SYNTHESIS OF THE ALKALOIDS HOPROMINE, HOPROMINOL AND HOPROMALINOL, USING TRANSAMIDATION METHODS

Synthesis of the unsymmetrical Homalium alkaloids hopromine, hopromino l and hopromalinol, in diastereoisomeric mixture form, is reported. Th e component eight-membered azalactams are first prepared. N-(3-Halogen opropyl)-4-pentyl- and -4-heptyl-azetidin-2-ones are aminated and ring expanded in liquid ammonia to give, after reductive methylation, the corresponding 4-alkyl-5-methyl-1,5-diazacyclooctan-2-ones. Synthesis o f the -hydroxyheptyl)-5-methyl-1,5-diazacyclooctan-2-one required for hoprominol and hopromalinol is carried out via 4-allyl beta-lactam rin g expansion to the eight-membered 4-allylazalactam, followed by methyl ation, epoxidation and epoxide opening with lithium dibutylcuprate. A similar epoxidation-cuprate sequence was carried out on the epoxypropy l beta-lactam, as its N-tert-butyldimethylsilyl derivative, and led to a convenient copper-catalysed N- to O-migration of the protection; th is migration is examined. Alkylation gave O-TBDMS-protected (3-chlorop ropyl)-4-(2-hydroxyheptyl)azetidin-2-one which could be aminated and t ransamidated in excellent yield, to give, after methylation, a superio r sequence to the required eight-membered hydroxy azalactam. Although satisfactory for attachment of the first azalactam unit, a dibromobuta ne coupling system proved unreactive for the second. Couplings with un methylated, methylated, and benzyloxycarbonyl-protected azalactams wer e examined using (E)-1,4-dibromobutene and (Z)-1,4-dichlorobutene as t he bridging unit. Employing the latter, coupling the first N-methylate d azalactam with potassium bis(trimethylsilyl)amide as the base, and t hen the second with bis(trimethylsilyl)amide-sodium hydride as the bas e system, provided a satisfactory synthetic outcome. Hydrogenation und er acidic conditions gave the unsymmetrical structures hopromine, hopr ominol and hopromalinol, as well as the more simple and symmetrical al kaloid, homaline.