Biomedical Engineering Reference
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CHO
O
H
2
N
SnBu
3
O
MS 4 Å
N
SnBu
3
+
O
O
OBn
OBn
183
184
185
SO
2
Ph
HF
·
Py
SO
2
Ph
O
O
N
N
OBn
H
H
73%
O
O
OBn
187
186
1. 10% aq HCl
2. NaBH
4
77%
H
H
SO
2
Ph
Li, NH
3
N
N
OH
OBn
87%
188
Indolizidine 239CD
SCHEME 13.38
in 73% yield. While the cycloaddition is nonselective in relation to the vinyl sulfone,
the
trans
-2,5 selectivity is excellent. Reductive amination of the mixture afforded
188
in 77% yield. Further cleavage of the sulfonyl group furnished indolizidine 239CD as
a single isomer in 87% yield.
The above method was expanded to a generalized three-component cascade.
For example, aldehydes with a pendant leaving group, such
189a
-
189c
, were
condensed with amine
190a
in the presence of a dipolarophile to give tricyclic
products (Scheme 13.39) [72]. Thus, heating
189a
,
190a
, and
N
-phenylmaleimide at
110
C produced indolizidine
191a
in 78% yield. A similar reaction involving silane
190b
also afforded
191a
, though in only 44%yield. Aldehyde
189b
reacted with
190a
and
N
-phenylmaleimide at 136
Ctogive
191b
in 88% yield. Interestingly,
189c
reacted under the same conditions to furnish
191c
, though in only 17% yield. These
last two structures are particularly significant in that the pyrrolo[1,2-
a
]azepine core in
191b
and the 1-azabicyclo[6.3.0]undecanemotif in
191c
are found in an increasing
number of natural products from several sources.
Interestingly, reactions involving aldehydes containing enolizable protons are
tolerated with the stannane-derived amines, but not for silane-derived amines. For
example,
192
reactedwith
190a
and
N
-phenylmaleimide in boiling toluene to produce
193
in 85% yield, while the same reaction involving amine
190b
gave only traces of
193
. After considerable experimentation, the predominant mechanism in operation
for generation of the azomethine ylide was proposed to involve condensation of the
amine with the aldehyde to generate an imine, such as
194
. Displacement of the
pendant halide then produces iminium ion
195
. Halogen-promoted destannylation/
desilylation provides the reactive dipole
196
, a process that appears to be more
efficient for the stannane derivatives.
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