Baran Group Meeting
The Chemistry of Barry B. Snider
Born:
-January 13th, 1950, Chicago, Illinois
Education:
-B.Sc. Chem. University of Michigan, Ann Arbor, MI, 1970
-Ph. D.: Harvard University, Cambridge, MA, 1973 (advisor: E.J. Corey)
-PostDoc: Columbia University, New York, NY 1973-1975 (advisor: Ronald Breslow)
Paul Krawczuk
Barry B. Snider
Independent Career:
-Assistant Professor, Princeton University, 1975-1981
-Associate Professor, Brandeis University, 1981-1985
-Professor, Brandeis University, 1985-present
Research Interests:
-Total synthesis of biologically active natural products with structural novelty of the ring system or functionality
-Method development especially oxidative free-radical cyclizations, ene reactions, Lewis acid catalyzed
reactions
1
The Chemistry of Barry B. Snider
Baran Group Meeting
Paul Krawczuk
Allylic Cyanobis(methylthio)methylation. Insertion of a Functionalized Carbon in an Allylic Carbon-Hydrogen Bond. JACS 1976, 98, 7116-7117.
S
S
MeS
SMe
S
CN
CN
110°C, PhMe
sealed tube
BuLi or LDA
MeI
CN
3:1 THF:HMPA
SMe
SMe
CN
SMe
CN
Raney-Ni
EtOH
72%
83%
83%
Nickel-Catalyzed Addition of Grignard Reagents to Silylacetylenes. Synthesis of Tetrasubstituted Alkenes. JACS 1978, 100, 4624-4626.
R
TMS
Me
MeMgBr
10% 1:1
Ni(acac)2/AlMe3
R
M
TMS
Me
E+
48-75%
R
E
TMS
Me
R
TMS
various electrophiles used:
Br
E
HCHO
I2
TMS group allows for separation on silica,
without it the olefin isomers are inseparable
Reactions of Phenylhydrazones with Electron-Deficient Alkenes. JOC 1979, 44, 218-221.
Ph
NPh
Ph
N
N
hydroquinone
N
H CN
in contrast to:
NH
120°C, PhH
N
CN
71%
CHO
Ph
MeI
30°C, PhH
with vinyl bromide a diene is
formed, presumably through a
nickel catalyzed process.
CO2
Br
Ph
HN N
O2N
also with methyl
acrylate in 48%
Ph
N N
air
Ph
Ph
NO2
NO2
Lewis Acid Induced Conjugate Additon of Alkenes to !,"-Unsaturated Ketones and Aldehydes. JACS 1980, 102, 5872-5880.
O
2 equiv.
EtAlCl2
O
OAlH
H
deuterium labeling studies show that there are two 1,2-hydride shifts
EtAlCl2
also
O
-AlO
H
H
O
2
The Chemistry of Barry B. Snider
Baran Group Meeting
Paul Krawczuk
C-20 Stereospecific Indroduction of a Steroid Side Chain. JACS, 1981, 103, 1293-1295.
O
CO2Me
1) EtPPh3I, KOt-Bu
CO2Me
EtAlCl2
2) Ac2O, Pyr
AcO
HO
AcO
2) Ac2O, Pyr
80%
HO
HO
1) HCHO
EtAlCl2
O
steps
OAc
O
8:1 trans:cis
OH
AcO
Pseudomonic Acid A
(formal synthesis)
Total Synthesis of (±) and (-)-Ptilocaulin. JACS, 1984, 106, 1443-1445.
O
1) CuBr-DMS O
O
Br
R
LDA
Me
BrMg
HN
O
NH2
O
O
O
nBu HCl, Dioxane
O
2) H2, Pt/C
COOH
8
O
O
OH
O
CO2Me
AcO
89%
Total Synthesis of (±)-Pseudomonic Acids A and C. JACS, 1982, 104, 1113-1114.
