An asymmetric sp3-sp3 cross-electrophile coupling using 'ene'-reductases.

The catalytic asymmetric construction of Csp3-Csp3 bonds remains one of the foremost challenges in organic synthesis1. Metal-catalysed cross-electrophile couplings (XECs) have emerged as a powerful tool for C-C bond formation2-5. However, coupling two distinct Csp3 electrophiles with high cross-selectivity and stereoselectivity continues as an unmet challenge. Here we report a highly chemoselective and enantioselective Csp3-Csp3 XEC between alkyl halides and nitroalkanes catalysed by flavin-dependent 'ene'-reductases (EREDs). Photoexcitation of the enzyme-templated charge-transfer complex between an alkyl halide and a flavin cofactor enables the chemoselective reduction of alkyl halide over the thermodynamically favoured nitroalkane partner. The key C-C bond-forming step occurs by means of the reaction of an alkyl radical with an in situ-generated nitronate to form a nitro radical anion that collapses to form nitrite and an alkyl radical. An enzyme-controlled hydrogen atom transfer (HAT) affords high levels of enantioselectivity. This reactivity is unknown in small-molecule catalysis and highlights the potential for enzymes to use new mechanisms to address long-standing synthetic challenges.

Photobiocatalytic Strategies for Organic Synthesis.

Biocatalysis has revolutionized chemical synthesis, providing sustainable methods for preparing various organic molecules. In enzyme-mediated organic synthesis, most reactions involve molecules operating from their ground states. Over the past 25 years, there has been an increased interest in enzymatic processes that utilize electronically excited states accessed through photoexcitation. These photobiocatalytic processes involve a diverse array of reaction mechanisms that are complementary to one another. This comprehensive review will describe the state-of-the-art strategies in photobiocatalysis for organic synthesis until December 2022. Apart from reviewing the relevant literature, a central goal of this review is to delineate the mechanistic differences between the general strategies employed in the field. We will organize this review based on the relationship between the photochemical step and the enzymatic transformations. The review will include mechanistic studies, substrate scopes, and protein optimization strategies. By clearly defining mechanistically-distinct strategies in photobiocatalytic chemistry, we hope to illuminate future synthetic opportunities in the area.

Atroposelective Synthesis of Axial Biaryls by Dynamic Kinetic Resolution Using Engineered Imine Reductases.

Axially chiral biaryls are ubiquitous scaffolds in natural products, bioactive molecules, chiral ligands and catalysts, but biocatalytic methods for their asymmetric synthesis are limited. Here, we report a highly efficient biocatalytic route for the atroposelective synthesis of biaryls via dynamic kinetic resolution (DKR). This DKR approach features a transient six-membered aza-acetal bridge-promoted racemization followed by an imine-reductase (IRED)-catalyzed stereoselective reduction to construct the axial chirality at ambient conditions. Directed evolution of an IRED from Streptomyces sp. GF3546 provided a variant (S-IRED-Ss-M11) capable of catalyzing the DKR process to access a variety of biaryl aminoalcohols in high yields and excellent enantioselectivities (up to 98% yield and >99:1 enantiomeric ratio). Molecular dynamics simulation studies on the S-IRED-Ss-M11 variant revealed the origin of its improved activity and atroposelectivity. By exploiting the substrate promiscuity of IREDs and the power of directed evolution, our work further extends the biocatalysts' toolbox to construct challenging axially chiral molecules.

Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis.

Tertiary nitroalkanes and the corresponding α-tertiary amines represent important motifs in bioactive molecules and natural products. The C-alkylation of secondary nitroalkanes with electrophiles is a straightforward strategy for constructing tertiary nitroalkanes; however, controlling the stereoselectivity of this type of reaction remains challenging. Here, we report a highly chemo- and stereoselective C-alkylation of nitroalkanes with alkyl halides catalyzed by an engineered flavin-dependent "ene"-reductase (ERED). Directed evolution of the old yellow enzyme from Geobacillus kaustophilus provided a triple mutant, GkOYE-G7, capable of synthesizing tertiary nitroalkanes in high yield and enantioselectivity. Mechanistic studies indicate that the excitation of an enzyme-templated charge-transfer complex formed between the substrates and cofactor is responsible for radical initiation. Moreover, a single-enzyme two-mechanism cascade reaction was developed to prepare tertiary nitroalkanes from simple nitroalkenes, highlighting the potential to use one enzyme for two mechanistically distinct reactions.

