The Career of Larry E. Overman
Pierce Group Meeting
Presented by Yunlong Shi
4/7/2015
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
164/129/457
Total synthesis / JACS / total
entries on Web of Science
* (under the name of Overman LE, as of 4/5/2015)
Awards / Honors
ACS Arthur. C. Cope Award (2003)
ACS Creative work in Synthetic Organic Chemistry (1995)
2011 - UCI Medal, University of California, Irvine, American Chemical
Society,
2010 - Herbert C. Brown Award for Creative Research in Synthetic
Methods,
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 for
Research,
2002 - Yamada Prize
1999 - 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 in
Synthetic Organic Chemistry,
1993 - 1994 - Guggenheim Fellowship,
1993 - C.S. Hamilton Award, University of Nebraska
1985 - 1992 - Javits Neuroscience Investigator Award
1989 - American Chemical Society Arthur C. Cope Scholar Award
- Visiting Miller Research Fellow, U.C. Berkeley
1985 - 1987 - Alexander von Humboldt U.S. Senior Scientist Award,
1976-1981 Camille and Henry Dreyfus Teacher-Scholar Award
1981 - U.C. Irvine School of Physical Sciences Distinguished Teaching
Award,
1979 - U.C. Irvine Alumni Association Distinguished Research Award
1975-1977 - Alfred P. Sloan Foundation Fellow
M
“
y 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
Contents of this talk...
Method Development
Selected Total Syntheses
•
•
•
•
• Strychnine
• Sarain A
• Polycyclic Guanidine Alkaloids
Overman Rearrangement
Aza-cope Mannich Reaction
Prins-Pinacol Rearrangement
Intramolecular Heck Reaction
Overman Rearrangement (1974)
Rearrangement of trichloroacetimidates
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
Overman Rearrangement: Applications
Synthesis of amino acids
Synthesis of glycosyl ureas
J. Am. Chem. Soc., 2002, 124, 12225
J. Am. Chem. Soc. 2008, 130, 11210.
Overman Rearrangement: Applications
Synthesis of amino acids
Synthesis of glycosyl ureas
J. Am. Chem. Soc., 2002, 124, 12225
J. Am. Chem. Soc. 2008, 130, 11210.
Aza-cope/Mannich Reaction (1979)
Homoallylic amines w/ an allylic hydroxyl group  3-acylpyrrolidines
Irreversibly traps the rearranged iminium ion
Positive charge
decreases the activation barrier
Alternative mechanism
Ruled out because:
1) Epimerization at C-(R1)
2) Reaction works well when R4 is EWG
J. Am. Chem. Soc. 1979, 101, 1310
J. Am. Chem. Soc. 1988, 110, 4329
Aza-cope/Mannich Reaction: Applications
Total 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
Construction of the DE ring
in the enantioselective total synthesis of
(+) and (-) strychnine
98%, multigram scale
J. Am. Chem. Soc., 1995, 117, 5776
Prins-Pinacol Rearrangement (1987)
Allylic acetals  tetrahydrofurans
J. Am. Chem. Soc., 1987, 109, 4748
Prins-Pinacol Rearrangement: Applications
Total syntheses enabled by Prins-Pinacol Rearrangement in Overman Lab
(-)-Magellanine
(+)-Shahamin K
(-)-7-Deacetoxyalcyonin Acetate
Briarellins E and F
and more...
Example: (-)-Magellanine Synthesis (1993)
J. Am. Chem. Soc. 1993, 115, 2992
Asymmetic Intramolecular Heck Reactions (1989)
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
Colorless crystalline
Pesticide (birds and rodents)
Neurotoxin, acts as an antagonist of glycine and acetylcholine
receptors
LD50 = 0.16 mg/kg in rats, 1-2 mg/kg orally in humans
1818 -- Isolation in pure form
1946/1947 -- 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
A List of
Strychnine
Total
Syntheses
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
Overman Synthesis of Strychnine: Retrosynthetic Analysis
Overman Synthesis of Strychnine: Retrosynthetic Analysis (cont’d)
Ketone reduction
Syn dehydration
DIBAL-H ester reduction
Enol triflate
Stille carbonylation
Epoxidation from less hindered face
SN 2
Intramolecular epoxide opening
Remove CF3CO
Indoline formation
Reduction from β-face
DIBAL-H reduction
Base-promoted epimerization
Known transformation
developed in 1950s
Intermediate
Sarain A
Two marcocycles, two sec-amines
>5 partial syntheses before this work
Monoreduction of diester
directed by α-hydroxyl group
Oxazoline formation
methyl
benzimidate
hydrochloride
> 20:1 dr (desired isomer)
Amidation by AlMe3
Oxazoline cleavage
and translactamization
Thermolysis of Boc
Allylation
Two-step reduction of pyrrolidinone (DIBAL-H/NaBH3CN)
Thermolysis of Boc (selective)
Lactonization
Reduction 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) marcocycle
One of the challenges for previous formal synthesis
d.r. = 3-4 : 1
(chelation of the
Grignard reagent)
Dia. separated
Finally
Forming the marcocycle by
intramolecular Stille coupling
End game – reveal the aldehydetertiary amine interaction
Biginelli Reaction and Polycyclic Guanidine Alkaloids
“Biomimetic”synthesis (example: Snider’s synthesis of ptilomycalin A)
Overman’s approach using tethered Biginelli reaction
J. Am. Chem. Soc., 1994, 116, 549
J. Am. Chem. Soc., 1995, 117, 265
Review: Chem. Commun., 2004, 253
Tethered Biginelli Reaction: Tuning the Stereoselectivity
Thermodynamically more
stable
How to control the
stereochemistry?
Chem. Commun., 2004, 253
Tethered Biginelli Reaction: Tuning the Stereoselectivity
Cis selectivity
Knoevenagel Pathway
Morpholinium acetate - basic condition
Trans selectivity
Imminium Pathway
PPE (Polyphosphate ester) - acidic dehydrating cond.
Exception: when X=NH2+ (guanidine)
Iminium pathway
Reason:
Guanidine is more electron rich than
urea 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
★
★
★
PNAS 2004, 101, 14079
Inhibition of protein-protein interaction
(at 5 µM)
Summary
Quaternary chiral centers
Overman’s
work
Method Development
Stereoselection