Roelfes, G.

ACS Cent. Sci. 2019, 5, 206-208, 10.1021/acscentsci.9b00015

Directed evolution generated an enzyme for the enantioselective synthesis of α-trifluoromethylated organoborons—potentially attractive synthons for fluorinated compounds.

Ward, T.R.

ACS Cent. Sci. 2019, 5, 1120-1136, 10.1021/acscentsci.9b00397

Artificial metalloenzymes (ArMs) result from the incorporation of an abiotic metal cofactor within a protein scaffold. From the earliest techniques of transition metals adsorbed on silk fibers, the field of ArMs has expanded dramatically over the past 60 years to encompass a range of reaction classes and inspired approaches: Assembly of the ArMs has taken multiple forms with both covalent and supramolecular anchoring strategies, while the scaffolds have been intuitively selected and evolved, repurposed, or designed in silico. Herein, we discuss some of the most prominent recent examples of ArMs to highlight the challenges and opportunities presented by the field.

Hartwig, J.F.

ACS Cent. Sci. 2017, 3, 302-308, 10.1021/acscentsci.6b00391

Enzymes catalyze organic transformations with exquisite levels of selectivity, including chemoselectivity, stereoselectivity, and substrate selectivity, but the types of reactions catalyzed by enzymes are more limited than those of chemical catalysts. Thus, the convergence of chemical catalysis and biocatalysis can enable enzymatic systems to catalyze abiological reactions with high selectivity. Recently, we disclosed artificial enzymes constructed from the apo form of heme proteins and iridium porphyrins that catalyze the insertion of carbenes into a C–H bond. We postulated that the same type of Ir(Me)-PIX enzymes could catalyze the cyclopropanation of a broad range of alkenes with control of multiple modes of selectivity. Here, we report the evolution of artificial enzymes that are highly active and highly stereoselective for the addition of carbenes to a wide range of alkenes. These enzymes catalyze the cyclopropanation of terminal and internal, activated and unactivated, electron-rich and electron-deficient, conjugated and nonconjugated alkenes. In particular, Ir(Me)-PIX enzymes derived from CYP119 catalyze highly enantio- and diastereoselective cyclopropanations of styrene with ±98% ee, >70:1 dr, >75% yield, and ∼10,000 turnovers (TON), as well as 1,2-disubstituted styrenes with up to 99% ee, 35:1 dr, and 54% yield. Moreover, Ir(Me)-PIX enzymes catalyze cyclopropanation of internal, unactivated alkenes with up to 99% stereoselectivity, 76% yield, and 1300 TON. They also catalyze cyclopropanation of natural products with diastereoselectivities that are complementary to those attained with standard transition metal catalysts. Finally, Ir(Me)-PIX P450 variants react with substrate selectivity that is reminiscent of natural enzymes; they react preferentially with less reactive internal alkenes in the presence of more reactive terminal alkenes. Together, the studies reveal the suitability of Ir-containing P450s to combine the broad reactivity and substrate scope of transition metal catalysts with the exquisite selectivity of enzymes, generating catalysts that enable reactions to occur with levels and modes of activity and selectivity previously unattainable with natural enzymes or transition metal complexes alone.

Head-Gordon, T.

ACS Cent. Sci. 2021, 7, 72-80, 10.1021/acscentsci.0c01556

As biocatalysts, enzymes are characterized by their high catalytic efficiency and strong specificity but are relatively fragile by requiring narrow and specific reactive conditions for activity. Synthetic catalysts offer an opportunity for more chemical versatility operating over a wider range of conditions but currently do not reach the remarkable performance of natural enzymes. Here we consider some new design strategies based on the contributions of nonlocal electric fields and thermodynamic fluctuations to both improve the catalytic step and turnover for rate acceleration in arbitrary synthetic catalysts through bioinspired studies of natural enzymes. With a focus on the enzyme as a whole catalytic construct, we illustrate the translational impact of natural enzyme principles to synthetic enzymes, supramolecular capsules, and electrocatalytic surfaces.