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