Journal of Organic Chemistry 2011-05-06

A general strategy for the synthesis of cyclic N-aryl hydroxamic acids via partial nitro group reduction.

Laura A McAllister, Bruce M Bechle, Amy B Dounay, Edelweiss Evrard, Xinmin Gan, Somraj Ghosh, Ji-Young Kim, Vinod D Parikh, Jamison B Tuttle, Patrick R Verhoest

Index: J. Org. Chem. 9th ed., 76 , 3484-3497, (2011)

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Abstract

We describe a generalized approach to stereocontrolled synthesis of substituted cyclic hydroxamic acids (3-amino-1-hydroxy-3,4-dihydroquinolinones) by selective reduction of substituted 2-nitrophenylalanine substrates. Compounds in this series have antibacterial properties and have also recently been reported as KAT II inhibitors. The key nitrophenyl alanine intermediates are prepared enantioselectively in excellent yield by phase transfer catalyzed alkylation of the corresponding nitrobenzyl bromides. The scope and limitations of the reductive cyclization transformation have been explored with attention to the effects of substitution pattern and electronics on reaction efficiency and byproduct formation. In addition, a novel activated trifluoroethyl ester cyclization strategy has been developed as an alternate approach to the most sterically demanding systems in this series.© 2011 American Chemical Society