The Career of Larry E. Overman
Pierce Group MeetingPresented by Yunlong Shi
4/7/2015
Awards / HonorsACS Arthur. C. Cope Award (2003)ACS Creative work in Synthetic Organic Chemistry (1995)2011 - UCI Medal, University of California, Irvine, American ChemicalSociety,2010 - Herbert C. Brown Award for Creative Research in SyntheticMethods,2008 - Tetrahedron Prize for Creativity in Organic Chemistry,2007 - The Nagoya Medal of Organic Chemistry,2005 - International Society of Heterocyclic Chemistry Senior Award,2004 - Ta-shue Chou Lectureship Award,2003 - American Chemical Society Arthur C. Cope Award,2002-2003 U.C. Irvine Distinguished Faculty Lectureship Award forResearch,2002 - Yamada Prize1999 - Japan Society for the Promotion of Science Fellowship,- S. T. Li Prize for Achievements in Science and Technology,- Earlham College Distinguished Faculty Award,1997 - Centenary Medal, Chemical Society, U.K.1995 - American Chemical Society Award for Creative Work inSynthetic Organic Chemistry,1993 - 1994 - Guggenheim Fellowship,1993 - C.S. Hamilton Award, University of Nebraska1985 - 1992 - Javits Neuroscience Investigator Award1989 - American Chemical Society Arthur C. Cope Scholar Award- Visiting Miller Research Fellow, U.C. Berkeley1985 - 1987 - Alexander von Humboldt U.S. Senior Scientist Award,1976-1981 Camille and Henry Dreyfus Teacher-Scholar Award1981 - U.C. Irvine School of Physical Sciences Distinguished TeachingAward,1979 - U.C. Irvine Alumni Association Distinguished Research Award1975-1977 - Alfred P. Sloan Foundation Fellow
164/129/457
* (under the name of Overman LE, as of 4/5/2015)
Total synthesis / JACS / totalentries on Web of Science
Larry E. Overman
• Born in 1943 (Chicago, Illinois)• B.A., Earlham College (-1965)• Ph.D., University of Wisconsin (-1969)
*Professor Howard W. Whitlock• NIH postdoctoral fellowship Columbia
University
*Professor Ronald Breslow (-1971)• Distinguished Professor of Chemistry,
University of California, Irvine • Editor-in-chief, Organic Reactions
“My fascination with rearrangement reactions is easily traced to the fall of 1965, just after I had begun graduate school in the Chemistry Department at the University of Wisconsin, Madison. I was in the office of Howard Whitlock, Jr. to discuss potential research opportunities in his laboratory. He outlined, gloriously as I remember with a fountain pen on white paper, the polyene cyclization and backbone rearrangement steps of the postulated biosynthesis of lanosterol from squalene oxide. As a potential dissertation project, Whitlock suggested examining in model systems whether or not backbone rearrangements take place in a concerted fashion. I was fascinated.”
Tetrahedron 2009, 65, 6432
Method Development Selected Total Syntheses
• Overman Rearrangement• Aza-cope Mannich Reaction• Prins-Pinacol Rearrangement• Intramolecular Heck Reaction
• Strychnine• Sarain A• Polycyclic Guanidine Alkaloids
Contents of this talk...
Overman Rearrangement (1974)
R
OH
R'
Cl3CCNcat. base
R
O
R'
CCl3
NH
heat
or PdII / HgII
R
O
R'
CCl3
NH 3 M NaOH
R R'
NH2
HN
CCl3
O
R
5% COP-Cl
DCM, 23-38oCHN
CCl3
O
R
73-98% yield92-97% ee
Catalytic Asymmetric Version (1997, 1999, 2003, 2012)
J. Am. Chem. Soc. 1974, 96, 597.J. Org. Chem. 1997, 62, 1449.J. Am. Chem. Soc., 1999, 121, 2933.J. Am. Chem. Soc. 2003, 125, 12412.J. Org. Chem. 2012, 77, 1939.
