PRACTICAL ASYMMETRIC-SYNTHESIS OF ROXY-1H-PYRANO[3,4-F]INDOLIZINE-3,6,10(4H)-TRIONE, A KEY INTERMEDIATE FOR THE SYNTHESIS OF IRINOTECAN ANDOTHER CAMPTOTHECIN ANALOGS
Ke. Henegar et al., PRACTICAL ASYMMETRIC-SYNTHESIS OF ROXY-1H-PYRANO[3,4-F]INDOLIZINE-3,6,10(4H)-TRIONE, A KEY INTERMEDIATE FOR THE SYNTHESIS OF IRINOTECAN ANDOTHER CAMPTOTHECIN ANALOGS, Journal of organic chemistry, 62(19), 1997, pp. 6588-6597
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 interme
diate for the synthesis of camptothecin analogs, was developed. Commer
cially 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 refuncti
onalization of the aldehyde, the chloropyridine is converted into an e
ster by a facile palladium-mediated carbonylation reaction. Wittig rea
ction and racemic osmylation produce the diol 16 which is resolved by
an efficient lipase resolution to an ee > 99%, and a one-pot recycle o
f the unwanted diol enantiomer was developed. A series of high-yieldin
g oxidation and deprotection steps convert (S)-16 into the pyridone 25
, which is then converted into 1 with an ee > 99.6%.