The
enzyme α-methylacyl-CoA racemase (AMACR) is overexpressed in prostate, colon,
and other cancers and has been partially validated as a potential therapeutic
target by siRNA knockdown of the AMACR gene. Analogs of the natural substrate
branched chain α-methylacyl coenzyme A esters, possessing one or more β-fluorine
atoms, have been synthesized using Wittig, conjugate addition and asymmetric
aldol reactions and found to be reversible competitive inhibitors. The CoA
esters were made from the racemic acids and tested as diastereoisomeric
mixtures. For the synthesis of compounds 171 and 173, A. J.
Carnell et al.68 employed an Evans asymmetric aldol reaction to have
control over absolute and relative stereochemistry of the 2-methyl and 3-fluoro
substituents (Scheme 28). Thus, asymmetric aldol reaction between the boron
enolate derived from oxazolidinone 167 and the tetradecanal afforded the
syn aldol product 168 as a single isomer.
68. A. J. Carnell, I. Hale, S. Denis, R. J. A. Wanders, W. B. Isaacs, B. A. Wilson, and S. Ferdinandusse, J. Med. Chem.,2007, 50, 2700.
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