Simplifying Access to Targeted Protein Degraders via Nickel Electrocatalytic Cross-Coupling.

C-C linked glutarimide-containing structures with direct utility in the preparation of cereblon-based degraders (PROTACs, CELMoDs) can be assessed in a single step from inexpensive, commercial α-bromoglutarimide through a unique Brønsted-acid assisted Ni-electrocatalytic approach. The reaction tolerates a broad array of functional groups that are historically problematic and can be applied to the simplified synthesis of dozens of known compounds that have only been procured through laborious, wasteful, multi-step sequences. The reaction is scalable in both batch and flow and features a trivial procedure wherein the most time-consuming aspect of reaction setup is weighing out the starting materials.

Simplified Modular Access to Enantiopure 1,2-Aminoalcohols via Ni-Electrocatalytic Decarboxylative Arylation.

Chiral aminoalcohols are omnipresent in bioactive compounds. Conventional strategies to access this motif involve multiple-step reactions to install the requisite functionalities stereoselectively using conventional polar bond analysis. This study reveals that a simple chiral oxazolidine-based carboxylic acid can be readily transformed to substituted chiral aminoalcohols with high stereochemical control by Ni-electrocatalytic decarboxylative arylation. This general, robust, and scalable coupling can be used to synthesize a variety of medicinally important compounds, avoiding protecting and functional group manipulations, thereby dramatically simplifying their preparation.

Nickel-Electrocatalytic Decarboxylative Arylation to Access Quaternary Centers.

There is a pressing need, particularly in the field of drug discovery, for general methods that will enable direct coupling of tertiary alkyl fragments to (hetero)aryl halides. Herein a uniquely powerful and simple set of conditions for achieving this transformation with unparalleled generality and chemoselectivity is disclosed. This new protocol is placed in context with other recently reported methods, applied to simplify the routes of known bioactive building blocks molecules, and scaled up in both batch and flow. The role of pyridine additive as well as the mechanism of this reaction are interrogated through Cyclic Voltammetry studies, titration experiments, control reactions with Ni(0) and Ni(II)-complexes, and ligand optimization data. Those studies indicate that the formation of a BINAPNi(0) is minimized and the formation of an active pyridine-stabilized Ni(I) species is sustained during the reaction. Our preliminary mechanistic studies ruled out the involvement of Ni(0) species in this electrochemical cross-coupling, which is mediated by Ni(I) species via a Ni(I)-Ni(II)-Ni(III)-Ni(I) catalytic cycle.

A Paradigm Shift in Catalysis: Electro- and Photomediated Nickel-Catalyzed Cross-Coupling Reactions.

ConspectusTransition-metal catalyzed cross-coupling reactions are fundamental reactions in organic chemistry, facilitating strategic bond formations for accessing natural products, organic materials, agrochemicals, and pharmaceuticals. Redox chemistry enables access to elusive cross-coupling mechanisms through single-electron processes as an alternative to classical two-electron strategies predominated by palladium catalysis. The seminal reports of Baran, MacMillan, Doyle, Molander, Weix, Lin, Fu, Reisman, and others in merging redox perturbation (photochemical, electrochemical, and purely chemical) with catalysis are pivotal to the current resurgence and mechanistic understanding of first-row transition metal-based catalysis. The hallmark of this redox platform is the systematic modulation of transition-metal oxidation states by a photoredox catalyst or at a heterogeneous electrode surface. Electrocatalysis and photocatalysis enhance transition metal catalysis' capacity for bond formation through electron- or energy-transfer processes that promote otherwise challenging elementary steps or elusive mechanisms. Cross-coupling conditions promoted by electrocatalysis and photocatalysis are mild, and bond formation proceeds with exceptionally high chemoselectivity and wide functional group tolerance. The interfacing of abundant first-row transition-metal catalysis with electrocatalysis and photocatalysis has brought about a paradigm shift in cross-coupling technology as practitioners are quickly applying these tools in synthesizing fine chemicals and pharmaceutically relevant motifs. In particular, the merger of Ni catalysis with electro- and photochemistry ushered in a new era for carbon-carbon and carbon-heteroatom cross-couplings with expanded generality compared to their thermally driven counterparts. Over the past decade, we have developed enabling photo- and electrochemical methods throughout our combined research experience in industry (BMS, AstraZeneca) and academia (Professor Baran, Scripps Research) in cross-disciplinary collaborative environments. In this Account, we will outline recent progress from our past and present laboratories in photo- and electrochemically mediated Ni-catalyzed cross-couplings. By highlighting these cross-coupling methodologies, we will also compare mechanistic features of both electro- and photochemical strategies for forging C(sp2)-C(sp3), C(sp3)-C(sp3), C-O, C-N, and C-S bonds. Through these side-by-side comparisons, we hope to demystify the subtle differences between the two complementary tools to enact redox control over transition metal catalysis. Finally, building off the collective experience of ourselves and the rest of the community, we propose a tactical user guide to photo- and electrochemically driven cross-coupling reactions to aid the practitioner in rapidly applying such tools in their synthetic designs.

