Biaryl compounds, with two connected aromatic rings, are found across medicine, materials science and asymmetric catalysis
. The necessity of joining arene building blocks to access these valuable ...compounds has inspired several approaches for biaryl bond formation and challenged chemists to develop increasingly concise and robust methods for this task
. Oxidative coupling of two C-H bonds offers an efficient strategy for the formation of a biaryl C-C bond; however, fundamental challenges remain in controlling the reactivity and selectivity for uniting a given pair of substrates
. Biocatalytic oxidative cross-coupling reactions have the potential to overcome limitations inherent to numerous small-molecule-mediated methods by providing a paradigm with catalyst-controlled selectivity
. Here we disclose a strategy for biocatalytic cross-coupling through oxidative C-C bond formation using cytochrome P450 enzymes. We demonstrate the ability to catalyse cross-coupling reactions on a panel of phenolic substrates using natural P450 catalysts. Moreover, we engineer a P450 to possess the desired reactivity, site selectivity and atroposelectivity by transforming a low-yielding, unselective reaction into a highly efficient and selective process. This streamlined method for constructing sterically hindered biaryl bonds provides a programmable platform for assembling molecules with catalyst-controlled reactivity and selectivity.
The impeccable control over chemo-, site-, and stereoselectivity possible in enzymatic reactions has led to a surge in the development of new biocatalytic methods. Despite carbon-carbon (C-C) bonds ...providing the central framework for organic molecules, development of biocatalytic methods for their formation has been largely confined to the use of a select few lyases over the last several decades, limiting the types of C-C bond-forming transformations possible through biocatalytic methods. This Review provides an update on the suite of enzymes available for highly selective biocatalytic C-C bond formation. Examples will be discussed in reference to the (1) native activity of enzymes, (2) alteration of activity through protein or substrate engineering for broader applicability, and (3) utility of the biocatalyst for abiotic synthesis.
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.
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.
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