Synthesis and crystal structure of 17-deaza-17-methyl thionium isomorphinan (isosulforphanol) perchlorate, an isostere of the opiate isolevorphanol

Abstract

No morphinan analog carrying a heteroatom other than nitrogen at position 17 has yet been synthesized. The synthesis of the position 17 sulfur analog of the perchlorate salt of (±)-isolevorphanol is described. The strategy adopted is based on the classical Grewe synthesis of morphinans and, under narrowly defined conditions, the title compound isosulforphanol (3a) and an intermediate by-product 13 resulting from an unusual non-bridged head ring closure of 11a were obtained. The X-ray structures of both 3a and 13 were determined. Crystals of 13 (C17H22OS) are monoclinic, space group P21/a, a = 17.080(2), b = 9.372(1), c = 9.327(1) Å, β = 108.67(1), V = 1414.4 Å3, Z = 4. Final R = 0.034 for 2545 reflections. The crystals of 3a(C17H23OS+•ClO4−)are orthorhombic, space group Pna21,a = 10.934(1), b = 9.219(1), c = 17.131(2) Å, V = 1726.8 Å3, Z = 4. Final R = 0.053 for 1018 reflections. The C17H23OS+ molecule has been identified by this X-ray analysis as S-methyl isosulforphanol (Fig. 2). The structure of 13 is shown in Fig. 1. The stereochemical outcome of the Grewe-like synthesis is thus established as proceeding in a reversed manner when sulfur replaces the nitrogen in the final cyclization step. Preliminary pharmacological studies showed that 3a is a potent agonist in the central nervous system but a potent antagonist on the guinea-pig ileum.