A Comparative Analysis ot the Syntheses of Reserpine

A Comparative Analysis
ot the Syntheses of
Reserpine
Joëlle Gauchet
5/12/92
References:
Woodward: JACS 1956, 78, 2023, 2657.
Tet 1958, 2, 1.
Pearlman: JACS 1979, 101, 6398, 6404.
Wender: JACS 1980, 102, 6157.
Het 1987, 25, 263.
Martin: JACS 1985, 107, 6124.
JACS 1987, 109, 4072.
Stork: Pure & Appl. Chem. 1989, 61, 439.
01-Reserpine 5/13/92 9:02 AM
X
X = OMe
X = H
Reserpine Alkaloids
A
N
H
2
14
B
3
N
15
C
21
MeOOC
22
16 18 O
Reserpine
Deserpidine
Yohimbine
5
H H
N
H
H
H
MeOOC
OMe
N
D
E
H
OMe
O
OMe
Reserpine was isolated in 1952 from the indian snake root
Rauwolfia serpentina
OMe
OMe

MeO
MeO
N
H
02-Woodward 5/10/92 4:50 PM
Woodward-Retrosynthesis
O
N
H
NH 2
N
H H
H
MeOOC O
O
MeOOC
MeOOC
H
ROOC
O
OMe
O
H
CHO
O
OAc
Cl
OMe
O
OMe
OMe
OMe OMe
COOR
OMe
OMe

O
Benzene
A
O H
ROOC
NaBH 4
B
O H
HOOC
PhCO 3H
C
O H
HOOC
D
O H
O
O
CO
O
H
OH
H
OH
H
O
H
O
1) AcOH 2) Ag2O ∆ MeI
E
O H
+
O
∆
Ac 2O AcONa
CO
H
OMe
OAc
COOR
Al(Oi-Pr) 3
Ac 2O
AcONa
Al(Oi-Pr) 3
03-Woodward 5/10/92 5:58 PM
H
O
O
H
G H
O H
L
O H
O
OsO 4
Py
O
H
O
Woodward-Synthesis of Ring E
CO
F
OH
H
H
PyO 2Os
O
Br 2
O H
N
Al(Oi-Pr) 3
MeONa
MeOH
O
O
O
O
M
CO
H
O
O
O
H
OMe
O
O
H
H
Br
O
OAc
H
OH
H
H
OMe
H 2CrO 4
M
MeONa
MeOH O H
I
O
J
O
O
H
H
HOOC
K
O
KOAc
H
HOOC
H
OMe
O
H
Zn AcOH
EtOH
O
H
O
H

M
O
1)
MeO
O
H
O
N
H
H
OMe
2) NaBH 4
1) POCl3, ∆
2) NaBH4 NBS
H2SO4 ∆
S
MeO
T
MeO
04-Woodward 5/10/92 5:57 PM
NH 2
Synthesis of Isoreserpine
R
O
OH
O
O
H
Br
O
MeOOC CHO
MeOOC
OMe
H
OMe
N OC N
H
H
3) CH2N2 OAc
H
MeOOC OAc
N
H
H
*
H
N
OMe
H 2CrO 4
AcOH
H
MeOOC OAc
OMe
1) OsO 4
2) HIO 4
P
O
O
O
O
H
H
MeOOC
Br
O
1) Zn, AcOH
2) CH2N2 3) Ac2O, Py
Q
H
OMe
H
OMe
OAc
Isoreserpine derivative

T
MeO
05-Woodward 5/10/92 5:08 PM
N
H H
N
1) KOH
* MeO
N *
H
2) DCC, Py
H H
H
MeOOC OAc
Reserpine
Woodward-Synthesis of Reserpine
OMe
1) MeONa, MeOH
Resolution of (l)reserpine-(d)camphor sulfonate gives (-)-Reserpine
2)
Cl
Py
O
OMe
OMe
OMe
U
V
MeO
N
H
H
Pivalic acid
Xylene, ∆
H
*
H
N
N
CO
H
OMe
CO
H
OMe
O
O

MeO
MeO
N
H
06-Pearlman 5/10/92 5:09 PM
Pearlman-Retrosynthesis
N
H
NH 2
N
H H
H
MeOOC O
ROOC
MeOOC
MeOOC
OMe
CHO
OMe
O
O
O
"Woodward intermediate"
OMe
OH
OMe
OMe
OMe
OMe
OMe
OMe

