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 b-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 (À)-(S)-malic acid (9) (Schemes 3 and 4). Key step in the preparation of 10b was the diastereoselective amination of the optically pure a,b-unsaturated d-hydroxy homoallylic ester 14 via conjugate intramolecular aza-Michael cyclization of the acylic d-(carbamoyloxy) intermediate 11.Introduction. ± Isolated from the leaves of the New Caledonian plant Homalium pronyense Guillaum. (Flacourtiaceae) [2], the four Homalium alkaloids homaline (1), hopromine (2), hoprominol (3), and hopromalinol (4) constitute a small family of optically active natural products characterized by a unique bis-eight-membered lactam structure incorporating a spermine (5) backbone (Fig.). The structures of the Homalium alkaloids were elucidated in the seventies by Pais and co-workers [3], and the correctness of the proposed formulae was confirmed by several total syntheses since then.A single-crystal X-ray analysis [4] as well as manifold asymmetric syntheses [5] [6] allowed the determination of the absolute (S,S)-configuration of the major alkaloid homaline (1). In a preceding paper [1], we presented a new, potent synthetic entry to the Homalium scaffold that enabled us to prepare (AE)-homaline (1) and (À)-hopromine (2) and, hence, to determine the absolute configuration of the natural hopromine (2) as being (R,R). Since, hitherto, all the syntheses of the remaining, unsymmetrically substituted parent molecules hoprominol (3) and hopromalinol (4) are nonstereospecific [7], the absolute configurations of the alkaloids 3 and 4 are still unknown. Hereafter, we now wish to report the application of our previously described synthetic strategy for building up the bicyclic Homalium core by the preparation of the N-and O-protected (R,R,R)-hoprominol precursor 6 (Fig.), with the higher aim of elucidating the yet-undefined configuration of the natural product (À)-homprominol (3).
