Deoxyiminoalditols from aldonic acids VI. Preparation of the four stereoisomeric 4-amino-3-hydroxypyrrolidines from bromodeoxytetronic acids. Discovery of a new alpha-mannosidase inhibitor

A convenient four step synthesis of 4-amino-3-hydroxy-pyrrolidines is prese nted. From the readily available D- and L-tetronic acids the four possible stereoisomeric 4-amino-3-hydroxy-pyrrolidines 14 (3R,4R), 15 (3R,4S), ent-1 4 (3S,4S) and ent-15 (3S,4R) could be obtained as crystalline compounds, av oiding any chromatographic purification. The key step in the reactions was the regioselective formation of either the 2,4-diamino-2,4-di-deoxy-D-threo no-1,4-lactam (5) or the 3,4-diamino-3,4-dideoxy-L-erythrono-1,4-lactam (10 ) by treatment of the methyl 4-bromo-4-deoxy-2,3-cis- or -2,3-trans-anhydro tetronates (3 or 9), respectively, with liquid ammonia. Thus opposite regio selectivity for the opening of the cia-configurated epoxide 3 (4.1, C-2/C-3 ) and the trans-configurated epoxide 9 (3.7, C-2/C-3) by ammonia was observ ed. Preliminary testing as glycosidase inhibitors of the 4-amino-3-hydroxyp yrrolidines formed by reduction of the lactams showed an inhibition of alph a-mannosidase (K-i 40 mu M) by isomer 14, (3R,4R)-4-amino-3-hydroxypyrrolid ine.