Difficulty: metal complexes the imidate nitrogen atom -- causing elimination
Rearrangement of trichloroacetimidates
Overman Rearrangement: Applications
Synthesis of amino acids
R
1) HBCy2
2) ZnMe2
3) L*, PhCHOR
OH
Ph
1) Cl3C-CN, KH
2) PhCH3, reflux R Ph
NHCHCCl3 [O]
R CO2H
NHCHCCl3
Synthesis of glycosyl ureas
SiO
O OOCl3C
NH
t-Bu
t-Bu Neutral Pd(II)Cationic Pd(II)SiO
O O
t-Bu
t-BuH
HNCCl3
O
SiO
O O
t-Bu
t-Bu HN
O
CCl3H
1) OsO4, NMO2) Cs2CO3, RR'NH
1) OsO4, NMO2) Cs2CO3, RR'NH
OOSiO
t-Bu
t-Bu OH HN O
NRR'
HOOOSi
O
t-Bu
t-Bu OH
HO
HN
O
CCl3
J. Am. Chem. Soc., 2002, 124, 12225J. Am. Chem. Soc. 2008, 130, 11210.
Overman Rearrangement: Applications
Synthesis of amino acids
R
1) HBCy2
2) ZnMe2
3) L*, PhCHOR
OH
Ph
1) Cl3C-CN, KH
2) PhCH3, reflux R Ph
NHCHCCl3 [O]
R CO2H
NHCHCCl3
J. Am. Chem. Soc., 2002, 124, 12225J. Am. Chem. Soc. 2008, 130, 11210.
Synthesis of glycosyl ureas
SiO
O OOCl3C
NH
t-Bu
t-Bu Neutral Pd(II)Cationic Pd(II)SiO
O O
t-Bu
t-BuH
HNCCl3
O
SiO
O O
t-Bu
t-Bu HN
O
CCl3H
1) OsO4, NMO2) Cs2CO3, RR'NH
1) OsO4, NMO2) Cs2CO3, RR'NH
OOSiO
t-Bu
t-Bu OH HN O
NRR'
HOOOSi
O
t-Bu
t-Bu OH
HO
HN
O
CCl3
Aza-cope/Mannich Reaction (1979)
N
R2
HO 2-aza-Coperearrangement
N
R2
OMannichcyclization
H
N
O
H
R2
NH
R2
HO
R3 R3
R3
H+
N
HO
R2
R3
pinacolrearrangement
R1
R3CHO
R1 R1
R1
R4 R4 R4 R4
R4aza-Prins
R1
Positive chargedecreases the activation barrier
Homoallylic amines w/ an allylic hydroxyl group 3-acylpyrrolidines
J. Am. Chem. Soc. 1979, 101, 1310J. Am. Chem. Soc. 1988, 110, 4329
Irreversibly traps the rearranged iminium ion
Alternative mechanism
Ruled out because:1) Epimerization at C-(R1)2) Reaction works well when R4 is EWG
Aza-cope/Mannich Reaction: ApplicationsTotal syntheses enabled by Aza-cope/Mannich reaction in Overman Lab:
(±)-Gelsemine (2005)(±)-Dehydrotubifoline and (±)-Akuammicine (1993)(+) and (-)-Strychnine (1995, 1993)(±)-Deoxoapodine, (±)-Meloscine, (±)-Epimeloscine and 1-Acetylaspidoalbidine* (1991)(±)-6a-Epipretazettine (1990)(-)-Crinine (1985)and more...* Formal Syntheses
NR2
N
H
HO
tBuO
(CH2O)n
Na2SO4
MeCN
80oC NR2
N
HO
tBuO
CH2
NR2
N
HO
tBuO
CH2
NR2
CH2
N
O
tBuO
98%, multigram scale
Construction of the DE ringin the enantioselective total synthesis of (+) and (-) strychnine
J. Am. Chem. Soc., 1995, 117, 5776
Prins-Pinacol Rearrangement (1987)Allylic acetals tetrahydrofurans
J. Am. Chem. Soc., 1987, 109, 4748
O
O
H3C
CH3
H3C
RR
CH3
Lewis acid(e.g SnCl4)
OH3C
CH3
R RO
O
CH3
R
RCH3
OH
H3CH3C
HO
HO
H3C
R
R
CH3H3C
Prins
Pinacol
6-endo-trig(5-endo-trig not permitted)
Prins-Pinacol Rearrangement: Applications
Example: (-)-Magellanine Synthesis (1993)
O
MeN
MeH
OH
H
H
H
Magellanine
H
HTIPSO
O O
SnCl4DCM, -78 to -23oC
O
H
O
H
H
H
57%, 2:1 dr
J. Am. Chem. Soc. 1993, 115, 2992
Total syntheses enabled by Prins-Pinacol Rearrangement in Overman Lab
(-)-Magellanine(+)-Shahamin K(-)-7-Deacetoxyalcyonin AcetateBriarellins E and Fand more...
