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

textA 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- andd-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.Chemistr

Total Synthesis of 8,14-Dihydromorphinandienone Alkaloids

A collective synthesis of 8,14-dihydronorsalutaridine, 8,14-dihydrosalutaridine, norisosinomenine, and isosinomenine is reported. The strategy provides direct access to the correct oxidation level of the products. The combination of an organocatalyst guanidine superbase, a tertiary amine base, and a dehydrating agent was necessary for the successful Henry–Michael–dehydration cascade to form the phenanthrene motif. The required selective aliphatic nitro reduction could only be achieved under heterogeneous transfer–hydrogenation conditions

Total Synthesis of 8,14-Dihydromorphinandienone Alkaloids

A collective synthesis of 8,14-dihydronorsalutaridine, 8,14-dihydrosalutaridine, norisosinomenine, and isosinomenine is reported. The strategy provides direct access to the correct oxidation level of the products. The combination of an organocatalyst guanidine superbase, a tertiary amine base, and a dehydrating agent was necessary for the successful Henry–Michael–dehydration cascade to form the phenanthrene motif. The required selective aliphatic nitro reduction could only be achieved under heterogeneous transfer–hydrogenation conditions