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

Abstract

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., (3 R)-3-(hydroxymethyl)swainsonine [( 10), (3 R)-HMS] and (3 S)-3-(hydroxymethyl)swainsonine [( 11), (3 S)-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 ⇒ 11 ) or an azido epoxide bearing a lactone (i.e. 27 ⇒ 10 ). Both (3 R)-HMS and (3 S)-HMS were found to be effective inhibitors of α-mannosidase from jack bean.