Selfridge Brandon R, Deschamps Jeffrey R, Jacobson Arthur E, Rice Kenner C
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.
J Org Chem. 2014 Jun 6;79(11):5007-18. doi: 10.1021/jo500568s. Epub 2014 May 6.
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.
10-去甲纳曲酮（3-(环丙基甲基)-4a,9-二羟基-2,3,4,4a,5,6-六氢-1H-苯并呋喃[3,2-e]异喹啉-7(7aH)-酮，1）在寻找更好的阿片样物质配体方面未得到充分利用，其对映体也未被探索。通过对中间体吡啶基化合物12进行非色谱优化合成，实现了反式异喹啉酮2（4-aH，9-O-反式-9-甲氧基-3-甲基-2,3,4,4a,5,6-六氢-1H-苯并呋喃[3,2-e]异喹啉-7(7aH)-酮）的合成。对2进行了光学拆分，并且将每种对映体用于“非天然”的4aR,7aS,12bR-(+)-1及其“天然”对映体(-)-1的高效合成中。在对映体异喹啉酮（(+)-和(-)-2）中添加一个14-羟基（4a-羟基）基团，得到(+)-和(-)-10-去甲纳曲酮。在合成过程中发现了一种结构独特的四环烯胺，(12bR)-7,9-二甲氧基-3-甲基-1,2,3,7-四氢-7,12b-亚甲基苯并[2,3]氧杂环辛并[5,4-c]吡啶，它为未来的研究提供了一种不同的阿片样骨架。
