Biomedical Engineering Reference
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OTMS
O
OTBS
10 steps
CO
2
Me
BnO
H
OTBS
31%
I
O
SiMe
2
Ph
(
Z
)-
anti
-
167
168
169
I
1.
TBDPSO
170
t
-BuLi, ZnCl
2
,
THF
-78°C to 0°C, 30 min
2. 10 mol% Pd(PPh
3
)
4
169
, THF, rt, overnight
3. CSA, MeOH, CH
2
Cl
2
58%
OTBS
5 steps
36%
Brevisamide
166
TBDPSO
OH
O
171
SCHEME 2.42
Convergent synthesis of brevisamide
166
.
cross-coupling [38,80]. Brevisamide
could thus be obtained in 17 steps and 6.4%
overall yield (Scheme 2.42) [89]. The organozinc species was prepared
in situ
via a
lithium-iodine exchange and a transmetalation with ZnCl
2
[38,80] starting fromvinyl
iodide
166
170
. It was then reactedwith the vinyl iodide polyoxygenated tetrahydropyrane
169
in the presence of a Pd(0) catalyst to afford the conjugated trisubstituted (
E
,
E
)-
diene
as a single regioisomer after TBS deprotection and chromatographic
purification. This method appears particularly powerful and useful for stereo-
chemically challenging systems. In fact, the use of the vinylstannane derivative of
intermediate
171
under Stille coupling conditions afforded the conjugated trisubsti-
tuted (
E
,
E
)-diene
171
together with the corresponding homocoupling product [90].
170
2.2.4.2. Pumiliotoxins A and B (
are toxic
alkaloids extracted from the skin of the Panamanian poison frog
Dendrobates pumilio
in 1967 [91], showing a modulatory effect on the voltage-dependent sodium
channels [92] (Figure 2.13). ANegishi cross-couplingwas involved in the synthesis of
both compounds in order to form the C12-C13 bond. Hence, by treating (
Z
)-
iodoalkylideneindolizidine
þ
)-Pumiliotoxins A
172
and B
173
179
under Pd(0)-catalyzed Negishi cross-coupling conditions, the authors were able to
synthesize (
174
[93] with the suitable (
E
)-vinyl iodide
176
and
þ
)-pumiliotoxins A
172
and B
173
, respectively (Scheme 2.43).
was first generated via a halogen-metal exchange, followed
by a transmetalation with ZnCl
2
. The cross-coupling with the (
E
)-vinyl iodide
Homoallylzinc
175
176
then afforded the precursor for (
þ
)-pumiliotoxin A
172
as a single stereoisomer
(Scheme 2.43).
OH
12
12
13
13
OH
OH
N
N
Negishi
coupling
Negishi
coupling
H
H
OH
OH
(+)-Pumiliotoxin A
172
(+)-Pumiliotoxin B
173
FIGURE 2.13
Retrosynthetic analysis of pumiliotoxins A and B.
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