N. Z. Burns Gilbert Stork

December 31, 1921: Born in Brussels, Belgium

1939: Moved to US

1942: BS, University of Florida

1945: Ph.D., University of Wisconsin Advisor: S.M. McElvain

1945-1946: Senior Research Chemist, Lakeside Laboratories

1946-1948: Instructor, Harvard University

1948-1953: Assistant Professor, Harvard University

1953-1955: Associate Professor, Columbia Universtiy

1955-1967: Professor, Columbia University

1967-1993: Eugene Higgins Professor, Columbia University

1993-Present: Professor Emeritus, Columbia University

First Publication: Synthesis of 3,4-Diaminocarbethoxyfuran

OEtO2CHN

EtO2CHN

Lakeside Laboratories work: Practical Synthesis of Tetralones

JACS, 1945, 67, 884

OH H2 (2500 psi), Pd/C

N-ethylmorpholine175˚

O

40 %

OMe H2 (3400 psi)

Raney Ni, AcOH130˚

OMe

CrO3

OMe

O 60 %

• pH control of naphthol [H]

Aromatic steroids

JACS, 1946, 68, 2172

JACS, 1947, 69, 576

Note to reader: the following review is a surveyof the published work of Gilbert Stork. It ispresented in roughly chronological order and is not comprehensive by any means.

1

Gilbert Stork, age 40

Much of the information here (including all quotes) was taken from an interview conducted by the Chemical Heritage Foundation on August 6, 1991.

"The major thing that I have been concerned with in my scientific career has been control. . . Myown interest has been the control ofregiospecifity and of stereospecifity. Thatconcern is central to practically everything thatwe've done."

N. Z. Burns

First planned stereospecific synthesis: cantharidinJACS, 1951, 74, 4501JACS, 1952, 75, 384

O

CO2Me

CO2Me

OCO2Me

CO2MeO

SEt

SEt

O

Me

Me

OH

OHO

Me

Me

1. LAH

2. MsCl3. KSEt

1. OsO42. Raney Ni

OH

O

O

Me

Me

OH

Ph

O

Me

MePh

O

Me

Me

O

O

OO3; H2O2

1. HIO4

2. ∆

1. Stearoyl Cl2. ∆

cantharidin

PhLi

Gilbert Stork

2

"Burgstahler was such a great experimentalist. He finished cantharadin on July 4th, 1951 at four o'clock in the morning. I know that because first, it was Independence Day, andsecondly, I was supposed to catch the plane to Mexico at seven a.m. Thirdly, we finishedthe synthesis at four a.m. I know, because I was there to provide moral support.Burgstahler was a fervent Catholic who, every half-hour, would go up to the roof of thebuilding to sing a Gregorian chant so that the final product would crystallize. [laughter]"

O

OMe

Me

HO

Me

H

HH

Me

Stork

Syntex Mexico City, 1951

Romo

Djerassi

Rosenkranz

O

O

OH

OHMeOMe

H

H

H

cortisonediosgenin

Stork is an author on 3 of the Syntex steroid papers. "They would do this as a friendlything. One of them I had something to do with, another one they put my name on it, and one of them was embarrassing because nobody could repeat it. . . I remember BillJohnson making a public statement about it at an ACS meeting, that people shouldn'tpublish papers unless they give all the details. . . There was a Life magazine picture . . .This picture is about putting the C11 hydroxyl group in. That was very nice chemistry."

N. Z. Burns Gilbert Stork

NNH H

H

HNN

H H

H

H

The Stereospecific Synthesis of dl-Alloyohimbane and dl-3-EpialloyohimbaneJACS, 1954, 76, 949

Alloyohimbane 3-epi-Alloyohimbane

OTsR

N

R

NH

Xylenes, ∆

The Stereochemistry of the SN2' Reaction, JACS, 1953, 75, 4119

"That was good and bad. It turned out to be sort of the wrong kind of reactionto get involved with. It was intriguing at the time. It turned out to be: a) enormouslymore complicated than anyone knows; even today no one understands it, and b)not important. . . It became a known piece of work because there were not that manyqualitative mechanistic things at that time"

R = Me, i-Pr, t-Bu

A New Synthesis of 2-Alkyl and 2-Acyl Ketones, JACS, 1954, 76, 2029.

• First enamine paper

N1. R-X

2. H2O

OR R = Me, Bn, CH2CO2Et,

CH2CH2CN, Bz.

