Synthesis of enantiopure 10-nornaltrexones in the search for Toll-like receptor 4 antagonists and opioid ligands.
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.
Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Brandon R
BR
Selfridge
Jeffrey R
JR
Deschamps
Arthur E
AE
Jacobson
Kenner C
KC
Rice
D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry*; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D035964:Oxocins / Q000138:chemical synthesis* / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000737:chemistry*
C000594690:(12bR)-7,9-dimethoxy-3-methyl-1,2,3,7-tetrahydro-7,12b-methanobenzo(2,3)oxocino(5,4-c)pyridine; C000594689:(3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-benzofuro(3,2-e)isoquinolin-7(7aH)-one; D000701:Analgesics, Opioid; D001572:Benzofurans; D007546:Isoquinolines; D035964:Oxocins; D011725:Pyridines; D051197:Toll-Like Receptor 4; D009271:Naltrexone