AN APPROACH TO CHIRAL TRISUBSTITUTED PYRROLIDINES BY ENOLATE CLAISEN REARRANGEMENT OF AZALACTONES DERIVED FROM ALPHA-AMINO-ACIDS

Homologation of the beta-amino acid derivatives 17a, 27a and 27b by N-alkylation using the cis-butenyl chloride 18 has been used to obtain the hydroxy acids 19b, 28c and 28d which were then converted into the 9-membered azalactones 20, 29a and 29b using Mukaiyama's reagent, 2-chloro-1-methylpyridinium iodide. Enolate Claisen rearrangements of these macrolides were then effected using a 'pre-mix' method in which the base (LDA) and the trapping agent (TBDMSCI) were mixed at low temperature before addition of these substrates and took place on warming to ambient temperature. Rearrangement of the azalactone 20 gave only the cis-3,4-disubstituted pyrrolidine 21a while rearrangements of the chiral lactones 29 led to the chiral trisubstituted pyrrolidines 30 in an enantiospecific fashion, via a boat-like transition state (e.g. 31).