Facile synthesis of diastereoisomerically and optically pure 2-substituted hexahydro-1H-pyrrolizin-3-ones

We report a short synthetic route that provides optically active 2-substituted hexahydro-1H-pyrrolizin-3-ones in four steps from commercially available Boc (tert-but(oxy)carbonyl)) -protected proline. Diastereoisomers (-)-11 and (-)-12 were assembled from the proline-derived aldehyde (-)-8 and ylide 9 via a Wittig reaction and subsequent catalytic hydrogenation (Scheme 3). Cleavage of the Boc protecting group under acidic conditions, followed by intramolecular cyclization, afforded the desired hexahydro-1H-pyrrolizinones (-)-1 and (+)-13. Applying the same protocol to ylide 19 afforded hexahydro-1H-pyrrolizinones (-)-25 and (-)-26 (Scheme 5). The absolute configuration of the target compounds was determined by a combination of NMR studies (Figs. 1 and 2) and X-ray crystallographic analysis (Fig. 3).