Ligand-Enabled β-C–H Arylation of α-Amino Acids Using a Simple and Practical Auxiliary

Abstract

Pd-catalyzed β-C–H functionalizations of carboxylic acid derivatives using an auxiliary as a directing group have been extensively explored in the past decade. In comparison to the most widely used auxiliaries in asymmetric synthesis, the simplicity and practicality of the auxiliaries developed for C–H activation remains to be improved. We previously developed a simple N-methoxyamide auxiliary to direct β-C–H activation, albeit this system was not compatible with carboxylic acids containing α-hydrogen atoms. Herein we report the development of a pyridine-type ligand that overcomes this limitation of the N-methoxyamide auxiliary, leading to a significant improvement of β-arylation of carboxylic acid derivatives, especially α-amino acids. The arylation using this practical auxiliary is applied to the gram-scale syntheses of unnatural amino acids, bioactive molecules and chiral bis(oxazoline) ligands.

Ligand‐Enabled β‐C–H Arylation of α‐Amino Acids Without Installing Exogenous Directing Groups

“…(3)]. Employing similar conditions to those reported in our CONHOMe-directed arylation, [10] we were pleased to find that L1 provided the desired arylated product in 45% yield (Scheme 2). A control experiment showed that no reaction occurred in the absence of ligand.…”

“…(1)]), [9,10] both of which serve as carboxylate surrogates in the Pd-catalyzed C–H activation of alanine derivatives, enabling the preparation of unnatural α -amino acids. Both of these reactions benefit from ligand acceleration by either pyridine- or quinoline-based ligands, though the installation and removal of these exogenous directing groups hampers the broad application of these methods.…”

1,1,1,3,3,3‐Hexafluoroisopropanol as a Remarkable Medium for Atroposelective Sulfoxide‐Directed Fujiwara–Moritani Reaction with Acrylates and Styrenes

“…Herein, we report our discoveries on the uniquea nd intriguing role of 1,1,1,3,3,3-hexafluoropropanol (HFIP) solvent in atropo-diastereoselective, sulfoxide-directed CÀCc oupling. Notably,t his polyfluorinated alcohol stood out recently as an optimal solventf or several challenging CÀHa ctivation reactions, [19] buti ts particularr ole has remained ambiguous. The mechanistic studies presented above indicate that the key feature of our catalytic system was the formation of hydrogen-bonded complex between the substrate and solvent facilitating the CÀHa ctivation step and improving the stereochemicalo utcome of this transformation.…”

Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids

“…1c)44454647. For example, N -methoxyamide has been used as a directing group4849 for β-C( sp 3 )-H arylation with a pyridine-type ligand, affording various non-natural amino acids from protected alanine derivatives49. These developments have greatly expanded the possible approaches to construct key structures of natural products, pharmaceutical agents and organic materials.…”