Me

HH

Me

OH

MeMe

Me

HH

MeMe

Me

The Structure of Cedrene, JACS, 1953, 75, 3291 (with R. Breslow).The Total Synthesis of Cedrol and Cedrene, JACS, 1955, 77, 1072.

"The [1953] paper was the first paper where there was actually an effort to correlate certain features of infrared with structure, specifically the difference between five and six membered cyclic anhydrides."

3

60 - 80 %

N. Z. Burns Gilbert Stork

Organic Colloquium, Harvard University, March 14, 1950.The Stereochemistry of Polyene Cyclization, JACS, 1955, 77, 5068.

Origin for Stork-Eschenmoser Hypothesis:

"The earliest documented suggestion that 1,5-polyolefin cyclizations to decalin ring systems might serve as the chemical model for the stereochemical relationship was made by Stork."- J. N. Johnston, Chem. Rev., 2005, 105, 4730.

". . . the conclusion being that cationic cencerted cyclization of a properly constructed acyclic polyene must necessarily give a trans polycyclic system. That's in there. But that the triterpene might come from squalene specifically, was not."

The Total Synthesis of a Naturally Ocurring Pentacyclic Triterpene SystemJACS, 1959, 81, 5516.JACS, 1963, 85, 3419.

O

OMe

1. MeMgBr

2. ArCO3H3. H3O+

Me

OMe

O

OMe

O

MeMVK, KOH

1. KOt-Bu, MeI2. H2, Pd/C

OMe

O

Me

Me

H

Me

1. Li/NH3

2. HCl3. Ac2O

O

AcO

Me

Me

H

Me

H1. O3; HIO4

2. CH2N23.

CO2Me

AcO

Me

Me

H

Me

H

HO OH

O

O 1. PhMgBr2. AcOH, ∆

3. Ac2O4. RuO4, NaIO4

CO2H

AcO

Me

Me

H

Me

HO

1. Resolution

2. Pt electrode 50 V

AcO

Me

Me

H

Me

HO

2

HO

Me

Me

H

Me

H

2

OEt

BrMg1.

2. H2SO43. KOH4. Cu, Quinoline ∆α-onocerin

4

N. Z. Burns Gilbert Stork

Stereochemistry of the Lithium-Ammonia Reduction of α,β-Unsaturated KetonesJACS, 1960, 82, 1512

O

MeOMe

O

MeOMe

H

Li/NH3

ROH

LiO

MeOMe

LiO

Me OMe

--

H R

"In reduction of an octalone system with lithium in ammonia the product will be the more stable of the two isomers (cis or trans) having the newly introduced hydrogen axial to the ketone ring."

The α-Alkylation of Enolates from Lithium-Ammonia Reductions of α,β-Unsaturated KetonesJACS, 1961, 83, 2965.

O

HLi/NH3;

MeI O

H

HMe

55 %

"a solution to the problem of directing alkylation to a specific α-carbon of an unsymmetrical ketone."

A Stereospecific Total Synthesis of GriseofulvinJACS, 1962, 84, 310.

O

OOMe

MeOCl

MeO

O

Me O

OOMe

MeOCl MeO

O

MeKOt-Bu

t-BuOH

griseofulvin(no epimer detected)

A Stereospecific Total Synthesis of 18-Substituted Steroids. Application to the Synthesis of dl-ConessineJACS, 1962, 84, 2018.

Me

H

CO2Me

Me

MeOH

Me

MeO

HOMe

O

O

1. O32. H+, MeOH

3. 4. LAH

HO OH

HMe

MeO

N MeO

H

1. TsCl2. H2, Pd/C3. H2NOH•HCl

HMe

HO

N Me

H

Ac

1. H2, Rh/C2. HBr

3. Ac2O

1. H2, Ru(OH)2

2. CrO3

5

N. Z. Burns

HMe

O

N Me

H

Ac

H

H

Gilbert Stork

HO

N Me

H

Ac

H

HHO2C

Me1. acrylonitrile, Triton B

2. H3O+

HO

N Me

H

Ac

H

H

Me

OH

N Me

H

Ac

H

H

Me

Me2N

1. MeMgI

2. HO-

3. Me2NH

1. NaBH4

2. Ca/NH33. HCO2H, H2CO

H

N Me

H

Me

H

H

Me

Me2N

conessine

Me

H2N

O

The Total Synthesis of dl-Aspidospermine and dl-QuebrachamineJACS, 1963, 85, 2872.