HOOC HOOC
94%
MeO
Me
MeOOC
O
CaSO 4
Ag 2O
48%
Me
O
OMe
O
Li
NH 3
O
MeOOC
MeOH
H2SO4 100%
O
MeO
+
MeOOC
OMe
MeOOC OMe
OMe
*
MeOOC
OH
OMe
07-Pearlman 5/13/92 9:05 AM
Pearlman-Synthesis of Ring E
A B
+
OMe
OH
Me
O O
MeOOC hν MeOOC
52%
O
OMe
OMe
1) H2O2 HCOOH
2) 180 °C
6%
H 2SO 4
MeOH, ∆
95%
0.003 M
30%
1) CF 3CO 3H
59%
2) H 2SO 4
MeOH
O
Ag 2O, CH 3I
CaSO 4
O
Me
91%
O
MeOOC
OH O
70%
OMe O
O
Me
O
OMe
H2SO4 MeOH
O
O
OMe

A +
MeO
MeO
B
1) (TMB) 2O
Py, DMAP
2) AcOH, H 2O
MeOOC CHO
MeOOC CHO
MeOOC OTMB
MeOOC OTMB
OMe
MeOOC OTMB
C
OMe
D
9% after chromatography
+
1) POCl 3, ∆
2) NaCNBH 3, AcOH
*
OMe
1) 6-methoxytriptamine
2) NaBH 4, MeOH
N OC N
H
N OC
H
N
H +
MeO
H
*
H
N
H
Pearlman-Synthesis of Isoreserpine
N
MeO
N
H H +
H H
H
MeOOC OTMB
OMe
26% (5 steps), 3:2 mixture
67% from C 58% from D
H
MeOOC OTMB
H
N
*
OMe
H
MeOOC OTMB
OMe
3-Epireserpine = Isoreserpine 3,20-Diepereserpine
08-Pearlman 5/10/92 5:18 PM

MeO
MeO
09-Wender 5/10/92 5:15 PM
N
H
Wender-Retrosynthesis
MeOOC
N
H
OTs
AcO
N
N
H H
H
MeOOC O
H
MeOOC
OMe
COOMe
N
OMe
H
OMe
COOMe
O
OAc
Cl
MeOOC
OMe
O
N
OMe
OMe
OMe
AcO COOMe
OMe
OMe

MeOOC
N
NaBH4, MeOH
Methyl chloroformate
N
MeOOC
MeOOC
243 °C
H
H
OAc
N
N
Wender-Synthesis of Ring D and Ring E
AcO
COOMe
H
OMe
COOMe
N
+
78%
H
OMe
10-Wender 5/11/92 8:02 AM
OAc
OAc
OMe
COOMe
H 2, Pd/C
95%
H 2, Pd/C
79%
(2 steps)
H
MeOOC
120 °C
76%
2:1 mixture
MeOOC
COOMe
N
H
OMe
AcO
N
1) Ac 2O, Et 3N, DMAP
2) TFA
3) CH 2N 2
H
OAc
65%
COOMe
N
H
OMe
OAc
MeOOC
OAc
LAH
78%
LiHMDS
AcCl
HO
N
MeOOC OAc
+
MeOOC
89%
H
OH
N
Ot-Bu
O O
N
OLi
COOMe
H
OMe
A
Ot -Bu
O

H
OH
COOMe
N
H
OMe
A
11-Wender 5/11/92 8:02 AM
O
Reserpine
Wender-Synthesis of Reserpine
1) Jones [o]
2) CH2N2 79%
H
MeOOC
COOMe
N
Sakai or
Martin
H
OMe
O
MeO
1) NaBH 4
2)
CeCl 3
2) (TMB) 2O
DMAP
92%
1) TMSI
MeO
MeOOC
N
H
N
H
H
H
MeOOC
COOMe
N
OTs
N
H
OMe
64%
H
OMe
OTMB
OTMB

MeO
MeO
12-Martin 5/10/92 5:26 PM
N
H
Martin-Retrosynthesis
Br
N
H
N
H H
H
MeOOC O
H
MOMO
H
MOMO
Bn
N
Bn
N
O
OMe
O
H
OMe
O
OCOR
Cl
OMe
O
MOMO
Bn
OMe
OMe
OMe
N O
O
OMe
OMe
O

