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Transition metal-catalyzed asymmetric hydrogenation is one of the most efficient methods for the preparation of chiral α-substituted propionic acids. However, research on this method, employing cleaner earth-abundant metal catalysts, is still insufficient in both academic and industrial contexts. Herein, we report an efficient nickel-catalyzed asymmetric hydrogenation of α-substituted acrylic acids affording the corresponding chiral α-substituted propionic acids with up to 99.4% ee (enantiomeric excess) and 10,000 S/C (substrate/catalyst). In particular, this method can be used to obtain (R)-dihydroartemisinic acid with 99.8:0.2 dr (diastereomeric ratio) and 5000 S/C, which is an essential intermediate for the preparation of the antimalarial drug Artemisinin. The reaction mechanism has been investigated via experiments and DFT (Density Functional Theory) calculations, which indicate that the protonolysis of the C-Ni bond of the key intermediate via an intramolecular proton transfer from the carboxylic acid group of the substrate, is the rate-determining step. Research on employing cleaner and more environmentally friendly earth-abundant metal catalysts for asymmetric hydrogenation is still insufficient in both academic and industrial contexts. Herein, the authors report the synthesis of chiral α-substituted propionic acids via nickel-catalyzed asymmetric hydrogenation of α-substituted acrylic acids using H2. [ABSTRACT FROM AUTHOR]

Fluorinated amino acids and related peptides/proteins have been found widespread applications in pharmaceutical and agricultural compounds. However, strategies for introducing a C−F bond into amino acids in an enantioselective manner are still limited and no such asymmetric catalysis strategy has been reported. Herein, we have successfully developed a Pd/Cu/Li ternary system for stereodivergent synthesis of chiral fluorinated amino acids. This method involves a sequential desymmetrization of geminal difluoromethylenes and allylic substitution with amino acid Schiff bases via Pd/Li and Pd/Cu dual activation, respectively. A series of non‐natural amino acids bearing a chiral allylic/benzylic fluorine motif are easily synthesized in high yields with excellent regio‐, diastereo‐, and enantioselectivities (up to >20 : 1 dr and >99 % ee). A density functional theory (DFT) study revealed the F−Cu interaction of the allylic substrate and the Cu catalyst significantly influence the stereoselectivity. [ABSTRACT FROM AUTHOR]

Chiral α,β‐unsaturated γ‐lactams bearing simple γ‐ substituents are found in biologically active molecules and natural products, however, their synthesis still remains difficult. Herein, we report an efficient kinetic resolution (KR) of γ‐substituted α,β‐unsaturated γ‐lactams via a Cu‐catalyzed asymmetric boron conjugate addition, which also leads to the efficient synthesis of chiral β‐hydroxy‐γ‐lactams with β,γ‐stereogenic carbon centers. The KR proceeded smoothly with a wide range of γ‐alkyl or aryl substituted substrates including those bearing aromatic heterocycles and different N‐protected substrates in up to 347 of s value. Their highly versatile transformations, synthetic utility in biologically active molecules, and inhibitory activities against cisplatin‐sensitive ovarian cancer cell A2780 have also been demonstrated. Differing from the well‐known mechanism involving Cu−B species in Cu‐catalyzed boron conjugate additions, our mechanistic studies using density functional theory (DFT) calculations and experiments indicate that a Lewis acid CuI‐catalyzed mechanism is the likely pathway in the catalytic reaction. [ABSTRACT FROM AUTHOR]