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

• Published in: Journal of organic chemistry Vol. 76; no. 9; pp. 3484 - 3497
• Main Authors: McAllister, Laura A, Bechle, Bruce M, Dounay, Amy B, Evrard, Edelweiss, Gan, Xinmin, Ghosh, Somraj, Kim, Ji-Young, Parikh, Vinod D, Tuttle, Jamison B, Verhoest, Patrick R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 06.05.2011; Amer Chemical Soc
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Chemistry; Chemistry, Organic; Cyclization; Esters; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Medical sciences; Nitro Compounds - chemistry; Organic chemistry; Oxidation-Reduction; Pharmacology. Drug treatments; Phenylalanine - analogs & derivatives; Phenylalanine - chemical synthesis; Phenylalanine - chemistry; Physical Sciences; Preparations and properties; Science & Technology; Sodium Acetate - chemistry; Substrate Specificity; Tin Compounds - chemistry; PHASE-TRANSFER; Phase transfer catalysis; Substituent effect; Nitro compound; Enantioselectivity; Nitrogen heterocycle; Selectivity; Alkylation; Chemical reduction; Stereoselectivity; Ester; Amine; Aromatic compound; Chemical synthesis; Quinolone derivatives; Alanine; Phenylalanine; Hydroxamic acid; Quinoline derivatives; Organic bromine compounds; α-Aminoacid; Cyclization; Cyclic compound; Aminoacid; Inhibitor; Antibacterial agent
• ISSN: 0022-3263; 1520-6904; 1520-6904
• DOI: 10.1021/jo200530j

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.