Biomedical Engineering Reference
In-Depth Information
CO
2
Me
O
CO
2
Me
CO
2
Me
Cu(acac)
2
H
+
OEt
CO
2
Et
N
R
N
N
ClCH
2
CH
2
Cl
62-81%
R
N
2
CO
2
Et
333a
(R = CH
2
Ph)
333b
(R =
n-
C
5
H
11
)
333c
(R = CH
2
CH=CH
2
)
R
332a
(R = CH
2
Ph)
332b
(R =
n-
C
5
H
11
)
332c
(R = CH
2
CH=CH
2
)
334a
(R = CH
2
Ph)
334b
(R =
n-
C
5
H
11
)
334c
(R = CH
2
CH=CH
2
)
O
CO
2
Et
R
R
Cu(acac)
2
R
N
Bn
N
N
+
+
N
Ph
OEt
PhCH
3
reflux
CO
2
Et
EtO
2
C
CO
2
Et
N
2
Ph
Ph
335
336a
(R = H)
336b
(R = CO
2
Et)
337a
(R = H)
337b
(R = CO
2
Et)
338a
(R = H; 67%)
338b
(R = CO
2
Et; 0%)
339
(59%)
SCHEME 13.63
this as a way to produce polysubstituted pyrrolidines. The Cu(acac)
2
-mediated
reaction of azetidines
332a
-
332c
with ethyl diazoacetate under microwave irradi-
ation conditions in dichloroethane gave pyrrolidines
334a
-
334c
in 62-81% yield
(Scheme 13.63) [110]. The formation of
334c
is particularly important for demon-
strating the role of the ring strain in driving the expansion because the intermediate
ammonium ylide
333c
can undergo a more facile [2,3]-rearrangement (see below).
The limits of ring strain in directing the reaction path were encountered with doubly
stabilized ylides, such as
337b
. Whereas heating a toluene solution of
335
and ethyl
diazoacetate with catalytic amounts of Cu powder at reflux produced
338a
in 67%
yield, the corresponding reaction of
335
with
336b
mediated by catalytic amounts
of Cu(acac)
2
produced
339
in 59% yield with no
338b
observed. Since doubly
stabilized ylides are much slower to rearrange than their monostabilized analogues, it
is thought that the migration may be more sensitive to the stability of the radical on the
migrating group.
The Stevens rearrangement can also be used to convert pyrrolidine into
piperidine systems. While a significant amount of mechanistic evidence supports
a diradical mechanism, moderate to high retention of configuration has been observed
when the migrating atom is chiral and has a conjugating group attached [111]. West
and Naidu took advantage of this feature and reported a five-step synthesis of
(
)-epilupinine from (
L
)-proline benzyl ester
340
[112,113].
N
-Alkylation of
340
with
341
produced
342
in 80% yield, and subjection of this diazoketone to catalytic
amounts of Cu(acac)
2
in toluene at reflux afforded
343
and its bridghead methine
epimer as a mixture (95:5) in 84% yield (Scheme 13.64). Dithiane
344
was formed in
64% yield upon reaction of
343
with ethane dithiol in the presence of BF
3
OEt
2
, and
subsequent LiAlH
4
reduction of the carboxyl group produced
345
. Final reduction of
the dithiane to produce (
)-epilupinine was accomplished by the action of sodium and
hydrazine. Analysis of the product by both optical rotation and itsMTPA ester showed
that the (
)-epilupinine was formed with 75% ee.
The stereoselective formation of ammonium ylide
348
comes from an
equilibration of the diastereomeric metal carbenoids
346
and
347
, which results from
inversion about the nitrogen. This equilibriumpresumably favors the pseudoequatorial
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