O Me

HN

O

O

1. LAH2. H3O+

3. HO-O Me

N

O

1.

2. KOt-Bu

Cl ClO

1.

2. LAH3. H3O+

HO OH

O Me

NOMe

NHNH21.

AcOH, ∆2. LAH3. Ac2O N

AcMe

N

OMeH

aspidospermine

7 steps to:

Stork Isoxazole Technology:JACS, 1967, 89, 5459.JACS, 1967, 89, 5460.JACS, 1967, 89, 5461.JACS, 1967, 89, 5463.JACS, 1967, 89, 5464.

NO2RN

R1

CO2Et

PhN O

Et3N N O

RCO2Et

R1

Synthesis:

N O

MeMe

Cl

1.

2. H2, Pd/C3. AcOH/NaOAc, ∆ N Me

O

Me

Application to Pyridines:

N

60 %

O

ON

Me Me

1. H2, Pd/C

2. KOH, ∆ O

Alternative to Robinson:

50 %

6

N. Z. Burns

Application to Steroids:

O

OHMe

ON

MeOO

Me

1. H2, Pd/C2. Raney Ni

3. KOH, ∆ Me

O

MeOH

H

HOO

Li/NH3;MeI

Me

O

MeOH

H

HOO

H

Me

MeOH

H

H

H

Me

Ohomotestosterone

1. H3O+

2. NaOMe

60 %

80 %

NH

OMe

O Me

H3PO4

HCO2H NH

OMe

O

Me

H

55 %

NTroc

OMe

Me

H 1. O3

2. SeO2, H2O2

1. NaOMe

2. Zn3. LAH4. CrO3

N

Me

H

NTroc

CO2MeOCHO

Me

H

OH

lycopodine

The Stereospecific Total Synthesis of dl-LycopodineJACS, 1968, 90, 1647.

Gilbert Stork

Isolation of Ketone Enolates as Trialklsilyl EthersJACS, 1968, 90, 4462.JACS, 1968, 90, 4464.

"One paper that I love is a paper by Ian Fleming . . . where the first sentance says, 'Stork introduced the TBS protecting group into organic chemistry,' which happens to be correct."

OSiMe3 OLiMeLi

SiMe4

A New Synthesis of Aldehydes via VinylsilanesJACS, 1971, 93, 2080.

R

1. Et3SiH cat. H2PtCl6

2. m-CPBA RSiEt3

O H3O+

RH

O

7

N. Z. Burns Gilbert Stork

The Total Synthesis of LupeolJACS, 1971, 93, 4945.

OBz

MeH

HO

O 3CH1. TsOH

2. ∆3. Et2AlCN

OBz

MeH

HO

CN

OBz

MeH

H

OH

O

O

HO OH1.2. LAH

3. Bz2O4. NaBH4

OH

MeH

HO

1. MsCl2. H+

3. HO-

OH

MeH

H

MeO

MeLi/NH3;

HMPA, MeI

OH

MeH

H

MeO

Me

O

1. Bz2O2. R2BH

3. Jones

1. EtMgBr2. HO-

3. Bz2O OBz

MeH

H

Me

Me

O

Me

OBz

MeH

H

Me

Me

O

Me

H

Li/NH3;

allylBr

MeH

H

Me

MeMe

H

HMe

Me

OAc

1. O3; NaBH42. CH2N2

3. TsCl4. NaHMDS, ∆

O

O

MeH

MeO2C

Me

H

H

Me

MeMe

H

HMe

MeHO

Me1. MeLi2. POCl3

3. H3O+

4. NaBH4

lupeol

Stork-Danheiser SynthesisJOC, 1973, 38, 1775.

O

O

Me

Me

1. LDA, allylBr

2. LAH; HCl80 %

O

O

O

O

R R2

R1

2,3,4-substituted cyclohexenones

RO

O1. Base, E+

2. Nu-; H+O

NuE

General:

i.e.:

8

N. Z. Burns Gilbert Stork

Stork-Ganem ReagentJACS, 1973, 95, 6152.

OLi

Et3SiMe

O1.

2. NaOMe O80 % (< 5 % with MVK)

Stork-Colvin ReagentJACS, 1974, 96, 3682.

