5714
J. Cossy et al. / Tetrahedron Letters 42 (2001) 5713–5715
Scheme 2. Synthesis of cisapride.
Piperidin-4-one hydrochloride 5 was transformed into
amide 6 by treatment with carboxylic acid 12 in the
presence of pivaloyl chloride and triethylamine in
refluxing toluene for 16 h (yield 61%). The introduction
of the methoxy group at the C-3 position of the pipe-
ridine was achieved in two steps. The first step involved
References
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oxidation of the amido ketone
6
by using
diacetoxyiodobenzene20 in the presence of KOH
(methanol, rt, 14 h), which afforded the hydroxy
methoxy ketal 7 (36%). Compound 7 was then trans-
formed into a-methoxy ketone 8 in 71% yield by treat-
ment with MeI in the presence of Ag2O (DMF, 3 h,
0°Crt). Deprotection of the ketone by using acetic
acid gave the 3-methoxy amido ketone 9 (80% yield),
which was condensed with O-benzylhydroxylamine
hydrochloride in the presence of pyridine in refluxing
toluene (Dean–Stark, 3 h) to yield the corresponding
oximino ether 10. The oxime was then reduced
diastereoselectively by using BH3·THF (THF, 0°Crt,
18 h). After treatment of the amine borane with acetic
acid (50°C, 1 h), the cis-amino ether 11 was isolated in
51% yield, with a diastereomeric excess of 96%. Treat-
ment of amine 11 with the carboxylic acid 13 (EtO-
COCl, 1-hydroxybenzotriazole, Et3N, DMF) gave
cisapride in 90% yield (Scheme 2).
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The synthesis of cisapride requires only seven steps and
proceeds in 4.5% overall yield. A key feature is the
highly stereoselective reduction of oximino ether 10
with BH3·THF.