INTRAMOLECULAR MICHAEL ADDITION OF N-CENTERED AND O-CENTERED NUCLEOPHILES TO TETHERED ACRYLATES - THE ROLE OF DOUBLE-BOND GEOMETRY IN CONTROLLING THE DIASTEREOSELECTIVITY OF CYCLIZATIONS LEADING TO 2,6-DISUBSTITUTED TETRAHYDROPYRANS AND PIPERIDINES

The oxyanion derived from hydroxyacrylate E-(5) undergoes smooth intra molecular Michael addition to give the trans-2,6-disubstituted tetrahy dropyran (7) as the major product of reaction. In contrast, the oxyani on obtained from isomer Z-(5) cyclizes to give the cis-2,6-disubstitut ed tetrahydropyran (6) as the major product. Such chemistry has been e xtended to the enantioselective synthesis of (+)-(6) the acquisition o f which constitutes a formal total synthesis of acid (+)-(2), a consti tuent of the glandular secretion from the civet cat (Viverra civetta). Reductive amination of keto acrylate (12) affords an intermediate ami ne which cyclizes, in situ, to give the cis-2,6-disubstituted piperidi ne (26). Analogous treatment of compound (13) delivers the isomeric tr ans-2,6-disubstituted piperidine (27) as the exclusive product of reac tion. Transition state structures have been proposed to account for th e diastereoselectivities observed in all of the cyclization reactions.