HHundreds of catalytic methods are developed each year to meet the demand for high-purity chiral compounds. The computational design of enantioselective organocatalysts remains a significant challenge, as catalysts are typically...

We present the NaviCatGA package, a versatile genetic algorithm capable of optimizing molecular catalyst structures using well‐suited fitness functions to achieve a set of targeted properties. The flexibility and generality of this tool are validated and demonstrated with two examples: i) Ligand optimization and exploration for Ni‐catalyzed aryl‐ether cleavage manipulating SMILES and using a fitness function derived from molecular volcano plots, ii) multi‐objective (i. e., activity/selectivity) optimization of bipyridine N,N‐dioxide Lewis basic organocatalysts for the asymmetric propargylation of benzaldehyde from 3D molecular fragments. We show that evolutionary optimization, enabled by NaviCatGA, is an efficient way of accelerating catalyst discovery through bypassing combinatorial scaling issues and incorporating compelling chemical constraints.

The automated construction of datasets has become increasingly relevant in computational chemistry. While transition-metal catalysis has greatly benefitted from bottom-up or top-down strategies for the curation of organometallic complexes libraries,...

Catalyst-controlled regioselectivity in palladium-catalyzed carbonylation of alkenes has been a long-standing goal of homogeneous catalysis. In general, monophosphines do favor branched regioselectivity, but lead to poor enantioselectivity, while diphosphines give mainly linear products. Previously, we reported the simultaneous control of regio-and enantioselectivity in the hydroxy-and methoxycarbonylation of vinyl arenes with Pd complexes of the Phanephos ligand. Herein, we present a density functional theory study (B3PW91-D3 level of theory) of the catalytic cycle, supported by deuterium labeling studies, to understand its mechanism. Alkene coordination to a Pd-hydride species was identified as the origin of asymmetric induction and regioselectivity in both the parent Pd/Xylyl-Phanephos catalyst and electron-deficient analogue, and rationalized according to a quadrant-diagram representation. The mechanism by which the preferentially formed pro-(S) Pd-alkene complex can isomerize via rotation around the palladium-(C=C) bond was investigated. In the parent system, this process is in competition with the methanolysis step that leads to the ester product, and is responsible for the overall loss of regioselectivity. On the other hand, the introduction of electron-withdrawing substituents on the catalyst framework results in the reduction of the methanolysis barriers, making the isomerization pathway energetically unfavorable and so leading simultaneously to high regiocontrol and good enantiomeric ratios. ASSOCIATED CONTENT Supporting InformationThe Supporting Information is available free of charge on the ACS Publications website.Computational details, 2 H and 13 C NMR spectra, deuterium labeling studies (PDF)Cartesian coordinates, electronic energies, zero-point energies, enthalpies, T×S, Gibbs free energies, basis set superposition energies (a.u.), imaginary frequencies (XYZ)

Bifunctional hydrogen-bond donors/amines are commonly encountered organocatalysts in asymmetric synthesis. Existing computational tools do not take full advantage of their modularity to suggest tailored designs because they generally rely on...