Asymmetric Carbohydroxylation of Alkenes Using Photoenzymatic Catalysis.

Alkene difunctionalizations enable the synthesis of structurally elaborated products from simple and ubiquitous starting materials in a single chemical step. Carbohydroxylations of olefins represent a family of reactivity that furnish structurally complex alcohols. While examples of this type of three-component coupling have been reported, catalytic asymmetric examples remain elusive. Here, we report an enzyme-catalyzed asymmetric carbohydroxylation of alkenes catalyzed by flavin-dependent "ene"-reductases to produce enantioenriched tertiary alcohols. Seven rounds of protein engineering reshape the enzyme's active site to increase activity and enantioselectivity. Mechanistic studies suggest that C-O bond formation occurs via a 5-endo-trig cyclization with the pendant ketone to afford an α-oxy radical which is oxidized and hydrolyzed to form the product. This work demonstrates photoenzymatic reactions involving "ene"-reductases can terminate radicals via mechanisms other than hydrogen atom transfer, expanding their utility in chemical synthesis.

Biosynthesis of the Immunosuppressant (-)-FR901483.

We report characterization of the biosynthetic pathway of the potent immunosuppressant (-)-FR901483 (1) through heterologous expression and enzymatic assays. The biosynthetic logic to form the azatricyclic alkaloid is consistent with those proposed in biomimetic syntheses and involves aza-spiro annulation of dityrosyl-piperazine to form a ketoaldehyde intermediate, followed by regioselective aldol condensation, stereoselective ketoreduction, and phosphorylation. A possible target of 1 is proposed based on the biosynthetic studies.

Iron-Catalyzed Regiodivergent Alkyne Hydrosilylation.

Although tremendous effort has been devoted to the development of methods for iron catalysis, few of the catalysts reported to date exhibit clear superiority to other metal catalysts, and the mechanisms of most iron catalysis remain unclear. Herein, we report that iron complexes bearing 2,9-diaryl-1,10-phenanthroline ligands exhibit not only unprecedented catalytic activity but also unusual ligand-controlled divergent regioselectivity in hydrosilylation reactions of various alkynes. The hydrosilylation protocol described herein provides a highly efficient method for preparing useful di- and trisubstituted olefins on a relatively large scale under mild conditions, and its use markedly improved the synthetic efficiency of a number of bioactive compounds. Mechanistic studies based on control experiments and density functional theory calculations were performed to understand the catalytic pathway and the observed regioselectivity.

Concise Biosynthesis of Phenylfuropyridones in Fungi.

Phenylfuropyridone natural products from fungi exhibit a range of antibacterial and cytotoxicity activities, and can potentiate azole antifungal compounds. We elucidated the biosynthetic pathway of compounds in the citridone family through heterologous reconstitution of the pfp pathway. We demonstrate that multiple members of this family can be accessed from a reactive ortho-quinone methide (o-QM) intermediate through electrocyclization, cycloisomerization, or conjugate addition. Formation of the quaternary carbon center in citridone B is catalyzed by an epoxide-forming P450 enzyme, followed by carbon skeletal rearrangement. Our results showcase how nature harvests the reactivities of an o-QM intermediate to biosynthesize complex natural products.

Iron-Catalyzed Dihydrosilylation of Alkynes: Efficient Access to Geminal Bis(silanes).

