Palladium Catalyzed Stereoselective 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 stereoselective arylation of the cyclohexadiene ring. The arylation proceeds with a highly selective 1,3-chirality transfer of stereogenic information installed in the microbial arene oxidation. 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, interestingly, by reversible carbopalladation in competing positions. 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 a planar molecule such as benzoic acid in just a few steps.

Version notes

version two


Supplementary material

Paterson Dunås SI 200123