baran group meeting frederick ziegler chad a. lewis · baran group meeting frederick ziegler chad...
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Baran Group Meeting
Born in Teaneck, N.J. 1938B. Sc. Fairleigh Dickinson University 1960M.S. Ph.D. Columbia University 1961, 1964 (Stork)NSF Postdoc MIT (Buchi)Joined Yale Faculty 1965Retired 2003, Emeritus 2007
Frederick Ziegler Chad A. Lewis
Stork
Büchi
Ziegler
Wender
Harran
Author of over 100 papersLilly Grantee Award 1966
NIH Career Development Award 1973-1978NIH Medicinal Chemistry A Study Section 1979-1983
Chairman for the construction of the new ChemistyResearch Building (9th chemistry building for Yale)
Baran Group Meeting Frederick Ziegler Chad A. Lewis
NH
N
Me
AcO
O
NH
N
Me
O
OH
NH
N Me
O NH
N
Me
O
NH
N
Me
N
NH2
O
Bz
Cl NaBH4, MeOHN
NH2
O
Bz
N
NH2
O
Bz
N
NH2
O
Bz
Me
O BzN
H2N
O
Me
O
13% (2 steps)
BzN
H2N
O
Me
HO
BzNH
N
O Me
MeO
O
BzN
Me
AcO
O
NH
N
O
O
Me
AcO
42% (2 steps)
NH
N
Me
HO
OH
68% (4 steps)94%
74%
Ibogamine (±)epiibogamine (±)
NaBH4, MeOH
NaClOMeOH, KOH
1) 6N H2SO4, 100 ºC2) Ac2O, pyr
1) MeOH, HCl,Pd/C, H22) !-indoylacetylchloride, Et3N
1) p-TsOH, AcOH2) Zn, AcOH
LAH, THF
NH
HN
Me
HO
OH
(not observed)
DCC, DMSO
50% quant.
NaOMe, MeOH Zn, AcOH
H2NNH2, KOH
NH
NMe
Ibogaine (±)
MeO
Ibogaine also synthesized following an identicalroute. JACS, 1966, 88, 3099-3109
JACS, 1965, 87, 2073-2075.
Postdoctoral Work with Büchi - Synthesis of Ibogamine and Ibogaine (1965 - 1966)
NH
NMe
Baran Group Meeting Frederick Ziegler Chad A. Lewis
Me
O
CN
BnN
Me
BnN
MeO2C44%
MeO
O1)
2) NaBH4, MeOH
1) Pd/C, H22) !-indoylacetylchloride3) saponification
NH
O
N
Et COOH
44%
NH
N
O
O
PPA
85%
NH
O
N PPA
COOH
Polymeric Products
N
Me
O
O
NH
IntramolecularCyclization
N
O
N
H
COOH
Polymerization
NH
N
Me
O
O
NaBH4, MeOH
NH
N
Me
O
OH
62%
NH
N
Me
O
ORR = Ac, Bz
Reducing Conditions
NH
N
Me
O
O
LAH, dioxane NH
N
Me
NH
N
Me
Quebrachamine (±)
6%
57%
NH
N
Me
N
Me
HN
Quebrachamine (±)
Synthesis of Quebrachamine (1969)
JACS, 1969, 91, 2342-2346.
3,4-Dehydroquebrachamine (±)
PtO or Pd/C, H2diimide or diboranemetal ammonianucleophiles
Et
Quebrachamine (±)
I
Me
Baran Group Meeting Frederick Ziegler Chad A. Lewis
The Wender Years
R R'
N
R R'
NC NHNHCO2MeHCN, MeOH
R R'
NC NNCO2MeBr2, NaHCO3
DCM
R R'
NC N NCO2Me
NaOMe, MeOH
LiOMe, MeIDME
LiOMe, DME(MeO)2CO
R R'
NC H
R R'
NC Me
R R'
NC CO2Me
NC NNCO2Me
Method A
Method B
Method C
NC NNCO2Me
NC NNCO2Me
Me
MeMeMe
Method Nitrile
Carbo-methoxy-nitrile
Methyl-nitrile
A 94 0
B 7 77
C 0 13 77
A 89 0
B 2 25 63 (73 (eq CN), 27 (ax CN))
A 97(58 (ax CN), 42 (eq CN))
C 1 23 70(76 (ax CN), 24 (eq CN))
JACS, 1971, 93, 4318-4319.
