Stereochemical Studies on Medicinal Agents. 17. Synthesis, Absolute Configuration, and Analgetic Potency of Enantiomeric Diastereomers of 3-Ethyl and 3-Propyl Derivatives of 1-Methyl-4-phenyl-4-propionoxypiperidine

We recently have reported²on the relative stereochemistries of racemic diastereomers of 1 and have noted that, unlike the prodines 2, the α isomer is considerably more potent than the β isomer. The corresponding allyl racemates also were found to possess a qualitatively similar stereostructure-activity relationship; however, on a quantitative basis (±)-α-3 is 15 times more potent than morphine and 24 times that of (±)-α-1. A subsequent report³on the optical isomers of 3 revealed that α-3 possesses high enantiomeric stereoselectivity [potency ratio, (3R,4S)/(3S,4R) = 260], while the much less active β-3 exhibits an enantiomeric potency ratio of unity. This is in marked contrast to the stereochemical behavior of α-2⁴where potency and enantiomeric stereoselectivity are one order of magnitude lower [(3R,4S)/(3S,4R) = 25] than α-3. Moreover, β-2⁴also shows a striking difference (when compared to β-3) in that it possesses moderate enantiomeric stereoselectivity [(3S,4S)/(3R,4R) = 13].