No abstract

An efficient asymmetric synthesis of a potent KRAS G12C covalent inhibitor, GDC-6036 (1), 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, W057-2, which afforded the desired Negishi coupling product ( R a )-3 in excellent selectivity. A subsequent telescoped reaction sequence of alkoxylation, global deprotection, and acrylamide formation, followed by a final adipate salt formation, furnished GDC-6036 (1) in 40% overall yield from starting materials pyridine 5 and quinazoline 6.

Asymmetric hydrogenation has evolved as one of the most powerful tools to construct stereocenters. However, the asymmetric hydrogenation of unfunctionalized tetrasubstituted acyclic olefins remains the pinnacle of asymmetric synthesis and an unsolved challenge. We report herein the discovery of an iridium catalyst for the first, generally applicable, highly enantio‐ and diastereoselective hydrogenation of such olefins and the mechanistic insights of the reaction. The power of this chemistry is demonstrated by the successful hydrogenation of a wide variety of electronically and sterically diverse olefins in excellent yield and high enantio‐ and diastereoselectivity.

An efficient synthesis of 1,5-disubstituted 3-amino-1H-1,2,4-triazoles has been achieved via a Negishi coupling of aryl or vinyl bromides and 1-substituted 3-amino-1H-1,2,4-triazoles in the presence of Knochel's base tetramethylpiperidinylzinc chloride lithium chloride (TMPZnCl·LiCl) and catalytic bis(di-tert-butylphenylphosphine)palladium chloride. This chemistry tolerates a variety of electronically diverse aryl or vinyl bromides and 1-substituted 3-amino-1H-1,2,4-triazoles.

The mass of the Milky Way is a critical quantity that, despite decades of research, remains uncertain within a factor of two. Until recently, most studies have used dynamical tracers in the inner regions of the halo, relying on extrapolations to estimate the mass of the Milky Way. In this paper, we extend the hierarchical Bayesian model applied in Eadie & Juri to study the mass distribution of the Milky Way halo; the new model allows for the use of all available 6D phase-space measurements. We use kinematic data of halo stars out to 142 kpc, obtained from the H3 survey and Gaia EDR3, to infer the mass of the Galaxy. Inference is carried out with the No-U-Turn sampler, a fast and scalable extension of Hamiltonian Monte Carlo. We report a median mass enclosed within 100 kpc of M ( < 100 kpc ) = 0.69 − 0.04 + 0.05 × 10 12 M ⊙ (68% Bayesian credible interval), or a virial mass of M 200 = M ( < 216.2 − 7.5 + 7.5 kpc ) = 1.08 − 0.11 + 0.12 × 10 12 M ⊙ , in good agreement with other recent estimates. We analyze our results using posterior predictive checks and find limitations in the model’s ability to describe the data. In particular, we find sensitivity with respect to substructure in the halo, which limits the precision of our mass estimates to ∼15%.