JOC, 1977, 42, 2001-2003.
O
Me
Me
O
Me
Me
95%single diasteromer
LiCu(CHCH2)2P(Bu)3Me
Me
O O
O
1) ketalization2) disiamyl borane3) CrO3, pyr
~70%
MeMe
O O
Me
MeO2CMe
PPh3
CO2Me
91%15/1 E/Z
MeMe
O O
Me
LAH, Et2O
95%
HO
93%
MeMe
O OEtO2C
Me
Pivalic acidethylorthoacetate
MeMe
Me
O
O
MeMe
Me
O
MeMe
Me
OHH
MeOH, NaOH(aq)
O
~5% 60%
O
MeMe
Me
34%
95%
O
MeMe
Me
O
MeMe
Me
OH
MeMe
Me
O
MeMe
Me
O
59%
22%
!
MeOH, H2O2 H2NNH2, AcOH
CrO3, pyr
Eremophilone (±)JOC, 1977, 42, 1991-2001.
NHCO2Me
Baran Group Meeting Frederick Ziegler Chad A. Lewis
Ullmann Coupling Modification
Br(I)
NC6H11
R1
Li
NC6H11BuLi, THF, -78 ºC
R1
CuI·L
Cu
NC6H11
R1 LPreformed Aryl Copper
Intermediate
THF, -78 ºC to rt
I
NC6H11
R2
NC6H11
R1
C6H11N
R2
O
O
NC6H11
Cu
L
O
O
NC6H11
IO
O
O
OO
O
44%THF, -78 ºC to rt
O
O
N
Cu
L
NC6H11
I
54%
THF, -78 ºC to rt
O
Me
Me
O
O
O
O
O
O
N
O
MeMe
C6H11N
JACS, 1976, 98, 8282-8283.
SCu
OMe
THF, -78 ºC to rt
NC6H11
I
OMe
MeO
MeO
OMeO
MeO
OMe
S
OMe
O
O
O
O1)
2) DCM, AcOH
82%
MeO
MeO
OMe
O
O
OCO2Me
CO2Me
Br
MeO
MeO
MeO
O
O O
CO2Me
CO2Me
t-BuOK, t-BuOHTHF, rt
73%
Ha
Hb
Ha ! = 2.76 ppmHb ! = 3.06 ppm
MeO
MeO
MeO
O
O O
CO2MeMeO
MeO
MeO
O
O O
CO2Me
1) KOH, H2O2) 200 ºC3) CH2N2
~95%
1:1
1) formalin, KOH2) Jones3) Thermal
50%
MeO
MeO
MeO
O
O O
O
O
H
H
1) LiAl(t-BuO)3H2) Ac2O, pyr
MeO
MeO
MeO
O
O OAc
O
O
H
H
Steganacin (±)
Steganacin Synthesis
TL, 1978, 31, 2767-2770.
P(OEt)3
JACS, 1980, 102, 790-798.
Baran Group Meeting Frederick Ziegler Chad A. Lewis
NH
N
Me
Total Synthesis of Tabersonine - Claisen Rearrangement
JACS, 1971, 93, 5930-5931.JACS, 1973, 95, 7458-7465.
