Synthesis of the novel mannosidase inhibitors (3R)- and (3S)-3-(hydroxymethyl)swainsonine

Swainsonine (9) is an important mannosidase inhibitor that has been examined clinically as an anticancer drug. The preparation of analogs of swainsonine bearing a hydroxymethyl group at C(3), i.e., (3R)-3-(hydroxymethyl)swainsonine [(10), (3R)-HMS] and (3S)-3-(hydroxymethyl)swainsonine [(11), (3S)-HMS] is described. The synthesis of each analog begins with D-ribose, and involves a Claisen rearrangement, a Sharpless osmylation, and a reductive double-cyclization of either an azido mesylate bearing a lactone (i.e. 24 double right arrow 11) or an azido epoxide bearing a lactone (i.e. 27 double right arrow 10). Both (3R)-HMS and (3S)-HMS were found to be effective inhibitors of a-mannosidase from jack bean. (C) 1997 Elsevier Science Ltd.