Geminal bis(silanes) are versatile synthetic building blocks owing to their stability and propensity to undergo a variety of transformations. However, the scarcity of catalytic methods for their synthesis limits their structural diversity and thus their utility for further applications. Herein we report a new method for synthesis of geminal bis(silanes) by means of iron-catalyzed dihydrosilylation of alkynes. Iron catalysts were distinctly superior to the other tested catalysts, which clearly demonstrates that novel reactivity can be found by using iron catalysts. This method features 100% atom economy, regiospecificity, mild reaction conditions, and readily available starting materials. Using this method, we prepared a new type of geminal bis(silane) with secondary silane moieties, the Si-H bonds of which can easily undergo various transformations, facilitating the synthetic applications of these compounds. Preliminary mechanistic studies demonstrated that the reaction proceeds via two iron-catalyzed hydrosilylation reactions, the first generating ß-( E)-vinylsilanes and the second producing geminal bis(silanes).

Spin effect on redox acceleration and regioselectivity in Fe-catalyzed alkyne hydrosilylation.

Iron catalysts are ideal transition metal catalysts because of the Earths abundant, cheap, biocompatible features of iron salts. Iron catalysts often have unique open-shell structures that easily undergo spin crossover in chemical transformations, a feature rarely found in noble metal catalysts. Unfortunately, little is known currently about how the open-shell structure and spin crossover affect the reactivity and selectivity of iron catalysts, which makes the development of iron catalysts a low efficient trial-and-error program. In this paper, a combination of experiments and theoretical calculations revealed that the iron-catalyzed hydrosilylation of alkynes is typical spin-crossover catalysis. Deep insight into the electronic structures of a set of well-defined open-shell active formal Fe(0) catalysts revealed that the spin-delocalization between the iron center and the 1,10-phenanthroline ligand effectively regulates the iron center's spin and oxidation state to meet the opposite electrostatic requirements of oxidative addition and reductive elimination, respectively, and the spin crossover is essential for this electron transfer process. The triplet transition state was essential for achieving high regioselectivity through tuning the nonbonding interactions. These findings provide an important reference for understanding the effect of catalyst spin state on reaction. It is inspiring for the development of iron catalysts and other Earth-abundant metal catalysts, especially from the point of view of ligand development.

A Photoenzyme for Challenging Lactam Radical Cyclizations.

Reductive radical cyclizations are ubiquitous in organic synthesis and have been applied to the synthesis of structurally complex molecules. N-heterocyclic motifs can be prepared through the cyclization of α-haloamides; however, slow rotation around the amide C-N bond results in preferential formation of an acyclic hydrodehalogenated product. Here, we compare four different methods for preparing γ, δ, ε, and ζ-lactams via radical cyclization. We found that a photoenzymatic method using flavin-dependent 'ene'-reductases affords the highest level of product selectivity. We suggest that through selective binding of the cis amide isomer, the enzyme preorganizes the substrate for cyclization, helping to avoid premature radical termination.

Cascade CuH-Catalysed Conversion of Alkynes to Enantioenriched 1,1-Disubstituted Products.

Enantioenriched α-aminoboronic acids play a unique role in medicinal chemistry and have emerged as privileged pharmacophores in proteasome inhibitors. Additionally, they represent synthetically useful chiral building blocks in organic synthesis. Recently, CuH-catalyzed asymmetric alkene hydrofunctionalization has become a powerful tool to construct stereogenic carbon centers. In contrast, applying CuH cascade catalysis to achieve reductive 1,1-difunctionalization of alkynes remains an important, but largely unaddressed, synthetic challenge. Herein, we report an efficient strategy to synthesize α-aminoboronates via CuH-catalyzed hydroboration/hydroamination cascade of readily available alkynes. Notably, this transformation selectively delivers the desired 1,1-heterodifunctionalized product in favor of alternative homodifunctionalized, 1,2-heterodifunctionalized, or reductively monofunctionalized byproducts, thereby offering rapid access to these privileged scaffolds with high chemo-, regio- and enantioselectivity.