Stereoselective Synthesis of Frans-(E)-N-{2-[4-(3,4-Dichlorophenyl)but-2-En-2-Yl]Cyclohexyl}Pyrrolidine as an Alkene Mimetic of the Arylacetamide Analgesics

Diethylaluminum trimethylsilylacctylide reacted stereospecifically with the mesylate of trans-2-(N- pyrrolidinyl)cyclohexanol (2) to give trans-N-2-(trimethylsilylacetylcnyl)cyclohexyl]pyrrolidine (3). The trimethylsilyl group in 3 was displaced with a 3,4-dichlorobenzoyl group to give ynone 4, which then underwent 1,4-addition with lithium dimethylcuprate to give trans enone 6 and its cis isomer 5 in a ratio 5:1. Reduction of the enones with NaBHVCeCl₃ resulted in cis and trans allylic alcohols 9 and 10. Both 9 and 10 were successfully deoxygenated with Znl₂-NaCNBH₃ reducing system to give trans-(E)-N-{2-4-(3,4- dichlorophenyl)bul-2-en-2-yl]cyclohexyl}pyrrolidine (11) as the onty product. Olefin 11, a carbon-carbon double bond isostere of the prototypek-selective opioid analgesic U-50488, showed a 10³ fold reduction in K-affinity (K_ik = 1.6 × 10⁴ nM vs 15 nM for U-50488).