Investigating the Origin of Epimerization Attenuation during Pd-Catalyzed Cross-Coupling Reactions.

Palladium-catalyzed cross-couplings remain among the most robust methodologies to form carbon-carbon and carbon-heteroatom bonds. In particular, carbon-nitrogen (C-N) couplings (Buchwald-Hartwig aminations) find widespread use in fine chemicals industries. The use of base in these reactions is critical for catalyst activation and proton sequestration.

Umpolung Flow Chemistry for the Synthesis of a 3-Oxo-3-spiro[benzofuran-2,4'-piperidine] Building Block.

An efficient and scalable route to -butyl 3-oxo-3-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate, a central prochiral intermediate in the synthesis of SHP2 inhibitor (), was achieved. Preparation of the title compound from readily available 2-fluorobenzaldehyde included formation of a modified Katritzky benzotriazole hemiaminal, which, upon deprotonation by -butyllithium, participated in umpolung reactivity via 1,2-addition to -butyl 4-oxopiperidine-1-carboxylate (-Boc-4-piperidone). Most notably, this reaction was developed as a robust plug-flow process that could be executed on multiple kilograms without the need for pilot-scale reaction vessels operating at low cryogenic temperatures.

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

A chromatography-free asymmetric synthesis of GDC-6036 () was achieved via a highly atroposelective Negishi coupling of aminopyridine and quinazoline catalyzed by 0.5 mol % [Pd(cin)Cl] and 1 mol % (,)-Chiraphite to afford the key intermediate ()-. An alkoxylation of ()- with ()--methylprolinol () and a global deprotection generates the penultimate heterobiaryl intermediate .

Atroposelective Negishi Coupling Optimization Guided by Multivariate Linear Regression Analysis: Asymmetric Synthesis of KRAS G12C Covalent Inhibitor GDC-6036.

An efficient asymmetric synthesis of a potent KRAS G12C covalent inhibitor, GDC-6036 (), is reported. The synthesis features a highly atroposelective Negishi coupling to construct the key C-C bond between two highly functionalized pyridine and quinazoline moieties by employing a Pd/Walphos catalytic system. Statistical modeling by comparing computational descriptors of a range of Walphos chiral bisphosphine ligands to a training set of experimental results was used to inform the selection of the best ligand, , which afforded the desired Negishi coupling product in excellent selectivity.

Stereoselective Synthesis of the IDO Inhibitor Navoximod.

A highly efficient asymmetric synthesis of the IDO inhibitor navoximod, featuring the stereoselective installation of two relative and two absolute stereocenters from an advanced racemic intermediate, is described. The stereocenters were set via a crystallization-induced dynamic resolution along with two selective ketone reductions: one via a biocatalytic ketoreductase transformation and one via substrate-controlled hydride delivery from LiAlH(OBu). Following this strategy, navoximod was synthesized in 10 steps from 2-fluorobenzaldehyde and isolated in 23% overall yield with 99.