86.1, 84.4, 81.2, 71.4, 65.1, 57.6, 56.9, 49.9, 30.2; HRMS (EI) m/z 246.1103
[calcd for C11H18O6 (M+) 246.1103].
197
Preparation of Diazoacetoacetate 181.
OO
O
181
OMeMeO
O
N2
Diazoacetoacetate 181. Triethylamine (3.2 mL, 22.96 mmol, 3.01 equiv) was
added dropwise to a stirred (0 °C) solution of acetoacetate 180 (1.881 g, 7.64 mmol, 1
equiv) and p-ABSA (2.110 g, 8.78 mmol, 1.15 equiv) in CH3CN (20 mL). After
allowing to warm to room temperature and stirring overnight, the reaction mixture was
concentrated in vacuo, triturated with 1:1 Et2O:petroleum ether (40 mL), filtered and
reconcentrated to an orange oil. Silica gel chromatography employing 6:4
hexanes:EtOAc as eluant furnished 181 (1.613 g, 78% yield) as a yellow oil. An
analytical sample (yellow oil) was obtained by a second flash chromatography using 6:4
hexanes:EtOAc as eluant: FTIR (thin film/NaCl) 2984 (w), 2932 (m), 2902 (m), 2825
(w), 2142 (s), 1717 (s), 1657 (s), 1457 (w), 1365 (m), 1312 (s), 1249 (m), 1195 (w), 1156
(m), 1106 (m), 1074 (s), 965 (w) cm-1; 1H NMR (500 MHz, CDCl3) δ 4.40 (dd, J=11.8,
4.4 Hz, 1H), 4.35 (dd, J=11.7, 6.0 Hz, 1H), 4.02-3.97 (m, 2H), 3.86 (dd, J=10.0, 4.0 Hz,
1H), 3.82-3.81 (m, 1H), 3.62 (d, J=3.3 Hz, 1H), 3.40 (s, 3H), 3.34 (s, 3H), 2.48 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 190.0, 161.1, 86.4, 84.3, 81.3, 71.2, 64.8, 57.6, 56.8,
28.2; HRMS (EI) m/z 273.1098 [calcd for C11H17N2O6 (M+H) 273.1087].
198
Preparation of TBS-enol ether 183.
OO
O
183
OMeMeO
TBSO
N2
TBS-enol ether 183. TBSOTf (290 µL, 1.26 mmol, 1.22 equiv) was added
dropwise to a stirred (0 °C) solution of diazoacetoacetate 181 (282 mg, 1.04 mmol, 1
equiv) and triethylamine (220 µL, 1.58 mmol, 1.52 equiv) in CH2Cl2 (2.5 mL). After
allowing to warm to room temperature and stirring for 2.5 h, the reaction mixture was
diluted with petroleum ether (10 mL) and washed with 1:1 saturated aqueous
NaHCO3:water (2 X 10 mL) and brine (10 mL). The aqueous washings were extracted
with petroleum ether (10 mL) and the combined organic phases were dried over MgSO4,
filtered and concentrated in vacuo to furnish 183 (350 mg, 87% yield) as an orange oil.
Typically this material was used without purification due to its instability. However, an
analytical sample (orange oil) was prepared by flash column chromatography employing
85:15:1 hexanes:EtOAc:Et3N as eluant: FTIR (thin film/NaCl) 2955 (m), 2932 (s), 2898
(m), 2859 (m), 2824 (m), 2104 (s), 1712 (s), 1635 (w), 1609 (m), 1471 (m), 1463 (m),
1388 (m), 1345 (s), 1258 (m), 1083 (s), 1003 (m), 839 (s), 784 (m), 744 (m) cm-1; 1H
NMR (400 MHz, CDCl3, Me4Si) δ 5.01 (d, J=2.2 Hz, 1H), 4.32 (d, J=5.4 Hz, 2H), 4.25
(d, J=2.2 Hz, 1H), 4.01-3.97 (m, 2H), 3.87 (dd, J=10.0, 4.0 Hz, 1H), 3.87-3.81 (m, 1H),
3.64 (d, J=3.2 Hz, 1H), 3.39 (s, 3H), 3.35 (s, 3H), 0.92 (s, 9H), 0.22 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 164.0, 140.7, 90.6, 86.5, 84.7, 81.4, 71.3, 64.5, 57.6, 56.9, 25.7,
199
18.2, -4.7; HRMS (CI, isobutane) m/z 387.1950 [calcd for C17H31N2O6Si (M+H)
387.1951].
Preparation of Diazoacetate 185.
OO
O
185
OMeMeO
N2
Diazoacetate 185. To a stirred solution of diazoacetoacetate 181 (430 mg, 1.58
mmol, 1 equiv) in CH3CN (24 mL) was added a solution of LiOH monohydrate (201 mg,
4.79 mmol, 3.03 equiv) in water (8 mL). The reaction mixture was stirred at room
temperature for 5 h, diluted with water (32 mL) and extracted with Et2O (4 X 10 mL).
The combined organic extracts were dried over MgSO4, filtered and concentrated in
vacuo. The residue contained water, so it was taken in CH2Cl2 (40 mL), dried over
MgSO4, filtered and reconcentrated. The resultant yellow oil was chromatographed on
silica employing 7:3 hexanes:EtOAc as eluant to furnish 185 (246 mg, 68% yield) as a
yellow oil. An analytical sample (yellow oil) was obtained by selecting fractions from
the flash chromatography: FTIR (thin film/NaCl) 3095 (w), 2984 (w), 2934 (m), 2903
(m), 2826 (w), 2112 (s), 1694 (s), 1458 (m), 1371 (m), 1341 (m), 1240 (m), 1186 (m),
1110 (m), 1036 (m), 953 (w) cm-1; 1H NMR (400 MHz, CDCl3) δ 4.80 (br s, 1H), 4.29
(dd, J=11.5, 4.8 Hz, 1H), 4.22 (dd, J=11.4, 6.8 Hz, 1H), 3.98-3.92 (m, 2H), 3.84 (dd,
J=10.0, 4.4 Hz, 1H), 3.79 (d, J=4.0 Hz, 1H), 3.58 (d, J=3.3 Hz, 1H), 3.36 (s, 3H), 3.32 (s,
200
3H); 13C NMR (100 MHz, CDCl3) δ 86.4, 84.6, 81.5, 71.3, 64.7, 57.6, 56.9, 46.5; HRMS
(EI) m/z 230.0900 [calcd for C9H14N2O5 (M+) 230.0903].
Preparation of Spirolactone 186.
OO
O
186
OMeMeO
Spirolactone 186. To a suspension of Rh2(OAc)4 (4.5 mg, 0.01 mmol, 1.0%
equiv) in CH2Cl2 (20 mL) at reflux was added dropwise (over a 10 h period via syringe
pump) a solution of diazoacetate 185 (231 mg, 1.00 mmol, 1 equiv) in CH2Cl2 (5 mL).
After allowing to cool to room temperature and concentrating in vacuo, the resultant
yellow oil was chromatographed on silica employing 1:1 hexanes:EtOAc as eluant to
furnish 186 (110 mg, 54% yield) as a colorless oil. An analytical sample (colorless oil)
was obtained by a second flash chromatography using 1:1 hexanes:EtOAc as eluant:
FTIR (thin film/NaCl) 2987 (w), 2939 (m), 2905 (m), 2831 (m), 1782 (s), 1463 (m), 1403
(w), 1374 (m), 1260 (m), 1176 (m), 1102 (s), 1077 (m), 1037 (m), 1015 (s), 967 (m), 857
(m) cm-1; 1H NMR (500 MHz, CDCl3, Me4Si) δ 4.31 (d, J=10.4 Hz, 1H), 4.28 (d,
J=10.1 Hz, 1H), 4.07 (dd, J=10.3, 5.1 Hz, 1H), 3.92-3.89 (m, 2H), 3.60 (d, J=1.5 Hz,
1H), 3.47 (s, 3H), 3.37 (s, 3H), 2.95 (d, J=18.5 Hz, 1H), 2.51 (d, J=18.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 175.3, 87.5, 86.5, 83.2, 76.2, 70.6, 58.3, 57.3, 34.8; HRMS
(EI) m/z 202.0840 [calcd for C9H14O5 (M+) 202.0841].
201
Preparation of 3-Methoxyphenylacetate 187.
OO
187
OMeMeO
O
MeO
3-Methoxyphenylacetate 187. To a stirred (0 °C) solution of alcohol 156 (306
mg, 1.89 mmol, 1 equiv), 3-methoxyphenylacetic acid (356 mg, 2.14 mmol, 1.14 equiv)
and DMAP (3 mg, 0.02 mmol, 1.3% equiv) in CH2Cl2 (5 mL) was added DCC (432 mg,
2.09 mmol, 1.11 equiv). After allowing to warm to room temperature and stirring for 4 h,
the resulting white precipitate was removed by filtration through a cotton plug. The
filtrate was concentrated in vacuo and the residue taken in CH3CN (5 mL), filtered
through a cotton plug and reconcentrated; this procedure was repeated using acetone (5
mL) and a red oil was recovered. Silica gel chromatography employing 6:4
hexanes:EtOAc as eluant furnished 187 (442 g, 75% yield) as a colorless oil. An
analytical sample (colorless oil) was obtained by selecting fractions from the flash
chromatography: FTIR (thin film/NaCl) 3053 (w), 2982 (m), 2936 (m), 2833 (m), 1738
(s), 1601 (m), 1586 (m), 1492 (m), 1456 (m), 1439 (m), 1262 (s), 1193 (m), 1151 (s),
1111 (s), 1050 (m), 953 (m), 858 (m), 773 (m), 720 (m), 692 (m) cm-1; 1H NMR (500
MHz, CDCl3, Me4Si) δ 7.23 (t, J=7.9 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 6.84 (s, 1H), 6.80
(dd, J=8.3, 2.3 Hz, 1H), 4.25 (dd, J=11.5, 5.2 Hz, 1H), 4.19 (dd, J=11.5, 6.7 Hz, 1H),
3.99-3.94 (m, 2H), 3.86 (dd, J=10.0, 4.1 Hz, 1H), 3.80-3.79 (m, 1H), 3.79 (s, 3H), 3.64
(s, 2H), 3.56 (d, J=3.3 Hz, 1H), 3.33 (s, 3H), 3.32 (s, 3H); 13C NMR (100 MHz, CDCl3)
202
δ 171.2, 156.7, 135.3, 129.5, 121.6, 121.7, 114.9, 112.7, 86.2, 84.5, 81.2, 71.2, 64.8, 57.5,
56.8, 55.2, 41.2; HRMS (EI) m/z 310.1419 [calcd for C16H22O6 (M+) 310.1416].
Preparation of 3-Methoxyphenyldiazoacetate 188.
OO
188
OMeMeO
O
MeON2
3-Methoxyphenyldiazoacetate 188. DBU (215 µL, 1.44 mmol, 1.10 equiv) was
added dropwise to a stirred (0 °C) solution of 3-methoxyphenylacetate 187 (406 mg, 1.31
mmol, 1 equiv) and p-ABSA (397 mg, 1.65 mmol, 1.26 equiv) in CH3CN (5 mL). After
allowing to warm to room temperature and stirring overnight, the reaction mixture was
treated with saturated aqueous NH4Cl (10 mL) and extracted with CH2Cl2 (2 X 10 mL).
The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo
to furnish an orange oil. Silica gel chromatography employing 3:1 hexanes:EtOAc as
eluant furnished 188 (141 mg, 32% yield) as an orange oil. An analytical sample (orange
oil) was obtained by selecting fractions from the flash chromatography: FTIR (thin
film/NaCl) 2984 (m), 2934 (m), 2904 (m), 2830 (m), 2092 (s), 1705 (s), 1600 (s), 1578
(m), 1494 (m), 1454 (m), 1437 (m), 1348 (m), 1294 (m), 1255 (s), 1182 (m), 1152 (s),
1112 (s), 1036 (s), 956 (w), 860 (m), 775 (m), 738 (m), 688 (m) cm-1; 1H NMR (500
MHz, CDCl3, Me4Si) δ 7.28 (t, J=8.0 Hz, 1H), 7.16 (s, 1H), 6.98 (dd, J=7.9, 1.0 Hz, 1H),
6.23 (dd, J=8.3, 2.0 Hz, 1H), 4.39 (d, J=5.8 Hz, 2H), 4.05-4.03 (m, 1H), 4.01 (d, J=10.8
Hz, 1H), 3.88 (dd, J=10.1, 4.4 Hz, 1H), 3.83-3.82 (m, 1H), 3.81 (s, 3H), 3.67 (d, J=3.4
203
Hz, 1H), 3.40 (s, 3H), 3.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.8, 160.1, 129.9,
126.9, 116.0, 111.6, 109.7, 86.5, 84.6, 81.5, 71.3, 64.7, 57.6, 56.9, 55.3; HRMS (EI) m/z
336.1318 [calcd for C16H20N2O6 (M+) 336.1321].
Preparation of (+)-Acetoacetate 190.
