The enantioselective
synthesis of fluorinated indolizidinone derivatives
has been developed. The process involved an enantioselective intramolecular
aza-Michael reaction of conjugated amides bearing a pendant α,β-unsaturated
ketone moiety, catalyzed by the (S)-TRIP-derived
phosphoric acid, followed by dimethyltitanocene methylenation and
ring closing metathesis (RCM). Final indolizidine-derived products
comprise a fluorine-containing tetrasubstituted double bond generated
by the RCM reaction, which is a challenging task. The whole synthetic
sequence took place in acceptable overall yields with excellent enantioselectivities.