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 .

Palladium-Catalyzed Carboamination of Allylic Alcohols Using a Trifluoroacetaldehyde-Derived Tether.

The selective palladium-catalyzed carboamination of allylic alcohols is reported on the basis of the use of an easily introduced trifluoroacetaldehyde-derived tether. Aminoalkynylation reactions were realized using alkynyl bromides and commercially available phosphine ligands. For aminoarylations, a new biaryl phosphine ligand, "Fu-XPhos", was introduced to overcome a competitive Heck pathway.

tether formation from amines and alcohols enabling highly selective Tsuji-Trost allylation and olefin functionalization.

The use of tethers allows to overcome reactivity and selectivity issues often encountered with intermolecular reactions. Although tethers have been successfully applied for decades, their installation and removal usually requires additional steps. This minireview highlights the recent development of tethers that can be installed on (homo)-allyl amines or alcohols for Tsuji-Trost allylation or double bond functionalization.

One-Pot Three-Component Synthesis of Vicinal Diamines via In Situ Aminal Formation and Carboamination.

A synthesis of vicinal diamines via in situ aminal formation and carboamination of allyl amines is reported. Employing highly electron-poor trifluoromethyl aldimines in their stable hemiaminal form was key to enable both a fast and complete aminal formation as well as the palladium-catalyzed carboamination step. The conditions developed allow the introduction of a wide variety of alkynyl, vinyl, aryl, and hetereoaryl groups with complete regioselectivity and high diastereoselectivity.

Palladium-catalyzed vicinal amino alcohols synthesis from allyl amines by in situ tether formation and carboetherification.

Vicinal amino alcohols are important structural motifs of bioactive compounds. Reported herein is an efficient method for their synthesis based on the palladium-catalyzed oxy-alkynylation, oxy-arylation, or oxy-vinylation of allylic amines. High regio- and stereoselectivity were ensured through the in situ formation of a hemiaminal tether using the cheap commercially available trifluoroacetaldehyde in its hemiacetal form.

The N-terminal nonapeptide of cephaibols A and C: a naturally occurring example of mismatched helical screw-sense control.

The N-terminal nonapeptide domain of the fungal nonribosomal peptide antibiotics cephaibol A and cephaibol C (AcPheAib4LeuIvaGly- Aib) is reported to adopt a right-handed helical conformation in the crystalline state. However, this conformation is at odds with the left-handed helicity observed in solution in related synthetic oligomers capped with Ac-L-PheAib4 fragments. We report the synthesis of four diastereoisomers of the cephaibol N-terminal nonapeptide, and show by NMR and CD spectroscopy that the peptide containing the chiral amino acids Phe and Leu in the naturally occurring relative configuration exists in solution as an interconverting mixture of helical screw-sense conformers.