efforts toward the total synthesis of...

EFFORTS TOWARD THE TOTAL SYNTHESIS OF BIELSCHOWSKYSIN

By

Nina Renee Collins

Thesis

Submitted to the Faculty of the

Graduate School of Vanderbilt University

in partial fulfillment of the requirements

for the degree of

MASTER OF SCIENCE

in

Chemistry

August, 2013

Nashville, Tennessee

Approved:

Professor Gary Sulikowski

Professor Carmelo Rizzo

ii

TABLE OF CONTENTS

Page

LIST OF FIGURES........................................................................................................... iii

LIST OF SCHEMES......................................................................................................... iv

Chapter

I. Background.................................................................................................................... 1

Introduction............................................................................................................ 1

Biosynthesis........................................................................................................... 1

Alternate Routes..................................................................................................... 3

II. Current Progress........................................................................................................... 12

Sulikowski Route.................................................................................................. 12

Model System....................................................................................................... 16

Future Plans.......................................................................................................... 18

Experimental Methods.......................................................................................... 20

Appendix

A. SPECTRA OF RELEVANT COMPOUNDS....................................................... 26

REFERENCES................................................................................................................. 41

iii

LIST OF FIGURES

Figures Page

1 Furanocembranoid Skeletons................................................................................. 1

A1 1H NMR spectra (400 MHz, CDCl3) of compound 103....................................... 27

A2 13C NMR spectra (100 MHz, CDCl3) of compound 103...................................... 28











A13 1H NMR spectra (400 MHz, CDCl3) of compound 84......................................... 39


iv

LIST OF SCHEMES

Scheme...........................................................................................................................Page

1. Conversion of Geranylgeranyl pyrophosphate to rubifolide.................................. 2

2. Proposed Biosynthesis of Bielschowskysin........................................................... 2

3. Lear’s Route........................................................................................................... 3

4. Nicolaou’s Route.................................................................................................... 4

5. Mulzer’s Route....................................................................................................... 6

6. Stoltz’s Synthesis of Enantiomeric Alcohols 47 and 48........................................ 7

7. Stoltz’s Approach to Cyclobutane 56.................................................................... 8

8. Stoltz’s Route to Unexpected Compound 61......................................................... 9

9. Theoretical Approach to Verrillin and Bielschowskysin........................................ 9

10. Theodorakis’ Synthesis of the C7–C12 fragment................................................. 10

11. Theodorakis’ Synthesis of the C1–C13 fragment................................................ 10

12. Theodorakis’ Completion of Route to Intermediate 79........................................ 11

13. Retrosynthetic Analysis of Bielschowskysin........................................................ 12

14. Revised Synthetic Analysis of Bielschowskysin.................................................. 13

15. Synthesis of Lactone 90........................................................................................ 14

16. Synthesis of Bis-Butenolide 96............................................................................. 15

17. Synthesis of Advanced Intermediate 84............................................................... 16

18. Synthesis of Aldehyde 104................................................................................... 17

19. Synthesis of Butenolide 112................................................................................. 17

20. Application of Model System Chemistry to Front End........................................ 18

v

21. Bielschowskysin End-Game Strategy................................................................... 19

22. Proposed conversion to the Tris-Butenolide 119.................................................. 19

1

CHAPTER 1

BACKGROUND

Introduction

Isolated from Pseudopterogorgia kallos by Rodriguez, bielschowskysin is a

unique furanocembranoid natural product.1 In addition to its structural novelty and

complexity, bielschowskysin exhibits antiplasmoidial activity against Plasmodium

falciparum (IC50 = 10 µg/ mL) as well as in vitro cytotoxicity against EKVX nonsmall

cell lung cancer (GI50 < 0.01 µM) and CAKI-1 renal cancer (GI50 < 0.51 µM). Its

structural and biological profile renders the natural product an interesting target for total

synthesis.

Biosynthesis

Bielschowskysin belongs to a unique class of diterpene natural products

assembled by gorgonian corals. These marine species are responsible for the production

of most known furanocembranoids, pseudopteranes and gersolanes. Differing most

markedly in carbocyclic ring size, these natural products are highly oxygenated – often

featuring furan and butenolide moieties – and biosynthetically related.2

66 O 33

O 1212

1111

O(furano)cembrane

skeleton

O

O

O

O

O

Opseudopterane

skeletongersolaneskeleton

2

Figure 1: Furanocembranoid skeletons

The proposed biosynthesis of the furanocembranoid ring system begins with

geranylgeranyl diphosphate 1. Cyclization leads to generation of the cembrane skeleton,

which upon deprotonation, forms neocembrane 3. Subsequent oxidation promotes

formation of rubifolide 4, a supposed precursor for more complex furanocembranoids.2

Scheme 1: Conversion of geranylgeranyl (1) diphosphate to rubifolide (4).

Trauner has postulated that biosynthesis of bielschowskysin occurs through

rubifolide 4. Advancement to intermediate 5 is accomplished through various oxidative

processes. Further oxidation and hydration generates compound 6 which undergoes [2+2]

photocycloaddition to yield the natural product.2

Scheme 2: Proposed biosynthesis of bielschowskysin (7).

OPP

- OPP- H - H+O

OO21 34

[O]

O

OO

4

O

5

O

O

O

HOAc

HOH O

H

HOH

O

OH

HO Me

OO

H

O

OAcOO

HO Me

H

H

H

Me

OOHH

H

6

7

[O] [O]H2O

[2 + 2]hv

OH

3

Alternate Routes

Due to its structural complexity, bielschowskysin has proven an interesting yet

elusive target. Several groups, in addition to ours, have undertaken a total synthesis

program. A noteworthy point of divergence among these routes is the manner in which

the core cyclobutane functionality is installed.

