The Career of Larry E. Overman Pierce Group Meeting Presented by Yunlong Shi 4/7/2015.

transcript

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)

Cl3CCNcat. base

or PdII / HgII

NH 3 M NaOH

5% COP-Cl

DCM, 23-38oCHN

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

1) HBCy2

2) ZnMe2

3) L*, PhCHOR

1) Cl3C-CN, KH

2) PhCH3, reflux R Ph

NHCHCCl3 [O]

R CO2H

NHCHCCl3

Synthesis of glycosyl ureas

O OOCl3C

t-Bu Neutral Pd(II)Cationic Pd(II)SiO

HNCCl3

t-Bu HN

1) OsO4, NMO2) Cs2CO3, RR'NH

t-Bu OH HN O

HOOOSi

t-Bu OH

J. Am. Chem. Soc., 2002, 124, 12225J. Am. Chem. Soc. 2008, 130, 11210.

Overman Rearrangement: Applications

Synthesis of amino acids

1) HBCy2

2) ZnMe2

3) L*, PhCHOR

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

O OOCl3C

t-Bu Neutral Pd(II)Cationic Pd(II)SiO

HNCCl3

t-Bu HN

1) OsO4, NMO2) Cs2CO3, RR'NH

t-Bu OH HN O

HOOOSi

t-Bu OH

Aza-cope/Mannich Reaction (1979)

HO 2-aza-Coperearrangement

OMannichcyclization

pinacolrearrangement

R4 R4 R4 R4

R4aza-Prins

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

(CH2O)n

Na2SO4

80oC NR2

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

Lewis acid(e.g SnCl4)

H3CH3C

CH3H3C

Pinacol

6-endo-trig(5-endo-trig not permitted)

Prins-Pinacol Rearrangement: Applications

Example: (-)-Magellanine Synthesis (1993)

Magellanine

HTIPSO

SnCl4DCM, -78 to -23oC

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)

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

Wieland-Gumlichaldehyde

Typically60-80% yield Reduction

Indolineformation

Aza-CopeMannich

Stillecoupling

Tsuji-Trost

OCO2Me

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

R=TBDPS

1:1 mixture of E/Z isomers

OMeH2N

4:1 mixture52%

NH3, NH4OAc, tBuOH

ORHN OH

1:1 mixture of two cis diastereomers

60 °C

ptiliomycalin A

“Biomimetic”synthesis (example: Snider’s synthesis of ptilomycalin A)

Overman’s approach using tethered Biginelli reaction

OOTBDMSN

OH morpholine, HOAc, EtOH

Na2SO4, 70 °C

TBDMSOH

dr = 7.5:1

ptilomycalin AJ. Am. Chem. Soc., 1994, 116, 549J. Am. Chem. Soc., 1995, 117, 265Review: Chem. Commun., 2004, 253

Tethered Biginelli Reaction: Tuning the Stereoselectivity

(CH2)6CH3

batzelladine F

Thermodynamically more stable

How to control the stereochemistry?

Chem. Commun., 2004, 253

Tethered Biginelli Reaction: Tuning the Stereoselectivity

(CH2)6CH3

batzelladine F

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

The Career of Larry E. Overman Pierce Group Meeting Presented by Yunlong Shi 4/7/2015.

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