Preparation and configuration of racemic and optically active analgesic cycloaminoalkylnaphthalenes

• Published in: Chirality (New York, N.Y.) Vol. 11; no. 1; pp. 21 - 28
• Main Authors: Ghislandi, Victor, Collina, Simona, Azzolina, Ornella, Barbieri, Annalisa, Lanza, Enrica, Tadini, Carla
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 1999
• Subjects: absolute configuration; Analgesics, Opioid - chemical synthesis; Analgesics, Opioid - pharmacology; Animals; conformational study; crystallographic analysis; Crystallography, X-Ray; Hydrogen Bonding; Male; Mice; Models, Molecular; Molecular Conformation; Morphine - pharmacology; Naphthalenes - chemical synthesis; Naphthalenes - pharmacology; opioid-like analgesics; optical resolution; Pain Measurement - drug effects; Stereoisomerism
• ISSN: 0899-0042; 1520-636X
• DOI: 10.1002/(SICI)1520-636X(1999)11:1<21::AID-CHIR4>3.0.CO;2-4

Cycloaminoalkylnaphthalene 3 shows interesting opioid‐like analgesic properties. It possesses two chiral centers and can exist as two racemic pairs and four diastereomers. Since the binding of opioids with receptors is stereoselective, it was important to have the two racemic pairs as well as the four 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‐hydroxynaphthyl)]‐3‐hydroxypyrrolidine 3 is considered and the determination of absolute configuration is described. The (2R,3S/2S,3R)‐3 racemate and the (2R,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 lithiation product obtained from 2‐bromo‐6‐tetrahydropyranyloxy‐naphthalene 1 and acidic hydrolysis. The above‐mentioned enantiomers of 3 were also obtained by optical resolution via fractional crystallization of the salts with d‐ and l‐tartaric acids. The configuration of the optically active compounds 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 enantiomer is able to induce opioid‐like analgesia with a relative potency 1.5 times that of (2R,3S/2S,3R)‐3 and ∼1.5 times that of morphine. Chirality 11:21–28, 1999. © 1999 Wiley‐Liss, Inc.