196609-07-1Relevant academic research and scientific papers
Conformational restriction approach to β-secretase (BACE1) inhibitors III: Effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration calorimetry and theoretical calculations
Yonezawa, Shuji,Fujiwara, Kenichiro,Yamamoto, Takahiko,Hattori, Kazunari,Yamakawa, Hidekuni,Muto, Chie,Hosono, Motoko,Tanaka, Yoshikazu,Nakano, Toru,Takemoto, Hiroshi,Arisawa, Mitsuhiro,Shuto, Satoshi
, p. 6506 - 6522 (2013/10/22)
For further investigation of BACE1 inhibitors using conformational restriction with sp3 hybridized carbon, we applied this approach to 6-substituted aminopyrimidone derivatives 3 to improve the inhibitory activity by reducing the entropic energy loss upon binding to BACE1. Among eight stereoisomers synthesized, [trans-(1′R,2′R),6S] isomer 6 exhibited the best BACE1 inhibitory activity, which was statistically superior to that of the corresponding ethylene linker compound (R)-3. Combinational examinations of the binding mode of 6 were performed, which included isothermal titration calorimetry (ITC), X-ray crystallographic structure analysis and theoretical calculations, to clarify the effect of our conformational restriction approach. From the ITC measurement, the binding entropy of 6 was found to be ～0.5 kcal larger than that of (R)-3, which is considered to be affected by conformational restriction with a cyclopropane ring.
The palladium-catalyzed aerobic kinetic resolution of secondary alcohols: Reaction development, scope, and applications
Ebner, David C.,Bagdanoff, Jeffrey T.,Ferreira, Eric M.,McFadden, Ryan M.,Caspi, Daniel D.,Trend, Raissa M.,Stoltz, Brian M.
supporting information; experimental part, p. 12978 - 12992 (2010/06/19)
The first palladium-catalyzed enantioselective oxidation of secondary alcohols has been developed, utilizing the readily available diamine (-)-sparteine as a chiral ligand and molecular oxygen as the stoichiometric oxidant. Mechanistic insights regarding the role of the base and hydrogen-bond donors have resulted in several improvements to the original system. Namely, addition of cesium carbonate and tert-butyl alcohol greatly enhances reaction rates, promoting rapid resolutions. The use of chloroform as solvent allows the use of ambient air as the terminal oxidant at 23°C, resulting in enhanced catalyst selectivity. These improved reaction conditions have permitted the successful kinetic resolution of benzylic, allylic, and cyclopropyl secondary alcohols to high enantiomeric excess with good-toexcellent selectivity factors. This catalyst system has also been applied to the desymmetrization of meso-diols, providing high yields of enantioenriched hydroxyketones.
High-diastereoselective and enantioselective cyclopropanation of α,β- unsaturated Fischer carbene complexes: Synthesis of chiral 1,2-disubstituted and 1,2,3-trisubstituted cyclopropanes
Barluenga,Bernad P.L.,Concellon
, p. 6870 - 6875 (2007/10/03)
Reaction of chiral vinylcarbene complexes 1 with in situ-generated iodomethyllithium or dibromomethyllithium gives cyclopropylcarbene complexes 4 and 13, respectively, with high diastereoselectivity (de > 91%). Different enantiopure 1,2-disubstituted and 1,2,3-trisubstituted cyclopropanes are obtained starting from chiral carbene complexes 4 and 13, respectively.
