Enantioselective entry to the Homalium alkaloid hoprominol: Synthesis of an (R,R,R)-hoprominol derivative

Article abstract of DOI:10.1002/hlca.200390016

The diastereoselective synthesis of the N- and O-protected hoprominol derivative (R,R,R)-6 is described. The building up of the bicyclic O-silylated and di(N-tosylated) asymmetric scaffold 6 succeeded by convergent preparation of the two basic chiral azalactam units 7a and 7b and their subsequent iterative linking by a known method (Scheme 5). Both 4-alkyl-hexahydro-1,5-diazocin-2(1H)-ones 7a and 7b were prepared from the chiral β-amino acid portions 10a and 10b, respectively, by application of a set of reactions (e.g., N-alkylation of 10a,b and Sb(OEt)₃-assisted cyclization of the resulting open-chain intermediates) already known. In comparison with the total syntheses of homaline (1) and homoprine (2), the newness of the described synthesis lies in the asymmetric approach to the difunctionalized fatty acid derivative 10b starting from (-)-(S)-malic acid (9) (Schemes 3 and 4). Key step in the preparation of 10b was the diastereoselective amination of the optically pure α,β-unsaturated δ-hydroxy homoallylic ester 14 via conjugate intramolecular aza-Michael cyclization of the acylic δ-(carbamoyloxy) intermediate 11.