OO
O
190
OHHO
O
(+)-Acetoacetate 190. Diketene (1.1 mL, 14.26 mmol, 1.04 equiv) was added
dropwise to a stirred (0 °C) solution of triol 98 (1.840 g, 13.72 mmol, 1 equiv) and
DMAP (17 mg, 0.14 mmol, 1.0% equiv) in THF (28 mL). After removing the cooling
bath and stirring at room temperature for 3 h, the reaction mixture was concentrated in
vacuo. The resultant yellow oil was chromatographed on silica employing 99:1
EtOAc:AcOH as eluant to furnish 190 (1.025 g, 34% yield) as a yellow oil. An analytical
sample (yellowish oil) was prepared by flash column chromatography employing 95:5
CH2Cl2:MeOH as eluant: [α]D20 +21.98° (c 0.41, MeOH); FTIR (thin film/NaCl) 3418
(br m), 2928 (w), 1741 (s), 1711 (s), 1412 (m), 1362 (m), 1317 (m), 1274 (m), 1154 (m),
1090 (m), 1058 (m), 1034 (m), 1008 (m), 978 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ
4.40 (dd, J=11.7, 5.0 Hz, 1H), 4.36 (dd, J=10.3, 4.8 Hz, 1H), 4.22 (m, 1H), 4.11 (m, 1H),
4.02 (dd, J=10.1, 4.4 Hz, 1H), 3.94 (q, J=4.7 Hz, 1H), 3.88 (dd, J=10.0, 2.2 Hz, 1H), 3.55
(d, J=2.2 Hz, 1H), 2.28 (s, 3H), 1.96 (br s, 2H); 13C NMR (125 MHz, acetone-d6) δ
204
201.1, 167.8, 84.1, 79.9, 78.5, 74.3, 66.0, 50.2, 30.0; HRMS (EI) m/z 219.0869 [calcd for
C9H15O6 (M+H) 219.0869].
Preparation of (+)-Diazoacetoacetate 194.
OO
O
194
OHHO
O
N2
(+)-Diazoacetoacetate 194. Diol protection: 2-Methoxypropene (1.6 mL, 16.71
mmol, 3.98 equiv) was added dropwise to a stirred solution of diol 190 (917 mg, 4.20
mmol, 1 equiv) and POCl3 (ca. 1 µL, 0.01 mmol, 0.3% equiv) in THF (10 mL) The
reaction mixture was stirred at room temperature for 1 h, quenched by adding
triethylamine and concentrated in vacuo to a turbid yellow oil which was used without
purification.
Diazo transfer: Triethylamine (1.8 mL, 12.91 mmol, 3.07 equiv) was added
dropwise to a stirred (0 °C) solution of the crude product of the previous reaction and p-
ABSA (1.244 g, 5.18 mmol, 1.23 equiv) in CH3CN (10 mL). After allowing to warm to
room temperature and stirring for 1 h, the reaction mixture was concentrated in vacuo,
triturated with 1:1 Et2O:petroleum ether (20 mL), filtered and reconcentrated to a yellow
oil which was used without purification.
Diol deprotection: To a solution of the crude product of the previous reaction in
MeOH (20 mL) was added p-TsOH monohydrate (81 mg, 0.43 mmol, 0.10 equiv). The
reaction mixture was stirred at room temperature for 15 min, quenched by adding
205
triethylamine and concentrated in vacuo to a yellow oil. Silica gel chromatography
employing EtOAc as eluant furnished 194 (938 mg, 91% yield) as a yellow oil. An
analytical sample (yellowish oil) was obtained by a second flash chromatography using
13:1 CH2Cl2:MeOH as eluant: [α]D20 +21.97° (c 0.58, MeOH); FTIR (thin film/NaCl)
3413 (br m), 2928 (w), 2147 (s), 1718 (s), 1652 (m), 1368 (m), 1317 (s), 1251 (m), 1156
(m), 1072 (s), 969 (m) cm-1; 1H NMR (400 MHz, CDCl3) δ 4.45 (d, J=5.3 Hz, 2H), 4.25
(m, 1H), 4.09-4.04 (m, 2H), 3.98 (q, J=4.8 Hz, 1H), 3.88 (dd, J=10.0, 2.1 Hz, 1H), 2.48
(s, 3H), 1.70 (br s, 2H); 13C NMR (100 MHz, acetone-d6) δ 189.8, 161.9, 84.2, 79.8,
78.4, 74.4, 66.0, 28.2; HRMS (EI) m/z 245.0775 [calcd for C9H13N2O6 (M+H)
245.0774].
Preparation of 3-Methoxyphenylacetate 196.
OO
196
OHHO
O
MeO
3-Methoxyphenylacetate 196. To a stirred solution of TBS-ether 166 (238 mg,
0.47 mmol, 1 equiv) in CH3CN (5 mL) was added 48% wt aq HBF4 (350 mg, 1.91 mmol,
4.11 equiv). The reaction mixture was stirred at room temperature for 30 min, diluted
with EtOAc (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and water (5
mL). The aqueous washings were extracted with EtOAc (5 mL) and the combined
organic phases were dried over MgSO4, filtered and concentrated in vacuo to a white
206
semisolid. Silica gel chromatography employing 1:3 hexanes:EtOAc as eluant furnished
196 (122 mg, 93% yield) as a white oil: FTIR (thin film/NaCl) 3428 (br m), 2941 (m),
2837 (w), 1734 (s), 1601 (m), 1586 (m), 1492 (m), 1455 (m), 1438 (m), 1264 (s), 1152
(s), 1090 (m), 1051 (s), 1009 (m), 874 (m), 774 (m), 720 (w), 692 (m) cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.25 (t, J=7.7 Hz, 1H), 6.87 (d, J=7.5 Hz, 1H), 6.85-6.82 (m, 2H),
4.31 (d, J=4.4 Hz, 1H), 4.15 (m, 1H), 4.00 (dd, J=9.8, 4.3 Hz, 1H), 3.99-3.97 (m, 1H),
3.91 (q, J=4.4 Hz, 1H), 3.83 (dd, J=9.9, 2.3 Hz, 1H), 3.81 (s, 3H), 3.65 (s, 2H), 1.81 (br s,
2H); 13C NMR (100 MHz, acetone-d6) δ 171.6, 160.5, 136.6, 130.0, 122.2, 115.6, 113.0,
84.0, 79.7, 78.3, 74.2, 65.7, 55.3, 41.2; HRMS (EI) m/z 282.1101 [calcd for C14H18O6
(M+) 282.1103].
Preparation of 3-Methoxyphenyldiazoacetate 199.
OO
O
199HO
N2
OH
MeO
3-Methoxyphenyldiazoacetate 199. Diol protection: 2-Methoxypropene (2 X
1.3 mL, 27.15 mmol, 7.98 equiv) was added dropwise in 2 portions separated by a 2 h
interval to a stirred solution of diol 196 (960 mg, 3.40 mmol, 1 equiv) and POCl3 (ca. 1
µL, 0.01 mmol, 0.3% equiv) in THF (10 mL). The reaction mixture was stirred at room
temperature for 2 h, quenched by adding triethylamine and concentrated in vacuo to a
colorless oil which was used without purification.
207
Diazo transfer: DBU (0.65 mL, 4.35 mmol, 1.28 equiv) was added dropwise to a
stirred (0 °C) solution of the crude product of the previous reaction and p-ABSA (1.262
g, 5.25 mmol, 1.55 equiv) in CH3CN (10 mL). After allowing to warm to room
temperature and stirring for 48 h, the reaction mixture was concentrated in vacuo and the
residue triturated with 1:1 Et2O:petroleum ether (20 mL), filtered and reconcentrated to
an orange oil which was used without purification.
Diol deprotection: To a solution of the crude product of the previous reaction in
MeOH (20 mL) was added p-TsOH monohydrate (69 mg, 0.36 mmol, 0.11 equiv). The
reaction mixture was stirred at room temperature for 30 min, quenched by adding
triethylamine and concentrated in vacuo to an orange oil. Silica gel chromatography
employing 95:15 CH2Cl2:MeOH as eluant furnished 199 (462 mg, 44% yield) as an
orange oil. An analytical sample (orange oil) was obtained by HPLC using 1:3
hexanes:EtOAc as eluant: FTIR (thin film/NaCl) 3418 (br m), 2941 (w), 2837 (w), 2091
(s), 1698 (s), 1600 (m), 1578 (m), 1494 (m), 1453 (m), 1352 (m), 1295 (m), 1255 (s),
1180 (m), 1152 (m), 1089 (m), 1030 (s), 866 (m), 774 (m), 738 (m), 687 (m) cm-1; 1H
NMR (500 MHz, acetone-d6) δ 7.32 (t, J=8.1 Hz, 1H), 7.22 (t, J=2.0 Hz, 1H), 7.04 (ddd,
J=7.9, 1.7, 0.8 Hz, 1H), 6.78 (ddd, J=8.1, 2.5, 0.7 Hz, 1H), 4.46 (d, J=4.1 Hz, 1H), 4.40
(d, J=5.9 Hz, 2H), 4.24 (d, J=3.8 Hz, 1H), 4.17 (m, 1H), 4.05 (m, 1H), 3.98-3.94 (m, 2H),
3.81 (s, 3H), 3.79 (dd, J=9.6, 2.4 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 165.1,
160.9, 130.6, 127.8, 116.5, 111.9, 110.4, 84.2, 79.7, 78.3, 74.3, 65.7, 55.4; HRMS (EI)
m/z 308.1004 [calcd for C14H16N2O6 (M+) 308.1008].
208
3.9 References.
(1) Doyle, M. P.; Dyatkin, A. B. J. Org. Chem. 1995, 60, 3035-3038.
(2) Acylation of alcohols using a carboxylic acid, DCC and DMAP were
performed following the procedure by Neises and Steglich or Hassner and Alexanian:
(a) Neises, B.; Steglich, W. Angew. Chem. Int. Ed. Engl. 1978, 7, 522-523. (b) Hassner,
A.; Alexanian, V. Tetrahedron Lett. 1978, 19, 4475-4478.
(3) Acylation of alcohols using diketene and DMAP were performed following
the procedure by Nudelman et al.9:
(4) Diazo transfer reactions using mesyl azide (MsN3) were performed following
the procedure by Taber et al.: Taber, D. F.; Ruckle, R. E., Jr.; Hennessy, M. J. J. Org.
Chem. 1986, 51, 4077-4078.
(5) Diazo transfer reactions using p-ABSA were performed following the
procedure by Baum et al.: Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D.
Synth. Commun. 1987, 17, 1709-1716.
(6) Intramolecular C-H insertion reactions were performed following the
procedure by Doyle and Dyatkin.1
209
(7) Diazoacetates were obtained from the corresponding diazoacetoacetates
following the procedure by Doyle and Dyatkin.1
(8) 2-Diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoates were obtained from the
corresponding diazoacetoacetates following the procedure by Davies et al.: Davies, H.
M. L.; Houser, J. H.; Thornley, C. J. Org. Chem. 1995, 60, 7529-7534.
(9) Nudelman, A.; Kelner, R.; Broida, N.; Gottlieb, H. E. Synthesis 1989, 387-
388.
(10) Wood, J. L.; Moniz, G. A.; Pflum, D. A.; Stoltz, B. M.; Holubec, A. A.;
Dietrich, H.-J. J. Am. Chem. Soc. 1999, 121, 1748-1746.
(11) Malonyl acylation was performed via a modified literature procedure: Box,
V. G. S.; Marinovic, N.; Yiannikouros, G. P. Heterocycles 1991, 32, 245-251
(12) (a) Padwa, A.; Kulkarni, Y. S.; Zhang, Z. J. Org. Chem. 1990, 55, 4144-
4153. (b) Pelliciari, R.; Natalini, B.; Sadeghpour, B. M.; Marinozzi, M.; Snyder, J. P.;
Williamson, B. L.; Kuethe, J. T.; Padwa, A. J. Am. Chem. Soc. 1996, 118, 1-12.
(13) Ozonolysis was performed following the method by Bunelle et al.: Bunelle,
W. H.; Rafferty, M. A.; Hodges, S. L. J. Org. Chem. 1987, 52, 1603-1605.
210
(14) Masamune, T.; Matsue, H.; Murase, H. Bull. Chem. Soc. Jpn. 1979, 52, 127-
134.
(15) Fujioka, H.; Kitagawa, H.; Kondo, M.; Kita, Y. Heterocycles 1994, 37, 743-
746.
(16) Disilylation of 157 and deprotection of 166 were effected following the
procedures by Crotti et al.: Crotti, P.; Di Bussolo, V.; Favero, L. Gozzi, C.; Pineschi, M.
Tetrahedron: Asymmetry 1997, 8, 1611-1621.
(17) Nicotra, F.; Panza, L.; Russo, G.; Zucchelli, L.. J. Org. Chem. 1992, 57,
2154-2158.
(18) Mukai, C.; Moharram, S. M.; Azukizawa, S.; Hanaoka, M. J. Org. Chem.
1997, 62, 8095-8103.
(19) Methylation was performed following the method by Aoyama and Shioiri:
Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1990, 31, 5507-5508.
(20) Benneck, J. A.; Gray, G. R. J. Org. Chem. 1987, 42, 892-897.
(21) Taber, D. F.; You, K. K.; Rheingold, A. L. J. Am. Chem. Soc. 1996, 118,
547-556.
211
(22) Padwa, A.; Austin, D. J. Angew. Chem. Int. Ed. Engl. 1994, 33, 1797-1815.
(23) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-2925.
(24) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512-
7515.
(25) The atomic coordinates for this structure have been deposited with the
Cambridge Crystallographic Data Centre.
212
Appendix 3
Spectra Relevant to Chapter 3.
213 21
3
8 6 4 2 0 ppm
Figure A.3.1 1H NMR (500 MHz, CDCl3) of Compound 115.
