Synthesis of the alkaloids hopromine, hoprominol and hopromalinol, using transamidation methods

Abstract

Synthesis of the unsymmetrical Homalium alkaloids hopromine, hoprominol and hopromalinol, in diastereoisomeric mixture form, is reported. The component eight-membered azalactams are first prepared. N-(3-Halogenopropyl)-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 of the 4-(2-hydroxyheptyl)-5-methyl-1,5-diazacyclooctan-2-one required for hoprominol and hopromalinol is carried out via 4-allyl β-lactam ring expansion to the eight-membered 4-allylazalactam, followed by methylation, epoxidation and epoxide opening with lithium dibutylcuprate. A similar epoxidation-cuprate sequence was carried out on the epoxypropyl β-lactam, as its N-tert-butyldimethylsilyl derivative, and led to a convenient copper-catalysed N- to O-migration of the protection; this migration is examined. Alkylation gave O-TBDMS-protected N-(3-chloropropyl)-4-(2-hydroxyheptyl)azetidin-2-one which could be aminated and transamidated in excellent yield, to give, after methylation, a superior sequence to the required eight-membered hydroxy azalactam.

Although satisfactory for attachment of the first azalactam unit, a dibromobutane coupling system proved unreactive for the second. Couplings with unmethylated, methylated, and benzyloxycarbonylprotected azalactams were examined using (E)-1,4-dibromobutene and (Z)-1,4-dichlorobutene as the bridging unit. Employing the latter, coupling the first N-methylated azalactam with potassium bis(trimethylsilyl)amide as the base, and then the second with bis(trimethylsilyl)amide-sodium hydride as the base system, provided a satisfactory synthetic outcome. Hydrogenation under acidic conditions gave the unsymmetrical structures hopromine, hoprominol and hopromalinol, as well as the more simple and symmetrical alkaloid, homaline.