Similar to our route, Lear proposes a transannular [2+2]-photocycloaddition

between an allene and a butenolide.3 In order to investigate the feasibility of this

transformation, the group implemented a model system.

Malic acid was reduced to triol 9 and converted to acetonide 10. Swern oxidation

of the primary alcohol, addition of methyl magnesium bromide, and subsequent oxidation

afforded methyl ketone 11. Ethynyl magnesium bromide addition resulted in tertiary

alcohol 12, which underwent transketalization to the benzylidene acetal. Oxidation of the

primary alcohol to the aldehyde followed by Wittig homologation yielded the

predominately cis α,β-unsaturated ester 15. Upon treatment with sulfuric acid, the diol

was liberated and spontaneously formed butenolide 16. Reaction of silyl ether 17 with

paraformaldehyde gave photocycloaddition precursor 18. Upon irradiation in a solution

of hexanes and dichloromethane, the allene butenolide was converted to cyclobutane 19.

As of yet, there have been no reports of this methodology being employed in a

transannular setting.

HO OH

O

O

OH BH3‚ãÖSMe2

95%HO OH

OH p-TsOH, CuSO4

acetone, 67% OH

OO

i. (COCl)2, DMSO, NEt3, CH2Cl2, - 78 °C

iii. PCC, NaOAcDCM43%

8 9 10

ii. MeMgBr, Et2O- 78 °C

4

Scheme 3: Lear’s Route.

Nicolaou and coworkers also favored a photochemical approach. They are able to

access the [9.3.0.0] tetradecane ring system (27, Scheme 4) of bielschowskysin in five

steps starting with furan 20. 4 Noyori reduction to the alcohol followed by CAN mediated

coupling with β-ketoester 30 yields compound 21 as a mixture of C3 epimers, 22 and 23.

Grubbs ring closing metathesis of 22 produced macrocycle 24, with the newly formed

olefin in a predominately trans orientation. Attempted photocycloaddition with this

substrate was unproductive. In an effort to render the olefin of the enol ether more

reactive, ketone 25 was reduced to the allylic alcohol 26. Irradiation of 26 resulted in 27

as a single diastereomer.

Me

OO

Oethynyl magnesium

bromide

Et2O, - 78 °C 72%

OO

HO Me

CH2Cl2, 75%

TsOH, PhCH(OMe)2 O OHO

Ph

Me (COCl)2, DMSO,

NEt3, CH2Cl2, - 78 °C

1112 13

O OO

Ph

MeNEt3, MeOH, 0 !C

60%

BrPCH2CO2Me O O

Ph

Me

CO2CH3

MeOH, 70%

H2SO4

O OH

HOMe

CH2Cl2, 0 !C 62%

TMSOTf/ 2,6-lutidine

O OH

TMSOMe • CH2

H

O OH

TMSOMe

dioxane, reflux, 68%

(CH2O)n, i-Pr2NH, CuBr

hexanes; CH2Cl2, 70%

h"#,

O OHH

TMSO Me H

H

14 15 16

17 1918

OO

OOH

O

MeO2C

O

OHOMe

O

MeO2C

O

OHOMe

20 2122 23

28, HCOONanBu4Cl

CH2Cl2/ H2O 84%, 92% ee

29, CAN

MeOH, 0 °C58%, 1:1 d.r.

5

Scheme 4: Nicolaou’s Route.

Mulzer opted for a non-photochemical approach and began his synthesis with

known bicyclic alcohol 31.5 Silyl ether 32 was converted to enone 33 via

photooxygenation. Conjugate addition of a methyl cuprate followed by silyl ether

formation and Saegusa oxidation yielded 35. Luche reduction and MOM-protection

afforded compound 36, which underwent Mukaiyama-Isayama reaction to the tertiary

alcohol. Silyl protection, selective deprotection yielded alcohol 38. Oxidation and

alkylation at the α-position with formalin generated the quaternary carbon of the

molecule. TES protection of the primary alcohols and treatment with Petasis’ reagent

gave methylene 40. Exposure to Jones reagent resulted in tandem liberation of the

primary alcohols and oxidation to the dicarboxylic acid. MOM deprotection was

accompanied by lactone formation. Selective reduction of the remaining carboxylic acid

O

MeO2C

O

OHOMe

O

MeO2C

O

OMe

OH

O

MeO2C

HO

OMe

OH

24 25

26

30, CH2Cl2

reflux, 90%trans/ cis 15:1

NaBH4

THF/ H2O, 0 °C83%

O

OHOMeO

OMe

H

HO

H

NTs

Ru

TsNPh

Ph

i-Pr

Me

Ru

P(Cy)3

PhP(Cy)3

ClCl

OCO2Me

28

27

2930

h!

C6H6, 90%

6

and subsequent oxidation to the aldehyde produced 43, establishing the eastern portion of

bielschowskysin.

Scheme 5: Mulzer’s Route.

Stoltz and coworkers propose a tandem cyclopropane fragmentation/ Michael

addition of intermediate 54 to arrive at 56. To this end, furan 43 was converted to the

boronic acid and coupled with iodide 50.6 The group later found that the electron

deficient olefin of the enone precluded cyclopropane formation. Thus, ketone 45 was

selectively reduced to afford allylic alcohol 46. This substrate is amenable to an oxidative

H

H

OH TBSCl, NEt3, DMAP

CH2Cl2, 94%

H

H

OTBSAc2O, pyr, DMAPporphyrin, O2, h!

