4.8 Article

Mechanistic insights into rhodium-catalyzed enantioselective allylic alkylation for quaternary stereogenic centers

Journal

CHEMICAL SCIENCE
Volume 12, Issue 7, Pages 2527-2539

Publisher

ROYAL SOC CHEMISTRY
DOI: 10.1039/d0sc04959j

Keywords

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Funding

  1. CSIR (New Delhi)

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The study investigates the nature of potential active catalyst, energetic features of the catalytic cycle, and the origin of high enantioselectivity in the asymmetric allylic alkylation reaction of alpha,alpha-disubstituted aldehydes. It is found that the in-situ formation of a Rh-phosphonate likely acts as an active catalyst, leading to the formation of a quaternary stereogenic center. The stereochemical preference for the formation of product on the re face is attributed to improved noncovalent interactions and less distortion in the enantiocontrolling C-C bond formation transition state. The computed enantioselectivity and activation barrier are in good agreement with experimental values.
Installing quaternary stereogenic carbon is an arduous task of contemporary importance in the domain of asymmetric catalysis. To this end, an asymmetric allylic alkylation of alpha,alpha-disubstituted aldehydes by using allyl benzoate in the presence of Wilkinson's catalyst [Rh(Cl)(PPh3)(3)], (R)-BINOL-P(OMe) as the external ligand, and LiHMDS as the base has been reported to offer high enantioselectivity. The mechanistic details of this important reaction remain vague, which prompted us to undertake a detailed density functional theory (SMD(THF)/B3LYP-D3) investigation on the nature of the potential active catalyst, energetic features of the catalytic cycle, and the origin of high enantioselectivity. We note that a chloride displacement from the native Rh-phosphine [Rh(Cl)(PPh3)(3)] by BINOL-P(OMe) phosphite and an ensuing MeCl elimination can result in the in situ formation of a Rh-phosphonate [Rh(BINOL-P = O)(PPh3)(3)]. A superior energetic span (delta E) noted with such a Rh-phosphonate suggests that it is likely to serve as an active catalyst. The uptake of allyl benzoate by the active catalyst followed by the turnover determining C-O bond oxidative addition furnishes a Rh-pi-allyl intermediate, which upon interception by (Z)-Li-enolate (derived from alpha,alpha-disubstituted aldehyde) in the enantiocontrolling C-C bond generates a quaternary stereogenic center. The addition of the re prochiral face of the (Z)-Li-enolate to the Rh-bound allyl moiety leading to the R enantiomer of the product is found to be 2.4 kcal mol(-1) more preferred over the addition through its si face. The origin of the stereochemical preference for the re face addition is traced to improved noncovalent interactions (NCIs) and less distortion in the enantiocontrolling C-C bond formation transition state than that in the si face addition. Computed enantioselectivity (96%) is in very good agreement with the experimental value (92%), so is the overall activation barrier (delta E of 17.1 kcal mol(-1)), which is in conformity with room temperature reaction conditions.

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