ENANTIOMERICALLY PURE AMINO-ALCOHOLS AND DIAMINO ALCOHOLS FROM L-ASPARTIC ACID - APPLICATION TO THE SYNTHESIS OF EPISLAFRAMINE AND DIEPISLAFRAMINE

Starting from natural aspartic acid (6) a practical method for the synthesis of enantiomerically pure 3-amino alcohols 8 including 3,4-diamino derivatives is described. After perbenzylation of 6 and reduction of both carboxylates, position 4 of the resultant (dibenzylamino)butanediol (11) could be regioselectively blocked to afford the silyloxy-protected intermediate 12a. Functionalization of position 1 was accomplished by nucleophilic displacement reactions including a 2-fold migration of the dibenzylamino substituent or by reductive amination of the amino aldehyde 15. Both routes proceeded under complete preservation of the optical purity. For envisioned SAR studies, we, furthermore, report on the application of this method to a chirospecific synthesis of epi- and diepislaframine (9a and 9b) as diastereomers of the highly bioactive indolizidine alkaloid slaframine (9c). Our first approach including reductive coupling of the chiral amino aldehyde 15 with 5-hydroxypyrrolidine failed when formation of a quaternary ammonium salt occurred, preventing the anticipated anionic cyclization. Therefore, we turned out attention to methodology developed by Wasserman. In fact, introduction of a 3-hydroxypyrrole-2-carboxylate fragment gave a cyclization precursor (30b) which could be successfully transformed into epi- and diepislaframine.