Rhodium-catalysed asymmetric allylic arylation of racemic halides with arylboronic acids

Abstract

Csp(2)-Csp(2) cross-coupling reactions between arylboronic acid and aryl halides are widely used in both academia and industry and are strategically important in the development of new agrochemicals and pharmaceuticals. Csp(2)-Csp(3) cross-coupling reactions have been developed, but enantioselective variations are rare and simply retaining the stereochemistry is a problem. Here we report a highly enantioselective Csp(2)-Csp(3) bond-forming method that couples arylboronic acids to racemic allyl chlorides. Both enantiomers of a cyclic chloride are converted into a single enantiomer of product via a dynamic kinetic asymmetric transformation. This Rh-catalysed method uses readily available and inexpensive building blocks and is mild and broadly applicable. For electron-deficient, electron-rich or ortho-substituted boronic acids better results are obtained with racemic allyl bromides. Oxygen substitution in the allyl halide is tolerated and the products can be functionalized to provide diverse building blocks. The approach fills a significant gap in the methods for catalytic asymmetric synthesis.

Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates

“…24) and 1,2-additions25, allylic arylations26, allylic vinylations27, desymmetrizing allylic additions2829, and allylic arylations to racemic substrates30. These work well with carbocyclic benzene derivatives, but the vast range of vinyl and heteroaromatic possibilities cannot generally be used202731.…”

“…Many vinylboronic acids cannot be used in asymmetric additions because they are unstable and readily undergo protodeboronation and polymerization3233. We previously reported catalytic asymmetric addition of nucleophiles to racemic allylic halide starting materials34353637 including a system for boronic acid addition30 involving [Rh(cod)(OH)] 2 and ( S )-Xyl-P-PHOS in the presence of Cs 2 CO 3 . Although this system was suitable for an array of carbocyclic nucleophiles and a few electron rich styrenyl-boronic acids, it was not useful with other vinyl or heteroaromatic species.…”

Enantioselective Nickel‐Catalyzed Intramolecular Allylic Alkenylations Enabled by Reversible Alkenylnickel E/Z Isomerization

“…Chiral copper–N‐heterocyclic carbene catalysts are highly effective in the enantioselective additions of alkenylaluminum,– alkenylboron,,, and allenylboron reagents to achiral allylic phosphates. Chiral iridium and rhodium catalysts are also effective in enantioselective additions of alkenylboron reagents to racemic allylic alcohols and allylic halides, respectively.…”

Concise and Stereodivergent Synthesis of Carbasugars Reveals Unexpected Structure-Activity Relationship (SAR) of SGLT2 Inhibition

“…4 and Table 1) 29 . This seemingly simple transformation, however, was not trivial, and required extensive optimization.…”