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

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%.