CH2Cl2, 0 °C,

H

H

OTBS

O

i. CuI, MeLi, Et2O -78 °C

ii. TMSOTf, 0 °C

31 32 33

H

H

OTBS

TMSO

Pd(OAc)2, O2

DMSO, 40 °C

H

H

OTBS

O

1. NaBH4, CeCl3MeOH, 0 °C

2. MOMCl, i-Pr2NEt

75% from X

H

H

OTBS

MOMO

Co(acac)2, O2PhSiH3

THF, 64%

H

H

OTBS

MOMO

HO 1. TBSOTf, 2,6-lutidineTHF, 0 °C, 86%

2. 70% HF"pyr

H

H

OH

MOMO

TBSO 1. IBX, EtOAcreflux

2. formalin, DBU90%

H

H

O

MOMO

TBSO

HO

OH

1. TESCl, imi CH2Cl2, 93%

2. Cp2TiMe2, toluene, 94%

H

HMOMO

TBSO

TESO

OTES

HTBSO

OH

1. Jones reagentacetone, 0 °C

2. Et3N, ethyl chloroformatethen NaBH4, 0 °C

54%

O O

H

(COCl)2, DMSOCH2Cl2, - 78 °C

then NEt3, 0 °C94%

HTBSO

OO O

H

34 35 36

37 38

3940

41 42

7

kinetic resolution protocol developed in Stoltz’s lab. Notably, either enantiomer could be

accessed from this method.

Scheme 6: Stoltz’s synthesis of enantiomeric alcohols (47) and (48).

Furan 46 was then acylated and coupled with a novel diazoacetoacetic acid reagent.

Cyclopropanation with Cu(TBSal)2 afforded 53. They envisioned acetate removal,

followed by oxidation with Dess Martin periodinane would arrive at key intermediate 54,

which would undergo furan-assisted cyclopropane cleavage and subsequent Michael

addition yielding the substituted cyclobutane.

OBr CO2Me

1. i-PrMgCl, -35 °C2. B(OMe)3, -35 °C

3. 1 M HCl, THF, 0 °CO(HO)2B CO2Me

50, Ag2O, 8 mol% AsPh35 mol% PdCl2(PhCN)2

THF/ H2O85% over 2 steps43 44

O

O

TBSO

CO2Me

CeCl3! 7 H2O"aBH4

MeOH/ CH2Cl2, -25 °C10:1 syn:anti

O

TBSO

CO2Me

HO 5 mol% Pd(nbd)Cl220 mol% (-)-sparteine

MS3A, O2 (1 atm)PhMe, 80 °C

(±)-

O

TBSO

CO2Me

> 95% ee

HO

O

TBSO

CO2Me

OCeCl3! 7 H2O

"aBH4

O

TBSO

CO2Me

HO

I

TBSO

O

50

45 46

47 48 49

8

Scheme 7: Stoltz’s approach to cyclobutane (56).

However, when intermediate 53 was subjected to acetate removal, a drastically different

compound, lactone 61, was obtained. Stoltz postulated that upon acetate cleavage of 53,

intramolecular trans-lactonization affords 58. Oxidation of the free alcohol at C5, results

in 59. Lewis acid promoted cleavage followed by addition of methanol yields

intermediate 60. Conversion of the cyclic ketone to the hemiacetal via addition of

methanol initiates a second trans –esterification to arrive at 61.

1. Ac2O, DMAPCH2Cl2

2. TBAF, THF, 0 °CO

TBSO

CO2Me

HO

85%

O

HO

CO2Me

AcO57, DCC, DMAP

CH2Cl2, 62%

O

O

CO2Me

AcO

O

N2

O

2 mol% Cu(TBSal)2PhMe, 110 °C

or

10 mol% Cu(TBSal)2µwave, DCE, !

50-55%

O

OAc

O

OCO2Me

O

1. K2CO3, MeOH0 °C

2. DMP, CH2Cl2

46 51

52 53

HON2

O O

O

O

OCO2Me

O

O

La(OTf)3

MeOH, -55 °C O

O

OCO2Me

O

OLa

La

OO

O

OCO2Me

OMeO H

H

57

54 55 56

9

Scheme 8: Stoltz’s route to unexpected compound (61).

Theodorakis proposes a novel biomimetic synthesis of bielschowskysin via

cembrenolide 62.7 He postulates that hydration, oxidation, and subsequent Michael

addition of this cembrenolide should lead to an intermediate that can undergo either aldol

closure to arrive at bielschowskysin or ketalization to arrive at verrillin.

Scheme 9: Theoretical approach to verrillin and bielschowskysin.

O

OAc

O

OCO2Me

O

K2CO3, MeOH0 °C DMP, CH2Cl2

53

80%HO

OO

O

OCO2Me

CH2Cl2, 97%

OO

O

OCO2MeO

MeOH, 55 °C, 55%

La(OTf)3

O

OH

O

O O

O

O CO2Me

58 59

61

OO

O

OCO2MeO

60

O

O

R1

OO

OH

OH

furan oxidation

hydrationO O

O

OHOHR1

OH

Michael Addition

O O

O

OHOHR1

OH

OR2

OR2

Aldol

Ketalization

R1 = Me R2 = Ac

R1 = Me R2 = H

O

OAcOO

HO Me

H

H

H

Me

OOH

H

OHH

O

O

OO

O

Me OH H

H

H

MeOH

O

MeH

65

62

63

64

7

10

The C7-C12 fragment of the cembrenolide was synthesized from butynol 66.