1) HCHO
Me2AlCl
H
H2, Pt/C
EtOAc
nBu
HN
Me
Me
HN
NH
NH2
nBu
PhH
reflux
Me
Synthesis of the Hexahydronapthalene Moiety of (±)-Compactin. JOC, 1982, 47, 2682-2684.
Br
HO
MeMgBr
6 mol % CuCl
OH R
H
HO
O
Me L-Selectride
75% 3 steps
(formal synthesis)
2) BrMg
80%
H
NaOMe
LiAlH4
R
R
1) Swern
R
OH
R
Me
PhH 150°C
sealed
tube
•
R
O
OH
60%
PCC-NaOAc
40°C KOt-Bu/HOt-Bu
•
R
OH
50%
3
The Chemistry of Barry B. Snider
Baran Group Meeting
An Approach to the Synthesis of Neplanocin A. JOC, 1985, 50, 1983-1985.
Br
Br
O
O
O
OsO4
DBN
O
Br
Br
Paul Krawczuk
could not be
elaborated
N
2
100%
BnN
70% BnN
BnN
62%
N
BnN
Br
Neoplanocin A
HO
OH
OH
HO
OH
Manganese(III)-Based Oxidative Free-Radical Cyclization. Synthesis of (±)-Podocarpic Acid. JOC, 1985, 3659-3661.
OMe
OMe
OMe
O
Me
Mn(OAc)3
HOAc
70%
O
Me
Me
Zn, HCl
2 equiv.Mn(OAc)3
CO2Me 1 equiv. Cu(OAc)2
O
Me
CO2Me
HOAc
41%
60%
CO2Et
O
H
CO2Et
(formal synthesis)
H
CO2Et
Me
Total Synthesis of Sesquiterpenes via Intramolecular Ketene Cycloadditions: Isocomene and !-cis- and !-trans-Bergamotenes, an Approach to Seychellene.
JOC, 1988, 53, 4508-4515.
O
O
O
OEt HO2C
LDA, THF reflux
1) LDA
•
1) NaBH4
then CCl4 reflux
TMS
1) (COCl)2
O
2) Diketene, DMAP
2) NaOH, EtOH
72%
2) TEA, PhMe
76%
78%
O
Reflux
O
O
(Carroll rearrangement)
O
Cl
TEA, PhMe
reflux
Li
HI,PhH
Me
O
quench
work up
then
Li
62%
O
51%
Me
O
O
Isocomene
(formal synthesis)
6 steps 10% yield
from commerical material
O
31%
4.5%
4
The Chemistry of Barry B. Snider
Baran Group Meeting
Paul Krawczuk
Synthesis of (-)-Reiswigin A. Assignment of Absolute and Relative Configuration. TL, 1989, 30, 2465-2468. JOC, 1990, 55, 4392-4399
HO
TMS
O
TiCl4
1) TsOH, (CH2OH)2, PhH HO
2) OsO4, NMO, acetone
78%
O
DCM, -40°C
88%
O
H
1) NaIO4, acetone
O
1
2) AcOH, piperidine PhMe
O
H
O
O
2
(L)-tert-leucine hexanes
tert-butyl ester mol. sieves
94%
O
OH
H
!=(-)-Reiswigin
"=ent-Reiswigin
1)
H
Me2AlCl
DCM, 0°C
1) PCC, DCM
2) TsOH, PhH, H2O
84%
O
HPLC
O
H
MgBr t-Bu-O
R
H R
2) MeI,HMPA
workup
32%
N
O
4 diasteriomers
R
Manganese(III)-Based Oxidative Free-Radical Tandem and Triple Cyclizations. JACS, 1990, 112, 2759-2767.