OO
N2
O
115
O
214 21
4
200
150
100
50PP
M
Figu
re A
.3.3
13C
NM
R (1
25 M
Hz,
CD
Cl 3)
of C
ompo
und
115.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.2
FTI
R S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
115.
215 21
5
8 6 4 2 0 ppm
Figure A.3.4 1H NMR (500 MHz, CDCl3) of Compound 117.
OO
N2
OTBS
117
O
216 21
6
200
150
100
500
PPM
Figu
re A
.3.6
13C
NM
R (1
25 M
Hz,
CD
Cl 3)
of C
ompo
und
117.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.5
FTI
R S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
117.
217 21
7
8 6 4 2 0 ppm
Figure A.3.7 1H NMR (500 MHz, CDCl3) of Compound 121.
121
OO OMe
O O
218 21
8
200
150
100
50PP
M
Figu
re A
.3.9
13C
NM
R (1
25 M
Hz,
CD
Cl 3)
of C
ompo
und
121.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.8
FTI
R S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
121.
219 21
9
8 6 4 2 0 ppm
Figure A.3.10 1H NMR (500 MHz, CDCl3) of Compound 122.
OO
N2
OMe
O
122
O
220 22
0
200
150
100
50PP
M
Figu
re A
.3.1
2 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 12
2.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.1
1 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
122.
221 22
1
8 6 4 2 0 ppm
Figure A.3.13 1H NMR (500 MHz, CDCl3) of Compound 125.
125
OO
O
OMe
222 22
2
200
150
100
50PP
M
Figu
re A
.3.1
5 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 12
5.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.1
4 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
125.
223 22
3
8 6 4 2 0 ppm
Figure A.3.16 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 126.
OO
N2
126
O
OMe
224 22
4
200
150
100
50PP
M
Figu
re A
.3.1
8 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 12
6.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.1
7 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
126.
225 22
5
8 6 4 2 0 ppm
Figure A.3.19 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 127.
OO
O
127
H
OMe
226 22
6
200
150
100
50PP
M
Figu
re A
.3.2
1 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 12
7.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.2
0 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
127.
227 22
7
8 6 4 2 0 ppm
Figure A.3.22 1H NMR (500 MHz, CDCl3) of Compound 129.
129
OO
O
228 22
8
200
150
100
50PP
M
Figu
re A
.3.2
4 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 12
9.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.2
3 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
129.
229 22
9
8 6 4 2 0 ppm
Figure A.3.25 1H NMR (500 MHz, CDCl3) of Compound 131.
OO
O
131
230 23
0
200
150
100
50PP
M
Figu
re A
.3.2
7 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 13
1.
7580859095
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.2
6 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
131.
231 23
1
8 6 4 2 0 ppm
Figure A.3.28 1H NMR (500 MHz, CDCl3) of Compound 134.
OO
N2
134
O
232 23
2
200
150
100
50PP
M
Figu
re A
.3.3
0 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 13
4.
20406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.2
9 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
134.
233 23
3
8 6 4 2 0 ppm
Figure A.3.31 1H NMR (500 MHz, CDCl3) of Compound 135.
OO
O
135
234 23
4
200
150
100
50PP
M
Figu
re A
.3.3
3 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 13
5.
20406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.3
2 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
135.
235 23
5
8 6 4 2 0 ppm
Figure A.3.34 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 140.
140
OO
O O
236 23
6
200
150
100
50PP
M
Figu
re A
.3.3
6 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 14
0.
20406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.3
5 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
140.
237 23
7
8 6 4 2 0 ppm
Figure A.3.37 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 141.
OO
N2
O
141
O
238 23
8
200
150
100
50PP
M
Figu
re A
.3.3
9 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 14
1.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.3
8 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
141.
239 23
9
8 6 4 2 0 ppm
Figure A.3.40 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 143.
OO
N2
OTBS
143
O
240 24
0
200
150
100
50PP
M
Figu
re A
.3.4
2 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 14
3.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.4
1 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
143.
241 24
1
8 6 4 2 0 ppm
Figure A.3.43 1H NMR (500 MHz, CDCl3) of Compound 145.
OO
N2
145
O
242 24
2
200
150
100
50PP
M
Figu
re A
.3.4
5 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 14
5.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
Figu
re A
.3.4
4 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
145.
243 24
3
8 6 4 2 0 ppm
Figure A.3.46 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 147.
147
OO
O
OMe
244 24
4
200
150
100
50PP
M
Figu
re A
.3.4
8 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 14
7.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.4
7 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
147.
245 24
5
8 6 4 2 0 ppm
Figure A.3.49 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 148.
OO
N2
148
O
OMe
246 24
6
200
150
100
500
PPM
Figu
re A
.3.5
1 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 14
8.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.5
0 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
148.
247 24
7
8 6 4 2 0 ppm
Figure A.3.52 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 149.
OO
O
149
H
OMe
248 24
8
200
150
100
500
PPM
Figu
re A
.3.5
4 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 14
9.
5055606570758085
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.5
3 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
149.
249 24
9
8 6 4 2 0 ppm
Figure A.3.55 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 151.
151
OO
OOMe
250 25
0
200
150
100
50PP
M
Figu
re A
.3.5
7 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 15
1.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.5
6 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
151.
251 25
1
8 6 4 2 0 ppm
Figure A.3.58 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 152.
OO
N2
152
OOMe
252 25
2
200
150
100
500
PPM
Figu
re A
.3.6
0 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 15
2.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.5
9 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
152.
253 25
3
8 6 4 2 0 ppm
Figure A.3.61 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 153.
OO
O
153
H
MeO
254 25
4
200
150
100
500
PPM
Figu
re A
.3.6
3 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 15
3.
30405060708090100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.6
2 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
153.
255 25
5
8 6 4 2 0 ppm
Figure A.3.64 1H NMR (400 MHz, CDCl3) of Compound 158.
OO
O
158
OTBSTBSO
256 25
6
200
150
100
500
PPM
Figu
re A
.3.6
6 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 15
8.
Figu
re A
.3.6
5 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
158.
60708090100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
257 25
7
8 6 4 2 0 ppm
Figure A.3.67 1H NMR (400 MHz, CDCl3) of Compound 154.
OHO
154
TBSO OTBS
258 25
8
200
150
100
500
PPM
Figu
re A
.3.6
9 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 15
4.
Figu
re A
.3.6
8 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
154.
708090100
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
259 25
9
8 6 4 2 0 ppm
Figure A.3.70 1H NMR (500 MHz, CDCl3) of Compound 159.
OO
O
159
OTBSTBSO
O
260 26
0
200
150
100
500
PPM
Figu
re A
.3.7
2 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 15
9.
Figu
re A
.3.7
1 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
159.
708090100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
261 26
1
8 6 4 2 0 ppm
Figure A.3.73 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 160.
OO
O
160
OTBSTBSO
O
N2
262 26
2
200
150
100
500
PPM
Figu
re A
.3.7
5 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 16
0.
5060708090100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.7
4 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
160.
263 26
3
8 6 4 2 0 ppm
Figure A.3.76 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 162.
OO
O
162
OTBSTBSO
TBSO
N2
264 26
4
200
150
100
500
PPM
Figu
re A
.3.7
8 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 16
2.
707580859095100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.7
7 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
162.
265 26
5
8 6 4 2 0 ppm
Figure A.3.79 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 164.
OO
O
164
OTBSTBSO
N2
266 26
6
200
150
100
500
PPM
Figu
re A
.3.8
1 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 16
4.
65707580859095100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.8
0 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
164.
267 26
7
8 6 4 2 0 ppm
Figure A.3.82 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 165.
OO
O
165
OTBSTBSO
268 26
8
200
150
100
500
PPM
Figu
re A
.3.8
4 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 16
5.
5060708090100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.8
3 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
165.
269 26
9
8 6 4 2 0 ppm
Figure A.3.85 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 166.
OO
166
OTBSTBSO
O
MeO
270 27
0
200
150
100
500
PPM
Figu
re A
.3.8
7 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 16
6.
Figu
re A
.3.8
6 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
166.
405060708090
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
271 27
1
8 6 4 2 0 ppm
Figure A.3.88 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 167.
OO
167
OTBSTBSO
O
MeON2
272 27
2
200
150
100
500
PPM
Figu
re A
.3.9
0 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 16
7.
Figu
re A
.3.8
9 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
167.
20406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
273 27
3
8 6 4 2 0 ppm
Figure A.3.91 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 168.
168
OO
O
HMeO OTBSOTBS
274 27
4
200
150
100
500
PPM
Figu
re A
.3.9
3 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 16
8.
Figu
re A
.3.9
2 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
168.
80859095100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
275 27
5
8 6 4 2 0 ppm
Figure A.3.94 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 169.
OO
O
169
OBnBnO
O
276 27
6
200
150
100
500
PPM
Figu
re A
.3.9
6 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 16
9.
Figu
re A
.3.9
5 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
169.
7075808590
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
277 27
7
8 6 4 2 0 ppm
Figure A.3.97 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 170.
OO
O
170
OBnBnO
O
N2
278 27
8
200
150
100
500
PPM
Figu
re A
.3.9
9 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 17
0.
Figu
re A
.3.9
8 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
170.
20406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
279 27
9
8 6 4 2 0 ppm
Figure A.3.100 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 172.
OO
O
172
OBnBnO
TBSO
N2
280 28
0
200
150
100
500
PPM
Figu
re A
.3.1
02 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 17
2.
30405060708090100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
Figu
re A
.3.1
01 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 17
2.
281 28
1
8 6 4 2 0 ppm
Figure A.3.103 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 174.
OO
O
174
OBnBnO
N2
282 28
2
200
150
100
500
PPM
Figu
re A
.3.1
05 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 17
4.
Figu
re A
.3.1
04 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 17
4.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
283 28
3
8 6 4 2 0 ppm
Figure A.3.106 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 176.
OO
176
OBnBnO
O
MeO
284 28
4
200
150
100
500
PPM
Figu
re A
.3.1
08 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 17
6.
Figu
re A
.3.1
07 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 17
6.
60708090
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
285 28
5
8 6 4 2 0 ppm
Figure A.3.109 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 177.
OO
177
OBnBnO
O
MeON2
286 28
6
200
150
100
500
PPM
Figu
re A
.3.1
11 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d 17
7.
Figu
re A
.3.1
10 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 17
7.
20406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
287 28
7
8 6 4 2 0 ppm
Figure A.3.112 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 178.
178
OO
O
HMeO OBnOBn
288 28
8
200
150
100
500
PPM
Figu
re A
.3.1
14 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 17
8.
Figu
re A
.3.1
13 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 17
8.
5060708090
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
289 28
9
8 6 4 2 0 ppm
Figure A.3.115 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 179.
OO
O
179
OMeMeO
290 29
0
200
150
100
500
PPM
Figu
re A
.3.1
17 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 17
9.
Figu
re A
.3.1
16 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 17
9.
20406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
291 29
1
8 6 4 2 0 ppm
Figure A.3.118 1H NMR (500 MHz, CDCl3) of Compound 156.
OHO
156
MeO OMe
292 29
2
200
150
100
500
PPM
Figu
re A
.3.1
20 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 15
6.
Figu
re A
.3.1
19 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 15
6.
20406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
293 29
3
8 6 4 2 0 ppm
Figure A.3.121 1H NMR (400 MHz, CDCl3) of Compound 180.
OO
O
180
OMeMeO
O
294 29
4
200
150
100
500
PPM
Figu
re A
.3.1
23 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 18
0.
Figu
re A
.3.1
22 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 18
0.
406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
295 29
5
8 6 4 2 0 ppm
Figure A.3.124 1H NMR (500 MHz, CDCl3) of Compound 181.
OO
O
181
OMeMeO
O
N2
296 29
6
200
150
100
500
PPM
Figu
re A
.3.1
26 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 18
1.
Figu
re A
.3.1
25 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 18
1.
708090100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
297 29
7
8 6 4 2 0 ppm
Figure A.3.127 1H NMR (400 MHz, CDCl3, Me4Si) of Compound 183.
OO
O
183
OMeMeO
TBSO
N2
298 29
8
200
150
100
500
PPM
Figu
re A
.3.1
29 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 18
3.
Figu
re A
.3.1
28 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 18
3.
20406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
299 29
9
8 6 4 2 0 ppm
Figure A.3.130 1H NMR (400 MHz, CDCl3) of Compound 185.
OO
O
185
OMeMeO
N2
300 30
0
200
150
100
500
PPM
Figu
re A
.3.1
32 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 18
5.
Figu
re A
.3.1
31 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 18
5.
5060708090100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
301 30
1
8 6 4 2 0 ppm
Figure A.3.133 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 186.
OO
O
186
OMeMeO
302 30
2
200
150
100
500
PPM
Figu
re A
.3.1
35 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 18
6.
Figu
re A
.3.1
34 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 18
6.
405060708090100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
303 30
3
8 6 4 2 0 ppm
Figure A.3.136 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 187.
OO
187
OMeMeO
O
MeO
304 30
4
200
150
100
500
PPM
Figu
re A
.3.1
38 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 18
7.
Figu
re A
.3.1
37 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 18
7.
60708090
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
305 30
5
8 6 4 2 0 ppm
Figure A.3.139 1H NMR (500 MHz, CDCl3, Me4Si) of Compound 188.
