Second-Generation Atroposelective Synthesis of KRAS G12C Covalent Inhibitor GDC-6036.

A chromatography-free asymmetric synthesis of GDC-6036 (1) was achieved via a highly atroposelective Negishi coupling of aminopyridine 5 and quinazoline 6b catalyzed by 0.5 mol % [Pd(cin)Cl]2 and 1 mol % (R,R)-Chiraphite to afford the key intermediate (Ra)-3. An alkoxylation of (Ra)-3 with (S)-N-methylprolinol (4) and a global deprotection generates the penultimate heterobiaryl intermediate 2. A controlled acrylamide installation by stepwise acylation/sulfone elimination and final adipate salt formation and crystallization delivered high-purity GDC-6036 (1).

Development of the Commercial Manufacturing Process for Ipatasertib.

Ipatasertib is a potent small molecule Akt kinase inhibitor currently being tested in Phase III clinical trials for the treatment of metastatic castration-resistant prostate cancer and triple negative metastatic breast cancer. In this paper an overview of the development achievements towards the commercial manufacturing process is given. The convergent synthesis consists of ten steps with eight isolated intermediates and utilizes a wide range of chemical techniques and technologies to build-up this complex drug. All three stereocenters are introduced using enzyme or metal catalysis.

A robust iron catalyst for the selective hydrogenation of substituted (iso)quinolones.

By applying N-doped carbon modified iron-based catalysts, the controlled hydrogenation of N-heteroarenes, especially (iso)quinolones, is achieved. Crucial for activity is the catalyst preparation by pyrolysis of a carbon-impregnated composite, obtained from iron(ii) acetate and N-aryliminopyridines. As demonstrated by TEM, XRD, XPS and Raman spectroscopy, the synthesized material is composed of Fe(0), Fe3C and FeN x in a N-doped carbon matrix. The decent catalytic activity of this robust and easily recyclable Fe-material allowed for the selective hydrogenation of various (iso)quinoline derivatives, even in the presence of reducible functional groups, such as nitriles, halogens, esters and amides. For a proof-of-concept, this nanostructured catalyst was implemented in the multistep synthesis of natural products and pharmaceutical lead compounds as well as modification of photoluminescent materials. As such this methodology constitutes the first heterogeneous iron-catalyzed hydrogenation of substituted (iso)quinolones with synthetic importance.

Correction: A robust iron catalyst for the selective hydrogenation of substituted (iso)quinolones.

[This corrects the article DOI: 10.1039/C8SC02744G.].

Synthesis and Characterization of Iron-Nitrogen-Doped Graphene/Core-Shell Catalysts: Efficient Oxidative Dehydrogenation of N-Heterocycles.

An important goal for nanocatalysis is the development of flexible and efficient methods for preparing active and stable core-shell catalysts. In this respect, we present the synthesis and characterization of iron oxides surrounded by nitrogen-doped-graphene shells immobilized on carbon support (labeled FeOx@NGr-C). Active catalytic materials are obtained in a simple, scalable and two-step method via pyrolysis of iron acetate and phenanthroline and subsequent selective leaching. The optimized FeOx@NGr-C catalyst showed high activity in oxidative dehydrogenations of several N-heterocycles. The utility of this benign methodology is demonstrated by the synthesis of pharmaceutically relevant quinolines. In addition, mechanistic studies prove that the reaction progresses via superoxide radical anions (·O2(-)).