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A Substituted Hypersensitive Radical Probe for Enzyme-Catalyzed Hydroxylations: Synthesis of Racemic and Enantiomerically Enriched Forms and Application in a Cytochrome P450-Catalyzed Oxidation
journal contribution
posted on 1997-12-26, 00:00 authored by Patrick H. Toy, Bhavani Dhanabalasingam, Martin Newcomb, Imad H. Hanna, Paul F. HollenbergThe syntheses of racemic and enantiomerically enriched
trans-1-methyl-2-(4-(trifluoromethyl)phenyl)cyclopropane (3) and the possible oxidation products
from enzyme-catalyzed hydroxylation of 3
at the methyl group are reported. The important intermediate in
the production of 3 was the
Weinreb amide of the 2-arylcyclopropanecarboxylic acid which could be
prepared in diastereomerically pure form and which also served as an intermediate for production
of the cyclic oxidation
products of 3. Hydroxylation of 3 by the
cytochrome P450 isozyme CYP2B1 gave cyclic and ring-opened products. The product ratios support an insertion mechanism
for the enzyme-catalyzed
hydroxylation reaction in which minor amounts of rearranged products
are produced by radical
fragmentation within the transition structure of the insertion and by a
competing reaction involving
a cationic species. Formation of cationic rearrangement products
by a heterolytic fragmentation
reaction of a first-formed protonated alcohol product is suggested on
the basis of the apparent
amounts of cationic products formed in the hydroxylation of
3. This pathway for cation production
appears to require that the activated enzyme complex (equivalent to
enzyme−substrate−H2O2)
oxidizes substrate before water dissociates to give an iron−oxo
species.
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cytochrome P 450 isozyme CYP 2Bmethyl groupEnantiomerically Enriched Formsoxidizes substratecationic rearrangement productstransition structureinsertion mechanismcyclic oxidation productsproduct ratios supportcationic productscationic speciesoxidation productscation productionWeinreb amidehydroxylationSubstituted Hypersensitive Radical Probeheterolytic fragmentation reaction
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