Synthesis of the alkaloid homaline in (±) and natural (S,S)-(–) forms, using amination and transamidative ring expansion in liquid ammonia

Abstract

Synthesis of the alkaloid homaline in (±) and natural (S,S)-(–) forms is reported. Linking of 2-azacyclooctanone units either directly or successively using 1,4-dihalogenobutanes or 1,4-dihalogenobut-2-ynes is examined. (±)-5-Methyl-4-phenyl-1,5-diazacyclooctan-2-one is first made by a 2,2′-dithiodipyridine/triphenylphosphine-mediated cyclisation, 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-methylated azalactam, or the unmethylated azalactam followed by methylation, gave homaline in (±) and meso forms.

(R)-(–)-Phenylglycine was converted via(S)-β-phenyl-β-alanine into an (S)-β-lactam which 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, gave (S,S)-(–)-homaline identical with the natural material.