Imidazophenothiazine-Based Thermally Activated Delayed Fluorescence Materials with Ultra-Long-Lived Excited States for Energy Transfer Photocatalysis.

Triplet-triplet energy transfer (EnT) is a powerful activation pathway in photocatalysis that unlocks new organic transformations and improves the sustainability of organic synthesis. Many current examples, however, still rely on platinum-group metal complexes as photosensitizers, with associated high costs and environmental impacts. Photosensitizers that exhibit thermally activated delayed fluorescence (TADF) are attractive fully organic alternatives in EnT photocatalysis. However, TADF photocatalysts incorporating heavy atoms remain rare, despite their utility in inducing efficient spin-orbit-coupling, intersystem-crossing, and consequently a high triplet population. Here, we describe the synthesis of imidazo-phenothiazine (IPTZ), a sulfur-containing heterocycle with a locked planar structure and a shallow LUMO level. This acceptor is used to prepare seven TADF-active photocatalysts with triplet energies up to 63.9 kcal mol-1. We show that sulfur incorporation improves spin-orbit coupling and increases triplet lifetimes up to 3.64 ms, while also allowing for tuning of photophysical properties via oxidation at the sulfur atom. These IPTZ materials are applied as photocatalysts in five seminal EnT reactions: [2 + 2] cycloaddition, the disulfide-ene reaction, and Ni-mediated C-O and C-N cross-coupling to afford etherification, esterification, and amination products, outcompeting the industry-standard TADF photocatalyst 2CzPN in four of the five studied scenarios. Detailed photophysical and theoretical studies are used to understand structure-activity relationships and to demonstrate the key role of the heavy atom effect in the design of TADF materials with superior photocatalytic performance.

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.

Photoenzymatic Catalysis in a New Light: Gluconobacter "Ene"-Reductase Conjugates Possessing High-Energy Reactivity with Tunable Low-Energy Excitation.

Non-natural light-driven enzymatic reactivity was recently developed to perform the highly stereoselective reactions required for pharmaceutical synthesis. However, photoenzymes require high-intensity light to function because of the poor absorption properties of their photoactive intermediates. Inspired by the modular architecture of photosynthesis, we designed a conjugate composed of a covalently linked photoenzyme and a light antenna to separate light capture from catalysis. Spectroscopic characterization of the conjugate showed the presence of efficient energy transfer from the light-harvesting components to the photoenzyme. In the presence of energy transfer, a ∼4-fold increase in product yield was observed for intramolecular hydroalkylation of alkenes, and reactivity was enabled for intermolecular hydroalkylation of alkenes. These improvements establish the power of incorporating nature's design into non-natural photoenzymatic catalysis.

Radical Termination via ß-Scission Enables Photoenzymatic Allylic Alkylation Using "Ene"-Reductases.

Allylations are practical transformations that forge C-C bonds while introducing an alkene for further chemical manipulations. Here, we report a photoenzymatic allylation of α-chloroamides with allyl silanes using flavin-dependent 'ene'-reductases (EREDs). An engineered ERED can catalyze annulative allylic alkylation to prepare 5, 6, and 7-membered lactams with high levels of enantioselectivity. Ultrafast transient absorption spectroscopy indicates that radical termination occurs via ß-scission of the silyl group to afford a silyl radical, a distinct mechanism by comparison to traditional radical allylations involving allyl silanes. Moreover, this represents an alternative strategy for radical termination using EREDs. This mechanism was applied to intermolecular couplings involving allyl sulfones and silyl enol ethers. Overall, this method highlights the opportunity for EREDs to catalyze radical termination strategies beyond hydrogen atom transfer.

Ground-State Electron Transfer as an Initiation Mechanism for Biocatalytic C-C Bond Forming Reactions.

