Stereoselective synthesis of (-)-cephalotaxine and C-7 alkylated analogues.

A total asymmetric synthesis of (-)-cephalotaxine is reported. The chemistry of alpha,beta-unsaturated gamma-lactams was used to access the 1-azaspiro[4.4]nonane skeleton in enantiomerically pure form via a stereocontrolled semipinacolic rearrangement of an alpha-hydroxyiminium ion. This spiro compound was transformed into (-)-cephalotaxine without any racemization or epimerization by following the racemic synthesis reported by Kuehne. We thus performed a total synthesis of (-)-cephalotaxine in 98.7% ee with an overall yield of 9.8% over a 16 steps sequence. This synthetic process was adaptable to the access of some alkylated analogues.