A general, modular method for the catalytic asymmetric synthesis of alkylboronate esters

Abstract

Due to the critical role of stereochemistry in determining properties such as biological activity, as well as growing interest in sustainability, there is a strong impetus to develop catalytic and enantioselective methods for synthesis. Alkylboranes are an important family of target compounds, serving as useful intermediates, as well as endpoints (medicines such as Velcade™), in fields such as pharmaceutical science and organic chemistry. Because C–B bonds can be transformed into a wide variety of C–X bonds (e.g., X = C, N, O, and halogen) with stereochemical fidelity, the ability to generate enantioenriched alkylboranes in which boron is bound to a stereogenic carbon represents an extremely powerful tool in synthesis, providing access to an enormous array of valuable classes of chiral molecules, including alcohols, amines, and alkyl halides. Despite progress in recent years, there is still a need for more versatile methods for the catalytic asymmetric synthesis of enantioenriched alkylboranes. In this report, we describe a novel approach toward this objective, specifically, the use of a chiral nickel catalyst to achieve stereoconvergent couplings of readily available racemic α-haloboranes with organozinc reagents under mild conditions. We demonstrate that this method provides straightforward access to a diverse array of enantioenriched alkylboranes, and we highlight the remarkable utility of these compounds in synthesis.

Enantioselective Radical Addition/Cross‐Coupling of Organozinc Reagents, Alkyl Iodides, and Alkenyl Boron Reagents

“…[7,8] If the intermediate radical might instead react with the Ni complex furnishing D,t hen catalyst-based stereocontrol might be realized even though the process involves radical intermediates.T he underlying principles that would enable such ap rocess are aligned with other metal-catalyzed intermolecular dicarbofunctionalizations [9] of alkenes,w hich take place either through carbometalation/cross-coupling [10] pathways or through radical addition/cross-coupling cascades. [8] Lastly,i nr egards to as tarting point for reaction conditions,w ec onsidered that asystem developed by Fu [13] and co-workers for the enantioconvergent cross-coupling of organozinc reagents to ahaloboronic esters would be appropriate as this process appears to involve selective recombination of aN ic omplex with an a-boryl radical similar to the transformation of C to D described above. [12] To begin our investigation of the transition-metal/radical process proposed in Scheme 1c,w ef irst sought as toichiometric organometallic reagent that would react with Ni-based intermediates,b ut would not react directly with threecoordinate vinylboron reagents.W hile organolithium, and to some extent Grignard reagents,w ill convert vinylB(pin) into the derived "ate" complex, it was found that neither aryl nor alkyl zinc reagents would react with vinylB(pin).…”

Rhodium‐Catalyzed Enantioselective Radical Addition of CX4 Reagents to Olefins

“…The Fu group defined a Ni-catalyzed cross-coupling of racemic alkyl bromides with a variety of electrophiles. [18] In these transformations a secondary radical likely combines with an alkyl metal species to provide a dialkyl metal species 6 . Reductive elimination generates the optically active cross-coupled product ( 7 ).…”

Cyclopropanation of Terminal Alkenes through Sequential Atom‐Transfer Radical Addition/1,3‐Elimination

“…[43][44][45] a-Haloboronic esters have been used in tin-mediated (Scheme 1A) [46][47][48][49] and metal-catalyzed radical processes. Finally,1 -borylated alkyl radicals were involved in the elegant nickel-catalyzed alkylation and arylation of a-haloboronic esters developed by the Fu [54] and Martin [55] groups,respectively.1-Borylated alkyl radicals have also been generated from Barton esters [56] and xanthates [45] as well as through radical addition to vinylboronates. [53] Interestingly,p inacol iodomethylboronic Figure 1.…”