Conversion to ester 67 was accomplished in three steps. Copper mediated reduction of

the alkyne followed by acid-induced cyclization afforded lactone 69. Treatment with

LHMDS and PhSeBr effected selenation at the alpha position.

Scheme 10: Theodorakis’ synthesis of the C7–C12 fragment.

Methyl zirconation and iodination of propargyl alcohol followed by silylation

yielded vinyl iodide 72. Lithium halogen exchange and addition of oxirane resulted in

homoallylic alcohol 73 which was further oxidized to the aldehyde completing the C1 –

C13 fragment of the cembrenolide intermediate.

Scheme 11: Theodorakis’ synthesis of the C1–C13.

Coupling of the two fragments and oxidation/ elimination of the selenide moiety

proceeded to give butenolide 75 as a mixture of diastereomers. Silyl protection followed

OH

i

HOCO2Et

i

HOEtO

O

OO

I

OO

I

SePh

NaBH4, CuI

- 78 °C

TsOH

benzene79% over 2 steps

LHMDS, PhSeBr

- 78 °C, 76%

1. Me3Al, Cp2ZrCl2 then I22. DMP, NaHCO3

3. CO2EtLDA, THF

6667

68

6970

HO

i. Me3Al, Cp2ZrCl2 then I2

ii. TBSCl, imi50% over 2 steps

TBSOI

t-BuLi

then OTBSO OH

55%71

72 73

DMP, NHCO3

95% TBSO O

74

11

by selective deprotection gave primary alcohol 76. Coupling of fufural 80 and iodide 77

was accomplished via a modified Stille. Appel reaction of the allylic alcohol resulted in

formation of the bromide, which underwent NHK cyclization to macrocycle 79.

However, attempted oxidation of the furan moiety with CAN led to a complex mixture of

products rather than enol ether 63.

Scheme 12: Theodorakis’ completion of route to common intermediate (79)

.

OO

I

SePhLHMDS, - 78 °C

TBSO O

74 70 OO

I

SePhOH

TBSOH2O2

THF/ EtOAc

78% over 2 steps

75

OO

I

SePhOH

TBSO

i. TBSCl, DCM

ii. PPTS, EtOH82% over 2 steps O

O

I

SePhOTBS

HO

7776

80, Pd(PPh3)4Cui

DMF

OO

SePhOTBS

HOO

CHO

1. NBS, PPh3

2. Cr2Cl2NiCl2(DME)

O

OO

OH

79

OTBS

78

OH

OMe3Sn

80

CANX complex

mixture

12

CHAPTER II

CURRENT PROGRESS

Sulikowski Route

Initially, efforts toward the molecule centered on construction of the tetracyclic

core. With this strategy in mind, bis-butenolide 82 was envisioned as a precursor to

cyclobutane 81 via a [2+2] photocycloaddition. The required bis-butenolide could

ultimately be derived from (-)-malic acid.

Scheme 13: Retrosynthetic analysis of bielschowskysin (7).

In a 2006 manuscript, Doroh and Sulikowski disclosed the synthesis of

intermediate 82 and its subsequent photocyclization to cyclobutane 81.8 Irradiation of an

acetone solution of bis-butenolide 9 resulted in a 5:1 mixture of [2+2] photoadducts with

the major product having the desired stereochemistry. Stereochemical assignments were

confirmed by NOE and single-crystal x-ray analysis.

With an established protocol for the [2+2] photocycloddition, the group’s focus

shifted to synthesis of an α–substituted butenolide which would provide a handle for

elaboration of the eastern portion of the molecule. After several failed attempts to install

O

OAcOO

HO Me

H

H

H

Me

OOH

H

OHH

OO

HO Me

H

H

HO

O

Me

7

HO Me OO

MeO

O

81

O

HOO

OH

OH

882

13

the substituted butenolide directly, the group resorted to Grieco’s method of selenation-

oxidation, accessing this moiety through lactone 85.9

In a revised synthetic analysis, it was envisioned that formation of the macrocycle

would arise from an intramolecular vinylogous aldol reaction of 83. Aldehyde 84 would

enable installation of the required butenolide for this key reaction. The

photocycloaddition precursor could be accessed from lactone 85, which could be derived

from epoxide 86. As before (-)-malic acid would serve as the starting point of the

synthesis.

Scheme 14: Revised synthetic analysis of bielschowskysin (7).

Dr. Steve Townsend developed the route to advanced intermediate 84. At the

outset of the synthesis, (-)-malic acid was converted to methyl ester 87 in three steps via

a protocol reported by Saito.8, 10 Formation of the Weinreb amide and subsequent reaction

with methyl Grignard generated ketone 11.11 Chelation-controlled addition of ethynyl

magnesium bromide resulted in a 6:1 mixture of tertiary alcohols 12 and 88, with the

major product having the desired 1,3 anti-oxygenated relationship observed in

bielschowskysin.12, 13 Subsequent benzyl protection of the free alcohol gave benzyl ether

O

OAcOO

HO Me

H

H

H

Me

OOH

H

OHH

OAcOO

HO Me

H

H

H

CHOO

O

Me

HO Me OO

MeO

O

O

HOO

OH

OH

783 84

858

HO MeO

86

OAcOO

BnO Me

H

H

HO

O

Me

O

CO2MeO

14

89. Exposure to acid liberated the diol, which upon addition to a slurry of sodium hydride

and tosyl chloride resulted in concomitant formation of epoxide 8614, 15 The action of

ynamine 91 on the epoxide followed by desilylation gave lactone 90 in 88% yield.16

Scheme 15: Synthesis of lactone (90).

