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).

The first copper(I)-catalyzed enantioselective borylation of racemic benzyl chlorides has been realized by aq uadrant-by-quadrant structure modulation of QuinoxP*type bisphosphine ligands.T his reaction converts racemic mixtures of secondary benzyl chlorides into the corresponding chiral benzylboronates with high enantioselectivity (up to 92 % ee). The results of mechanistic studies suggest the formation of ab enzylic radical intermediate.T he results of DFT calculations indicate that the optimal bisphosphine-copper(I) catalyst engages in noncovalent interactions that efficiently recognize the radical intermediate,a nd leads to high levels of enantioselectivity. Scheme 1. Copper(I)-catalyzed borylation of alkyl electrophiles.

This review describes recent advances in direct borylation reactions of organic halides, including both transition-metal-catalyzed and metal-free methods. Since the pioneering work on palladium-catalyzed boryl substitution of aryl halides with a diboron compound reported by Miyaura and co-workers in 1995, various catalytic systems for the borylation of aryl, alkneyl, and alkyl halides have been developed to give a wide range of organoboronate esters that cannot be synthesized using conventional methods. Borylative cyclization of alkyl halides is also discussed.

A new method has been developed for the Markovnikov hydroboration of alkyl-substituted terminal alkenes. Notably, the use of a bulky bisphosphine-copper(i) catalyst system resulted in high regioselectivity to afford secondary alkylboronates from the corresponding terminal alkenes (branch/linear = 92 : 8-97 : 3). This method also exhibited good functional group compatibility.

Abstract:The first enantioselective borylative dearomatization of a heteroaromatic compound has been achieved using a copper(I) catalyst and a diboron reagent. This reaction involves the unprecedented regio-and enantioselective addition of active borylcopper(I) species to indole-2-carboxylates, followed by the diastereoselective protonation of the resulting copper(I) enolate to give the corresponding chiral indolines bearing consecutive stereogenic centers.