OO
188OMeMeO
O
MeON2
306 30
6
200
150
100
500
PPM
Figu
re A
.3.1
41 13
C N
MR
(100
MH
z, C
DC
l 3) o
f Com
poun
d 18
8.
Figu
re A
.3.1
40 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 18
8.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
307 30
7
8 6 4 2 0 ppm
Figure A.3.142 1H NMR (500 MHz, CDCl3) of Compound 190.
OO
O
190
OHHO
O
308 30
8
200
150
100
500
PPM
Figu
re A
.3.1
44 13
C N
MR
(125
MH
z, a
ceto
ne-d
6) o
f Com
poun
d 19
0.
Figu
re A
.3.1
43 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 19
0.
60708090100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
309 30
9
8 6 4 2 0 ppm
Figure A.3.145 1H NMR (400 MHz, CDCl3) of Compound 194.
OO
O
194
OHHO
O
N2
310 31
0
200
150
100
500
PPM
Figu
re A
.3.1
47 13
C N
MR
(100
MH
z, a
ceto
ne-d
6) o
f Com
poun
d 19
4.
Figu
re A
.3.1
46 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 19
4.
406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
311 31
1
8 6 4 2 0 ppm
Figure A.3.148 1H NMR (500 MHz, CDCl3) of Compound 196.
OO
196
OHHO
O
MeO
312 31
2
200
150
100
500
PPM
Figu
re A
.3.1
50 13
C N
MR
(100
MH
z, a
ceto
ne-d
6) o
f Com
poun
d 19
6.
Figu
re A
.3.1
49 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 19
6.
020406080100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
313 31
3
8 6 4 2 0 ppm
Figure A.3.151 1H NMR (500 MHz, acetone-d6) of Compound 199.
OO
O
199HO
N2
OH
MeO
314 31
4
200
150
100
500
PPM
Figu
re A
.3.1
53 13
C N
MR
(100
MH
z, a
ceto
ne-d
6) o
f Com
poun
d 19
9.
Figu
re A
.3.1
52 F
TIR
Spe
ctru
m (t
hin
film
/NaC
l) of
Com
poun
d 19
9.
60657075808590
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
315
Appendix 4
X-ray Structure Reports Relevant to Chapter 3.
A.4.1 X-ray Structure Report for Spirolactone 127.
OO
O
127
H
OMe
O1
O2
O3
O4
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 C11
C12
C13
C14
H1
Figure A.4.1 ORTEP plot of Spirolactone 127.
A.4.1.1 Crystal Data.
Empirical Formula C14H16O4 Formula Weight 248.28 Crystal Color, Habit colorless, plate Crystal Dimensions 0.09 × 0.28 × 0.45 mm Crystal System monoclinic Lattice Type Primitive Lattice Parameters a = 7.9014(3)Å b = 9.0387(3) Å c = 17.686(1) Å β = 99.494(2)o V = 1245.81(8) Å3 Space Group P21/n (#14) Z value 4 Dcalc 1.324 g/cm3 F000 528.00 µ(MoKα) 0.96 cm-1
316
A.4.1.2 Intensity Measurements.
Diffractometer Nonius KappaCCD Radiation MoKα (λ = 0.71069 Å) graphite monochromated Crystal to Detector Distance 33 mm Temperature -90.0oC 2θmax 55.0o No. of Reflections Measured Total: 3039 Corrections Lorentz-polarization
A.4.1.3 Structure Solution and Refinement.
Structure Solution Direct Methods (SIR92) Refinement Full-matrix least-squares Function Minimized Σ w (|Fo| - |Fc|)2 Least Squares Weights 1/σ2 = 4Fo2/σ2(Fo2) p-factor 0.0100 Anomalous Dispersion All non-hydrogen atoms No. Observations (I>5.00σ(I)) 1910 No. Variables 227 Reflection/Parameter Ratio 8.41 Residuals: R; Rw 0.039 ; 0.045 Goodness of Fit Indicator 2.89 Max Shift/Error in Final Cycle 0.00 Maximum peak in Final Diff. Map 0.29 e-/Å3 Minimum peak in Final Diff. Map -0.20 e-/Å
317
A.4.1.4 Atomic coordinates and Biso/Beq.
Table A.4.1 Atomic coordinates and Biso/Beq for Spirolactone 127.
atom x y z Beq O(1) 0.6153(2) 0.7506(1) 0.16361(6) 3.72(3) O(2) 0.4356(1) 0.5605(1) 0.14188(6) 3.58(3) O(3) 0.3197(1) 0.5786(1) 0.29058(6) 2.97(2) O(4) 0.6156(1) 1.0182(1) 0.40874(6) 3.20(3) C(1) 0.6080(2) 0.5616(2) 0.26287(8) 2.27(3) C(2) 0.5596(2) 0.6387(2) 0.18664(8) 2.69(3) C(3) 0.3859(3) 0.4353(2) 0.18477(10) 3.45(4) C(4) 0.4410(2) 0.4759(2) 0.26836(8) 2.39(3) C(5) 0.4515(2) 0.3475(2) 0.32442(9) 3.02(4) C(6) 0.3873(3) 0.4126(2) 0.3925(1) 5.18(6) C(7) 0.2630(3) 0.5267(3) 0.3585(1) 5.32(6) C(8) 0.6824(2) 0.6562(2) 0.33032(8) 2.13(3) C(9) 0.8116(2) 0.5988(2) 0.38601(8) 2.52(3) C(10) 0.8752(2) 0.6810(2) 0.44971(9) 2.83(3) C(11) 0.8142(2) 0.8225(2) 0.45992(9) 2.58(3) C(12) 0.6866(2) 0.8802(2) 0.40472(8) 2.35(3) C(13) 0.6213(2) 0.7977(2) 0.33996(8) 2.31(3) C(14) 0.6797(3) 1.1051(2) 0.4748(1) 3.57(4) H(1) 0.694(2) 0.486(2) 0.2537(8) 2.7(3) H(2) 0.448(2) 0.345(2) 0.1709(9) 3.9(4) H(3) 0.262(2) 0.427(2) 0.1716(9) 4.6(4) H(4) 0.563(3) 0.305(2) 0.3357(10) 4.6(4) H(5) 0.374(3) 0.274(2) 0.302(1) 5.7(5) H(6) 0.341(3) 0.341(2) 0.423(1) 5.8(5) H(7) 0.504(3) 0.463(3) 0.438(1) 9.8(7) H(8) 0.152(4) 0.477(3) 0.344(2) 11.3(9) H(9) 0.243(3) 0.616(3) 0.390(1) 7.5(6) H(10) 0.851(2) 0.502(2) 0.3792(8) 2.9(3) H(11) 0.968(2) 0.642(2) 0.4881(8) 3.4(3) H(12) 0.854(2) 0.878(2) 0.5024(8) 2.7(3) H(13) 0.532(2) 0.844(2) 0.3004(8) 2.7(3) H(14) 0.807(3) 1.125(2) 0.4768(10) 4.7(4) H(15) 0.662(2) 1.050(2) 0.523(1) 4.0(4) H(16) 0.620(2) 1.201(2) 0.471(1) 5.3(4)
Beq = 8/3 π2(U11(aa*)2 + U22(bb*)2 + U33(cc*)2 + 2U12(aa*bb*)cos γ + 2U13(aa*cc*)cos β + 2U23(bb*cc*)cos α)
318
A.4.2 X-ray Structure Report for Spirolactone 149.
OO
O
149
H
OMe
O1
O2
O3
O4
C1
C2
C3
C4 C5 C6
C7
C8
C9
C10 C11
C12
C13
C14
H3
Figure A.4.2 ORTEP plot of Spirolactone 149.
A.4.2.1 Crystal Data.
Empirical Formula C14H14O4 Formula Weight 246.26 Crystal Color, Habit colorless, prism Crystal Dimensions 0.27 X 0.30 X 0.32 mm Crystal System monoclinic Lattice Type Primitive Lattice Parameters a = 7.6868(4)Å b = 8.9354(4) Å c = 18.155(1) Å β = 100.994(3)o V = 1224.08(10) Å3 Space Group P21/n (#14) Z value 4 Dcalc 1.336 g/cm3 F000 520.00 µ(MoKα) 0.98 cm-1
319
A.4.2.2 Intensity Measurements.
Diffractometer Nonius KappaCCD Radiation MoKα (λ = 0.71069 Å) graphite monochromated Take-off Angle 2.8o Crystal to Detector Distance 35 mm Temperature -90.0oC Scan Rate 14s/frame Scan Width 1.4o/frame 2θmax 55.0o No. of Reflections Measured Total: 2977 Corrections Lorentz-polarization
A.4.2.3 Structure Solution and Refinement.
Structure Solution Direct Methods (SIR92) Refinement Full-matrix least-squares Function Minimized Σ w (|Fo| - |Fc|)2 Least Squares Weights 1/σ2(Fo) p-factor 0.0100 Anomalous Dispersion All non-hydrogen atoms No. Observations (I>5.00σ(I)) 1717 No. Variables 219 Reflection/Parameter Ratio 7.84 Residuals: R; Rw 0.037 ; 0.043 Goodness of Fit Indicator 2.75 Max Shift/Error in Final Cycle 0.00 Maximum peak in Final Diff. Map 0.23 e-/Å3 Minimum peak in Final Diff. Map -0.14 e-/Å3
320
A.4.2.4 Atomic coordinates and Biso/Beq.
Table A.4.2 Atomic coordinates and Biso/Beq for Spirolactone 149.
atom x y z Beq O(1) 0.0552(1) 0.5682(1) 0.85703(6) 3.70(3) O(2) -0.1324(2) 0.7573(1) 0.82836(7) 4.06(3) O(3) 0.1987(1) 0.5835(1) 0.71546(7) 3.63(3) O(4) -0.1125(1) 1.0327(1) 0.59483(6) 3.68(3) C(1) 0.0700(2) 0.4817(2) 0.73499(9) 2.98(4) C(2) 0.1192(3) 0.4435(2) 0.8183(1) 3.87(5) C(3) -0.0684(2) 0.6451(2) 0.80877(9) 2.99(4) C(4) -0.1055(2) 0.5667(2) 0.73399(9) 2.63(4) C(5) 0.0669(2) 0.3541(2) 0.6823(1) 3.48(4) C(6) 0.1708(3) 0.3836(2) 0.6346(1) 5.10(6) C(7) 0.2576(3) 0.5300(2) 0.6503(1) 5.04(6) C(8) -0.1726(2) 0.6605(2) 0.66587(9) 2.57(3) C(9) -0.2909(2) 0.5977(2) 0.60584(10) 3.13(4) C(10) -0.3506(2) 0.6806(2) 0.5423(1) 3.47(4) C(11) -0.2954(2) 0.8270(2) 0.5361(1) 3.14(4) C(12) -0.1779(2) 0.8893(2) 0.59489(9) 2.80(4) C(13) -0.1168(2) 0.8065(2) 0.65968(10) 2.75(4) C(14) -0.1802(3) 1.1231(2) 0.5310(1) 4.02(5) H(1) 0.246(3) 0.443(2) 0.835(1) 4.9(4) H(2) 0.057(2) 0.352(2) 0.829(1) 4.1(4) H(3) -0.193(2) 0.491(2) 0.7393(8) 2.5(3) H(4) -0.009(2) 0.271(2) 0.6855(10) 4.0(4) H(5) 0.195(3) 0.321(2) 0.597(1) 6.7(5) H(6) 0.229(2) 0.601(2) 0.603(1) 4.1(4) H(7) 0.387(3) 0.532(2) 0.660(1) 6.0(5) H(8) -0.329(2) 0.496(2) 0.6079(9) 3.5(3) H(9) -0.436(2) 0.638(2) 0.5008(10) 3.9(4) H(10) -0.335(2) 0.884(2) 0.492(1) 4.0(4) H(11) -0.037(2) 0.852(1) 0.6988(9) 2.6(3) H(12) -0.311(3) 1.132(2) 0.525(1) 5.5(5) H(13) -0.126(3) 1.221(2) 0.543(1) 6.3(5) H(14) -0.144(2) 1.080(2) 0.486(1) 5.1(5)
Beq = 8/3 π2(U11(aa*)2 + U22(bb*)2 + U33(cc*)2 + 2U12(aa*bb*)cos γ + 2U13(aa*cc*)cos β + 2U23(bb*cc*)cos α)
321
A.4.3 X-ray Structure Report for Spirolactone 153.
OO
O
153
H
OMe
O1
O2 O3
O4
C1
C2
C3
C4 C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
H7
Figure A.4.3 ORTEP plot of Spirolactone 153.
A.4.3.1 Crystal Data.
Empirical Formula C14H14O4 Formula Weight 246.26 Crystal Color, Habit colorless, plate Crystal Dimensions 0.10 X 0.15 X 0.34 mm Crystal System monoclinic Lattice Type Primitive Lattice Parameters a = 14.774(1)Å b = 5.581(1) Å c = 14.820(1) Å β = 90.475(6)o V = 1222.0(2) Å3 Space Group P21/c (#14) Z value 4 Dcalc 1.338 g/cm3 F000 520.00 µ(MoKα) 0.98 cm-1
322
A.4.3.2 Intensity Measurements.
Diffractometer Nonius KappaCCD Radiation MoKα (λ = 0.71069 Å) graphite monochromated Take-off Angle 2.8o Crystal to Detector Distance 33 mm Temperature -90.0oC Scan Rate 60s/frame Scan Width 2.0o/frame 2θmax 54.9o No. of Reflections Measured Total: 2682 Corrections Lorentz-polarization
A.4.3.3 Structure Solution and Refinement.
