(R)- and (S)-4-methylaminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole: synthesis, absolute configuration, conformation, and analgesic activity

Abstract

(R)- and (S)-4-Methylaminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b] indole (2) have been synthesized and their conformation studied. (RS)-(2) Has been found to be a potent non-narcotic analgesic agent. The crucial step was regio- and stereo-specific cyclization of indolyl alkyl sulphides (S)- and (R)-(9) to both enantiomers of (10) using an intramolecular indole Grignard reaction. Optical purities and the absolute configuration were established. The analgesic activity of (R)-(2) is more potent than that of the (S)-isomer. The thiopyrano ring moiety of (2) was shown to adopt a half-chair conformation with pseudoaxial orientation of the side chain by X-ray and NMR methods. In the crystal structure of the p-bromobenzylamino derivative of (2), two six-membered aromatic rings were found to adopt a perpendicular edge-to-face arrangement, which has led us to propose a model for drug-receptor binding. The roles of configuration and conformation as they affect the analgesic activity are discussed.