Good for trapping regiospecifically generated enolates

Me

SiMe3

I

OLiMe

O

MeMe

O1.

2. m-CPBA82 %

MeOt-Bu

O

MeOt-Bu

TMSOH

MeOt-Bu

HO

MeOO

Me

OSiEt3

OOLi/NH3;

TMSCl

88 %

74 %

1. MeLi;

2. NaOMe

Stork-Ganem ShowcaseJACS, 1974, 96, 6181

Vinylogous Aldols and PolyenonesJACS, 1976, 98, 2351.

Me

Me

OMeMe

OMe

OLi Me

Me

MeMe

Me

HO Me O

then Red-Al; H3O+

40 %

α-Alkylation and Arylation of α,β-Unsaturated KetonesJOC, 1976, 41, 2937.

ONNMe2

Me1. PhMgBr

2. HCl, EtOH, ∆ MePh

O

77 %

Total Synthesis of (+)-15-(S)-Prostaglandin A2JACS, 1976, 98, 1583.

O O

OH OCO2Me

MeMe

1. MeC(OMe)3, H+, ∆ (83 %)

2. AcOH/H2O; Et3N

MeO2C

O

O

OHO

C(OMe)3

CO2Me

∆ then

K2CO3, MeOH59 %

from L-erythrose

9

N. Z. Burns Gilbert Stork

OHMeO2C

MeO2CCO2Me

OHH

OTsMeO2C

MeO2C

OEEH

CO2Me33 1. H2, Pd-BaSO4

2. TsCl3. Vinyl-ethyl ether (79 % overall)

Me

CO2H

O H

HOEE

4

3

1. n-Bu2CuLi2. t-BuOK3. NaOH (77 %)

Me

CO2H

O H

HOH

4

31. LDA; PhSeCl2. NaIO4

3. H3O+ (46 %)

(+)-15-(S)-Prostaglandin A2

OMe

O Me

Me OH

H2NNH2,

MeOH, ∆85 %

Five-and Six-Membered-Ring Formation from Olefinic α,β-Epoxy Ketones and HydrazineJACS, 1977, 99, 7067

A New Route to 11-Oxygenated SteroidsJACS, 1981, 103, 4948.

O

HO2CH

Me OTBS Me

Li4 equiv.

H

Me OTBSMe

MeO

OH

90 %

2 equiv. TFA

–78˚, 70 %

H

Me OTBSMe

O

Me

H

H 1. O3, 85 %

2. 40˚, 90 %

O

H

Me OTBS

Me

H

H

O

Cyclization of Vinyl Radicals: A New Versatile Method for the Construction of Five- andSix-Membered RingsJACS, 1982, 104, 2321.

MeMe

CO2MeMeO2C

Br

Me

CO2MeMeO2C

Me

Br

CO2MeMeO2CBu3SnH, AIBN

hv, ∆, 75 %

Bu3SnH, AIBN

hv, ∆, 75 %

OH

Me

CN

Br

Me

CNOH

Bu3SnH, AIBN

hv, ∆, 70 %

Me

H

O O ClO O

Cl

BrMe Bu3SnH, AIBN

hv, ∆, 75 %

Vinyl Radical Cyclization. 2JACS, 1983, 105, 3720.

10

N. Z. Burns Gilbert Stork

Control of Ring Junction Stereochemistry via Radical CyclizationJACS, 1985, 107, 500.

Me Ot-Bu

HOSiMe

Me

Me Ot-Bu

OSiMe

Me Br

Bu3SnH, AIBN

hv, ∆, 36 %(unoptimized)

A Catalytic Tin System for Trapping of Radicals from Cyclization ReactionsJACS, 1986, 108, 303.

OOI

OEt OEt

CN

20 eq. t-BuNC0.1 eq. Bu3SnCl

0.1 eq. AIBN

2 eq. NaBH3CNt-BuOH, ∆, 60 %

O O

Me

Me

O O

Me

Me

O O

Me

MeO O

Me

Me

O O

Me

Me

OH

OH

MeMe

Me OH

OH

Me

Iterative Butenolide Construction of Polypropionate ChainsJACS, 1987, 109, 1564.

O O

Me

Me

OHMe 1. TMSNMe22.

