A General Strategy for the Synthesis of Cyclic N-Aryl Hydroxamic Acids via Partial Nitro Group Reduction

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.

Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia

“…The potential advantages of irreversible inhibitors include low dose requirements and reduced off-target toxicity. , Furthermore, this irreversible inhibitor does not covalently bind to the protein, which should significantly reduce the potential for an immune response. To fully explore the structure–activity relationship (SAR) around the PF-04859989 scaffold, several synthetic approaches were developed (see Scheme ); detailed descriptions of these methods have recently been disclosed. , In general, the synthesis of 7 and its analogues requires access to α-amino acids or α-amino esters, which undergo reductive cyclization to afford 3-amino-1-hydroxy-3,4-dihydroquinolin-2­(1 H )-ones. In the case of 7 itself, direct catalytic reductive cyclization using Pt/C and H 2 (method A) provided clean conversion to the desired product without competitive over-reduction to the corresponding lactam.…”

Synthesis and Anti‐proliferative Activity of Novel Polysubstitued Indazole Derivatives

“…It is noteworthy that reduction of aromatic nitro compounds with metals in protic solvents such as alcohols is usually presumed to proceed by way of hydroxylamine‐like intermediates .…”

SnCl2/EtOH-Mediated Synthesis of Novel 4-Ethoxy- and 4-Chloroindazoles Bearing Sulfonamide Moieties

“…The reduction of aromatic nitro compounds with metals in protic solvents such as alcohols is usually presumed to proceed by way of hydroxylamine-like intermediates [13,[22][23][24][25] .…”