Biomedical Engineering Reference
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TBSO
Me
Me
N
O
O
Me
Me
TBSO
O
Boc
Boc
O
O
Me
Me
Me
Me
1. PdCl
2
(3 equiv)
AgBF
4
(2 equiv)
MeCN, rt, 48 h
N
H
N
Me
O
O
Me
Me
O
7 steps
37%
Me
OM
e
O
2. NaBH
4
, EtOH, 0°C
63%
H
N
N
N
36
37
(+)-Paraherquamide B
35
N
N
O
O
SCHEME 1.11
Synthesis of (
þ
)-paraherquamide B by Williams and coworkers.
amination of
provided the desired precursor for the key carbon-carbon bond
forming event. Treatment of
33
with stoichiometric PdCl
2
(CH
3
CN)
2
, silver tetra-
fluoroborate, and triethylamine in acetonitrile, followed by reductive NaBH
4
workup
to cleave the palladated intermediate, gave (
34
) in a 4:1 er. The
mechanism of this key cyclization step was investigated using NaBD
4
inMeOD since
this reductive workup for
s
-palladium complexes had been previously shown to
proceed with retention of stereochemistry [47]. Deuterio-ibogamine was isolated
with deuterium incorporation occurring
syn
to the indole motif. This observation
eliminated the possibility of product formation via initial complexation of palladium
to the olefin, activating it toward nucleophilic attack by the electron-rich indole
moiety, as this would lead to an
anti
-relationship between the nucleophile and the
palladium. However, the
syn
deuterium incorporation lends strong support for a
reaction pathway involving indole palladation via C-H bond functionalization, olefin
coordination, and
syn
1,2-insertion (Scheme 1.10).
The first total synthesis of (
þ
)-ibogamine (
30
), the simplest member of
a family of antiparasitic agents possessing a complex heptacyclic core, was reported
byWilliams and coworkers in 1993 (Scheme 1.11) [48]. Their synthetic plan featured
an indole cyclization to simultaneously form a new carbon-carbon bond and the
heptacyclic tetrahydrocarbazole core. Unfortunately, all attempts to effect the cat-
ionic cyclization of
þ
)-paraherquamide B (
35
using strong protic acids, Lewis acids, or TMSOTf were
unsuccessful and led to decomposition of the startingmaterial. Inspired by thework of
Trost and coworkers [46,49], indole
36
to
37
was treated with a premixed solution of PdCl
2
(3 equiv) and AgBF
4
(2 equiv) in acetonitrile at room temperature for 48 h.
Subsequent slow addition of NaBH
4
at 0
C afforded tetrahydrocarbazole
36
37
in
63% yield [48b]. Intermediate
37
was then converted to (
þ
)-paraherquamide B
(
35
), the enantiomer of the naturally occurring compound.
In 2002, Baran and Corey reported the first enantioselective total synthesis of
þ
38
(
) using an intriguing palladium-mediated carbon-carbon bond-
forming cyclization at an indole C-H bond (Scheme 1.12) [50]. The viability of
converting an intermediate such as indoloazocine
)-austamide (
having been previously
demonstrated byHutchison and Kishi [51], Baran and Corey set out to develop a novel
method for the rapid construction of
39
to
38
, prepared
quantitatively in three steps from the methyl ester of (
S
)-tryptophan, was treated with
Pd(OAc)
2
(1 equiv) in acidic media under an oxygen atmosphere at room temperature
to afford
39
. Thus,
N
-prenylated intermediate
40
) was obtained
in four steps. On the basis of the success of this C-H functionalization protocol, Corey
and coworkers employed the same strategy in their synthesis of okaramine N, a
structural analogue of austamide
39
in 29% yield. From this intermediate, (
þ
)-austamide (
38
38
[52].
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