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Achieving convergent synthetic strategies has long been a gold standard in constructing complex molecular skeletons, allowing for the rapid generation of complexity in comparatively streamlined synthetic routes. Traditionally, biocatalysis has not played a prominent role in convergent laboratory synthesis, with the application of biocatalysts in convergent strategies primarily limited to the synthesis of chiral fragments. Although the use of enzymes to enable convergent synthetic approaches is relatively new and emerging, combining the efficiency of convergent transformations with the selectivity achievable through biocatalysis creates new opportunities for efficient synthetic strategies. This Perspective provides an overview of recent developments in biocatalytic strategies for convergent transformations and offers insights into the advantages of these methods compared to their small molecule-based counterparts.

Biocatalysis offers compelling advantages in synthesis, often becoming the method of choice based on sustainability, safety, and selectivity considerations. Despite these advantages, enzymes in synthesis are typically dedicated to functional group intercon versions in linear synthetic sequences and have not been broadly integrated into the retrosynthetic logic for carbon skeleton assembly. In this article, we disclose a biocatalytic platform for fragment coupling to assemble target molecules convergently. Specifically, we report a strategy for biocatalytic phenolic cross-coupling through oxidative C-C bond formation. Using cytochrome P450 enzymes, we demonstrate the ability to catalyze cross-coupling reactions on a panel of phenolic substrates and further demonstrate the ability to tune these catalysts to possess the desired reactivity, site-, and atroposelectivity. This streamlined method for constructing sterically-hindered biaryl bonds provides an engineerable platform for assembling molecules with programmable catalyst-controlled reactivity and selectivity unprecedented with small molecule catalysts.Convergent synthetic strategies enable the efficient construction of carbon frameworks, quickly generating complexity by stitching individual building blocks together. 1 Chemists depend on transformations, such as cross-coupling reactions, that can reliably be programmed into synthetic routes for convergent approaches. 2 Ideally, reactions planned for the assembly phase of a convergent synthesis are both perfectly selective and tolerate a breadth of functional groups to minimize the production of undesired products, installation of protecting groups, or unnecessary redox manipulations. 3 These qualities are common in biocatalytic reactions due to the catalyst-controlled selectivity possible with large molecule catalysts; 4 however, the enzymatic transformations most commonly applied in synthesis are confined to functional group interconversions, not convergent steps within a synthetic route. [5][6][7][8][9][10][11] To enable convergent biocatalytic strategies, a handful of biocatalytic methods have recently been developed, [12][13][14][15] foreshadowing the potential of convergent biocatalysis in synthesis. Based on the paucity of enzyme-mediated methods for uniting substantial fragments, we developed an intense interest in expanding the repertoire of biocatalysts capable of convergent fragment couplings. As a first step toward this goal, we sought to develop a platform for the biocatalytic assembly of carbon frameworks through oxidative cross-coupling reactions, thus providing a solution for this transformation's outstanding reactivity and selectivity challenges through biocatalysis and enabling convergent synthetic routes (Figure 1a).We chose to target biaryl bond formation as a model transformation for convergent cross-coupling reactions, given the ubiquitous nature of biaryl scaffolds in drugs, materials, and ligands for asymmetric catalysis (Figure 1b) and the fundamental synthetic challenges presented by the...

Despite the diverse and potent bioactivities displayed by axially chiral biaryl natural products, their application in drug discovery is limited by restricted access to these complex molecular scaffolds. In particular, fundamental challenges remain in controlling the site- and atroposelectivity in biaryl coupling reactions. In contrast, Nature has a wealth of biosynthetic enzymes that catalyze biaryl coupling reactions with catalyst-controlled selectivity. In particular, a growing subset of fungal P450s have been identified to catalyze site- and atroposelective biaryl couplings. Herein, we optimize a whole-cell biocatalytic platform in Pichia pastoris to synthesize biaryl molecules through the recombinant production of the fungal P450 KtnC. Moreover, engineering redox self-sufficient fusion enzymes further improves the efficiency of the system. Altogether, this work provides a platform for biaryl coupling reactions in yeast that can be applied to engineering a currently underexplored pool of fungal P450s into selective biocatalysts for the synthesis of complex biaryl compounds.