Synthesis and receptor affinity of 7[beta]-substituted analogs of codeine : total synthesis of 8,14-dihydromorphinandienone alkaloids

Abstract

A series of morphinan-based compounds inspired by the semi-synthetic opioid metopon have been synthesized. An expedient route from (-)-codeine to the key intermediate, 6,7-a-epoxide has been developed giving access to enantio-enriched analogs. Classical diaxial opening of the a-epoxide has allowed for introduction of b-substituents at C7, emulating the 5b-methyl group in metopon. Several analogs exhibited dual agonist activity at the m- andd-receptors while lacking significant affinity for k-receptors, fulfilling a requirement for an opioid with a diminished side-effect profile. Additionally, a collective synthesis of 8,14-dihydronorsalutaridine, 8,14-dihydrosalutaridine, norisosinomenine and isosinomenine is reported. The strategy employed provides direct access to the correct oxidation level of the products by avoiding the biomimetic strategy of o, p-phenolic oxidative coupling. The combination of an organocatalyst guanidine superbase, a tertiary amine base and a dehydrating agent was found necessary for the successful Henry-Michael-dehydration cascade to form the phenanthrene motif. The requirement for an efficient and selective aliphatic nitro reduction could be achieved only under heterogeneous transfer-hydrogenation conditions. Conversion of 8,14-dihydrosalutaridine into salutaridine by oxidation of the C8-C14 into a double bond would allow for subsequent biomimetic transformation of the resultant dienone structures consecutively into thebaine and codeine. The combination of these routes provide a highly practical racemic synthesis of certain 8,14-dihydromorphinandienone alkaloids, and by extension, of thebaine and codeine.