Structure Solution Direct Methods (SIR92) Refinement Full-matrix least-squares Function Minimized Σ w (|Fo| - |Fc|)2 Least Squares Weights 1/σ2(Fo) p-factor 0.0100 Anomalous Dispersion All non-hydrogen atoms No. Observations (I>5.00σ(I)) 1273 No. Variables 163 Reflection/Parameter Ratio 7.81 Residuals: R; Rw 0.037 ; 0.043 Goodness of Fit Indicator 1.94 Max Shift/Error in Final Cycle 0.00 Maximum peak in Final Diff. Map 0.16 e-/Å3 Minimum peak in Final Diff. Map -0.16 e-/Å3
323
A.4.3.4 Atomic coordinates and Biso/Beq.
Table A.4.3 Atomic coordinates and Biso/Beq for Spirolactone 149.
atom x y z Beq O(1) 0.33265(10) -0.1797(3) 0.2417(1) 3.40(4) O(2) 0.45348(9) -0.0442(3) 0.3169(1) 2.88(4) O(3) 0.35590(8) 0.0777(3) 0.48365(9) 2.55(4) O(4) -0.05317(10) 0.2099(3) 0.3898(1) 4.24(5) C(1) 0.3659(1) -0.0288(4) 0.2893(2) 2.57(6) C(2) 0.4745(1) 0.1530(4) 0.3773(1) 2.76(5) C(3) 0.3836(1) 0.2365(4) 0.4129(1) 2.18(5) C(4) 0.3794(1) 0.4791(4) 0.4540(2) 2.90(6) C(5) 0.3426(2) 0.4679(4) 0.5340(2) 3.59(6) C(6) 0.3206(1) 0.2172(5) 0.5573(2) 3.52(6) C(7) 0.3241(1) 0.1961(4) 0.3281(1) 2.33(5) C(8) 0.2234(1) 0.1968(4) 0.3402(1) 2.28(5) C(9) 0.1721(1) 0.3868(4) 0.3090(2) 2.82(6) C(10) 0.0793(1) 0.3991(4) 0.3242(2) 3.13(6) C(11) 0.0375(1) 0.2180(4) 0.3708(2) 2.86(6) C(12) 0.0876(1) 0.0240(4) 0.4013(2) 3.05(6) C(13) 0.1792(1) 0.0121(4) 0.3858(1) 2.63(6) C(14) -0.1061(2) 0.4150(6) 0.3663(2) 5.57(8) H(1) 0.5123 0.1004 0.4255 3.3150 H(2) 0.5037 0.2788 0.3456 3.3150 H(3) 0.4004 0.6219 0.4262 3.4774 H(4) 0.3316 0.6022 0.5718 4.3088 H(5) 0.2570 0.1963 0.5620 4.2229 H(6) 0.3489 0.1727 0.6127 4.2229 H(7) 0.3376 0.3225 0.2874 2.7954 H(8) 0.2007 0.5120 0.2765 3.3877 H(9) 0.0451 0.5317 0.3025 3.7574 H(10) 0.0585 -0.1017 0.4331 3.6642 H(11) 0.2127 -0.1229 0.4064 3.1597 H(12) -0.0827 0.5518 0.3967 6.6796 H(13) -0.1671 0.3895 0.3837 6.6796 H(14) -0.1036 0.4401 0.3030 6.6796
Beq = 8/3 π2(U11(aa*)2 + U22(bb*)2 + U33(cc*)2 + 2U12(aa*bb*)cos γ + 2U13(aa*cc*)cos β + 2U23(bb*cc*)cos α)
324
A.4.4 X-ray Structure Report for Spirolactone 168.
168
O
OO
OTBS
OTBSH
MeO
Si1
Si2
O1
O2
O3
O4
O5
O6
C1
C2 C3
C4
C5 C6
C7
C8 C9
C10
C11
C12
C13
C14
C15
C16 C17
C18
C19
C20
C21
C22
C23
C24
C25
C26
H1 H11
H12
Figure A.4.4 ORTEP plot of Spirolactone 168.
A.4.4.1 Crystal Data.
Empirical Formula C26H44O6Si2 Formula Weight 508.80 Crystal Color, Habit colorless, plate Crystal Dimensions 0.06 X 0.11 X 0.13 mm Crystal System monoclinic Lattice Type Primitive Lattice Parameters a = 18.637(1)Å b = 7.8057(3) Å c = 19.887(1) Å β = 93.434(2)o V = 2887.8(2) Å3 Space Group P21/c (#14) Z value 4 Dcalc 1.170 g/cm3 F000 1104.00 µ(MoKα) 1.58 cm-1
325
A.4.4.2 Intensity Measurements.
Diffractometer Nonius KappaCCD Radiation MoKα (λ = 0.71069 Å) graphite monochromated Take-off Angle 2.8o Crystal to Detector Distance 35 mm Temperature -90.0oC Scan Rate 114s/frame Scan Width 1.9o/frame 2θmax 52.0o No. of Reflections Measured Total: 6129 Corrections Lorentz-polarization
A.4.4.3 Structure Solution and Refinement.
Structure Solution Direct Methods (SIR92) Refinement Full-matrix least-squares Function Minimized Σ w (|Fo| - |Fc|)2 Least Squares Weights 1/σ 2(Fo) p-factor 0.0100 Anomalous Dispersion All non-hydrogen atoms No. Observations (I>3.00σ(I)) 3386 No. Variables 483 Reflection/Parameter Ratio 7.01 Residuals: R; Rw 0.038 ; 0.035 Goodness of Fit Indicator 1.79 Max Shift/Error in Final Cycle 0.00 Maximum peak in Final Diff. Map 0.20 e-/Å3 Minimum peak in Final Diff. Map -0.26 e-/Å3
326
A.4.4.4 Atomic coordinates and Biso/Beq.
Table A.4.4 Atomic coordinates and Biso/Beq for Spirolactone 168.
atom x y z Beq Si(1) 0.26556(3) 0.46474(8) 0.57811(3) 2.34(1) Si(2) 0.38262(3) 0.24483(8) 0.36641(3) 2.65(2) O(1) -0.04152(8) 0.4228(2) 0.41459(8) 3.67(4) O(2) 0.00962(7) 0.2285(2) 0.48415(8) 3.09(4) O(3) 0.06618(9) 0.4261(2) 0.17833(8) 4.47(5) O(4) 0.12929(7) 0.1158(2) 0.39887(7) 2.73(4) O(5) 0.22434(7) 0.4247(2) 0.50346(7) 2.24(3) O(6) 0.31950(7) 0.1921(2) 0.41802(7) 2.64(4) C(1) 0.1301(1) 0.2401(3) 0.4523(1) 2.14(5) C(2) 0.0900(1) 0.4033(3) 0.4290(1) 2.09(5) C(3) 0.0122(1) 0.3578(3) 0.4388(1) 2.68(6) C(4) 0.0821(1) 0.1762(4) 0.5063(1) 2.89(6) C(5) 0.1063(1) 0.4773(3) 0.3612(1) 2.08(5) C(6) 0.1546(1) 0.6111(3) 0.3586(1) 2.54(6) C(7) 0.1737(1) 0.6753(3) 0.2972(1) 3.10(6) C(8) 0.1434(1) 0.6095(3) 0.2385(1) 3.18(6) C(9) 0.0939(1) 0.4775(3) 0.2402(1) 2.89(6) C(10) 0.0757(1) 0.4097(3) 0.3013(1) 2.49(6) C(11) 0.0089(2) 0.3073(6) 0.1759(2) 6.3(1) C(12) 0.2099(1) 0.2633(3) 0.4740(1) 2.05(5) C(13) 0.2456(1) 0.2369(3) 0.4087(1) 2.16(5) C(14) 0.2004(1) 0.0949(4) 0.3763(2) 3.09(7) C(15) 0.2067(2) 0.4056(4) 0.6465(1) 3.40(7) C(16) 0.3510(2) 0.3420(4) 0.5881(2) 3.73(8) C(17) 0.2808(1) 0.7019(3) 0.5752(1) 2.43(5) C(18) 0.3148(2) 0.7643(4) 0.6429(1) 3.78(8) C(19) 0.3314(2) 0.7490(4) 0.5200(2) 3.75(8) C(20) 0.2091(1) 0.7948(4) 0.5606(1) 3.05(7) C(21) 0.3411(2) 0.3523(5) 0.2905(2) 4.44(8) C(22) 0.4467(2) 0.3940(5) 0.4108(2) 4.86(9) C(23) 0.4289(1) 0.0407(3) 0.3442(1) 2.71(6) C(24) 0.4720(2) -0.0321(5) 0.4055(2) 4.55(9) C(25) 0.4804(2) 0.0735(5) 0.2879(2) 4.43(9) C(26) 0.3730(2) -0.0934(4) 0.3195(2) 4.32(8) H(1) 0.1005(9) 0.489(2) 0.4629(9) 1.3(4) H(2) 0.095(1) 0.228(3) 0.550(1) 2.4(5) H(3) 0.083(1) 0.053(3) 0.5112(10) 2.6(5)
327
Table A.4.4 Atomic coordinates and Biso/Beq for Spirolactone 168 (Continued). H(4) 0.1762(10) 0.652(3) 0.3993(10) 2.2(5) H(5) 0.206(1) 0.766(3) 0.2968(10) 3.0(5) H(6) 0.154(1) 0.655(3) 0.197(1) 3.7(5) H(7) 0.043(1) 0.322(3) 0.3032(10) 2.3(5) H(8) 0.032(1) 0.193(4) 0.197(1) 6.4(9) H(9) -0.029(1) 0.348(3) 0.202(1) 5.3(7) H(10) -0.007(1) 0.296(3) 0.128(1) 5.6(7) H(11) 0.2239(9) 0.172(2) 0.5039(9) 1.1(4) H(12) 0.2408(9) 0.339(2) 0.3835(8) 1.0(4) H(13) 0.218(1) -0.017(3) 0.392(1) 3.5(6) H(14) 0.197(1) 0.104(3) 0.327(1) 3.7(6) H(15) 0.201(1) 0.290(3) 0.647(1) 4.9(7) H(16) 0.229(1) 0.438(3) 0.689(1) 4.4(6) H(17) 0.159(1) 0.460(3) 0.641(1) 4.8(6) H(18) 0.376(1) 0.364(4) 0.630(1) 6.5(8) H(19) 0.343(2) 0.226(4) 0.590(2) 7.8(10) H(20) 0.382(2) 0.364(4) 0.556(1) 6.4(8) H(21) 0.361(1) 0.709(3) 0.653(1) 3.7(6) H(22) 0.323(1) 0.885(4) 0.643(1) 5.3(7) H(23) 0.280(1) 0.740(3) 0.682(1) 5.4(6) H(24) 0.381(1) 0.695(3) 0.528(1) 5.4(7) H(25) 0.315(1) 0.707(3) 0.476(1) 3.7(6) H(26) 0.336(1) 0.880(4) 0.514(1) 5.6(7) H(27) 0.190(1) 0.775(3) 0.513(1) 4.1(6) H(28) 0.215(1) 0.919(3) 0.568(1) 4.3(6) H(29) 0.171(1) 0.757(3) 0.589(1) 3.6(5) H(30) 0.305(2) 0.286(4) 0.269(1) 6.9(9) H(31) 0.316(2) 0.453(4) 0.303(1) 7.1(9) H(32) 0.377(1) 0.379(3) 0.260(1) 5.4(7) H(33) 0.463(1) 0.348(4) 0.453(1) 6.0(9) H(34) 0.485(2) 0.421(3) 0.382(1) 6.7(8) H(35) 0.424(2) 0.502(4) 0.419(1) 7.6(9) H(36) 0.491(1) -0.136(4) 0.393(1) 6.1(8) H(37) 0.443(1) -0.053(3) 0.444(1) 5.4(7) H(38) 0.511(1) 0.047(3) 0.420(1) 4.2(6) H(39) 0.517(1) 0.161(3) 0.301(1) 4.2(6) H(40) 0.506(1) -0.031(4) 0.279(1) 5.7(7) H(41) 0.454(2) 0.117(4) 0.247(1) 6.8(9) H(42) 0.396(1) -0.203(4) 0.307(1) 5.5(7) H(43) 0.343(1) -0.126(3) 0.358(1) 5.6(7) H(44) 0.345(1) -0.045(4) 0.280(1) 6.3(8)
Beq = 8/3 π2(U11(aa*)2 + U22(bb*)2 + U33(cc*)2 + 2U12(aa*bb*)cos γ + 2U13(aa*cc*)cos β + 2U23(bb*cc*)cos α)
328
Chapter 4
Syributins: Background and Introduction.
4.1 Syributins and Secosyrins: Isolation and Characterization.
In 1995 Sims et al.1 reported the isolation and structure elucidation of syributin 1
(201), syributin 2 (202), secosyrin 1 (204), and secosyrin 2 (205), the major coproducts of
syringolides 1 and 2. Unlike the syringolides, the syributins and secosyrins are not active
elicitors of a hypersensitive response on soybean cultivars carrying the resistance gene
Rpg4. Through a combination of NMR experiments and chemical methods Sims et al.
determined the structures illustrated in Figure 4.1.
