Preparation and configuration of racemic and optically active analgesic cycloaminoalkylnaphthalenes

Cycloaminoalkylnaphthalene 3 shows interesting opioid-like analgesic proper ties. It possesses two chiral centers and can exist as two racemic pairs an d four diastereomers. Since the binding of opioids with receptors is stereo selective, it was important to have the two racemic pairs as well as the fo ur diastereomers. In this paper the synthesis of the (2R,3S/2S,3R) racemate and the (2R,3S) and (2S,3R) enantiomers of the 1,2-dimethyl-3-[2-(6-hydrox ynaphthyl)]-3-hydroxypyrrolidine 3 is considered and the determination of a bsolute configuration is described. The (2R,3S/2S,3R)-3 racemate and the (2 R,3S)-3 and (2S,3R)-3 enantiomers were prepared by reaction of the racemic and optically active 1,2-dimethyl-3-pyrrolidone 2, respectively, with the l ithiation product obtained from 2-bromo-6-tetrahydropyranyloxy-naphthalene 1 and acidic hydrolysis. The above-mentioned enantiomers of 3 were also obt ained by optical resolution via fractional crystallization of the salts wit h D- and L-tartaric acids. The configuration of the optically active compou nds was determined by X-ray analysis of a crystal of (-)-(2S,3R)-3 . HCl . H2O. The pharmacological test HPT showed that (-)-(2S,3R)-3 . HCl . H2O ena ntiomer is able to induce opioid-like analgesia with a relative potency 1.5 times that of (2R,3S/2S,3R)-3 and similar to 1.5 times that of morphine. C hirality 11:21-28, 1999. (C) 1999 Wiley-Liss, Inc.