Enantioselective and Diastereoselective Ir-Catalyzed Hydrogenation of α‑Substituted β‑Ketoesters via Dynamic Kinetic Resolution

An iridium/f-amphol catalytic system for the enantioselective hydrogenation of α-substituted β-ketoesters via dynamic kinetic resolution is reported. The desired <i>anti</i> products were obtained in high yields (up to 98%) with good diastereoselectivity (up to 96:4 diastereometic ratio (dr)) and excellent enantioselectivity (up to >99% enantiomeric excess (ee)). A catalytic model is proposed to explain the stereoselectivity

Enantioselective Iridium-Catalyzed Hydrogenation of α‑Keto Amides to α‑Hydroxy Amides

A highly enantioselective iridium-catalyzed hydrogenation of α-keto amides to form α-hydroxy amides has been achieved with excellent results (up to >99% conversion and up to >99% ee, TON up to 100 000). As an example, this protocol was applied to the synthesis of (<i>S</i>)-4-(2-amino-1-hydroxyethyl)­benzene-1,2-diol, the enantiomer of norepinephrine, which is widely used as an injectable drug for the treatment of critically low blood pressure. Density functional theory (DFT) calculations were also carried out to reveal the reaction mechanism

Discovery and Extensive <i>in Vitro</i> Evaluations of NK-HDAC-1: A Chiral Histone Deacetylase Inhibitor as a Promising Lead

Herein, further SAR studies of lead compound NSC746457 (Shen, J.; Woodward, R.; Kedenburg, J. P.; Liu, X. W.; Chen, M.; Fang, L. Y.; Sun; D. X.; Wang. P. G. J. Med. Chem. 2008, 51, 7417−7427) were performed, including the replacement of the <i>trans-styryl</i> moiety with a 2-substituted benzo-hetero aromatic ring and the introduction of a substituent onto the central methylene carbon. A promising chiral lead, <i>S</i>-(<i>E</i>)-3-(1-(1-(benzo­[<i>d</i>]­oxazol-2-yl)-2-methylpropyl)-1<i>H</i>-1,2,3-triazol-4-yl)-<i>N</i>-hydroxyacrylamide (<b>12</b>, NK-HDAC-1), was discovered and showed about 1 order of magnitude more potency than SAHA in both enzymatic and cellular assays. For the <i>in vitro</i> safety tests, NK-HDAC-1 was far less toxic to nontransformed cells than tumor cells and showed no significant inhibition activity against CYP-3A4. The pharmaceutical properties (LogD, solubility, liver micrsomal stability (<i>t</i>1/2), plasma stability (<i>t</i>1/2), and apparent permeability) strongly suggested that NK-HDAC-1 might be superior to SAHA in bioavailability and <i>in vivo</i> half-life