Diversity-oriented synthesis of cyclohexenes by combining enzymatic intermolecular Diels-Alder reactions and decarboxylative functionalizations

Abstract

Substituted cyclohexanes are common scaffolds found in both natural products and drug molecules. Diels-Alderases that can efficiently catalyze intermolecular Diels-Alder reactions to generate cyclohexene ring systems have received considerable interest. However, the synthetic power of Diels-Alderases is incomparable with chemo-catalysts due to their limited substrate scopes. Here, we report a new chemo-enzymatic strategy for the diversity-oriented syntheses of functionalized cyclohexenes. We first applied focused rational iterative site-specific mutagenesis to generate a natural Diels-Alderase variant M3, which shows a 34-fold increase in catalytic efficiency, broad substrate scope, and good to perfect stereoselectivity. Then, we used diverse transition-metal-catalyzed decarboxylative coupling reactions to functionalize the enzymatic Diels-Alder products. This work offers an efficient synthetic route to structurally diverse cyclohexenes that are not accessible by solely using biocatalysis or chemo-catalysis and illustrates how chemo-catalysis can cooperate with biocatalysis to expand the synthetic application of biocatalysts. • Rapid engineering of the intermolecular Diels-Alderase has expanded its substrate scope • A new chemo-enzymatic strategy for the synthesis of cyclohexenes has been developed • Many structurally diverse cyclohexenes have been efficiently prepared Selectivity and structural diversity are the two important factors chemists need to manipulate precisely in their synthetic designs. Despite their exceptionally high chemo-, regio-, and stereoselectivity, biocatalysts are typically featured with limitations in both substrate scope and reaction types, which, on the contrary, are the innate advantages of chemo-catalysts. Thus, combining biocatalysis and chemo-catalysis is one of the most promising ways to overcome the synthetic challenges in the efficient synthesis of structurally complex and diverse molecules. To enhance the synthetic power of the intermolecular Diels-Alderase, protein engineering was performed to increase the catalytic efficiency toward dienophiles containing an ester group as a functional handle. After enzymatic transformation, the optically pure Diels-Alder (D-A) products were further functionalized by several decarboxylative cross-coupling reactions, thus rapidly generating a panel of structurally diverse cyclohexene scaffolds. Wang et al. describe a new chemo-enzymatic strategy toward the diversity-orientated synthesis of enantiopure cyclohexenes. This strategy features an intermolecular Diels-Alder reaction catalyzed by an engineered Diels-Alderase followed by various transition-metal-catalyzed decarboxylative functionalizations. Both stereoselectivity and structural diversity have been achieved by this chemo-enzymatic strategy, enabling efficient access to useful synthetic building blocks, natural products, and privileged structures for drug discovery that are difficult to be obtained by solely using biocatalyst or chemo-catalyst.