Asymmetric syntheses of (-)-8-epi-swainsonine triacetate and (+)-1, 2-Di-epi-swainsonine. Carbonyl addition thwarted by an unprecedented aza-pinacol rearrangement.

Indolizidines (-)-8-epi-swainsonine triacetate and (+)-1, 2-di-epi-swainsonine were synthesized from the O'Donnell Schiff base ester 1 derived from D-serine. Reductive-alkenylation of 1 with (i)()Bu(5)Al(2)H/H(2)C=CHMgBr followed by substrate-directed dihydroxylation of the pendant allylic group with OsO(4), reduction of imine, and cyclization with Ph(3)P/CCl(4) gave the polyhydroxylated pyrrolidines 8a and 8b as advanced intermediates. Efficient protecting group manipulations converted pyrrolidines 8a and 8b to their corresponding partially protected analogues 10a and 10b, which upon Swern oxidation and diastereoselective Keck-type allylation with BF(3).Et(2)O afforded the required three-carbon homologues (10a, >20:1 de; 10b, 3.5:1 de). Use of the chelating Lewis acid MgBr(2) instead of BF(3).Et(2)O with 10a led to a novel aza-pinacol rearrangement and allylation at the alpha-carbon to yield amino alcohol 17, which is similar to a hydride migration in the biosynthetic pathway of indolizidine alkaloids. Subsequent hydroboration, cyclization, and deprotection furnished (-)-8-epi-swainsonine triacetate 15a and (+)-1,2-di-epi-swainsonine 16b in good overall yields (6.3% for 1 --> 15a, 13 steps, and 4.0% for 1 --> 16b, 14 steps).