Synthesis of (−)- and (+)-2-hydroxy-6-keto-N-methylmorphinans, their O-methyl ethers, and 2-deoxy congeners

Abstract

Bischler–Napieralski cyclization of the known phenylacetamide 1, followed by selective ether cleavage of the 3,4-dihydroisoquinoline 2 and sodium borohydride reduction, afforded the tetrahydroisoquinoline 4. Optical resolution of 4 with tartaric acid gave the optical isomers 4a,b, which were converted into the 6-ketomorphinans 9a,b and their O-methyl ethers 10a,b by the following reaction sequence: Birch reduction, N-formylation of the dihydro bases, Grewe cyclization, removal of the N-formyl protecting groups, reductive N-methylation, and O-methylation. The 2-deoxy congeners 12a,b were obtained from 9a,b by phenyltetrazolylation, and catalytic removal of the heterocyclic etherfunction. The (−)-enantiomer 12a obtained by this synthesis was identical with material prepared from natural morphine, and exhibited the high antinociceptive potency already reported.