Mechanistic investigation of Rh(i)-catalysed asymmetric Suzuki–Miyaura coupling with racemic allyl halides

Abstract

Understanding how catalytic asymmetric reactions with racemic starting materials can operate would enable new enantioselective cross coupling reactions giving chiral products. Here we propose a catalytic cycle for the highly enantioselective Rh(I)-catalysed Suzuki-Miyaura coupling of boronic acids and racemic allyl halides. Natural abundance 13 C kinetic isotope effects provide quantitative information about the transition state structures of two key elementary steps in the catalytic cycle -transmetalation and oxidative addition. Experiments using configurationally stable, deuterium labelled substrates reveal oxidative addition can happen via syn-or antipathways which controls diastereoselectivity. DFT calculations attribute the extremely high enantioselectivity to reductive elimination from a common Rh complex formed from both allyl halide enantiomers. Our conclusions are supported by analysis of the reaction kinetics. These insights into the sequence of bond-forming steps and their transition state structures will contribute to understanding asymmetric Rh-allyl chemistry and enable the discovery and application of asymmetric reactions with racemic substrates.

Additions to Racemates: A Strategy for Developing Asymmetric Cross-Coupling Reactions

“…We aimed to get an in-depth understanding of rhodium-catalyzed arylation. 29 Contrary to our initial expectations, it turned out to work nothing like the copper chemistry described above. Under the optimized conditions, the reactions are quite fast and many of the starting allylic halides are labile, which made our initial attempts at mechanistic studies difficult.…”

“…A description of these KIE experiments is beyond the scope of this Account, but they are described elsewhere. 29 In combination with isotope-labeling experiments using derivatives of configurationally stable 8, our competition experiments and detailed kinetic investigations allowed us to propose a reasonable mechanism.…”

“…We suggest that fast and irreversible transmetalation of the arylboronic acid to a rhodium(I) complex (I to II) is followed by irreversible oxidative addition to both enantiomers of the allylic halide to give a common pseudo-prochiral η 3 -allylic complex (II to III). 28,29 Enantiodetermining reductive elimination and active catalyst regeneration aided by base complete the proposed catalytic cycle. Experiments with 5-phenyl-substituted allylic chloride (±)-16 resulted in overall enantioselective inversion of the relative stereochemistry suggesting an anti-oxidative addition (Scheme 7c), but we know from our other studies that both syn-and anti-oxidative addition are viable pathways (cf.…”

“…Scheme 10 below). 28,29 We subsequently expanded this work in the directions of both the allylic halide and the boronic acid coupling partner. The extension from arylboronic acids to alkenylboronic acids in asymmetric addition reactions is often not straightforward due to their different shape and electronics.…”

Asymmetric synthesis of nortropanes via Rh-catalysed allylic arylation

“…The deracemization is believed to occur via the formation of a common pseudo-prochiral or meso Rh-π-allyl complex (DYKAT type II). [33][34] We wondered if we could apply a related strategy to the catalytic asymmetric synthesis of sterically congested bicyclic N-heterocycles, and by that develop an asymmetric crosscoupling approach to the nortropane scaffold.…”