HO
H
MOMO
90%
H
Bn
N
Bn
N
MOMO OH
1) MOMBr
PhNEt2 95%
2) BuLi,
81%
O
O
O
BuCH(Et)COOH
BuCH(Et)COOLi
DME, ∆
H
MeOOC
R
N
O
MOMO
H
MOMO
OH
Bn
N
H 2
Pd/CaCO 3
/PbO
96%
O
Bn
N
MOMO
Xylene
Reflux
93%
MOMO
OH
Bn
N O
CaSO4
Pd(OH)
H
2/C
98% 90%
OCOR
OCOR
H
OMe
13-Martin 5/10/92 5:33 PM
Martin-Synthesis of Ring D and Ring E
m-CPBA
88%
MeI, Ag 2O
O
MOMO OMe
1) TsOH, MeOH, ∆
2) PDC
3) CH 2N 2
1) AlH3 2) H2, Pd/C
H
MeOOC
Bn
N
O
OMe
OCOR
H 2
1) TsCl, Py
90%
2) PhCH2NH2 NaI, DMSO
85%
O
O
H
Cl
Bn
N
MOMO
O
O
O
H
MOMO OMe
1) AlH3 2) TsOH, MeOH, ∆
3) Ac2O, Py, DMAP
4) Methyl chloroformate
H
COOMe
N
H
O
OCOR
NHBn
Et 3N
OAc
AcO OMe
Wender intermediate
89%

H
Bn
N
O
H
MOMO OMe
H
MeOOC
Bn
N
OMe
H 2, AcOH
Pd(OH) 2/C 94%
H
MeOOC
H
N
H
OMe
14-Martin 5/10/92 5:30 PM
H
Martin-Synthesis of Reserpine
OCOR
OTMB
OTMB
MeO
1) TsOH, MeOH, ∆
2) PDC
3) CH2N2 75%
1) TsOH, MeOH, ∆
81%
2) TMBCl, Py, DMAP
91%
N
H
(i-Pr) 2NEt, DMSO
69%
Reserpine + Isoreserpine
35%
8%
Br
H
MeOOC
H
MeOOC
MeO
Bn
N
Bn
N
O
H
OMe
AlH 3 80%
H
OMe
N
H
1) Hg(OAc) 2
AcOH, ∆
OCOR
OCOR
H
MeOOC
N
OMe
2) Zn, HClO 4
H
OTMB

MeO
MeO
15-Stork 5/10/92 5:36 PM
N
H
O
Stork-Retrosynthesis
Si
O
N
H
NH 2
N
H H
H
MeOOC O
MeOOC
Si
MeOOC
O
OHC
COOMe
OMe
LiO
O
OTs
OH
Cl
OMe
O
OMe
OMe
OMe OMe
CH 2OBn
CH 2OBn
OMe
OMe

+
O
CH 2OBn
O
O
Si
O
O
MeOOC
F
Si
O
MeOOC O
HO
16-Stork 5/10/92 5:42 PM
CH 2OBn
OH
COOMe
+
LiO
m-CPBA, Et 3N
O
Stork-Synthesis of Ring E
1) TiCl4 73%
2) LiOH
97%
TL 1985, 26, 3095
PhSe
CH 2OTs
CH 2OTs
CH 2OBn
OH
CH 2OBn
COOH
O
CH 2OBn
O
O
MeOOC
Si
O
MeOOC
F
Si
CHO
O
HO
CH 2OTs
O
MeOOC OH
OMe
I
CH 2OH
I
CH 2OBn
CH 2OBn
TBAF, THF, ∆

CHO
CH 2OTs
MeOOC OH
MeO
17-Stork 5/10/92 5:42 PM
OMe
N
H
H
MeO
H
Isoreserpine
Stork-Synthesis of Reserpine
KCN, Base
N
N
H
NH 2
1) CH 3CN, ∆
2) TMBCl, Base
H
MeOOC OTMB
OMe
MeO
MeO
N
H NC
N
H
H
Reserpine
N
H
MeOOC OH
H
OMe
1) CH3CN, ∆
2) AgBF or HCl, THF
4
3) TMBCl, Base
H
N
H
MeOOC OTMB
OMe