CO2Me
H
BnN
MeOH
BnN
Me
NMe2
O
Me NMe2
OMeMeO
diglyme reflux, 45%
O Cl
O
N
Me
NMe2
O
O OPh
DCM, rt, 71%
HN
Me
CO2Me
83%
1) KOH,methyl cellosolve2) MeOH, HCl
NH
N
O
EtMeO2C
!-indoylacetylchloride, THFNa2CO3, H2O
87%
NH
N
Me
O
O
PPA
66%
NH
N
Me
OH
20%
LAH, THF0 ºC
44%
MsCl, pyr
NH
N
Me
NH
N
Me
CN
KCN, DMF"
1) KOH, ethylene glycol2) MeOH, HCl then CH2N288% (2 steps)
3) Pt, O2, 30%
Tabersonine (±)
Cope-Claisen Rearrangement
"...this reaction sequence is viable and that it serves to shift unfavorable Cope equilibria by an irreversible Claisen rearrangement."
Me
Me O
Me
Me
O
57%
hexane, 525 ºC, 10s
Me
O
375 ºC, 2 min
CHO
Me
87%55/45 d.r.
Me
O
185 ºC, 3.5 hr
50/50 d.r.
O
380 ºC, 10 sec OHC
91%
OH
Me
O
(CH2CH)2CuLi, Me2S, THF Me
O
OH
Hb
Hc
OHb
Hc
Me1) EtOCHCH2Hg(OAc)22) Ph3PCH2, THF
290 ºC, 4.5 hrMe
OHC
Hc
Hb
Ha
Ha
JACS, 1979, 101, 1611-1612.
HOO
Me
Methyl Cellosolve
Ha
Me
OHc
Hb
Ha
Baran Group Meeting Frederick Ziegler Chad A. Lewis
Me
HMe
O
Me
HMe
O
Me
HMe
O
Me
HMe
O
HMe
CHO
Me
HMe
CHO
Me
HMe
CHO
Me
HMe
CHO
Me
trans
cis
trans
cis
A
B
A/B 79/21
ObservedCalc'd
70 67
9 14
18 19
3 0
JACS, 1980, 102, 6576-6577.
Interception of the Cope Chairlike Transition-State during the Tandem Cope-Claisen Rearrangement
140 ºC, 14 h
Tandem Cope-Claisen Rearrangement Syntheses
MeO
Me
MeO
CHOMe
H370 ºC, 20s
2/1 d.r.60%
1) O3, DMS, DCM, 70%2) MeONa, MeOH, 69%
MeO
O
CHOOMe
H
H
H
1)TiCl3, Zn/AgDME, reflux, 56%2) K/NH3, CrO3
MeO
H
Me O
HH
Estrone methyl ether (±)JOC, 1982, 47, 5229-5230.
OO
OMe
O
Me
Me
Me
O
HO
Tirandamycic acid
OO
Me
MeMe
OH
OH
TL, 1984, 25, 617-620.
O
CNMe
HO
OH
O
MeMe
HO
OH
MeOH
SambucinolJACS, 1987, 109, 3987-3991.
Formal synthesis of tirandamycic acid
Synthesis of 1,3-dioxolane rings
Review of Claisen Rearrangements in Natural Product Synthesis
ACR, 1977, 10, 227-232.
JACS, 1982, 104, 7181-7190.
Review of Tandem Cope-Claisen Rearrangements
CR, 1988, 88, 1423-1452.
Me
O
Me H
C‡
A
Me
O
Me
Me
O
Me
B‡
Me
O
MeH
B
O
Baran Group Meeting Frederick Ziegler Chad A. Lewis
Dithiane Generation and Conjugate Additions
S
S
Me
Me Me
O1) BuLi, THF, 0 ºC2)
3) -78 ºC, CuI·(MeO)3Pthen
50%
O Me
H
Me
S
SMe
R1 R2
SHSLDA (2 equiv.)
or nBuLi
R1 R2
SLiLiS
R1 R2
SR3R3SR3X
JOC, 1978, 43, 3065-3066.