General Mechanism:
O
O
CO2Me Mn(OAc)3
O
O
CO2Me
CO2Me
CO2Me
Cu(OAc)2
HOAc
O
O
CO2Me
Cu(OAc)2
CO2Me
-HOAc
-CuOAc
86%
(AcO)2Cu
(14% without Cu(OAc)2)
Examples:
O
O
CO2Me
CO2Me
O
CO2Me
Mn(OAc)3
Cu(OAc)2
HOAc
O
CO2Me
Mn(OAc)3
Cu(OAc)2
HOAc
60%
H
39%
O
21%
CO2Me
H
H
H
5
The Chemistry of Barry B. Snider
Baran Group Meeting
Paul Krawczuk
Total Synthesis of (±)-Chondrillin, (±)-Plakorin, and Related Peroxy Ketals. Development of a General Route to 3,6-Dihydro-1,2-dioxin-3-ols.
JACS, 1992, 114, 1790-1800.
O
O
OMOM
OMOM
OAc
1) nBuLi, TMEDA
1) TsOH, MeOH
hv, MeOH
1) Na2CO3, MeOH
R
R
MeO
R
2) RX
2) Pb(OAc)4, AcOH
R
OAc 2) TsOH, mol. sieves, PhH
73-89%
68%
O
al
HC(OMe)3, PhH
beng
e
s
o
r
TsOH, reflux
H
,
O
hv, O 2DCM:Me
OH
O
MeO H
R
MeO H
R
41%
19:1
2:3
R
hv (visible)
OH
OMe
O O
OH
O
O O
O
O
MeOH, O2 MeO
R
O
R
MeO H
R
rose bengal
43%
chondrillin
H+, MeOH
O
O
H
R=C16H33
O O OMe
O
OMe
O
O
Synthesis of (±)-Allocyanthin B2 and (+)-Erinacine A. JACS, 1996, 118, 7644-7645.
O
1) Proton Sponge, Tf2O
1) BrMg
2) Pd(OAc)2, PPh3, CO
i-Pr2EtN, MeOH
3) DIBALH
4) MnO2
69%
CuBr-DMS
CHO TMSCl, HMPA
2) KOt-Bu, MeI
68%
OH
O
1) LAH
2) MnO2
CHO 84%
allocyanthin B2
87%
1) Pd(OAc)2, PPh3, CO
i-Pr2EtN, MeOH
2) TEA, MeOH
CO2Me
71%
Oi-PrDMS
15:1 !:" 1) Me AlCl
2
CHO
2) i-PrDMSCl, imid.
H
1) OsO4, KIO4
2) LHMDS, PhSeCl, H2O2
Oi-PrDMS 55%
O
1) HOAc, H2O, THF
H
2) DMP
OTf 3) KHMDS, PhNTf2
54%
H
O
Synthesis of 2,3-Dihydrofurans by Mn(OAc)3-Based Oxidative Cycloaddition of 2-Cyclohexenones with Alkenes. Synthesis of (±)-Conocarpan.
JACS, 1997, 62, 6978-6984.
O
OMe
O
OMe 1) KOt-Bu,
O
O
O
THF, 65°C
Mn(OAc)3
Mn(OAc)3
PhH, Reflux
2) LiPPh2, THF
Cl
PhH, Reflux
25%
77%
R1
R3
25-42%
R1
R3
Cl
Conocarpan
R2
R2
OH
6
The Chemistry of Barry B. Snider
Baran Group Meeting
Total Synthesis of (-)-FR901483. JACS, 1999, 127, 778-7786.
1)
O
O
O
EtOH
O
MeO2C
O
MeOPh
OMe
O
2)
N
MeOPh
NOH
PhH reflux
O
OMe
77%
O
O
45 psi H2, Pd/C
AcOH, 24 hours
86%
O
1) TsCl, DMAP, TEA
2) NaN3, DMF
O
O
OH
N
HO
O
5%
O
MeHN
(-)-FR901483
N
N
HO
PhOMe
NHMe
O
MeHN
H
N
H2N
O
HO
HN
OH
HN
NH
hv, (350nm)
D2O
H2N
48%
HN
N
HO
HN
H2N
NH
O
NH
O
OH
Cycloanchinopeptolide D
(bis-TFA salt)
OHC
H2N
HN
H
N
N
HO
NH
O
N
H
H
N
O
NH
Ar
BocN
Ar
NMe
Boc
H
N
O
OAc
KOH, MeOH, THF(1:1)
58%
0°C, 20 min
H
N
BocHN
HN
BocHN
NBoc
O
HO
TFA, DCM
O
Anchinopeptolide D
(bis-TFA salt)
hv, (350nm) CD3OD
trans to cis isomerization
O
36%
O
HO
N
MeOPh
O
MeHN
16%
PhOMe 2)TFA, DCM
Total Synthesis of (±)-Anchinopeptolide D and (±)-Cycloanchinopeptolide D. JOC, 2000, 65, 793-800.
