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Synthesis of tritium labelled (3R*, 5S*)‐3, 5‐dihydroxy‐9, 9‐diphenyl‐6, 8‐nonadienoate
Author(s) -
Wint Lewin T.,
McCarthy Peter A.
Publication year - 1988
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.2580251116
Subject(s) - chemistry , tritium , sodium borohydride , reductase , yield (engineering) , specific activity , coenzyme a , moiety , radiochemistry , catalysis , nuclear chemistry , stereochemistry , organic chemistry , enzyme , physics , materials science , nuclear physics , metallurgy
Methyl (3 R *, 5S*)‐(E)‐3,5‐dihydroxy‐9,9‐diphenyl‐6,8‐nonadienoate ( 1 ) is a competitive inhibitor of HMG‐CoA reductase, the rate‐limiting step in cholesterol biosynthesis. We synthesized 1 with a tritium label at C 3 in order to investigate tissue selectivity. The synthesis began with β‐phenyl‐ cinnamaldehyde which was homologated to (E)‐5,5‐diphenyl‐2,4‐pentadienal in three steps. Addition of the dianion of methyl acetoacetate gave methyl (E)‐5‐hydroxy‐ 9,9‐diphenyl‐3‐oxo‐6,8‐nonadienoate. Diastereoselective introduction of the tritium label was achieved using tritium labelled sodium borohydride, triethylborane and a catalytic amount of pivalic acid. The radiochemical yield for this step was 7.5 %, the specific activity was 13.3 mCi/mmole, and the product was >95% radiochemically pure. This method may be applicable to the preparation of other radiolabelled HMG‐CoA reductase inhibitors which possess a 3,5‐dihydroxy acid moiety.