Difluorophenylglycinols as New Modulators of Proteolytic Processing of Amyloid Precursor Proteins

Abstract

Synthesis and evaluation of difluorophenylglycinols as new modulators of proteolytic processing of the amyloid-β precursor proteins for Alzheimer's therapies were described. A range of N-substituted (R)- and (S)-difluorophenylglycinols, structured on the amino alcohol framework, were explored by incorporating the arylsulfonyl moieties and various N-substituents. Evans' chiral auxiliary strategy was employed for the asymmetric synthesis of these enantiomeric difluorophenylglycinols. Compounds with effects on the γ-secretase inhibition and ERK-mediated signaling pathways were evaluated on cell-based assays. Among them, N-cyclopropylmethyl derivatives R-12c and R-13c showed modest γ-secretase inhibition as well as ERK-dependent activation.

Enantioselective Access to Chiral Cyclic Sulfamidates Through Iridium‐Catalyzed Asymmetric Hydrogenation

“…[10h,l] The chiral difluorophenylglycinol could be further derivatized to work as new modulator of proteolytic processing of the amyloid-b precursor proteins for Alzheimer's therapies. [13] Table 2. Screening solvents for the Ir/NÀMe-ZhaoPhos L2catalyzed asymmetric hydrogenation of 4-phenyl-5H- [1,2,3] oxathiazole 2,2-dioxide (1 a).…”