ENANTIOSELECTIVE SYNTHESIS OF INDOLIZINE DERIVATIVES BY REARRANGEMENT-CYCLIZATION OF ISOXAZOLINE-5-SPIROCYCLOPROPANES

(3S,7S,8aS)-3-Methyl-7-hydroxyoctahydroindolizine (13) was prepared with an enantiomeric excess of 74%. in five steps starting from enantiomerically pure (S)-(+)-5-nitro-2-pentanol (5). (3S,5S,7S,8aS)-(-)-3-Methyl-5-phenyl-7-hydroxyoctahydroindolizine (15) and (3S,5R,7R,8aR)-(+)-3-methyl-5-phenyl-7-hydroxyoctahydroindolizine (16) were also obtained starting from (5) with an ee of 96%. The synthetic strategy required the enantioselective enzymatic reduction of 5-nitro-2-pentanone (4) to 5 (> 99% ee) and its conversion to (R)-(-)-2-chloro-5-nitropentane (7) (> 90% ee). Cycloadditions of the corresponding nitrile oxide prepared in situ from 7 with methylenecyclopropane (8) or 1-methylene-2-phenylcyclopropane (9) produced chiral isoxazolines 1 and 2, which were converted by thermolysis to 2,3,5,6-tetrahydro-3-methylindolizin-7(1H)-one (10), and 2,3,5,6-tetrahydro-3-methyl-5-phenylindolizin-7(1H)-ones (11) and (12) respectively. The enantioselectivity of the thermal rearrangement is dependent on the experimental conditions and on the structures of the chiral isoxazolines. Catalytic hydrogenation of the indolizinones 10, 11 and 12, afforded the substituted hydroxyoctahydroindolizines 13, 15 and 16 with high stereoselective control of all stereogenic centers.