Background: 3-[4-(Benzyloxy)phenyl]propanoic acid moiety is central to
many advanced agonists of free fatty acid receptor 1 (FFA1 or GPR40) which are a
new, promising class of antidiabetic drugs. An aldehydo carboxylic acid tert-butyl
ester building block is required for speedy SAR exploration of analogs of Eli Lilly’s
GPR40 agonist LY2881835 which was in phase I clinical trials.
Methods: The aldehyde functionality of the target building block was masked as
methyl carboxylate. The phenylpropionic acid tert-butyl ester portion was constructed
using Horner-Wadsworth-Emmons chemistry followed by olefin hydrogenation.
The aldehyde function was unmasked via methyl ester hydrolysis, mixed
anhydride reduction to alcohol and back-oxidation with manganese (IV) dioxide.
Results: The synthesis of the target building block was realized in 7 chemical steps (the final three of
which were conducted in succession not requiring interim purifications) involving isolation and characterization
of four hitherto undescribed intermediates.
Conclusion: The method described is suitable for production of the target alehydo carboxylic acid tertbutyl
ester building block on a multigram scale, which will facilitate the parallel synthesis of
LY2881835 analogs and expedite the respective SAR exploration.
Keywords: 3-[4-(benzyloxy)phenyl]propanoic acid core, Horner-Wadsworth-Emmons olefination, mixed anhydride reduction,
GPR40 agonists, structure-activity relationships, free fatty acid ligands, reductive amination, tert-butyl ester.
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