Copper-catalyzed asymmetric direct alkynylation of α-ketoesters with terminal alkynes with chiral prolinol–phosphine ligands, most preferably (αR,2S)-1-(2-dicyclohexylphosphinobenzyl)-α-neopentyl-2-pyrrolidinemethanol, afforded various enantioenriched chiral propargylic tertiary alcohols. Quantum-chemical calculations using the BP86 density functional including Grimme's empirical dispersion correction [DF-BP86-D3(BJ)-PCM(tBuOH)/TZVPP//DF-BP86-D3(BJ)/SVP] show the occurrence of OH⋯O/sp³-CH⋯O two-point hydrogen bonding between the chiral ligand and the carbonyl group of the ketoester in the stereo-determining transition states. Combined with the hydrogen-bonding interactions orienting the ketoester substrate, dispersive attractions between the chiral ligand (P-cyclohexyl groups) and the ketoester in the favored transition states, rather than steric repulsions in the disfavored transition state explain the enantioselectivity of the asymmetric copper catalysis.

We explored the reaction mechanism of the cationic rhodium(I)–BINAP complex catalysed isomerisation of allylic amines using the artificial force induced reaction method with the global reaction route mapping strategy, which enabled us to search for various reaction paths without assumption of transition states. The entire reaction network was reproduced in the form of a graph, and reasonable paths were selected from the complicated network using Prim’s algorithm. As a result, a new dissociative reaction mechanism was proposed. Our comprehensive reaction path search provided rationales for the E/Z and S/R selectivities of the stereoselective reaction.

2-Hydroxypropyl-β-cyclodextrin (HPβCD) has unique properties to enhance the stability and the solubility of low water-soluble compounds by inclusion complexation. An understanding of the structural properties of HPβCD and its derivatives, based on the number of 2-hydroxypropyl (HP) substituents at the α-d-glucopyranose subunits is rather important. In this work, replica exchange molecular dynamics simulations were performed to investigate the conformational changes of single- and double-sided HP-substitution, called 6-HPβCDs and 2,6-HPβCDs, respectively. The results show that the glucose subunits in both 6-HPβCDs and 2,6-HPβCDs have a lower chance of flipping than in βCD. Also, HP groups occasionally block the hydrophobic cavity of HPβCDs, thus hindering drug inclusion. We found that HPβCDs with a high number of HP-substitutions are more likely to be blocked, while HPβCDs with double-sided HP-substitutions have an even higher probability of being blocked. Overall, 6-HPβCDs with three and four HP-substitutions are highlighted as the most suitable structures for guest encapsulation, based on our conformational analyses, such as structural distortion, the radius of gyration, circularity, and cavity self-closure of the HPβCDs.

Cross-coupling reactions between short-lifetime radicals are challenging reactions in organic chemistry. Here, we report the development of an N-heterocyclic carbene (NHC)-mediated radical coupling reaction based on the catalytic machinery of thiamine- and flavin-dependent enzymes. Through a series of enzyme screenings, we found that acetolactate synthase from Thermobispora bispora (TbALS) and its engineered variants exhibit promising catalytic activity toward abiotic radical acylation reactions of α-bromo carbonyl compounds. Notably, the TbALS variant has higher catalytic activity for small nonaromatic substrates despite forming less stable radical intermediates. Furthermore, the catalytic system of TbALS can be applied to photocatalytic reactions utilizing the photoredox properties of FAD. Nonbenzylic alkyl radicals generated from N-acyloxyphthalimides are efficiently converted into the corresponding dialkyl ketones under irradiation of a blue LED. These findings highlight the utility of thiamine- and flavin-dependent enzymes for achieving selective cross-coupling reactions of short-lifetime radicals.