Practical Asymmetric Synthesis of
(S)-4-Ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-
3,6,10(4H)-trione, a Key Intermediate for the Synthesis of
Irinotecan and Other Camptothecin Analogs
posted on 1997-09-19, 00:00authored byKevin E. Henegar, Scott W. Ashford, Ted A. Baughman, John C. Sih, Rui-Lin Gu
A practical asymmetric synthesis of (S)
4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (1), a versatile intermediate
for the synthesis of camptothecin analogs, was
developed. Commercially available citrazinic acid is converted in
four steps into the 2-chloro-6-methoxypyridine 5. An ortho-directed metalation followed
by reaction with a formamide produces
an aldehyde with the required 2,3,4,6-substituted pyridine
(6) with high regioselectivity. After
refunctionalization of the aldehyde, the chloropyridine is converted
into an ester by a facile
palladium-mediated carbonylation reaction. Wittig reaction and
racemic osmylation produce the
diol 16 which is resolved by an efficient lipase resolution
to an ee > 99%, and a one-pot recycle of
the unwanted diol enantiomer was developed. A series of
high-yielding oxidation and deprotection
steps convert (S)-16 into the pyridone
25, which is then converted into 1 with an ee >
99.6%.