Glucokinase Activator: Practical Asymmetric Hydrogenation and Scalable Synthesis of an API Fragment

The enantioselective synthesis of (<i>R</i>)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl propionic acid (<i>R</i>)-<b>2</b> is described. The key intermediate (<i>E</i>)-<b>7</b>, a trisubstituted α-aryl β-alkyl acrylic acid, was conveniently accessed as its dicyclohexylamine salt by Perkin reaction in good yield and purity. Subsequent asymmetric hydrogenation with ruthenium catalysts was achieved with complete conversion and catalyst loadings up to <i>S</i>/<i>C</i> 75000 and enantiomeric excess up to 99% after crystallization

An Efficient Through-Process for Chk1 Kinase Inhibitor GDC-0575

We report an efficient route to prepare Chk1 kinase inhibitor GDC-0575 from 5-bromo-4-chloro-3-nitro-7-azaindole featuring a sequence of nucleophilic aromatic substitution, hydrogenative nitro-reduction, and a robust, high-yielding end-game involving deprotection–crystallization steps. The developed route was demonstrated on 10 kg scale in 30% overall yield to provide the target API in >99.8 A % HPLC purity

Practical Asymmetric Hydrogenation-Based Synthesis of a Class-Selective Histone Deacetylase Inhibitor

Two syntheses of the class-selective histone deacetylase inhibitor <b>1</b> are reported. In the first, eight-step entailing synthesis, the key transformations were a highly efficient [3 + 2] dipolar cycloaddition affording <i>trans</i>-<i>rac</i>-<b>5</b> and its resolution. In the second, asymmetric approach, the key steps were a highly selective asymmetric hydrogenation to produce the <i>cis</i>-(<i>S,S</i>)-3,4-disubstituted pyrrolidine <b>18</b> followed by an amide formation with simultaneous chiral inversion of the carboxy stereocenter to generate the key intermediate <i>trans</i>-(<i>R,S</i>)-3,4-disubstituted pyrrolidine <b>19</b>. The overall yield increased from ∼6% for the resolution approach to ∼26% for the enantioselective approach

Correction to “Synthesis and Characterization of Iron–Nitrogen-Doped Graphene/Core–Shell Catalysts: Efficient Oxidative Dehydrogenation of <i>N</i>‑Heterocycles”

Correction to “Synthesis and Characterization of Iron–Nitrogen-Doped Graphene/Core–Shell Catalysts: Efficient Oxidative Dehydrogenation of <i>N</i>‑Heterocycles

Asymmetric Synthesis of Akt Kinase Inhibitor Ipatasertib

A highly efficient asymmetric synthesis of the Akt kinase inhibitor ipatasertib (<b>1</b>) is reported. The bicyclic pyrimidine <b>2</b> starting material was prepared via a nitrilase biocatalytic resolution, halogen–metal exchange/anionic cyclization, and a highly diastereoselective biocatalytic ketone reduction as key steps. The route also features a halide activated, Ru-catalyzed asymmetric hydrogenation of a vinylogous carbamic acid to produce α-aryl-β-amino acid <b>3</b> in high yield and enantioselectivity. The API was assembled in a convergent manner through a late-stage amidation/deprotection/monohydrochloride salt formation sequence