H
NBoc
O
NBoc
O
N
1) HOBt, DCC
H2N
BocHN
N
N
BocHN
N
OH
2) DMP
O
H
H
H
OAc
40%
O
OH
O
MeO2C
1) KOt-Bu, HOt-Bu
MeOPh
N
OH
O
3) H2, Pd/C, Boc2O MeOPh
N
4) NaH, MeI, DMF
65%
O
NMe
OH
1) LiBH4, THF, then
Boc
HCl, AcOH/H2O
92%
2) Boc2O, TEA
O
3) DMP
a
b
N
MeOPh
O
OMe
(HO)2OP O
O
O
MeO2C
9:1
CO2Me
Paul Krawczuk
N
HO
O
N
H
H
N
O
NH
OH
O
24% other diastereomers
OH
7
The Chemistry of Barry B. Snider
Baran Group Meeting
Paul Krawczuk
Total Synthesis of (-)-Fumiquinazolines A, B, C, E, H and I. Approaches to the Synthesis of Fiscalin A. JOC, 2003, 68, 545-563.
CO2Me
Bu
CO2Me
CO2Me
TrocHN
CO2Me
O
TrocHN
TrocHN
HO
N
1)Cbz-L-Ala-PhNO2, TrocHN
Pd2(dba), P(o-tolyl)3
S
KF, i-Pr2EtN
OMe
K2CO3, PhH, reflux
O2
2) Hg(OTFA)2, KI, I2
NCbz
MeOH, DCM
I
NCbz
64%
N
N
N
78%
N
65%
H
NHCbz
O
O
O
1) NaBH4, AcOH
2) SiO2, DCM
N
O
NH
N
OH
O
H
NCbz
N
O
1)PPh3, Br2, TEA FmocHN
Fmoc-L-Ala,
EDAC, MeCN
NH O
2) excess piperidine
3) MeCN reflux
H2N
O
TrocHN
NH
NH
O
N
O
Fumiquinazoline A and B
O
H
NCbz
N
O
O
H
NCbz
2) EDAC, MeCN
NH2
O
O
FmocHN
CO2H
EDAC, MeCN
84%
O
H2, Pd/C 77%
OMe
N
N
OH
N
O
O
H
NCbz
HCl, MeOH
61%
O
NH
N
OH
N
O
H 56%
NCbz
HN
O
H
CbzN
O
MeCN, HOAc,
reflux 12 hours
O
FmocHN
N
O
96%
PhSe
Fumiquinazoline C
NH
O
H
NCbz
O
Fumiquinazoline E
N
N
OH
O
H2, Pd/C
O
1) Zn, AcOH
NH
O
NH
PhSe
N
1)PPh3, Br2, TEA, 81%
O
N
14%
2) excess piperidine
3) MeCN, HOAc,
reflux 2 hours
N
O
O
H
NCbz
O
O
50%
8
The Chemistry of Barry B. Snider
Baran Group Meeting
Paul Krawczuk
Synthesis of the Carbocyclic Skeleton of Abyssomicins C and D. Org. Lett. 2005, 7, 4939-4941.
