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-Al₂H/H₂C=CHMgBr followed by substrate-directed dihydroxylation of the pendant allylic group with OsO₄, reduction of imine, and cyclization with Ph₃P/CCl₄ 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 BF₃·Et₂O afforded the required three-carbon homologues (10a, > 20:1 de; 10b, 3.5:1 de). Use of the chelating Lewis acid MgBr₂ instead of BF₃·Et₂O with 10a led to a novel aza-pinacol rearrangement and allylation at the α-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).