Asymmetic Intramolecular Heck Reactions (1989)
O
OTf10 mol% Pd(OAc)2 10 mol% (R,R)-DIOP
NEt3, benzene, rtO
90%, 45% ee(R,R)-DIOP
First report (also see Shibasaki, M. J. Org. Chem. 1989, 54, 4738)
J. Org. Chem. 1989, 54, 5846
Tandem Heck-πallyl reactions in total synthesis
Strychnine
1818 -- Isolation in pure form1946/1947 -- Structure Determination (R. Robinson and R. B. Woodward)
“For its molecular size it is the most complex substance known”
-- R. Robinson (Nobel Prize for Chemistry, Alkaloid Chemistry, 1947)
1954 -- Woodward First Total Synthesis 28 Steps, 0.00006% yield “If we can't make strychnine, we'll take strychnine!"”
-- R. B. Woodward
Colorless crystalline Pesticide (birds and rodents)Neurotoxin, acts as an antagonist of glycine and acetylcholine receptorsLD50 = 0.16 mg/kg in rats, 1-2 mg/kg orally in humans
Christopher D. Vanderwal Racemic Formal synthesis 2011
David W. C. MacMillan Single enantiomer Total synthesis 2011
Hans-Ulrich Reissig Racemic Formal synthesis 2010
Rodrigo B. Andrade Racemic Total synthesis 2010
Albert Padwa Racemic Total synthesis 2007
Tohru Fukuyama Single enantiomer Total synthesis 2004
Graham J. Bodwell Racemic Formal synthesis 2002
Masakatsu Shibasaki Single enantiomer Total synthesis 2002
Miwako Mori Single enantiomer Total synthesis 2002
Stephen F. Martin Racemic Formal synthesis 2001
Joan Bosch Single enantiomer Total synthesis 2000
Peter C. Vollhardt Racemic Formal synthesis 2000
Martin E. Kuehne Single enantiomer Total synthesis 1998
Viresh H. Rawal Racemic Formal synthesis 1994
Larry E. Overman Single enantiomer Total synthesis 1993
Martin E. Kuehne Racemic Total synthesis 1993
Philip Magnus Single enantiomer Total synthesis 1992
Robert B. Woodward Single enantiomer Total synthesis 1954
Source: Synarchive.com
A List ofStrychnineTotalSyntheses
Overman Synthesis of Strychnine: Retrosynthetic Analysis
N
N
OO
H H
A B C
DE
FG
NHHO
N
OH H
Wieland-Gumlichaldehyde
Typically60-80% yield Reduction
NH
CO2Me
N
H H
OH
Indolineformation
NR2N
OtBu
O
HNR2
CH2
N
O
tBuO
Aza-CopeMannich
NR2
N
H
HO
tBuO
NR2
N
H
HO
tBuO
NR2
tBuO
NR2O
NR2
O
OTIPS
tBuO
Stillecoupling
NR2
OTIPS
tBuO
SnMe3
I
OTIPS
tBuO
O
Tsuji-Trost
OEt
tBuO
AcO
OCO2Me
OO
Obtained fromenzymatic resolutionw/ high ee (>99%)
Overman Synthesis of Strychnine: Retrosynthetic Analysis (cont’d)
Syn dehydration
Ketone reduction
DIBAL-H ester reduction
Enol triflate
Stille carbonylation
Epoxidation from less hindered face
SN2 Intramolecular epoxide opening
Remove CF3CO
Indoline formation
Reduction from β-face Base-promoted epimerization