HMPA
Me
RS SR SRSR
RS SR1) LDA/THF -25 ºC
2)
-78 to 25 ºC
Br
R ! " yield
with HMPA without HMPA
! " yield
94 6 88 88 12 71
Me 73 27 66 74 26 82
t-Bu 45 55 94 43 57 89
S
S
Li
CuI·(MeO)3P
S
S
Cu·P(MeO)3
RX
S
S
R
! "
Br
Nu
Nu
90 10
Me OP(OEt)2
O
Me
Nu
Me Nu95 5
Me
OP(OEt)2
O
Me
Me
Me
Nu Me
Nu
Me43 57
yield
85
91
84
JOC, 1979, 44, 3428-3430.
Application of Dithiane Conjugate Addition to Total Synthesis
O Me
O
HO
Me
Me
O Me
HMe
O
HO Me
HMe
OH
HO Me
HMe
CONMe2 HO Me
HMe
I
O
O
HO Me
HMe
O
OHO Me
HMe
O
O
O Me
HMe
O
O
Confertin (±)
JOC, 1981, 46, 825-827.
65%
1) O3, -78 ºC2) HOAc, H2O
1) KOH, H2O83%2) P2O5, MsOH
LAH, Et2O
49%
72%
89%
Me NMe2
MeO OMe
I2, THF, H2O
DBN, 53 ºC
94%
Known Steps
PtO2, H2
73%
(CH2)3
Br
xylene, refluxMeOH, K2CO3
O Me
HMe
O
O
Aromatin (±)
also prepared en route to Confertin
Baran Group Meeting Frederick Ziegler Chad A. Lewis
Radical Cyclizations
O
Me
MeO
1) DIBAL, tol, -78 ºC2) Me
MgBr
90% Me
Me
OH
OH
Me
1) NaH/THF CS22) MeI, 12h
72%
O
Me
Me
Me
Me
SMe
S
S SMe
OnBu3SnH, AIBN
benzene, 3h reflux
45%
Me
Me
Me
Me
5/1 cis/trans
SMe
N
O
N
MeO
O
S
nBu3SnH, AIBNbenzene, 3h reflux
98%
MeHO Me MeHO Me
TL, 1987, 28, 5973-5976.
SMe
N
O
N
O
O
S
Me
nBu3SnH, AIBNbenzene, 3h reflux
65%
~ 1/1
Me
Me
OH
Me
Me
OH
Me
Me
OH
57%
37%
6%
O SMe
S
S SMe
O1909 Oddo and
del Rosso
Radical Cyclization of Indoles
NN
XnBu3SnH, AIBNbenzene, reflux
X = Br, 48-58%X = I (E), 65%
N
CO2Me
61%
N
CO2Me
55%
N
CO2Me
N
CO2Me
CO2Me
N
X = Br, 33-42%X = I, 31%
32% exo16% endo
50%
JOC, 1991, 56, 3479-3486.
N
CN
O
O O
N O
HCN
N
NC
O
H33%
13% byproducts
UV, 0.05M THFrt, 12 min
N O
H
CN
N O
H
CN
N
CN
O
UV, 0.0075M THFrt, 8h
52%1.7:1
26%TL, 1993, 34, 4505-4508.
JOC, 1993, 58, 2768-2773.
Harran
Me
N S
Baran Group Meeting Frederick Ziegler Chad A. Lewis
Chiral Aziridinyl Radicals - Core of FR-900482
NH
OBn
MeO2C
TfOCO2Me
NBoc
44%N
OBn
MeO2C
CO2Me
NBoc
N
OBn
MeO2C
Br
NBoc
N
OBn
MeO2C
NBoc
46%11% debromo
nBu3SnH, ACCNtoluene, reflux
N
OH
O O
OCONH2
OH
NH
N
OBn
MeO2C
NBoc
OH
H
N
OBn
MeO2C
NBoc
O
H
OHC
N
OBn
MeO2C
NBoc
O
H
OHC
OBn
O
O
OBn
O
N
OBn
MeO2C
NBoc
O
OH
OHC OBn
O
N
OBn
MeO2C
NBoc
O
H
OHC OBn
O
HO13:1
N
OBn
MeO2CO
OH
NBoc
OHCO OBn
O
N
OH
MeO2CO NBoc
O
OMe
Me
N
OH
O O
OCONH2
OH
NH
1) DMP, DCM2) Formaldehyde, H2ONaHCO3 (86% 2 steps)3) CDI, BnOH, 71%
mCPBA, 0 ºC
~98%
81%
mCPBA, DCM, 0 ºC
1) HOAc, Pd/C, H2EtOH, 92%2) DCM, TsOH
Me Me
MeO OMe
OHC
N
OH
MeO2CO NBoc
O
OMe
Me
70%
(PPh3)3RhCl130 ºC
77%
FR-900482
Ac2O, THF, 0 ºCthen H2O
73%
JOC, 1997, 62, 1083-1094.
