Palladium Catalyzed Stereospecific Arylation of Biocatalytically Derived Cyclic 1,3-Dienes: Chirality Transfer via a Heck-Type Mechanism


Microbial arene oxidation of benzoic acid with Ralstonia eutropha B9 provides a chiral highly functionalized cyclohexadiene, suitable for further structural diversification. Subjecting this scaffold to a palladium-catalyzed Heck reaction effects a regioselective and stereospecific arylation of the cyclohexadiene ring, with transfer of the stereogenic information installed in the microbial arene oxidation. Functional groups that were well tolerated on the diene substrate included a range of esters, amides and a Weinreb amide, affording a total of 23 different products in good yields. These products, which can be considered as latent enolic nucleophiles, also possess a unique three dimensional structure which can be utilized in further stereoselective transformations. This was demonstrated by subjecting one of the products, which contained a protected aldehyde, to a tandem deprotection – cyclization sequence. The reaction proceeded with complete stereoselectivity and afforded a tricyclic ketone product possessing four stereogenic centers. This demonstrates the capability of the method to introduce stereochemical complexity from non-chiral benzoic acid in just a few steps. Quantum chemical calculations have provided insight into the mechanism of the palladium-catalyzed arylation. The high selectivity can be explained both by a kinetic preference for the observed arylation position and by reversible carbopalladation in competing positions.


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Supplementary material

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Paterson Dunås SI 191116