3. K2CO3, MeOH 54 %

OEt

OLi O

OO

H

OH

MeMe

Me 1. BnBr, PTC2. Ac2O, (54 %)

OO

BnO

Me

MeOAc

MeO

O

Me

MeOAc

Me 1. H2, Rh/alumina

2. MsCl, Et3N (90 %)

HH

An Approach to Gelsemine TL, 1987, 28, 1035.

O

BrMeO2C

H

OEt

Bu3SnH, AIBN

∆, 95 %

O

MeO2C

H

OEtH

OH

OBocH

O

O

Ph

O

O

OPh

OBoc

O

O O

PhTMSOTf

67 %

O

HO O

Ph LDA, TMSCl

96 %

O

NHO

NMe

gelsemine

11

etc.

N. Z. Burns Gilbert Stork

Stork-Zhao DethioacetalizationTL, 1989, 30, 287.

RS

S 1.5 eq. PhI(TFA)2

9:1 MeOH/H2OR

O

H1-10 min.84-99 %

R = ester, nitrile, amide, OH halide, alkene, alkyne.

In pure methanol, dimethyl acetal formed.Works on ketones too.

The Stereospecific Synthesis of ReserpinePAC, 1989, 61, 439.

OLi

BnOSi

CO2Me

Me MeO

–78˚

88 %

OMeO2C

Si

OBn

OMe

Me

1. TBAF, RT2. H2, Pd/C

3. TsCl (64 %)

OMeO2C

SiMe2F

OTs1. m-CPBA, (60 %)

2. MeI, Ag2O3. DiBAL-H, (84 %)

OMeOHMeO2C

OTs

OMeO-tryptamine,

KCN, (87 %)

OMeOHMeO2C

NNH

MeONC

HCl/THF (90 %)

OMeOHMeO2C

NNH

MeOH

H

H H

H

methyl reserpate

Total Synthesis of (–)-HistrionicotoxinJACS, 1990, 112, 5875.

CO2Me OTBS

OBr

LDA, –78˚ to RT;

LDA, –78˚ to RT(43 %)

O

OOTBS

3

1. O32. (52 %)

Ph3PI

O

OOTBS

3II

1. HCl/THF2. PPh3, CBr4 (53 %)

3. NH4Cl, AlMe3

OHBr

3II

H2N O

1. Ac2O (70 %)2. PhI(TFA)23. Et3N, ∆ (31 %)

OAc

I

HNI

1. Pd(PPh3)4, CuI

2. TBAF3. K2CO3 (40 %)

TMS

OHHN

histrionicotoxin

O

OMeO

BnOBnO

O

Bn

SiMe2Cl OBnO

BnO

OBnOH

SPh

OBnO

BnO

OBnOH

O

OMeO

BnOBnO

Bn

O1.

2. m-CPBA; Tf2O, pyr. (61 %)

Stereocontrolled Synthesis of Disaccharides via the Temporary Silicon ConnectionJACS, 1992, 114, 1087.

12

N. Z. Burns Gilbert Stork

The Total Synthesis of a Natural Cardenolide: (+)-DigitoxigeninJACS, 1996, 118, 10660.

O

O

O

Me

H

1. TMSCl, Et3N2. O3

3. NaBH44. NaIO4, (71 %)

O

O

O

Me

H

O

MeMe

HS S

O

O

Me

H

O

O

S

SMe

H

H 200˚

36 h (75 %)

Me

H

MeH

HTBSO

OH

Me

H

Me

H

HTBSO

OH

Bu3SnH, AIBN

then SiO2 (40 %)

Me

H

Me

H

HHO

OH

O

O

digitoxigenin

The First Stereoselective Total Synthesis of QuinineJACS, 2001, 123, 3239.

OO

1. Et2NH, AlMe3; TBSCl

2. LDA, (62 %)

I OTBDPS

Et2NOTBS

O

OTBDPS

PPTS; ∆

(93 %)

OO

TBDPSO1. DiBAl-H;

2. PPh3, DEAD DPPA; HCl (56 %)

Ph3POMe

TBDPSO

N3O

NMeO

Li

NMeO

O N3

OTBDPS

1. 2. Swern (60 %)

NMeO

NH

OTBDPS

H1. PPh3, ∆

2. NaBH4 (74 %)

N

N

MeO

1. HF2. MsCl3. ∆ (65 %)

NaH/DMSO; O2

(dr 14:1, 78 %)

N

N

MeO

OH

(–)-quinine

13