With formation of the lactone complete, the synthesis was directed toward

extension of the carbon chain for construction of the alkylidene butenolide. Sonogashira

coupling of alkyne 90 and vinyl iodide 97 resulted in enyne 92.17, 18 Generation of the

lithium enolate of 92 followed by addition of diphenyl diselenide resulted in 93. In the

same manner, conversion to the disubstitued lactone was achieved upon aldol reaction

with D-glyceraldehyde acetonide (98), producing the aldol adduct as a single

diastereomer. Acylation was followed by TBAF deprotection and allylic oxidation to the

aldehyde. Pinnick oxidation simultaneously resulted in conversion of the aldehyde to the

carboxylic acid and oxidative elimination of the phenyl selenoxide to give the butenolide.

OO

OMe

OO

O

Me

OO

O HO Me OO Me OH

87 11 12 88

HCCMgBri. (Meo)MeNH•HClii. MeMgBr, THF

77-91%CH2Cl286%, 6:1

BnO MeOOO BnO Me BnO MeO

O

O N TMS

91

89 8690

BnBr, NaH 1) 2N HCl, CH3CN2) TsCl, NaH, DMF

i. BF3OEt2, 91CH2Cl2

ii. aq. KHF2, CH3CN

DMF85 - 95% 90%

78-88%

15

Completion of photocycloadditon precursor 96 was realized upon silver catalyzed

cycloisomerization of acid 95.19, 20

Scheme 16: Synthesis of bis-butenolide (96).

Using the previously established protocol for the [2+2] photocycloaddition,

irradiation of bis-butenolide 96 in acetone afforded cyclobutane 99 as a single isomer.8

Subsequent TFA removal of the acetonide and lead tetraacetate cleavage of the resultant

diol provided aldehyde 84. With the aldehyde in place, our focus shifted to

functionalization of the eastern portion of the molecule and pursuit of an end-game

strategy for bielschowskysin.

PhSe

BnO MeOO BnO MeO

O

Me

OTBS

90 92

97, CuI, Pd(PPh3)4

NEt3, CH3CN

i. LDA, THF

1) LHMDS, 98

2) Ac2O, DMAP pyr, CH2Cl2

ii. PhSe2, HMPA

BnO MeOO

Me

OTBS

93

BnO MeOO

Me

OTBS

PhSe

AcO

OO

94

85-91% 80-91%

76-80%

> 95%

BnO MeOO

Me

OAcO

OO

HO BnO Me OO

MeO

O

AcO

O O95 96

I OTBS97

O

HOO

98

1) TBAF, THF, 70%

3) NaOCl2, 85%

AgNO3aq. MeOH

2) MnO2, 90% 92%

16

Scheme 17: Synthesis of advanced intermediate (84).

Model System

To complete our synthetic vision of a vinylogous aldol to install the C2, C3 bond,

a final butenolide must be constructed from aldehyde 12. In the interest of conserving

valuable material, a model system was adopted to develop methodology before applying

it to any advanced intermediates.

Octenol, 101, serves as the starting point of our exploratory synthesis. The alcohol

was smoothly converted to ester 102. Lemieux Johnson oxidation resulted in aldehyde

104 in modest yield.21 The aldehyde was also obtained via a separate dihydroxylation/

sodium periodate cleavage pathway, a route more consistent with the reactions to be

applied to the actual system.22 At this point the model system resembles C13 and C14 of

intermediate 84.

BnO Me OO

MeO

O

AcO

O O96

hvacetone86-95%

OAcOO

BnO Me

H

H

HO

O

Me

OO

99

OAcOO

BnO Me

H

H

HO

O

Me

OO

OAcOO

BnO Me

H

H

HO

O

Me

OHOH

1313OAcO

O

BnO Me

H

H

H

CHO1414OO

Me

99100 84

TFACHCl3

Pb(OAc)4EtOAc

70% 62%

17

Scheme 18: Synthesis of aldehyde (104).

Wittig olefination with triphenyl phosphorane 105 afforded homologated

aldehyde 106. Sodium borohydride reduction resulted in allylic alcohol 107, an

important intermediate allowing for synthetic divergence within the model system.

Transformation of 107 to bromoacetal 108 was accomplished with NBS and neat ethyl

vinyl ether. Employing a protocol established by Stork, radical cyclization of the

bromoacetal was observed upon reflux with Bu3SnH and AIBN in benzene for five

hours.23 Jones’ oxidation of the lactol yielded lactone 110. Subsequent enolization and

reaction with Mander’s reagent provided the substituted lactone. Presumably, selenation

followed by oxidation elimination would provide butenolide 112. Satisfied with the

preliminary findings of the model system, we shifted our efforts toward scale-up of

material and application of the newly explored chemistry to the front end.

OH

1014

Ac2O, DMAPpyr, CH2Cl2

(91%)

OAc

1024

OsO4, NaIO4THF50%

OOAc

1044

OsO4, NMOacetone, H2O

57 ! 81%O

OAc

1044

NaIO4THF/ H2O

82%

OAc

103

4OH

OH

OAc

107

4OH

ONBS78%

OAc

108

4O OEt

Br

Bu3SnH, AIBN

benzene, 80°C75%

OAc

109

4

OOEt

OOAc

1044

Ph3PCHO

105CH2Cl2

87%

OAc

106

4 CHO EtOH78%

NaBH4

18

Scheme 19: Synthesis of butenolide (112).

Aldehyde 84 was converted to α,β-unsaturated aldehyde 113 without incident.

However, attempted reduction to the allylic alcohol resulted in decomposition.