O
O
HO
HOO
O
O
O
HO
HOO
O
O
O
HO
HOO
O
O
O
HO
O
O
O
O
O
HO
O
O
O
O
O
HO
O
O
O
(+)-Syributin 1 (201) (+)-Syributin 2 (202) (+)-Syributin 3 (203)
(+)-Secosyrin 1 (204) (+)-Secosyrin 2 (205) Secosyrin 3 (206)
Figure 4.1 Syributins and Secosyrins.
329
As mentioned in Chapter 1, in 1994 Yucel et al.2 reported that two different
classes of avrD alleles occur in Pseudomonas syringae pathovars: class I and class II
alleles. Class I alleles include the avrD allele 1 from P. s. pv. lachrimans and the avrD
allele from P. s. pv. tomato. Class II alleles include the avrD allele 2 from P. s. pv.
lachrimans and the avrD allele from P. s. pv. phaseolicola. The same year Yucel and co-
workers3 reported that the two classes of alleles direct the production of different
syringolides, syributins and secosyrins. Class I avrD alleles are responsible for the
biosynthesis of syringolides 1 and 2 and their accompanying syributins 1 (201) and 2
(202) and secosyrins 1 (204) and 2 (205) while class II avrD alleles direct the production
of syringolides 1 and 3 and their accompanying syributins 1 (201) and 3 (203) and
secosyrins 1 (204) and 3 (206).
4.2 Proposed Biosynthesis of Syributins and Secosyrins.
Sims et al.1 proposed in the original syributins and secosyrins isolation and
characterization paper a possible biosynthesis for these compounds from syringolides
(Scheme 4.1). Reverse Claisen cleavage of syringolides (1-3) would furnish the
corresponding secosyrins (204-206) and a reverse Michael reaction from secosyrins,
followed by a 1,3-acyl migration of the intermediates 207-209, would result in the
formation of the corresponding syributins (201-203). This is supported by experiments
wherein base treatment of secosyrin 1 was shown to furnish syributin 14a and by the base
promoted sequential transformation of the syringolides into the corresponding secosyrins
and syributins.5
330
OO
O
HO
O
n
Syringolide 1 (1), n = 3Syringolide 2 (2), n = 5Syringolide 3 (3), n = 1
OH
O
O
O
HOOH
O
O
HO
O
O
O
Scheme 4.1 Proposed Biosynthesis of Secosyrins and Syributins.
207, n = 3208, n = 5209, n = 1
Secosyrin 1 (204), n = 3Secosyrin 2 (205), n = 5Secosyrin 3 (206), n = 1
n
n
HH
O
O
HO
HOO
O
Syributin 1 (201), n = 3Syributin 2 (202), n = 5Syributin 3 (203), n = 1
n
O
4.3 Syntheses of Secosyrins and Syributins.
Since 1996 there have been reported four different total syntheses of syributins 1
and 24a,6-8 and a formal one9 and two different syntheses of secosyrins 1 and 24,7 and a
formal one.9 However, just as syringolide 3, syributin 3 and secosyrin 3 have yet to be
synthesized. All the syributin and secosyrin syntheses reported to date are outlined
below.
331
O
O
HO
OTBSOH
O
O
44OTBS
O
O
42
B
OTBS43
+
TfO
O
O
O
O
HO
OO
O
O
O
OO
AD-mixβMeSO2NH2
1:1 t-BuOH:H2O, 0 °C(85%)
45
2,2-Dimethoxypropane
PPTS, DMF(80%)
46
210a
Pyridine, CH2Cl2, 0 °C (94%)
211a
(Ph3P)2PdCl2K3PO4, THF
70 °C (48%)
Scheme 4.2 Honda et al.: Total Synthesis of (+)-Syributin 1.
Cl3
O
O
3 1 N HCl THF
(100%)
O
O
HO
HOO
O201
3
4.3.1 Honda et al.: Total Synthesis of (+)-Syributin 1.
In 1996 Honda et al.6 published the first total synthesis of syributin 1 along with
the fifth total synthesis of syringolides (section 1.6.5). Sharpless asymmetric
dihydroxylation of either 44 (Scheme 4.2) or 213 (Scheme 4.3) was the source of
asymmetry and 46 was a common intermediate used in the syringolide synthesis.
Deprotection of 211a to furnish 201 showed that 1,3-acyl migration could be the final
step of syributin biosynthesis as proposed by Sims et al. (Scheme 4.1).
332
Scheme 4.3 Honda et al.: Total Synthesis of (+)-Syributin 1.
O
O
44OTBS
O
O
212OH
O
O
213
O
O3
210a
Et3N, CH2Cl2, 0 °C (96%)
Cl3
O
AD-mixβMeSO2NH2
1:1 t-BuOH:H2O, 0 °C(72%)
2:1:1AcOH:THF:H2O
(99%)
O
O
HO
HOO
O
201
3
4.3.2 Wong et al.: Total Syntheses of (+)-Syributins 1 and 2 and (+)-Secosyrins 1 and
2.
In 1997 Wong et al.7 published the second total syntheses of syributins and
secosyrins (the first total synthesis of secosyrins will be described in the following
section). They used (+)-2,3-O-isopropylidene-D-glyceraldehyde (63) as the source of
asymmetry (Scheme 4.4). Compound 214 was a common intermediate for the syntheses
of syributins and secosyrins (Schemes 4.4 and 4.5) and compound 47 was used in the
seventh total synthesis of syringolides10 (section 1.6.7).
333
O
SiMe3
TBSO
OO
O
O
TBSO
OO
TBSCl, Et3N, DMAP
DMF (96%)
47
Scheme 4.4 Wong et al.: Total Synthesis (+)-Syributins 1 and 2
OTBSO
OO
67
OHO
OO
64(70% from 62a)(62% from 62b)
OR
LiBEt3H, THF
-78 °C (100%)
1. n-BuLi, THF, -78 °C
2.
62a, R = Sn(n-Bu)362b, R = Br
HO
OO
63
OO
OO
65
PDC, CH2Cl2
(95%)
OHO
OO
66
1. n-BuLi, THF,-78 °C
2. TMSCl(82%, two steps)
68
32% AcOOH, NaOAc
CH2Cl2(70%)
O
O
TBSO
214
OHOH
O
O
TBSO
OOH
O
Et3N, CH2Cl2, 0 °C (70-73%)
Cln
O
n
210a, n = 3210b, n = 5
215a, n = 3215b, n = 5
80% AcOH
(95%)
(n-Bu)4NF,THF
0°C (87-90%)
O
O
HO
OOH
On
201, n = 3202, n = 5
334
Scheme 4.5 Wong et al.: Total Synthesis (+)-Secosyrins 1 and 2.
O
O
TBSO
214OH
OH
Et3N, DMAP, CH2Cl20 °C (98-93%)
Cln
O
210a, n = 3210b, n = 5
204, n = 3205, n = 5
O
O
HO
O
O
O
n
O
O
HO
O
TBSOO
O
HO
O
TBSO
216(12%)
217(60%)
+Et3N, CH2Cl2, 0 °C
O
O
HO
O
TBSO
217
O
O
MOMO
O
TBSO
218
O
O
MOMO
O
HO
219
MOMCl, i-Pr2NEt
THF, 0 °C (95%)
TBAF, THF
-10 °C (60%)
O
O
MOMO
O
O
O
n
220a, n = 3220b, n = 5
PhSH, BF3·Et2O
THF (95-97%)
4.3.3 Mukai and co-workers: Total Syntheses (+)-Syributins 1 and 2 and (+)-
Secosyrins 1 and 2.
In 1997 Mukai and co-workers published the third total synthesis of syributins4a
and the first total synthesis of secosyrins.4 For the syributins Mukai et al. employed the
monosylilated alcohol 11 as the source of asymmetry (Scheme 4.6) while for syributins
335
monoprotected alcohol 227 was used (Scheme 4.7). Both starting materials were
prepared from diisopropyl tartrate. Mukai et al.4a also proved that secosyrin 1 (204) can
be converted into syributin 1 (201) under basic conditions (Scheme 4.8).
Scheme 4.6 Mukai et al.: Total Synthesis of (+)-Syributins 1 and 2.
10% HCl
(72%)
OTBSOHO
O
OTBS
O
O
O
O
11
OTBS
O
O
221
OEt
O
OTBS
O
O
222
OEt
O
NO2
n
OTBS
O
O
O
O
223
224
OH
O
O
O
O
225
O
O
O
O
O
On
O
O
O
O
HO
HO
1. Swern oxidation
2. (Et2O)POCH2CO2Et, NaH(85%, two steps)
CH3NO2, DBU
(80%)
1. KOH2. KMnO4, MgSO4, H2O
3. NaBH4(72%, three steps)
1. LHMDS, TMSCl
2. Pd(OAc)2, benzoquinone(74%, two steps)
TBAF, HF
Et3N, DMAP, CH2Cl2(81-85%, two steps)
Cln
O
210a, n = 3210b, n = 5
226a, n = 3226b, n = 5
201, n = 3202, n = 5
336
Scheme 4.7 Mukai and co-workers: Total Synthesis of (+)-Secosyrins 1 and 2.
227
1. Swern oxidation2. Phenylacetylene, n-BuLi, THF
3. Swern oxidation(72%, three steps)
H2, Lindlar cat.
(78%)
1. O3, pyridine, CH2Cl22. NaBH4, MeOH
3. DBU, CH2Cl2(75%, three steps)
LHMDS, MeCOS(t-Bu)
THF, -78 °C (94%)
THF, DMAP (70-78%)
]2On[
O
234a, n = 3234b, n = 5
BnO
BnO
228
BnO
BnOOTBS OTBS
OOH
Ph
229
BnO
BnOOTBS
S(t-Bu)
OHO
Ph
1. TBAF, HF (95%)
2. Co2(CO)8, Et2O (98%)
230
BnO
BnOOTBS
S(t-Bu)
OHO
(CO)3Co
(CO)3CoPh 1. BF3·Et2O, CH2Cl2
2. CAN, MeOH(74%, two steps) O
BnO
BnO
O
S(t-Bu)Ph
231
OBnO
BnO
O
S(t-Bu)
232
Ph
O
O
BnO
O
BnO
211, n = 3212, n = 5
O
O
HO
O
O
O
n
175
O
O
HO
O
HO
233
H2, Pd/C
(90%)
337
Scheme 4.8 Mukai et al.: Synthesis of (+)-Secosyrin 1 from (+)-Syributin 1.
204
O
O
HO
O
O
O
O
O
O
O
HO
HO
LHMDS, THF
-78 °C (100%)
201
Scheme 4.9 Yoda et al.: Total Synthesis of (+)-Syributin 1.
240
3
235 236
237
O
O
O
O
3
O
O
HO
HO
1. Me2C(OMe)2, acetone,p-TSOH (94%)
2. CF3SO2Cl, Et3N, DMAP,CH2Cl2 (78%)
PCC, MS4A,
CH2Cl2 (92%)
1. NaBH4, EtOH(99%)
2. TBSCl, Et3N,DMAP (93%)
Pd (black),4.4% HCO2H-MeOH
40 °C (80%)
DCC, DMAP, CH2Cl2(98%,)
Cl3
O
210a
226a 201
9:1 TFA:H2O
(70%)
OBnO
BnOOH
OBnBnO
BnOOTBS
OHOBn
BnO
BnOOTBS
OOBn
BnO
BnO
OBnOEt
O
HO
HO
HO
HO O
O
238
1. CH2=C(OLi)OEt,-78 °C (86%)
2. p-TsOH, MeOH(90%)
BnO
BnO
OBnOEt
O
HO
239
3O
O
O
O3
OH
O
O
O
O
338
4.3.4 Yoda et al.: Total Synthesis of (+)-Syributin 1.
Yoda et al.8 reported in 1997 the fourth syributin total synthesis. In this approach
2,3,5-tri-O-benzyl-β-D-arabinofuranose (235) was used as the source of asymmetry
(Scheme 4.9).
Scheme 4.10 Carda et al.: Formal Synthesis of (+)-Secosyrins and (+)-Syributins.
O
O
BnO
O
BnO
175
O3, CH2Cl2,
NaOH, MeOH
OH
HO
HO
OOH
6
TBDPSCl, imidazole,
DMAP, DMF (75%)
1. CH2=CH-CH2Br,In, THF, H2O
2. BnBr, NaH, THF(50%, two steps)
OTBDPS
HO
HO
OOTBDPS
241
OTBDPS
BnO
BnO
OTBDPS
242
HO
OTBDPS
BnO
BnO
OTBDPS
243
HO
O
OH
OTBDPS
BnO
BnO244
HO O
O
TBAF, THF
(50%, two steps)
p-TsCl, Et3N,
DMAP, CH2Cl2 (72%)
4.3.5 Carda et al.: Formal Synthesis of (+)-Secosyrins and (+)-Syributins.
In 1998 Carda et al.9 reported a formal synthesis of secosyrins and syributins
using D-xylulose (6) as the source of asymmetry (Scheme 4.10). Carda et al.
accomplished the synthesis of the secosyrins precursor 175, previously reported by
Mukai and co-workers.4 As mentioned in section 4.3.3, Mukai et al.4a proved that
339
secosyrin 1 can be converted into syributin 1 under basic conditions. Therefore, any total
or formal synthesis of secosyrin 1 could be considered as a formal synthesis of syributin
1.
4.4 References.
(1) Midland, S. L.; Keen, N. T.; Sims, J. J. J. Org. Chem. 1995, 60, 1118-1119.
(2) Yucel, I.; Boyd, C.; Debnam, Q.; Keen, N. T. Mol. Plant-Microbe Interact.
