Enantioselective syntheses of 2-alkyl-, 2,6-dialkylpiperidines and indolizidine alkaloids through diastereoselective Mannich-Michael reactions

Article abstract of DOI:10.1055/s-1997-3185

Aldimines of 2,3,4,6-tetra-O-pivaloyl-β-D-galactosylamine react with 1-methoxy-3-trimethylsilyloxybuta-1,3-diene in a Mannich-Michael condensation reaction sequence to give 2-substituted N-galactosyl-5,6-dehydropiperidin-4-ones 3 with high diastereoselectivity. The X-ray analysis of the 2-propyl derivative 3a proved (R)-configuration of the major diastereomer and led to the correction of our earlier assignment of configuration for (-)-coniine hydrochloride 9a obtained from this intermediate. Despite their low reactivity, these enaminones 3 can be converted into chiral 2,6-cis-disubstituted piperidinones 12 with high stereoselectivity by reaction with organocuprates in combination with hard electrophiles. Enantiomerically pure alkaloids such as (-)-dihydropinidine and gephyrotoxine 167B have been synthesized according to this methodology.