Abstract
Finding optimal chiral ligands for transition-metal-catalyzed asymmetric reactions using trial-and-error methods is often time-consuming and costly, even if the details of the reaction mechanism are already known. Although modern computational analyses allow the prediction of the stereoselectivity, there are only very few examples for the attempted design of chiral ligands using a computational approach for the improvement of the stereoselectivity. Herein, we report a systematic method for the design of chiral ligands for the enantioselective Markovnikov hydroboration of aliphatic terminal alkenes based on a computational and experimental evaluation sequence. We developed a three-hindered-quadrant P-chirogenic bisphosphine ligand that was designed in accordance with the design guidelines derived from this method, which allowed the Markovnikov hydroboration to proceed with high enantioselectivity (up to 99% ee).
Highlights
Finding optimal chiral ligands for transition-metal-catalyzed asymmetric reactions using trialand-error methods is often time-consuming and costly, even if the details of the reaction mechanism are already known
We focused on regio- and enantioselective transformations of aliphatic terminal alkenes (α-olefins), which are feedstock chemicals obtained from petrochemicals
Given the target reaction and ligand preparation procedure, we based the three-step ligand-design cycle on a combination of a computational analysis and an experimental evaluation: the first step is the experimental evaluation of a ligand for the regio- and enantioselectivity in the borylation of an aliphatic terminal alkene, the second step is the density functional theory (DFT) calculation on the borylation with the ligand, followed by confirming the validity of the calculations by comparing the experimental and calculated selectivities, which delivers design guidelines in the form of a quadrant-by-quadrant structural analysis of the transition states, the third step is the synthesis of ligands via the modular coupling of chiral phosphine module (CP), achiral phosphine module (AP), and the 2,3-dichloroquinoxaline core
Summary
Finding optimal chiral ligands for transition-metal-catalyzed asymmetric reactions using trialand-error methods is often time-consuming and costly, even if the details of the reaction mechanism are already known. Given the target reaction and ligand preparation procedure, we based the three-step ligand-design cycle on a combination of a computational analysis and an experimental evaluation: the first step is the experimental evaluation of a ligand for the regio- and enantioselectivity in the borylation of an aliphatic terminal alkene, the second step is the DFT calculation on the borylation with the ligand, followed by confirming the validity of the calculations by comparing the experimental and calculated selectivities, which delivers design guidelines in the form of a quadrant-by-quadrant structural analysis of the transition states, the third step is the synthesis of ligands via the modular coupling of CP, AP, and the 2,3-dichloroquinoxaline core. We identified a chiral ligand that shows a Ligand evaluation Markovnikov hydroboration of aliphatic terminal alkenes “Target reaction”
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