1994, 7, 131-139.
(3) (a) Yucel, I.; Midland, S. L.; Sims, J. J.; Keen, N. T. Mol. Plant-Microbe
Interact. 1994, 7, 148-150. (b) Keen, N.; Midland, S. L.; Boyd, C.; Yucel, I.; Tsurushima,
T.; Lorang, J.; Sims, J. J. In Advances in Molecular Genetics of Plant-Microbe
Interactions; Daniels, M. J.; Downie, J. A.; Osburn, A. E., Eds.; Kluwer Academic:
Boston, 1994; Vol. 3, pp 41-48.
(4) (a) Mukai, C.; Moharram, S. M.; Azukizawa, S.; Hanaoka, M. J. Org Chem.
1997, 62, 8095-8103. (b) Mukai, C.; Moharram, S. M.; Hanaoka, M. Tetrahedron Lett.
1997, 38, 2511-2512.
(5) Wood, J. L. and Navarro Villalobos, M., unpublished results (Yale University,
Department of Chemistry).
340
(6) Honda, T.; Mizutani, H.; Kanai, K. J. Org. Chem. 1996, 61, 9374-9378.
(7) Yu, P.; Yang, Y.; Zhang, Z. Y.; Mak, T. C. W.; Wong, H. N. C. J. Org Chem.
1997, 62, 6359-6366.
(8) Yoda, H.; Kawauchi, M.; Takabe, K.; Hosoya, K. Heterocycles 1997, 45,
1903-1906.
(9) Carda, M; Castillo, E.; Rodríguez, S.; Falomir, E.; Marco, J. A. Tetrahedron
Lett. 1998, 39, 8895-8896.
(10) Yu, P.; Wang, Q.-G.; Mak, T. C. W.; Wong, H. N. C. Tetrahedron, 1998, 54,
1783-1788.
363 36
3
8 6 4 2 0 ppm
OO
(-)-246
O
OOTBS
OBr
Figure A.5.1 1H NMR (500 MHz, CDCl3) of Compound (-)-246.
364 36
4
200
150
100
500
PPM
Figu
re A
.5.3
13C
NM
R (1
25 M
Hz,
CD
Cl 3)
of C
ompo
und
(-)-
246.
Figu
re A
.5.2
FTI
R S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
246.
30405060708090100 3
500
300
0 2
500
200
0 1
500
100
0
Wav
enum
bers
% Transmittance
365 36
5
8 6 4 2 0 ppm
OO
(+)-246
O
OOTBS
OBr
Figure A.5.4 1H NMR (500 MHz, CDCl3) of Compound (+)-246.
366 36
6
200
150
100
500
PPM
Figu
re A
.5.6
13C
NM
R (1
25 M
Hz,
CD
Cl 3)
of C
ompo
und
(+)-
246.
Figu
re A
.5.5
FTI
R S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
246.
859095100
105 3
500
300
0 2
500
200
0 1
500
100
0
Wav
enum
bers
% Transmittance
367 36
7
8 6 4 2 0 ppm
Figure A.5.7 1H NMR (500 MHz, CDCl3) of Compound (+)-226c.
O
O
O
O
O
O(+)-226c
368 36
8
200
150
100
500
PPM
Figu
re A
.5.9
13C
NM
R (1
25 M
Hz,
CD
Cl 3)
of C
ompo
und
(+)-
226c
.
Figu
re A
.5.8
FTI
R S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
226c
.
60708090100
110
300
0 2
500
200
0 1
500
100
0 5
00
Wav
enum
bers
% Transmittance
369 36
9
8 6 4 2 0 ppm
Figure A.5.10 1H NMR (500 MHz, CDCl3) of Compound (-)-226c.
O
O
O
O
O
O(-)-226c
370 37
0
200
150
100
500
PPM
Figu
re A
.5.1
2 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-22
6c.
Figu
re A
.5.1
1 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
226c
.
406080100
120
300
0 2
500
200
0 1
500
100
0
Wav
enum
bers
% Transmittance
371 37
1
8 6 4 2 0 ppm
Figure A.5.13 1H NMR (500 MHz, CDCl3) of Compound (+)-201.
O
O
HO
HO
(+)-Syributin 1(+)-201
O
O
372 37
2
200
150
100
500
PPM
Figu
re A
.5.1
5 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (+
)-20
1.
Figu
re A
.5.1
4 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
201.
80859095
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
373 37
3
8 6 4 2 0 ppm
Figure A.5.16 1H NMR (500 MHz, CDCl3) of Compound (-)-201.
O
O
OH
OH
(-)-Syributin 1(-)-201
O
O
374 37
4
200
150
100
500
PPM
Figu
re A
.5.1
8 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-20
1.
Figu
re A
.5.1
7 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
201.
75808590
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
375 37
5
8 6 4 2 0 ppm
Figure A.5.19 1H NMR (500 MHz, CDCl3) of Compound (+)-202.
O
O
HO
HO
(+)-Syributin 2(+)-202
O
O
376 37
6
200
150
100
500
PPM
Figu
re A
.5.2
1 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (+
)-20
2.
Figu
re A
.5.2
0 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
202.
93949596
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
377 37
7
8 6 4 2 0 ppm
Figure A.5.22 1H NMR (500 MHz, CDCl3) of Compound (-)-202.
O
O
OH
OH
(-)-Syributin 2(-)-202
O
O
378 37
8
200
150
100
500
PPM
Figu
re A
.5.2
4 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-20
2.
86878889909192
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
Figu
re A
.5.2
3 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
202.
379 37
9
8 6 4 2 0 ppm
Figure A.5.25 1H NMR (500 MHz, CDCl3) of Compound (+)-203.
O
O
HO
HO
(+)-Syributin 3(+)-203
O
O
380 38
0
200
150
100
500
PPM
Figu
re A
.5.2
7 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (+
)-20
3.
Figu
re A
.5.2
6 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
203.
405060708090100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
381 38
1
8 6 4 2 0 ppm
Figure A.5.28 1H NMR (500 MHz, CDCl3) of Compound (-)-203.
O
O
OH
OH
(-)-Syributin 3(-)-203
O
O
382 38
2
200
150
100
500
PPM
Figu
re A
.5.3
0 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-20
3.
80859095
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
Figu
re A
.5.2
9 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
203.
363 36
3
8 6 4 2 0 ppm
OO
(-)-246
O
OOTBS
OBr
Figure A.5.1 1H NMR (500 MHz, CDCl3) of Compound (-)-246.
364 36
4
200
150
100
500
PPM
Figu
re A
.5.3
13C
NM
R (1
25 M
Hz,
CD
Cl 3)
of C
ompo
und
(-)-
246.
Figu
re A
.5.2
FTI
R S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
246.
30405060708090100 3
500
300
0 2
500
200
0 1
500
100
0
Wav
enum
bers
% Transmittance
365 36
5
8 6 4 2 0 ppm
OO
(+)-246
O
OOTBS
OBr
Figure A.5.4 1H NMR (500 MHz, CDCl3) of Compound (+)-246.
366 36
6
200
150
100
500
PPM
Figu
re A
.5.6
13C
NM
R (1
25 M
Hz,
CD
Cl 3)
of C
ompo
und
(+)-
246.
Figu
re A
.5.5
FTI
R S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
246.
859095100
105 3
500
300
0 2
500
200
0 1
500
100
0
Wav
enum
bers
% Transmittance
367 36
7
8 6 4 2 0 ppm
Figure A.5.7 1H NMR (500 MHz, CDCl3) of Compound (+)-226c.
O
O
O
O
O
O(+)-226c
368 36
8
200
150
100
500
PPM
Figu
re A
.5.9
13C
NM
R (1
25 M
Hz,
CD
Cl 3)
of C
ompo
und
(+)-
226c
.
Figu
re A
.5.8
FTI
R S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
226c
.
60708090100
110
300
0 2
500
200
0 1
500
100
0 5
00
Wav
enum
bers
% Transmittance
369 36
9
8 6 4 2 0 ppm
Figure A.5.10 1H NMR (500 MHz, CDCl3) of Compound (-)-226c.
O
O
O
O
O
O(-)-226c
370 37
0
200
150
100
500
PPM
Figu
re A
.5.1
2 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-22
6c.
Figu
re A
.5.1
1 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
226c
.
406080100
120
300
0 2
500
200
0 1
500
100
0
Wav
enum
bers
% Transmittance
371 37
1
8 6 4 2 0 ppm
Figure A.5.13 1H NMR (500 MHz, CDCl3) of Compound (+)-201.
O
O
HO
HO
(+)-Syributin 1(+)-201
O
O
372 37
2
200
150
100
500
PPM
Figu
re A
.5.1
5 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (+
)-20
1.
Figu
re A
.5.1
4 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
201.
80859095
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
373 37
3
8 6 4 2 0 ppm
Figure A.5.16 1H NMR (500 MHz, CDCl3) of Compound (-)-201.
O
O
OH
OH
(-)-Syributin 1(-)-201
O
O
374 37
4
200
150
100
500
PPM
Figu
re A
.5.1
8 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-20
1.
Figu
re A
.5.1
7 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
201.
75808590
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
375 37
5
8 6 4 2 0 ppm
Figure A.5.19 1H NMR (500 MHz, CDCl3) of Compound (+)-202.
O
O
HO
HO
(+)-Syributin 2(+)-202
O
O
376 37
6
200
150
100
500
PPM
Figu
re A
.5.2
1 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (+
)-20
2.
Figu
re A
.5.2
0 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
202.
93949596
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
377 37
7
8 6 4 2 0 ppm
Figure A.5.22 1H NMR (500 MHz, CDCl3) of Compound (-)-202.
O
O
OH
OH
(-)-Syributin 2(-)-202
O
O
378 37
8
200
150
100
500
PPM
Figu
re A
.5.2
4 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-20
2.
86878889909192
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
Figu
re A
.5.2
3 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
202.
379 37
9
8 6 4 2 0 ppm
Figure A.5.25 1H NMR (500 MHz, CDCl3) of Compound (+)-203.
O
O
HO
HO
(+)-Syributin 3(+)-203
O
O
380 38
0
200
150
100
500
PPM
Figu
re A
.5.2
7 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (+
)-20
3.
Figu
re A
.5.2
6 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(+)-
203.
405060708090100
350
0 3
000
250
0 2
000
150
0 1
000
500
Wav
enum
bers
% Transmittance
381 38
1
8 6 4 2 0 ppm
Figure A.5.28 1H NMR (500 MHz, CDCl3) of Compound (-)-203.
O
O
OH
OH
(-)-Syributin 3(-)-203
O
O
382 38
2
200
150
100
500
PPM
Figu
re A
.5.3
0 13
C N
MR
(125
MH
z, C
DC
l 3) o
f Com
poun
d (-
)-20
3.
80859095
350
0 3
000
250
0 2
000
150
0 1
000
Wav
enum
bers
% Transmittance
Figu
re A
.5.2
9 FT
IR S
pect
rum
(thi
n fil
m/N
aCl)
of C
ompo
und
(-)-
203.
383
Appendix 6
Notebook Cross Reference.
The following notebook cross reference has been included to facilitate access to
the original spectroscopic data obtained for the compounds presented in this work. For
each compound a folder name is given (e.g., MNV.0X.099) which corresponds to an
archived characterization folder hard copy and folders stored on a ZIP and a compact
disks. For each folder a characterization notebook page number (e.g., 099) is given and
for each spectrum a code (i.e.: 0H for 1H NMR, 0C for 13C NMR and 0I for FTIR) and a
number (e.g., 099) are given. The characterization notebook, spectral data and disks are
stored in the Wood Group archives.
Table A.6.1 Compounds Appearing in Chapter 2.
Compound Folder 1H NMR 13C NMR FTIR
(-)-1 MNV.0X.045
MNV.0H.045
MNV.0Ha.045 MNV.0C.045 MNV.0I.045
(+)-1 MNV.0X.051
MNV.0H.051
MNV.0Ha.051 MNV.0C.051 MNV.0I.051
(-)-2 MNV.0X.047
MNV.0H.047
MNV.0Ha.047 MNV.0C.047 MNV.0I.047
(+)-2 MNV.0X.053
MNV.0H.053
MNV.0Ha.053 MNV.0C.053 MNV.0I.053
(-)-3 MNV.0X.049 MNV.0H.049 MNV.0C.049 MNV.0I.049
(+)-3 MNV.0X.055 MNV.0H.055 MNV.0C.055 MNV.0I.055
384
Table A.6.1 Compounds Appearing in Chapter 2 (Continued).
