A General Synthetic Strategy toward the Truxillate Natural Products via Solid-State Photocycloadditions.

The truxillates constitute a large class of dimeric natural products featuring a central, highly substituted cyclobutane core. In principle, these structures could be efficiently synthesized via [2 + 2] photocycloaddition. However, the difficulty in controlling the high-energy electronically excited reactive intermediates in the solution state can lead to poor regio- and diastereocontrol. This has limited the use of photocycloaddition methodology toward the synthesis of this important class of natural products. Herein, we demonstrate that acid-controlled precipitation of C-acyl imidazoles promotes a highly selective solid-state photocycloaddition, and the products of this reaction can be quickly transformed into truxillate natural products.

Predicting Emission of Heteroleptic Iridium Complexes using Artificial Chemical Intelligence.

We report a deep learning-based approach to accurately predict the emission spectra of phosphorescent heteroleptic [Ir(C^N)2(NN)]+ complexes, enabling the rapid discovery of novel Ir(III) chromophores for diverse applications including organic light-emitting diodes and solar fuel cells. The deep learning models utilize graph neural networks and other chemical features in architectures that reflect the inherent structure of the heteroleptic complexes, composed of C^N and N^N ligands, and are thus geared towards efficient training over the dataset. By leveraging experimental emission data, our models reliably predict the full emission spectra of these complexes across various emission profiles, surpassing the accuracy of conventional DFT and correlated wavefunction methods, while simultaneously achieving robustness to the presence of imperfect (noisy, low-quality) training spectra. We showcase the potential applications for these and related models for \insilico\ prediction of complexes with tailored emission properties, as well as in "design of experiment'' contexts to reduce the synthetic burden of high-throughput screening. In the latter case, we demonstrate that the models allow to exploit a limited amount of experimental data to explore a wide range of chemical space, thus leveraging a modest synthetic effort.

Cu(II) salts as terminal oxidants in visible-light photochemical oxidation reactions.

Photochemistry provides an important platform for the discovery of synthetically useful transformations. The development of new oxidative photoreactions, however, has proven to be relatively challenging. The importance of the identity of the terminal oxidant has been an underappreciated consideration in the design of these reactions. Many of the most common terminal oxidants used in ground-state catalytic methods are poorly compatible with the one-electron oxidation state changes characteristic of photoredox reactions and result in hard-to-control deleterious side reactions. As an alternative, Cu(II) salts have emerged as versatile terminal oxidants in photochemical oxidation reactions that are terrestrially abundant, cost-effective, and readily compatible with one-electron oxidation state changes. This review highlights recent reaction methods that leverage Cu(II) oxidation in combination with the photochemical activation of substrates or that use Cu(II) salts as both the active chromophore and terminal oxidant.

Highly Enantioselective 6π Photoelectrocyclizations Engineered by Hydrogen Bonding.

Photochemical electrocyclization reactions are valued for both their ability to produce structurally complex molecules and their central role in elucidating fundamental mechanistic principles of photochemistry. We present herein a highly enantioselective 6π photoelectrocyclization catalyzed by a chiral Ir(III) photosensitizer. This transformation was successfully realized by engineering a strong hydrogen-bonding interaction between a pyrazole moiety on the catalyst and a basic imidazolyl ketone on the substrate. To shed light on the origin of stereoinduction, we conducted a comprehensive investigation combining experimental and computational mechanistic studies. Results from density functional theory calculations underscore the crucial role played by the prochirality and the torquoselectivity in the electrocyclization process as well as the steric demand in the subsequent [1,4]-H shift step. Our findings not only offer valuable guidance for developing chiral photocatalysts but also serve as a significant reference for achieving high levels of enantioselectivity in the 6π photoelectrocyclization reaction.

A General Strategy for the Synthesis of Truxinate Natural Products Enabled by Enantioselective [2+2] Photocycloadditions.

Pseudodimeric cyclobutanes constitute a large class of natural products that could, in principle, be efficiently synthesized via [2+2] photocycloadditions. However, the difficulty in developing chemo-, regio-, diastereo-, and enantioselective cycloadditions has limited their use in asymmetric syntheses. Herein, we show that chiral acid catalysts promote highly selective visible-light photocycloadditions, the products of which can be quickly transformed into truxinate natural products. This general approach has enabled the synthesis of both dimeric and pseudodimeric cyclobutane natural products with excellent enantioselectivity.

