Premium
Improvements in the Total Synthesis of Morphine
Author(s) -
Meuzelaar Gerrit J.,
van Vliet Michiel C. A.,
Maat Leendert,
Sheldon Roger A.
Publication year - 1999
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/(sici)1099-0690(199909)1999:9<2315::aid-ejoc2315>3.0.co;2-v
Subject(s) - chemistry , tetrahydroisoquinoline , transfer hydrogenation , yield (engineering) , ruthenium , imine , raw material , organic chemistry , enantioselective synthesis , stereochemistry , medicinal chemistry , combinatorial chemistry , catalysis , materials science , metallurgy
The chiral 1,2,3,4‐tetrahydroisoquinoline intermediates in the Rice and Beyerman routes to morphine, (+)‐( R )‐1‐(3‐hydroxy‐4‐methoxybenzyl)‐6‐methoxy‐1,2,3,4‐tetrahydroisoquinoline ( 6 ) and (+)‐( R )‐1‐(3,5‐dibenzyloxy‐4‐methoxybenzyl)‐6‐methoxy‐1,2,3,4‐tetrahydroisoquinoline ( 5 ), were prepared in high ee by ruthenium‐catalyzed asymmetric transfer hydrogenation of the corresponding imine precursors (Noyori method). The yield of the key raw material in the Beyerman route, 3,5‐dibenzyloxy‐4‐methoxyphenylacetic acid ( 1 ), starting from gallic acid methyl ester ( 7 ) was improved by a factor of 5 over previously described syntheses. Key steps in the new procedure are the selective formation of methyl 3,5‐dihydroxy‐4‐methoxybenzoate ( 9 ) via the 3,5‐diacetate and an improved benzylation of the hydroxyl groups in 9 .