Compound Folder 1H NMR 13C NMR FTIR
(-)-12 MNV.0X.025 MNV.0H.025 MNV.0C.025 MNV.0I.025
(+)-12 MNV.0X.031 MNV.0H.031 MNV.0C.031 MNV.0I.031
(-)-13 MNV.0X.027 MNV.0H.027 MNV.0C.027 MNV.0I.027
(+)-13 MNV.0X.033 MNV.0H.033 MNV.0C.033 MNV.0I.033
(-)-16a MNV.0X.029 MNV.0H.029 MNV.0C.029 MNV.0I.029
(+)-16a MNV.0X.035 MNV.0H.035 MNV.0C.035 MNV.0I.035
(-)-16b MNV.0X.037 MNV.0H.037 MNV.0C.037 MNV.0I.037
(+)-16b MNV.0X.041 MNV.0H.041 MNV.0C.041 MNV.0I.041
(-)-16c MNV.0X.039 MNV.0H.039 MNV.0C.039 MNV.0I.039
(-)-16c MNV.0X.043 MNV.0H.043 MNV.0C.043 MNV.0I.043
(-)-51a MNV.0X.057 MNV.0H.057 MNV.0C.057 MNV.0I.057
(+)-51a MNV.0X.063 MNV.0H.063 MNV.0C.063 MNV.0I.063
(-)-51b MNV.0X.059 MNV.0H.059 MNV.0C.059 MNV.0I.059
(+)-51b MNV.0X.065 MNV.0H.065 MNV.0C.065 MNV.0I.065
(-)-51c MNV.0X.061 MNV.0H.061 MNV.0C.061 MNV.0I.061
(+)-51c MNV.0X.067 MNV.0H.067 MNV.0C.067 MNV.0I.067
(-)-91 MNV.0X.113 MNV.0H.114 MNV.0C.114 MNV.0I.113
(-)-92 MNV.0X.115
MNV.0H.116
MNV.0H.115 MNV.0C.116 MNV.0I.116
(-)-93 MNV.0X.117 MNV.0H.117 MNV.0C.117 MNV.0I.117
385
Table A.6.2 Compounds Appearing in Chapter 3.
Compound Folder 1H NMR 13C NMR FTIR
115 MNV.0X.119 MNV.0H.120 MNV.0C.119 MNV.0I.119
117 MNV.0X.121 MNV.0H.122 MNV.0C.121 MNV.0I.121
121 MNV.0X.123 MNV.0H.124 MNV.0C.123 MNV.0I.123
122 MNV.0X.125 MNV.0H.125 MNV.0C.125 MNV.0I.125
125 MNV.0X.127 MNV.0H.127 MNV.0C.127 MNV.0I.127
126 MNV.0X.129 MNV.0Ha.129 MNV.0C.129 MNV.0I.129
127 MNV.0X.131 MNV.0Ha.131 MNV.0C.131 MNV.0I.131
129 MNV.0X.133 MNV.0H.134 MNV.0C.133 MNV.0I.133
130 MNV.0X.135 MNV.0H.136 MNV.0C.136 MNV.0I.136
131 MNV.0X.137 MNV.0H.138 MNV.0C.138 MNV.0I.137
134 MNV.0X.142 MNV.0H.142 MNV.0Ca.141 MNV.0I.141
135 MNV.0X.143 MNV.0H.143 MNV.0C.143 MNV.0I.143
140 MNV.0X.145 MNV.0Ha.145 MNV.0C.146 MNV.0I.145
141 MNV.0X.147 MNV.0H.148 MNV.0C.148 MNV.0I.147
143 MNV.0X.151 MNV.0Ha.152 MNV.0C.152 MNV.0I.151
145 MNV.0X.149 MNV.0H.150 MNV.0C.149 MNV.0I.149
147 MNV.0X.153 MNV.0Ha.154 MNV.0C.153 MNV.0I.153
148 MNV.0X.155 MNV.0H.155 MNV.0C.155 MNV.0I.155
149 MNV.0X.157 MNV.0H.157 MNV.0C.157 MNV.0I.157
151 MNV.0X.159 MNV.0H.160 MNV.0C.159 MNV.0I.159
152 MNV.0X.161 MNV.0H.161 MNV.0C.161 MNV.0I.161
153 MNV.0X.163 MNV.0Ha.163 MNV.0C.163 MNV.0I.163
154 MNV.0X.181 MNV.0Ha.181 MNV.0C.181 MNV.0I.181
156 MNV.0X.185 MNV.0H.186 MNV.0C.185 MNV.0I.185
158 MNV.0X.179 MNV.0H.180 MNV.0C.180 MNV.0I.180
159 MNV.0X.205 MNV.0Ha.206 MNV.0C.205 MNV.0I.205
160 MNV.0X.207 MNV.0H.208 MNV.0C.207 MNV.0I.207
386
Table A.6.2 Compounds Appearing in Chapter 3 (Continued).
Compound Folder 1H NMR 13C NMR FTIR
162 MNV.0X.211 MNV.0Ha.212 MNV.0C.212 MNV.0I.211
164 MNV.0X.209 MNV.0Ha.210 MNV.0C.209 MNV.0I.209
165 MNV.0X.213 MNV.0Hb.214 MNV.0C.213 MNV.0I.213
166 MNV.0X.199 MNV.0H.199 MNV.0C.199 MNV.0I.199
167 MNV.0X.221 MNV.0H.222 MNV.0C.221 MNV.0I.221
168 MNV.0X.226 MNV.0H.226 MNV.0C.225 MNV.0I.225
169 MNV.0X.171 MNV.0H.171 MNV.0C.171 MNV.0I.171
171 MNV.0X.173 MNV.0H.174 MNV.0C.173 MNV.0I.173
172 MNV.0X.177 MNV.0H.177 MNV.0C.178 MNV.0I.177
174 MNV.0X.175 MNV.0H.176 MNV.0C.175 MNV.0I.175
176 MNV.0X.167 MNV.0H.167 MNV.0C.167 MNV.0I.167
177 MNV.0X.169 MNV.0H.169 MNV.0C.169 MNV.0I.169
178 MNV.0X.227 MNV.0H.227 MNV.0C.227 MNV.0I.227
179 MNV.0X.183 MNV.0H.183 MNV.0C.183 MNV.0I.183
180 MNV.0X.191 MNV.0Ha.191 MNV.0C.191 MNV.0I.191
181 MNV.0X.193 MNV.0H.194 MNV.0C.194 MNV.0I.193
183 MNV.0X.197 MNV.0Hb.197 MNV.0C.198 MNV.0I.197
185 MNV.0X.195 MNV.0H.195 MNV.0C.196 MNV.0I.195
186 MNV.0X.203 MNV.0Hc.204 MNV.0C.203 MNV.0I.203
187 MNV.0X.187 MNV.0H.187 MNV.0C.188 MNV.0I.187
188 MNV.0X.189 MNV.0Ha.189 MNV.0C.189 MNV.0I.189
190 MNV.0X.215 MNV.0H.216 MNV.0C.216 MNV.0I.215
194 MNV.0X.217 MNV.0H.217 MNV.0C.217 MNV.0I.217
196 MNV.0X.201 MNV.0Ha.201 MNV.0C.201 MNV.0I.201
199 MNV.0X.223 MNV.0Hb.223 MNV.0C.224 MNV.0I.223
387
Table A.6.3 Compounds Appearing in Chapter 5.
Compound Folder 1H NMR 13C NMR FTIR
(+)-201 MNV.0X.081 MNV.0H.081 MNV.0C.081 MNV.0I.081
(-)-201 MNV.0X.087 MNV.0H.087 MNV.0C.087 MNV.0I.087
(+)-202 MNV.0X.083 MNV.0H.083 MNV.0C.083 MNV.0I.083
(-)-202 MNV.0X.089 MNV.0H.089 MNV.0C.089 MNV.0I.089
(+)-203 MNV.0X.085 MNV.0H.085 MNV.0C.085 MNV.0I.085
(-)-203 MNV.0X.091 MNV.0H.091 MNV.0C.092 MNV.0I.092
(+)-226c MNV.0X.101 MNV.0H.101 MNV.0C.101 MNV.0I.101
(-)-226c MNV.0X.111 MNV.0H.111 MNV.0C.111 MNV.0I.111
(-)-246 MNV.0X.093 MNV.0H.093 MNV.0C.093 MNV.0I.093
(+)-246 MNV.0X.103 MNV.0H.103 MNV.0C.103 MNV.0I.103
388
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392
Index
1,3-Acyl migration, 329, 331
Affinity chromatography, 3-5, 7, 26, 32
1,4-Anhydroarabinityl Esters, 134, 139, 142, 146, 147
Anti orientation, 125, 127, 128, 132, 133, 138, 142, 149, 150
avrD, 2, 329
Biomimetic, 25, 27-29, 31, 32
Biosynthesis, 1, 2, 4-6, 10, 25, 329-331
Butenolide, 4, 26, 29, 31, 38-43, 46, 49, 52, 54, 55, 58, 151, 341, 342, 344, 348, 349, 351, 353
α-Bromoketone, 26, 27, 29, 31, 31, 36, 37, 39, 40, 43, 54, 344
(-)-N-(Carbobenzyloxy)-8-aminosyringolide 1, 31, 32, 55
C-H insertion, 120-123, 125, 127, 129, 131, 132, 134, 138, 141, 142, 149-151, 208
Cyclohexenyldiazoacetate, 127, 129, 149, 164, 165
Diazo transfer, 120-122, 125, 126, 129, 132, 133, 135, 138, 139, 141, 143, 145-147, 204, 207, 208
Diazoacetate, 120, 122, 127, 129, 131, 137, 141, 144, 151, 163, 169, 181, 182, 189, 190, 199, 200, 209
Diazoacetoacetate, 122-124, 129-131, 135-137, 139-141, 143, 144, 146, 150, 153, 154, 167-169, 179-181, 187-189, 197-199, 204, 209
2-Diazo-3-[(t-butyldimethylsilyl)oxy]-3-butenoate, 122, 124, 130, 136, 140, 143, 150, 209
α-Diazoester, 120-122
α-Diazoketone, 34, 35, 341, 342, 346
Diazomalonate, 123, 125, 156
2,5-Dihydrofuranyl, 132, 133
2,5-Dihydrofurfuryl esters, 129
Elicitor, 1, 2, 4, 13, 32, 328
β-Elimination, 128, 150, 151
Hypersensitive response (HR), 1-4, 13, 32, 328
β-Ketoacid, 4, 7, 14, 25, 26, 28, 29, 31, 39, 40, 43, 54, 58, 120
393
Knoevenagel, 4, 25, 26, 29
3-Methoxyphenyldiazoacetate, 123, 125, 126, 129, 132, 138, 141, 145-147, 158, 159, 171, 172, 184, 185, 192, 193, 202, 206
4-Methoxyphenyldiazoacetate, 123, 129, 133, 174, 175
Michael addition, 5, 25
Model system, 121, 126, 134, 139, 142, 146, 150, 151
Model studies, 122, 123, 129, 134
Molecular probe, 3, 31, 128
O-H insertion, 124, 136, 341, 342
Pathogen, 1, 3
Polihydrofurany, l49
Pseudomonas, 2, 329
Radiolabel, 3, 5, 7, 8, 14, 20, 26
Receptor, 1, 3, 4, 8, 14, 20, 31, 128
Relative stereochemistry, 29, 51, 126-128, 132, 133, 138, 149, 150, 159, 172, 175, 185
Retrosynthetic analysis, 25, 26, 28, 120, 121, 341
Reverse Claisen, 329
Reverse Michael, 329
Rhodium (Rh), 120, 121, 123-125, 127, 130-133, 135-139, 141, 143-146, 148, 159, 162, 165, 172, 175, 182, 185, 190, 193, 200, 342, 346
Rpg4, 2-4, 13, 32, 328
Secosyrin, 16, 328-330, 332, 334-339
Soybean, 2-4, 13, 31, 32, 128, 328
Spirolactone, 120, 122-128, 130-133, 135-141, 143-146, 148-151, 159, 162, 165, 172, 175, 182, 185, 190, 193, 200, 315, 317, 318, 320, 321, 323, 324, 326, 327
Syributin, 16, 328-335, 337-339, 341-344, 355-360 Syringolide, 1-20, 25-32, 44, 46, 48-53, 59, 117, 119-122, 126, 128, 149-151, 328-332, 341, 343
Tetrahydrofuranyl, 127, 128, 138, 142, 150
Wittig olefination, 342, 344, 360
Tetrahydrofurfuryl Ester, 125, 125, 131
Trans diol, 121, 123, 129, 134, 146
Vinyldiazoacetate, 123, 126, 159, 162
394
Xylose, 13
Xylulose, 4, 10, 18, 25, 338
X-ray, 2, 29, 34, 51, 117, 125, 126, 132, 133, 138, 142, 149, 150, 153, 159, 172, 175, 185, 315, 318, 321, 324
395
About the Author
Mauricio Navarro Villalobos was born in Mexico City in May, 1971. His given
name is Mauricio and his full surname is Navarro Villalobos. He does not have a middle
name. As customary in Spanish-speaking countries, his first surname (i.e., Navarro) is
the first surname of his father and his second surname (i.e., Villalobos) is the first
surname of his mother. Mr. Navarro was very surprised when he learned that in many
countries people only have one surname.
He attended the Instituto Tecnológico y de Estudios Superiores de Monterrey,
Campus Monterrey in Mexico where he worked in the laboratories of Dr. Teófilo Dieck
Abularach and had outstanding teachers such as Dr. Xorge A. Domínguez, Ing. Javier
Rivas Ramos and Dr. Elsa Guajardo Touché. There he earned the degree of Licenciado
en Ciencias Químicas in 1994.
At Yale University he worked under the direction of Professor John L. Wood and
also had excellent teachers, that is: Professor Frederick E. Ziegler, Professor William L.
Jorgensen, Professor Martin Saunders, Professor Jack W. Faller and Professor Wood.
There he earned the degree of Master of Science in 1995 and is currently a candidate for
the degree of Doctor of Philosophy.
Mr. Navarro has accepted a post-doctoral position in the laboratories of Professor
David Gin at the University of Illinois at Urbana-Champaign starting in September, 2000
and is planning to return to Mexico afterwards.