The development of non-natural reaction mechanisms is an attractive strategy for expanding the synthetic capabilities of substrate promiscuous enzymes. Here, we report an "ene"-reductase catalyzed asymmetric hydroalkylation of olefins using α-bromoketones as radical precursors. Radical initiation occurs via ground-state electron transfer from the flavin cofactor located within the enzyme active site, an underrepresented mechanism in flavin biocatalysis. Four rounds of site saturation mutagenesis were used to access a variant of the "ene"-reductase nicotinamide-dependent cyclohexanone reductase (NCR) from Zymomonas mobiles capable of catalyzing a cyclization to furnish ß-chiral cyclopentanones with high levels of enantioselectivity. Additionally, wild-type NCR can catalyze intermolecular couplings with precise stereochemical control over the radical termination step. This report highlights the utility for ground-state electron transfers to enable non-natural biocatalytic C-C bond forming reactions.

Active-Site Environmental Factors Customize the Photophysics of Photoenzymatic Old Yellow Enzymes.

The development of non-natural photoenzymatic systems has reinvigorated the study of photoinduced electron transfer (ET) within protein active sites, providing new and unique platforms for understanding how biological environments affect photochemical processes. In this work, we use ultrafast spectroscopy to compare the photoinduced electron transfer in known photoenzymes. 12-Oxophytodienoate reductase 1 (OPR1) is compared to Old Yellow Enzyme 1 (OYE1) and morphinone reductase (MR). The latter enzymes are structurally homologous to OPR1. We find that slight differences in the amino acid composition of the active sites of these proteins determine their distinct electron-transfer dynamics. Our work suggests that the inside of a protein active site is a complex/heterogeneous dielectric network where genetically programmed heterogeneity near the site of biological ET can significantly affect the presence and lifetime of various intermediate states. Our work motivates additional tunability of Old Yellow Enzyme active-site reorganization energy and electron-transfer energetics that could be leveraged for photoenzymatic redox approaches.

Catalytic promiscuity enabled by photoredox catalysis in nicotinamide-dependent oxidoreductases.

Strategies that provide enzymes with the ability to catalyse non-natural reactions are of considerable synthetic value. Photoredox catalysis has proved adept at expanding the synthetic repertoire of existing catalytic platforms, yet, in the realm of biocatalysis it has primarily been used for cofactor regeneration. Here we show that photoredox catalysts can be used to enable new catalytic function in nicotinamide-dependent enzymes. Under visible-light irradiation, xanthene-based photocatalysts enable a double-bond reductase to catalyse an enantioselective deacetoxylation. Mechanistic experiments support the intermediacy of an α-acyl radical, formed after the elimination of acetate. Isotopic labelling experiments support nicotinamide as the source of the hydrogen atom. Preliminary calculations and mechanistic experiments suggest that binding to the protein attenuates the reduction potential of the starting material, an important feature for localizing radical formation to the enzyme active site. The generality of this approach is highlighted with the radical dehalogenation of α-bromoamides catalysed by ketoreductases with Eosin Y as a photocatalyst.

Accessing non-natural reactivity by irradiating nicotinamide-dependent enzymes with light.

Enzymes are ideal for use in asymmetric catalysis by the chemical industry, because their chemical compositions can be tailored to a specific substrate and selectivity pattern while providing efficiencies and selectivities that surpass those of classical synthetic methods. However, enzymes are limited to reactions that are found in nature and, as such, facilitate fewer types of transformation than do other forms of catalysis. Thus, a longstanding challenge in the field of biologically mediated catalysis has been to develop enzymes with new catalytic functions. Here we describe a method for achieving catalytic promiscuity that uses the photoexcited state of nicotinamide co-factors (molecules that assist enzyme-mediated catalysis). Under irradiation with visible light, the nicotinamide-dependent enzyme known as ketoreductase can be transformed from a carbonyl reductase into an initiator of radical species and a chiral source of hydrogen atoms. We demonstrate this new reactivity through a highly enantioselective radical dehalogenation of lactones-a challenging transformation for small-molecule catalysts. Mechanistic experiments support the theory that a radical species acts as an intermediate in this reaction, with NADH and NADPH (the reduced forms of nicotinamide adenine nucleotide and nicotinamide adenine dinucleotide phosphate, respectively) serving as both a photoreductant and the source of hydrogen atoms. To our knowledge, this method represents the first example of photo-induced enzyme promiscuity, and highlights the potential for accessing new reactivity from existing enzymes simply by using the excited states of common biological co-factors. This represents a departure from existing light-driven biocatalytic techniques, which are typically explored in the context of co-factor regeneration.