2-Cyano-Δ3-piperidines. 5. Toward the Synthesis of Corynanthe-Type Indole Alkaloids. Computer-Assisted Study of the Conformations of an "Inside" Indoloquinolizidine Series

Article abstract of DOI:10.1021/jo00144a009

1-<β-a-(Phenylsulfonyl)indol-3-yl>ethyl>-2-cyano-Δ³-piperidines 21 and 26 have been used to mimic the two-step reaction sequence 7 -> 8 (Scheme I) in which a 5,6-dihydropyridinium salt, 7, acts as a potential precursor of the tetracyclic corynanthe-type indole alkaloids.The required amino nitriles 21 and 26 were prepared by an established four-step procedure from the corresponding pyridinium salts.Amino nitrile 21 was successfully condensed with sodium dimethyl malonate, giving the enamine 27 which in certain experiments was reacted with KCN to give the corresponding amino nitriles 32 and 34.The benzenesulfonyl protecting group of 27, 32, and 34 was efficiently removed by using t-BuOK in THF and the C ring subsequently closed by reaction with HCl in MeOH.Three tetracyclic indoles (29-31) were obtained on cyclization of the deprotected enamine 28 (51percent overall yield from 21).In accord with this mechanism, on cyclization of deprotected amino nitrile 33, indoles 30 and 31 were formed, and on ring closure of amino nitrile 35, indole 29 only was formed.Because 30 and 31 were observed a priori to adopt unfavorable conformations where the malonyl and ethyl substituents were axial, a detailed analysis of the relative energies of the conformational possibilities for these products were undertaken with the aid of the computer program SCRIPT.Similarly, the unsubstituted amino nitrile 26 was sequentially reacted with sodium dimethyl malonate and KCN, giving compound 37 in 75percent yield.Removal of the benzenesulfonyl protecting group with t-BuOK in THF and cyclization by using a two-step "one pot" procedure (AgBF4, HCl/MeOH) led to the formation of two tetracyclic indoles, 39 and 40.The predominant product 40 was shown to possess the trans H-3,15 configuration typical of the alkaloid antirhine 6.