SYNTHESIS OF THE ALKALOID HOMALINE IN (+ -) AND NATURAL (S,S)-(-) FORMS, USING AMINATION AND TRANSAMIDATIVE RING EXPANSION IN LIQUID-AMMONIA/

Synthesis of the alkaloid homaline in (+/-) and natural (S,S)-(-) form s is reported. Linking of 2-azacyclooctanone units either directly or successively using 1,4-dihalogenobutanes or 1,4-dihalogenobut-2-ynes i s examined. (+/-)-5-Methyl-4-phenyl-1,5-diazacyclooctan-2-one is first made by a 2,2'-dithiodipyridine/triphenylphosphine-mediated cyclisati on, and then by amination and transamidative ring expansion from N-(3- chloropropyl)-4-phenylazetidin-2-one in liquid ammonia, followed by N- methylation. Coupling through a 1,4-dihalogenobutane of either the N-m ethylated azalactam, or the unmethylated azalactam followed by methyla tion, gave homaline in (+/-) and meso forms. (R)-(-)-Phenylglycine was converted via (S)-beta-phenyl-beta-alanine into an (S)-beta-lactam wh ich was then alkylated with 1-bromo-3-chloropropane, and aminated and ring expanded in liquid ammonia. Coupling of the homochiral azalactam (2 mol) so formed with 1,4-dibromobutane, followed by N-methylation, g ave (S,S)-(-)-homaline identical with the natural material.