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Chemoenzymatic Formal Total Synthesis of ent ‐Codeine and Other Morphinans via Nitrone Cycloadditions and/or Radical Cyclizations. Comparison of Strategies for Control of C‐9/C‐14 Stereogenic Centers
Author(s) -
EndomaArias Mary Ann A.,
Hudlicky Jason Reed,
Simionescu Razvan,
Hudlicky Tomas
Publication year - 2014
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201400016
Subject(s) - chemistry , nitrone , stereocenter , radical cyclization , stereochemistry , dihydroxylation , heck reaction , total synthesis , nitrile , aldehyde , antimycobacterial , codeine , hydrocodone , olefin fiber , organic chemistry , enantioselective synthesis , cycloaddition , palladium , medicine , morphine , pharmacology , catalysis , mycobacterium tuberculosis , tuberculosis , biochemistry , oxycodone , receptor , polymer , pathology , opioid
Formal total syntheses of ent ‐codeine and other morphinans were accomplished from 1‐phenyl‐2‐acetoxyethane, which was subjected to enzymatic dihydroxylation by toluene dioxygenase overexpressed in Eschericia coli JM109 (pDTG601A). The resulting cis ‐dihydroarenediol was coupled with a phenol derived from bromoisovanillin and a subsequent Heck reaction was used to establish the C‐13 quaternary center. Two strategies were employed to set the C‐14 center: nitrone and nitrile oxide cycloadditions to the C‐8/C‐14 olefin and a radical cyclization of an aldehyde to C‐14. Both strategies yielded tetracyclic products that were converted to known intermediates for the synthesis of ent ‐codeine, ent ‐codeinone, and ent ‐hydrocodone. Experimental and spectral data are provided for all new compounds.