LiCH2PO(OMe)2,
then BuLi, TESCl
O
OTES
(MeO)2OP
85%
O
1) tBuOK, 2,4-hexadienal, THF
CHO
2) THF/AcOH/H2O
3) DMP
64%
O
O
1)
Li
O
2) DMP
O
HO
O
O
O
O
O
O
O
MeO
LiCl, DMSO O
O
CHCl3, hydroquinone
70°C 2 days
O
O
O
O
31%
MeO
O MeO
O
O
O
HO
Abyssomicin C
A Short, Formal, Biomimetic Synthesis of (±)-Polgalolides A and B. Org. Lett. 2007, 9, 873-874.
O
O
O
O
O
O TEA, DCM
O
AcO
34%
O
OAc
O
O
AcO
OAc
O
O
OAc
O
O
AcO
AcO
Cs2CO3
1:1 THF/H2O
O
then acidify to pH 1
O
O
O
Polygalolide B
O
O
OMe
MeO
OH
O
O
O
O
O
O
(formal synthesis)
O
O
O
O
O
O
O
O
9
The Chemistry of Barry B. Snider
Baran Group Meeting
Paul Krawczuk
Formal Synthesis of (±)-Platensimycin. Org. Lett. 2007, 9, 1825-1828.
OMe 1) K, NH3, Et2O, t-BuOH,
-78°C, 15 min
H
O
O
NaBH4, EtOH
84%
Br
O
H
AIBN, n-Bu3SnH, PhH
+
2) LiBr, 30 min.
3)
Br
Br
4) HCl, THF
O
H
O
O
H
87%
Br
OH
O
O
51% (70% after HCl)
35%
HCl/THF
O
H
MnO2 HO
O
H
O
94%
H
SeO2 (3 equiv.)
dioxane microwave
O
83% (7% enone)
H
Tf2O, pyr., DCM
then i-PrOH
then silica gel
84%
O
TFA/DCM
then K2CO3, MeOH
H
L-Selectride
83%
OH
90%
OH
OH
(formal synthesis)
Biomimetic Synthesis of the Tetracyclic Core of Berkelic Acid. Org. Lett. 2007, ASAP.
O
O
1) LDA, THF
DIBALH
O O O
O O O HO
O
+
2) Dowex H , MeOH
O
O
H
unstable
HO
H
O
O
MeO2C
O
CO2Me
OH
O
CO2Me
OH
O
O
Berkelic Acid
O
C5H11
O
O
24%
50% after TFA
desired
(thermodynamically most stable)
2) CH2N2, Et2O
3) 0.2% TFA in CDCl3, 12 hours
C5H11
CO2Me
OH
O
C5H11
CO2H
OH 1) Dowex H+ MeOH
O
O
CO2Me
OH
O
C5H11
6%
6% after TFA
O
O
CO2Me
OH
O
C5H11
24%
<2% after TFA
C5H11
6%
0% after TFA
10
The Chemistry of Barry B. Snider
Baran Group Meeting
Paul Krawczuk
Suggested further reading:
Me
HO
H
Cl
Me
H
N
H
N
H OH
OHC
O
H
N
N
O
OH
O
OH
O
NH
OH
AcO
HO
Me
H
Total Synthesis of (±)-Cylindrospermopsin.
JACS, 2000, 122, 5017-5024.
Formal Synthesis of (±)-Guanacastepene A.
JOC, 2003, 68, 1030-1042.
O
H
Me
O
Total Synthesis of (±)-Leporin A.
JOC, 1996, 61, 2839-2844.
OH
O
Efficient Syntheses of Rugulosin Analogues.
JOC, 2005, 70, 6863-6869.
HO
H
N
OMe
OHO OH
N
H
HO
N
H
(CH2)10
(CH2)10
N
Cl-
Syntheses of Ficuseptine, Juliprosine, and Juliprosopine by
Biomimetic Intramolecular Chichibabin Pyridine Syntheses
Org. Lett. 2005, 7, 2715-2718.
H
H
O
H
O
H
C7H15
Total Synthesis of (±)-DeoxypenostatinA
JOC, 1999, 64, 1088-1089.