Synthesis of (+)-9a-Desmethoxymitomycin A
N
O
Me
NH
H
O
MeO ONH2
O
TL, 1998, 39, 2455-2458.
Baran Group Meeting Frederick Ziegler Chad A. Lewis
OO SMe
S
O
OMe
O O
OMe
Tandem Cyclopropylcarbinyl/Oxiranylcarbinyl RadicalRearrangements
nBu3SnH, AIBNtol, 75 ºC, 2h R1
O
R2O
R1O
H
R2
O
R1O
H
R2
O
R1O
HR2
O
R1O
R2
OH
R1O
R2
OH Tin salts
55% (2 steps)
O
O
OMe
O O
OH
Me
Prostaglandin B1 SeriesTL, 1996, 37, 809-812.
OO
OMe
I O
OMe
O1) t-BuLi, Et2O
2) (i) LDA, THF (ii) CS2 (iii) MeI, 60%
21%
D-XyloseMeO
O
OBn
OBn
OBn
OBn
OBn
BnO
MeO2C
Grubbs I, DCM
92%
OBn
OBn
BnO
O
I
O
1) LiOH, THF2) KI, I2, KHCO3
92%
1) DIBALH, 85%2) PhI(OAc)2, I2500 W W-Lamp 78%3) KOH, THF 76%
OBn
OBn
BnO
IO
nBu3SnH, O2
OBn
OBn
HO
HOO
OBn
OBn
BnO
HOO
10% 70%
Pd(OH)2/C, H2MeOH, 12 h
85%OH
OH
HO
HOO
(+)-Cyclophellitol JOC, 1998, 63, 7920-7930.
MeO
O
OBn
OBn
OBn
O
OON
S
OBn
OBn
BnO
MeO2CO
nBu3SnH, hv
MeO
O
OBn
OBn
OBn
O
OON
S
OBn
OBn
BnO
MeO2CO
30%
D-Xylose
Attempted and Successful Synthesis of (+)-Cyclophellitol
Synthon Approach
JOC, 1998, 63, 426-427.
Baran Group Meeting Frederick Ziegler Chad A. Lewis
JACS, 1988, 110, 5434-5442.
Polypropionates via Butyrolactone Claisen Rearrangements
O
O
Me
OO
Me
OO
Me MeMe
OHOH
Me Me
!-butyrolactone
Claisen
O
Me
O
Me
OO
Me Me
OO
Me Me
OO
Me Me
OO
Me Me
O
Me
O
O
Me
O
Me
O
Me
O
Me
Ct
Bt
Cc
Bc
Refluxing toluene, propionic acid cat.
