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

Abstract

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<br>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<br>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<br>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.<br>