ABSTRACT
In solid-phase organic synthesis, Wang resin is traditionally used for the immobilization of acids, alcohols, phenols, and amines. We report the use of Wang resin for the traceless synthesis of ketones via acid-labile enol ethers. We demonstrate the practicality of this synthetic strategy on the solid-phase synthesis of pyrrolidine-2,4-diones, which represent the core structure of several natural products, including tetramic acid. Base-triggered condensation of pyrrolidine-2,4-diones yielded 4-hydroxy-1,1',2',5-tetrahydro-2H,5'H-[3,3'-bipyrrole]-2,5'-diones.
Subject(s)
Alcohols , Ketones , Alcohols/chemical synthesis , Alcohols/chemistry , Amines/chemistry , Ketones/chemical synthesis , Ketones/chemistryABSTRACT
Nitrobenzothiazinones are among the most potent antituberculosis agents. Herein, we disclose an unprecedented inâ vivo reduction process that affords Meisenheimer complexes of the clinical candidates BTZ043 and PBTZ169. The reduction is reversible, occurs in all mammalian species investigated, has a profound influence on the inâ vivo ADME characteristics, and has considerable implications for the design and implementation of clinical studies. The reduction was confirmed by chemical studies that enabled the complete characterization of the Meisenheimer complex and its subsequent chemistry. Combination of the inâ vivo and chemical studies with LC-MS characterization and assay development also provides a basis for rational lead optimization of this very promising class of antituberculosis agents.
Subject(s)
Antitubercular Agents/chemistry , Piperazines/chemistry , Spiro Compounds/chemistry , Thiazines/chemistry , Animals , Antitubercular Agents/blood , Antitubercular Agents/metabolism , Chromatography, Liquid , Drug Discovery , Humans , Mice , Mice, Inbred C57BL , Oxidation-Reduction , Piperazines/blood , Piperazines/metabolism , Spiro Compounds/blood , Tandem Mass Spectrometry , Thiazines/blood , Thiazines/metabolismABSTRACT
We report an efficient synthesis of 4H-benzo[b][1,4]thiazine 1,1-dioxides via unprecedented ring contraction of 2,5-dihydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxides under mild conditions involving carbon-sulfur bond formation. 2,5-Dihydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxides are easily accessible from commercially available building blocks, including Fmoc-protected amino acids, 2-nitrobenzenesulfonyl chlorides, and bromo ketones. Benzothiazine 1,1-dioxides represent pharmacologically relevant derivatives with biological, medicinal, and industrial applications.