Synthesis of the indolizidine alkaloid swainsonine from d-glucose

Abstract

Since the stereochemistry of the alkaloid exactly matches that of 3-amino-3-deoxy- d-mannose, the latter compound is an ideal chiron for the synthesis of the former. Selective tosylation of methyl 3-benzyloxycarbonylamino-3-deoxy-α- d-mannopyranoside, followed by removal of the benzyloxycarbonyl group and cyclisation, afforded the 3,6-imine which was converted into its benzyloxycarbonyl derivative. Hydrolysis of the glycosidic group then afforded 3,6-benzyloxycarbonylimino-3,6-dideoxy- d-mannose. The attempted addition of a C 2 unit at C-1 by the Wittig or the Wadsworth—Emmons—Horner reaction either failed to give the required product or was followed by Michael addition of one of the hydroxyl groups to the newly formed double-bond. 2,4,5-Tri- O-acetyl-3,6-benzyloxycarbonylimino-3,6-dideoxy- aldehydo- d-mannose was prepared via the diethyl dithioacetal and condensed with ethoxycarbonylmethylenetriphenylphosphorane to give the Wittig adduct in good yield, which, on catalytic reduction, underwent hydrogenation of the double bond, loss of the benzyloxycarbonyl group, and attack of the released amino group on either the terminal ethoxycarbonyl group or the 2- O-acetyl group to give a mixture of the required cyclic lactam and the N-acetyl derivative. Reduction of the lactam with the borane—dimethyl sulphide complex afforded swainsonine triacetate, from which the parent alkaloid was obtained.