Yield
74%
14%
12%
0%
O
Me
O
Me
OO
Me Me
O
Me
O
O
Me
O
Me
R
Me
O
Me
Ct
n-Bu
n-Bu
OO
Me Me
n-Bu
88%
(eq)
n-Bu
R
R = n-Bu
R
(ax)
(ax)(eq)
R = n-Bu
O
Me
O
Me
OO
Me Me
O
Me
O
O
Me
O
Me
O
Me
O
Me
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
OO
Me MeBt
n-Bu
OO
Me Me
n-Bu
55%
(eq)
45%
CC
(eq)
(ax)
(ax)
97:3 equilibration
Disfavored
Disfavored
Baran Group Meeting Frederick Ziegler Chad A. Lewis
Synthesis of Polypropionates via Butyrolactone Method
OO
Me Me
OO
Me Me
i-Pr
Me
Me
1) tol, pivalic acidreflux, 48h2) t-BuOK, t-BuOHEt2O
98/2 d.r., 94%
1) MeLi, Et2O, 0 ºC2) H2O2, HOAc, THF3) Ac2O, DMAP, DCMthen 40 ºC4) LAH5) Me2C(OMe)2, TsOH
"Criegee rearrangementsequence"
82%
O
Me
Me
MeO
Me Me
Me1) O3, MeOH2) LAH, Et2O3) TsCl, pyr4) NaCN, DMSO, 95 ºC5) HCl, H2O/MeOH refluxt-BuPh2SiCl, imid
63%O
MeMe
TBDPSO
O
1) LDA, HMPA, -78 ºC2) NCCO2Me
98%O
MeMe
TBDPSO
O
CO2Me
O
MeMe
TBDPSO
O
1) NaH, THF2)
MeMe
Me
OP(OEt)2
O
3) LiCl, DMSO, H2O190 ºC
Me
Me
Me
73%
O
MeMe
TBDPSO
O
Me
Me
Me
21%
1) LDA, THF-78 ºC2) HOAc (19:1)
HET, 1987, 25, 105-108.
O
MeMe
TBDPSO
O
Me
Me
Me
1) MeLi, Et2O, 0 ºC2) H2O2, HOAc, THF3) Ac2O, DMAP, DCMthen 40 ºC4) LAH5) Me2C(OMe)2, TsOH
"Criegee rearrangementsequence"
31%
O
MeMe
TBDPSO
O
Me
Me
Me
Me Me
O
MeMe
O O
Me
Me MeO
1) O3, MeOH2) LAH, Et2O3) TsCl, pyr4) NaCN, DMSO,95 ºC
64%
O
MeMe
O O
Me
Me MeO
1) LDA, HMPA, -78 ºC2) NCCO2Me
93% O
MeMe
O O
Me
Me MeO
CO2Me
Me
Me
Me
87%
1) NaH, THF2)
MeMe
Me
OP(OEt)2
O
3) LiCl, DMSO, H2O200 ºC
(Ph3P)4Pd
JACS, 1988, 110, 5442-5452.
O
MeMe
O O
Me
Me Me
O
Me
Me Me
OTBDPS
C19 - C27 Fragment of Rifamycin STL, 1987, 28, 1725-1728.
JACS, 1988, 110, 5434-5442.
(Ph3P)4Pd
Me
i-Pr
OH
Me
OH
Me
O
Me
TBDPSOO
Me
O
Me
TBDPSOO
Me
i-Pr
Me
O
Me
OBnO
Me
O
Me
OBnO
Me
i-Pr
Translational Iteration
Linear Iteration
R alc = !S alc = "
R alc = "S alc = !
Baran Group Meeting Frederick Ziegler Chad A. Lewis
Me Me Me Me
O O
Me
O O
MeMe Me
O
Me
OMe
5% oxalic acid1:1 THF:H2O50% conversion
O
Me Me Me Me
O O
MeMeOH
Me
OH
Me
H
4.6 1 6 1 69
1 4.7 1 8 72
! " ! " Yield
SM Product
Denticulatins A and B JOC, 1990, 55, 2800-2805.
Me Me Me Me
OO
Me
O O
MeMe Me
O
Me
OMe
1) LDA, 86%, 3 isomers
2) Swern2.7:1 !:"
81%
Polypropionates the Sequel
OO
Me Me
OO
Me Me
Me
MeMe
Me
O
MeMe
TBDPSO
O
Me
Me Me
O
Me
OH
CO2t-Bu
O
O
CO2t-Bu
MeMe
Me
Me O HN
Known Steps
O
O
MeMe
Me
Me O HN
N
O
CO2H
NHMe
(-) CalcimycinJOC, 1989, 54, 3347-3353.