Scheme 20: Application of model system chemistry to front end.

Future Plans

Once intermediate 84 is advanced to butenolide 83, we will turn our attention to

the completion of the molecule. We propose deprotonation at C2 will lead to a

vinylogous aldol reaction resulting in formation of macrocycle 115. DIBAL reduction

and subsequent hydrogenation is expected to provide lactol 116. Tosylation of the free

primary alcohol followed by Mitsunobu reaction should correct the stereochemistry at

C16. Subsequent reaction of 117 with p-toluensulfonyl hydrazide is expected to install

Jones OAc

110

4

OO

LHMDS OAc

111

4

OO

CO2Me

1) LHMDS, Ph2Se2

2) [O]

OAc

112

4

OO

CO2Me67% CNCO2Me61%

OAcOO

BnO Me

H

H

HO

O

Me

OO

OAcOO

BnO Me

H

H

HO

O

Me

OHOH

OAcOO

BnO Me

H

H

H

CHOO

O

Me

TFA

CHCl3

Pb(OAc)4

EtOAc

DCM

OAcOO

BnO Me

H

H

HO

O

Me

CHO

Ph3PCHO

NaBH4

EtOH

OAcOO

BnO Me

H

H

HO

O

Me

OH

70% 62%

58%

x

113

99 100 84

114

19

the exocyclic olefin and trans ring juncture simultaneously via an intermediate diazene.24

Finally benzoate removal will result in bielschowskysin, 7.

Scheme 21: Bielschowskysin end-game strategy.

In an alternate strategy, we envision advancing bis-butenolide 96 to tris-

butenolide 119 via the model system chemistry and then attempting the

photocycloaddition.

Scheme 22: Proposed conversion to tris-butenolide 119.

O OH

83

base O

OAcOO

BnO Me

H

H

H

Me

O

CO2Me

OHH

115

1) DIBAL

2) H2, Pd(OH)2

O

OAcOO

HO Me

H

H

H

Me

OOHH

116

OHOAcOO

BnO Me

H

H

HO

O

Me

O

CO2MeO

1) TsCl, pyr2) PPh3, DEAD PhCOOH

OBzO

OAcOO

HO Me

H

H

H

Me

OOHH

117

OTs

NH2NHTsbase ORO

OAcOO

HO Me

H

H

H

Me

OOHH

H

118 R = Bzbielschowskysin (7, R = H)

BnO Me OO

MeO

O

AcO

O O

BnO Me OO

MeO

O

AcO

OMeO2C

O

OAcOO

BnO Me

H

H

HO

O

Me

O

O

hv

MeO2C

1199683

20

Experimental Methods

General. All non-aqueous reactions were performed under an argon atmosphere in oven-

dried glassware. Reagents were purchased at the highest commercial quality and used

without further purification, unless otherwise stated. Diethyl ether (Et2O), acetonitrile

(CH3CN), dichloromethane (CH2Cl2), and dimethylformamide (DMF) were obtained by

passing commercially available formulations through activated alumina columns

(MBraun MB-SPS solvent system). Tetrahydrofuran (THF) was obtained by distillation

from benzophenone-sodium. Triethylamine (Et3N) and diisopropylamine were distilled

from calcium hydride and stored over potassium hydroxide. Reactions were monitored by

thin-layer chromatography (TLC) using E. Merck precoated silica gel 60 F254 plates.

Visualization was accomplished with UV light and aqueous stain followed by charring on

a hot plate. Flash chromatography was conducted using the indicated solvents and silica

gel (230-400 mesh). Yields refer to chromatographically and spectroscopically

homogenous materials. 1H and 13C NMR spectra were recorded on a Bruker 400 MHz

spectrometer and are reported relative to deuterated solvent signals (7.26 and 77.2).

Preparative Procedures

To a solution of alcohol 101 (1.0 eq, 9.5 g, 74.1 mmol) in CH2Cl2 (120

mL) at ambient temperature was added pyridine (100 mL), acetic

anhydride (60 mL), and DMAP (1 crystal). The reaction was stirred 1 h, washed with 1 N

HCl (3 x 50 mL), brine (1 x50 mL), dried (MgSO4), filtered, and concentrated in vacuo.

OAc

102

21

The crude residue was purified by distillation (72-74 °C) to provide acetate 102 (12.0 g,

70.0 mmol, 95%) as colorless oil. Spectral data was consistent with reported values.25

To a solution of acetate 102 (1.0 eq, 3.0 g, 17.6 mmol) in THF (90 mL)

at ambient temperature was added OsO4 (1 crystal) and sodium

periodate (1.5 eq, 5.7 g, 26.5 mmol) as a slurry in water (25 mL). The reaction was stirred

4 h, diluted with Et2O (100 mL) and washed with saturated sodium bicarbonate (3 x 50

mL), brine (1 x 50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude

residue was purified by column chromatography (7:1 hexanes/ ethyl acetate) to provide

aldehyde 104 (1.84 g, 10.7 mmol, 61%) as a colorless oil. Spectral data was consistent

with reported values. 25

To a solution of aldehyde 104 (1.0 eq, 900 mg, 5.2 mmol) in

CH2Cl2 (50 mL) at ambient temperature was added

formylmethylene triphenylphosphorane (1.0 eq, 1.6 g, 5.2 mmol). After warming to

reflux, the reaction was stirred 3 h. Celite (1 g) was added and the reaction was

concentrated in vacuo. The crude residue was purified by column chromatography (4:1

hexanes/ ethyl acetate) to provide aldehyde 106 (680 mg, 3.4 mmol, 66%) as a pale

yellow oil. 1H NMR (400 MHz CDCl3): δ 9.7 (d, J = 7.6 Hz, 1H), 6.75 (dd, J = 15.6, 4.8

Hz, 1 H), 6.21 (dd, J = 15.6, 7.6 Hz, 1H), 5.52 (dd, J = 6.8, 5.2, 1H), 2.13 (s, 3H), 1.75-

1.69 (m, 2H), 1.44-1.27 (m, 6H), 0.93-0.89 (m, 3H); 13C (100 MHz, CDCl3) δ 192.9,

170.0, 153.9, 131.4, 33.5, 31.3, 24.6, 22.3, 20.9, 13.9.

