n. z. burns gilbert stork - the scripps research … ni, acoh 130˚ ome cro3 ome o60% • ph control...
TRANSCRIPT
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