Improvements in the Total Synthesis of Morphine

✍ Scribed by Gerrit J. Meuzelaar; Michiel C. A. van Vliet; Leendert Maat; Roger A. Sheldon

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 206 KB
• Volume: 1999
• Category: Article
• ISSN: 1434-193X
• DOI: 10.1002/(sici)1099-0690(199909)1999:9<2315::aid-ejoc2315>3.0.co;2-v

✦ Synopsis

The chiral 1,2,3,4-tetrahydroisoquinoline intermediates in the the key raw material in the Beyerman route, 3,5-dibenzyloxy-4-methoxyphenylacetic acid (1), starting from gallic acid methyl Rice and Beyerman routes to morphine, (+)-(R)-1-(3-hydroxy-4methoxybenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline ( 6) ester ( 7) was improved by a factor of 5 over previously described syntheses. Key steps in the new procedure are the and (+)-(R)-1-(3,5-dibenzyloxy-4-methoxybenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (5), were prepared in high ee by selective formation of methyl 3,5-dihydroxy-4-methoxybenzoate (9) via the 3,5-diacetate and an improved benzylation ruthenium-catalyzed asymmetric transfer hydrogenation of the corresponding imine precursors (Noyori method). The yield of of the hydroxyl groups in 9.