OAcO

103

OAc

106

CHO

22

To a solution of aldehyde 106 (1.0 eq, 198 mg, 1 mmol) in

EtOH (10 mL) at ambient temperature was added sodium

borohydride (1,0 eq, 380 mg, 10 mmol) and the reaction was stirred 1 h. The reaction

mixture was concentrated in vacuo and the crude residue dissolved in ethyl acetate (10

mL). The organics were washed with water (1 x 10 mL), brine (1 x 10 mL), dried

(MgSO4), filtered and concentrated in vacuo. The crude alcohol was lowered to – 20 °C.

Ethyl vinyl ether (10 eq, 740 mg, 10 mmol) was added and the reaction was allowed to

stir 5 minutes. N-bromosuccinimide (1.0 eq, 178 mg, 1 mmol) was added while

maintaining an internal temperature below 0 C. After 30 min, hexanes (10 mmol) was

added and the reaction filtered through a plug of celite. The organics were washed with

1N HCl (3 x 10 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude

residue was purified by flash column chromatography (6:1 hexanes/ ethyl acetate) to

provide acetal 108 (284 mg, 0.81 mmol, 81%) as a colorless oil. 1H NMR (400 MHz,

CDCl3) δ 5.83-5.68 (m, 2H), 5.27 (dd, J = 6.8, 6.4 Hz, 1 H), 4.71 (t, J = 5.6 Hz, 1H),

4.19-4.07 (m, 2H), 3.74-3.56 (m, 2H), 3.38 (d, J = 5.6 Hz, 1H), 2.06 (s, 3H), 1.66-1.54

(m, 2H), 1.30-1.21 (m, 6H), 0.91-0.88 (m, 3H); 13C (100 MHz, CDCl3) δ 170.3, 131.4,

128.3, 100.9, 73.9, 66.3, 62.4, 34.2, 31.6, 31.4, 24.7, 22.4, 21.2, 15.1, 13.9.

To a solution of bromoacetal 108 (1.0 eq, 40 mg, 0.11 mmol) in

benzene (5 mL) was added tributyl tin hydride (1.1 eq, 30 µL, 0.12

mmol). The solution was degassed and then AIBN (1 crystal) was added. Heated to reflux

(80 °C). After 3 hours, concentrated in vacuo. The residue was dissolved in Et2O (5 ml),

washed 2 x 5 mL 10% KF, dried (MgSO4), filtered through Celite, and concentrated in

OAc

108

O OEt

Br

OAc

109

4

OOEt

23

vacuo. The crude residue was purified by column chromatography (8:1 hexanes/ ethyl

acetate) to provide lactol 109 (23 mg, 0.08 mmol, 75%) as a colorless oil. 1H NMR (400

MHz, CDCl3) δ 5.29 (s, 1H), 5.12-5.08 (m, 1H), 4.91-4.83 (m, 1H), 3.78 (dt, J = 24, 8

Hz, 1H), 3.72 (ddd, J = 8, 7, 1 Hz, 1H), 3.47 (m, 2H), 2.35-2.15 (m, 2H), 2.04 (s, 3H),

1.73-1.60 (m, 2H), 1.49-1.43 (m, 4H), 1.30-1.19 (m, 6H), 0,9-0.86 (m, 3H) 13C (100

MHz, CDCl3) δ 170.7, 104.1, 73.4, 73.2, 71.6, 71.5, 39.3, 39.1, 37.3, 37.2, 35.4, 31.2,

24.8, 22.4, 15.1, 13.9.

To a solution of lactol 109 (1.0 eq, 80 mg, 0.30 mmol) in acetone (3

mL) added 1 mL of a solution of Jones reagent (1:9 Jones reagent:

acetone). The reaction was monitored by TLC. After 30 minutes, the reaction was

quenched with ethanol (1 mL). The reaction was diluted with ether (5 mL) and washed

with H2O (1 x 5 mL), sodium bicarbonate (1 x 5 mL), and brine (1 x 5 mL). The organics

were dried (MgSO4) and filtered. The crude residue was purified by column

chromatography (4:1 hexanes/ ethyl acetate) to provide lactone 110 (50 mg, 0.20 mmol,

71%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.90 (m, 1H), 4,42 (m, 1H), 3.93

(dd, J = 16, 8 Hz, 1H), 2.70-2.55 (m, 2H), 2.21 (dd, J = 16, 8 Hz, 2H), 2.06 (s, 3H), 1.73

(m, 2H), 1.58-1.53 (m, 3H), 1.27 (m, 6H), 0.90-0.87 (m, 3H) 13C (100 MHz, CDCl3) δ

176.7, 170.7, 73.2, 72.9, 72.4, 72.1, 37.4, 32.8, 31.5, 24.8, 22.4, 21.1, 13.9.

To a freshly prepared solution of LDA (1.0 eq, 0.10 mmol) in THF (1

mL) was added lactone 110 (1.0 eq, 25 mg, 0.10 mmol) at 0 °C.

