Synthesis of enantiopure 10-nornaltrexones in the search for toll-like receptor 4 antagonists and opioid ligands

Abstract

10-Nornaltrexones (3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6- hexahydro-1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one, 1) have been underexploited in the search for better opioid ligands, and their enantiomers have been unexplored. The synthesis of trans-isoquinolinone 2 (4-aH, 9-O-trans-9-methoxy- 3-methyl-2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one) was achieved through a nonchromatographic optimized synthesis of the intermediate pyridinyl compound 12. Optical resolution was carried out on 2, and each of the enantiomers were used in efficient syntheses of the "unnatural" 4aR,7aS,12bR-(+)-1) and its "natural" enantiomer (-)-1. Addition of a 14-hydroxy (the 4a-hydroxy) group in the enantiomeric isoquinolinones, (+)- and (-)-2), gave (+)- and (-)-10-nornaltrexones. A structurally unique tetracyclic enamine, (12bR)-7,9-dimethoxy-3-methyl-1,2,3,7-tetrahydro-7,12b-methanobenzo[2, 3]oxocino[5,4-c]pyridine, was found as a byproduct in the syntheses and offers a different opioid-like skeleton for future study. © This article not subject to U.S. Copyright. Published 2014 by the American Chemical Society.