Deoxyiminoalditols from Aldonic Acids VI. Preparation of the Four Stereoisomeric 4-Amino-3-hydroxypyrrolidines from Bromodeoxytetronic Acids. Discovery of a New α-Mannosidase Inhibitor

A convenient four step synthesis of 4-amino-3-hydroxy-pyrrolidines is presented. 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-14 (3S,4S) and ent-15 (3S,4R) could be obtained as crystalline compounds, avoiding any chromatographic purification. The key step in the reactions was the regioselective formation of either the 2,4-diamino-2,4-di-deoxy-d-threono-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-anhydrotetronates (3 or 9), respectively, with liquid ammonia. Thus, opposite regioselectivity for the opening of the cis-configurated epoxide 3 (4 : 1, C-2/C-3) and the trans-configurated epoxide 9 (3 : 7, C-2/C-3) by ammonia was observed. Preliminary testing as glycosidase inhibitors of the 4-amino-3-hydroxypyrrolidines formed by reduction of the lactams showed an inhibition of α-mannosidase (K_i 40 μM) by isomer 14, (3R,4R)-4-amino-3-hydroxypyrrolidine.

4-amino-3-hydroxypyrrolidines - tetrono-1,4-lactams - α-mannosidase inhibitor