Stirred at 0 °C for 1 hour, then cooled to -78 °C and added HMPA (20 µL) and methyl

OAc

110

4

OO

OAc

111

4

OO

CO2Me

24

cyanoformate (1.0 eq, 10 µL, 0.10 mmol). Stirred 30 min at -78 °C then poured reaction

into cold water (1 mL). Extracted (3 x 5 mL) Et2O, dried (MgSO4), and concentrated with

Celite. The crude residue was purified by column chromatography (4:1 hexanes/ ethyl

acetate) to provide ester 111 (18 mg, 0.07 mmol, 70%) as a colorless oil. 1H NMR (400

MHz, CDCl3) δ 4.69 (m, 1H), 4.46 (t, J = 8 Hz, 1H), 3.94 (t, J = 8 Hz, 1 H), 3.78 (s, 3H),

3.47 (d, J = 8 Hz, IH), 3.15 (dd, J = 16, 8 Hz, 1H), 2.43 (s, 3H), 1.78 – 1.74 (m, 2H),

1.35-1.20 (m, 6H), 0.90-0.88 (m, 3H).

To a solution of acetonide 99 (1.0 eq, 5 mg, 10 µmol) in CDCl3 (600

µL) in an NMR tube was added 1 drop of trifluoroacetic acid.

Reaction progress was monitored by NMR. After 1 hour, the reaction

was concentrated in vacuo and the crude residue was purified by column chromatography

(1:1 hexanes/ ethyl acetate) to provide diol 100 (2 mg, 4.0 µmol, 50%) as a white solid.

1H NMR (400 MHz, CDCl3) δ 7.37-7.31 (m, 5H), 6.95 (d, J = 1.5 Hz, 1H), 5.69 (d, J = 4,

1 Hz, 1H), 5.33 (td, J = 11.4, 4 Hz, 1H), 4.37 (dd, J = 18, 11.2 Hz, 2H), 4.14 (dd, J = 14,

6.7 Hz, 1H), 3.95 (m, 1H), 3.68-3.63 (m, 2H), 3.55 (dd, J = 7.8, 1.5 Hz, 1H), 3.35 (t, J =

8 Hz, 1H), 3.15 (t, J = 6 Hz, 1H), 2.90 (ddd, J = 10, 8, 1.8 Hz, 1H), 2.15 (s, 3H), 2.05 (d,

J = 1.8 Hz, 1H), 1.95 (s, 3H), 1.34 (s, 3H).

To a solution of diol 100 (1.0 eq, 3 mg, 6.0 µmol) in ethyl acetate (500

µL) at ambient temperature was added lead tetraacetate (3 mg). After 30

min, filtered reaction through a plug of celite and obtained aldehyde 84

(2 mg, 4 µmol, 75%) as a pure white solid. 1H NMR (400 MHz, CDCl3) δ 9.43 (s, 1H),

OAcOO

BnO Me

H

H

HO

O

Me

OHOH

100

OAcOO

BnO Me

H

H

H

CHOO

O

Me

84

25

7.38-7.31 (m, 5H), 7.02 (d, J = 1.4 Hz, 1H), 5.76 (s, 1H), 5.35 m, 1H), 4.37 (dd, J = 19,

11.4 Hz, 2H), 4.14 (dd, J = 14, 7 Hz, 1H), 3.59-3.51 (m, 2H), 2.90 (ddd, J = 10, 8, 2 Hz,

1H), 2.23 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H).

To a solution of aldehyde 84 (1.0 eq, 3 mg, 7.0 µmol) in CH2Cl2 (1

mL) was added formylmethylene triphenylphosphorane (1.0 eq, 2 mg,

7.0 µmol). The reaction was heated to reflux (40 °C). After 2 hours,

concentrated reaction with Celite and purified residue by column chromatography (1:1

hexanes/ ethyl acetate) to provide aldehyde 113 (2 mg, 4.0 µmol, 61%) as a white solid.

1H NMR (400 MHz, CDCl3) δ 9.53 (d, J = 7.6 Hz, 1H), 7.38-7.31 (m, 5H), 7.02 (d, J =

1.4 Hz, 1H), 6.73 (dd, J = 15, 6 Hz, 1H), 6.29 (dd J = 15.7, 6.7 Hz, 1H), 6.1 (d, J = 5.1

Hz, 1H), 5.29-5.25 (m, 1H), 4.35 (dd, J = 20, 11.3 Hz, 1H), 2.87 (dd, J = 16, 8 Hz, 1H),

2.16 (s, 3H), 1.91 (s, 3H), 1.5 (s, 3H).

OAcOO

BnO Me

H

H

HO

O

Me

CHO

113

26

Appendix A:

Spectra of Relevant Compounds

27

Figure A1 1H NMR spectra (400 MHz, CDCl3) of compound 103

OAc

O

103

28

Figure A2 13C NMR spectra (100 MHz, CDCl3) of compound 103

OAc

O

103

29


OAc

106

CHO

30


OAc

106

CHO

31


OAc

108

OOEt

Br

32


OAc

108

OOEt

Br

33


OAc

109

4

OOEt

34


OAc

109

4

OOEt

35


OAc 11

0

4

OO

36


OAc 11

0

4

OO

37


OAc 11

1

4

OO

CO2Me

38


OAc

OO

BnOMe

H

H

HO

O

Me

OH

OH

100

39


OAc

OO

BnOMe

H

H

H

CHO

OO

Me

84

40


OAc

OO

BnOMe

H

H

HO

O

Me

CHO

113

41

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