Biomedical Engineering Reference
In-Depth Information
HO
HO
HO
CO
2
Me
OH
H
HO
H
TMS
AgF
CH
3
CN
DiBAL-H
CO
2
Me
N
N
N
55%
95%
TMS
N
171
172
173
(+)-Retronecine
SCHEME 13.36
with AgF generated dipole
172
that, when added to methyl propiolate, produced
173
in 55% yield, along with 17% of the corresponding regioisomer. DIBAL-H reduction
of the methyl ester provided (
)-retronecine in 95% yield.
The utility of this approach was also examined for the synthesis of alkaloids
containing 7-azabicyclo[2.2.1]heptane skeleton. Epibatidine
178b
has been a target
of particular interest because of its potent analgesic activity (Scheme 13.37). The
synthesis of epibatidine by Pandey and coworkers is particularly short, beginningwith
the desilylation of
174
with AgF to generate ylide
175
that underwent cycloaddition
with cinnamic acid derivative
176
to give
177
in 82% yield [68]. Hydrolysis of the
ester followed by Barton decarboxylation gave
178a
in 71%yield. Finally, removal of
the benzyl group by hydrogenolysis afforded epibatidine
178b
in 90% yield.
The toxicity of epibatidine spurred efforts to develop related analogues. Hence,
Pandey and coworkers examined the use of
174
to facilitate the synthesis of such
analogues [69]. Adding ethyl acrylate to amixture of
174
andAgF produced amixture
(4:1) of diastereomeric adducts
179
and
180
, predominating in the former, in 75%
yield. The mixture was converted to carbamates
181
and
182
, and
182
could be
quantitatively epimerized to
181
, which has the proper configuration for epibatidine.
Pearson and coworkers devised an alternative way to produce azomethine
ylides derived from
รพ
-stannyl amines [70]. For example, condensation of aldehyde
183
with amine
184
provided imine
185
(Scheme 13.38) [71]. Without purification,
185
was exposed to HF.Py to generate azomethine ylide
186
that was then added to
phenyl vinyl sulfone to give a nearly equal mixture of the four pyrrolidine isomers
187
a
Cl
Cl
CO
2
Et
TMS
N
N
Cl
N
1
.
LiOH, MeOH
Bn
R
176
AgF
N
N
N
Bn
N
Bn
2
.
(COCl)
2
t
-BuSH
Ph-H
82%
N
ONa
O
TMS
174
CO
2
Et
CO
2
Et
175
177
178a
(R = Bn; 71%)
H
2
Pd/C
178b
(
R = H; 90%)
174
AgF
Bn
Bn
Boc
Boc
N
N
N
N
CO
2
Et
1
.
Pd(OH)
2
/H
2
CO
2
Et
EtO
2
C
+
+
2
.
(Boc)
2
O, Et
3
N
CO
2
Et
CO
2
Et
182
180
(15%)
181
179
(60%)
1
.
K
2
CO
3
, MeOH
2
.
SOCl
2
, EtOH
95%
SCHEME 13.37
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