DIBAL-H reductionKnown transformationdeveloped in 1950s
Intermediate
Sarain A
Two marcocycles, two sec-amines>5 partial syntheses before this work
Monoreduction of diesterdirected by α-hydroxyl group
Oxazoline formation
methyl benzimidate
hydrochloride
> 20:1 dr (desired isomer)Thermolysis of Boc
AllylationAmidation by AlMe3
Oxazoline cleavageand translactamization
Allylation
Two-step reduction of pyrrolidinone (DIBAL-H/NaBH3CN)
Thermolysis of Boc (selective)
LactonizationReduction of lactone to lactol Tetracycle formation
Direct conversion to OTIPS enolate was not successful
N-Ts Removal
Reductive amination
Selective removal of TBS Rearrangement
Goal – bulid the second (triene) marcocycleOne of the challenges for previous formal synthesis
d.r. = 3-4 : 1(chelation of theGrignard reagent)
Dia. separated
FinallyForming the marcocycle by intramolecular Stille coupling
End game – reveal the aldehyde-tertiary amine interaction
Biginelli Reaction and Polycyclic Guanidine Alkaloids
Me
OR
O ORO
R=TBDPS
MeO2C
1:1 mixture of E/Z isomers
NH
OMeH2N
Me
OR
N O
Me
RO
MeO2C
N
OMe
H H
4:1 mixture52%
NH3, NH4OAc, tBuOH
72%
Me
ORHN OH
Me
RO
MeO2C
NH H
HN
1:1 mixture of two cis diastereomers
60 °C
Me
NH
N
NH OO
Me
HH
MeX-
CO2R
ptiliomycalin A
“Biomimetic”synthesis (example: Snider’s synthesis of ptilomycalin A)
Overman’s approach using tethered Biginelli reaction
CO2R
OOTBDMSN
O
H2N
HO
OH morpholine, HOAc, EtOH
Na2SO4, 70 °C
N
OH
HN
O
CO2R
TBDMSOH
dr = 7.5:1
+NH
N
NH OO
Me
HH
MeX-
CO2R
ptilomycalin AJ. Am. Chem. Soc., 1994, 116, 549J. Am. Chem. Soc., 1995, 117, 265Review: Chem. Commun., 2004, 253
Tethered Biginelli Reaction: Tuning the Stereoselectivity
NH
N
NH
(CH2)6CH3
H
HH
H
HO
MeNH
N
NH
H
HH
H
Me 5
O
batzelladine F
Me2X-
Thermodynamically more stable
How to control the stereochemistry?
Chem. Commun., 2004, 253
Tethered Biginelli Reaction: Tuning the Stereoselectivity
NH
N
NH
(CH2)6CH3
H
HH
H
HO
MeNH
N
NH
H
HH
H
Me 5
O
batzelladine F
Me2X-
Cis selectivityKnoevenagel PathwayMorpholinium acetate - basic condition
Trans selectivity Imminium PathwayPPE (Polyphosphate ester) - acidic dehydrating cond.
Exception: when X=NH2+ (guanidine)
Iminium pathway
Reason:Guanidine is more electron rich thanurea and N-sufonylguanidine Loss of HY more favorable Favors iminium formation
Chem. Commun., 2004, 253
Small-molecule Inhibitors of the HIV-1 Protein Nef.
Missing Nef protein = fail to progress to AIDS
Inhibition of protein-protein interaction(at 5 µM)★
★
★
PNAS 2004, 101, 14079
Summary
Quaternary chiral centers
Method Development Stereoselection
Overman’swork