Iron-mediated modular decarboxylative cross-nucleophile coupling.

Carboxylic acids are valuable building blocks for pharmaceutical discovery because of their chemical stability, commercial availability, and structural diversity. Decarboxylative coupling reactions enable versatile functionalization of these feedstock chemicals, but many of the most general methods require prefunctionalization of carboxylic acids with redox-active moieties. These internal oxidants can be costly, their installation impedes rapid library synthesis, and their use results in environmentally problematic organic byproducts. We report herein a method for the direct decarboxylative cross-coupling of native carboxylic acids with nucleophilic coupling partners mediated by inexpensive, terrestrially abundant, and nontoxic Fe(III) salts. This method involves an initial photochemical decarboxylation followed by radical-polar crossover, which enables the construction of diverse carbon-carbon, carbon-oxygen, and carbon-nitrogen bonds with remarkable generality.

Allylic Amination of Highly Substituted Alkenes Enabled by Photoredox Catalysis and Cu(II)-Mediated Radical-Polar Crossover.

Allylic amination reactions enable the conversion of alkene feedstocks into value-added products with significant synthetic versatility. Here we describe a method for allylic amination involving photoredox activation and Cu(II)-mediated radical-polar crossover. A range of structurally varied allylic amines can be accessed using this strategy. The regioselectivity of this process is complementary to those of conventional methods for allylic amination.

Investigating the Effect of Lewis Acid Co-catalysts on Photosensitized Visible-Light De Mayo Reactions.

Herein, we describe studies showing that Lewis acid co-catalysts can significantly broaden the scope of alkenes that can be incorporated into the photosensitized visible-light De Mayo reaction. Mechanistic studies suggest that the primary benefit of the Lewis acid is not on substrate sensitization but rather on bond-forming steps downstream of energy transfer, highlighting the diverse effects that Lewis acids can have on sensitized photoreactions.

Selective Cross-Ketonization of Carboxylic Acids Enabled by Metallaphotoredox Catalysis.

Carboxylic acids are attractive building blocks for synthetic chemistry because they are chemically stable, abundant, and commercially available with substantial structural diversity. The process of combining two carboxylic acids to furnish a ketone is termed ketonization. This is a potentially valuable transformation that has been underutilized in organic synthesis due to the harsh reaction conditions generally required and the lack of selectivity obtained when coupling two distinct carboxylic acids. We report herein a metallaphotoredox strategy that selectively generates unsymmetrical ketones via cross-ketonization of two structurally dissimilar carboxylic acids. Cross-selectivity is achieved by exploiting divergent reactivity of differentially substituted acids towards critical one- and two-electron processes in the proposed coupling mechanism. This method is broadly applicable to a variety of functionalized carboxylic acids. It can also be applied to acids of similar steric profile by exploiting differences in their relative rates of decarboxylation.

Asymmetric Photochemical [2 + 2]-Cycloaddition of Acyclic Vinylpyridines through Ternary Complex Formation and an Uncontrolled Sensitization Mechanism.

Stereochemical control of photochemical reactions that occur via triplet energy transfer remains a challenge. Suppressing off-catalyst stereorandom reactivity is difficult for highly reactive open-shell intermediates. Strategies for suppressing racemate-producing, off-catalyst pathways have long focused on formation of ground state, substrate-catalyst chiral complexes that are primed for triplet energy transfer via a photocatalyst in contrast to their off-catalyst counterparts. Herein, we describe a strategy where both a chiral catalyst-associated vinylpyridine and a nonassociated, free vinylpyridine substrate can be sensitized by an Ir(III) photocatalyst, yet high levels of diastereo- and enantioselectivity in a [2 + 2] photocycloaddition are achieved through a preferred, highly organized transition state. This mechanistic paradigm is distinct from, yet complementary to current approaches for achieving high levels of stereocontrol in photochemical transformations.

Variable Temperature LED-NMR: Rapid Insights into a Photocatalytic Mechanism from Reaction Progress Kinetic Analysis.

A multitude of techniques are available to obtain a useful understanding of photocatalytic mechanisms. The combination of LED illumination with nuclear magnetic resonance spectroscopy (LED-NMR) provides a rapid, convenient means to directly monitor a photocatalytic reaction in situ. Herein, we describe a study of the mechanism of an enantioselective intermolecular [2 + 2] photocycloaddition catalyzed by a chiral Ir photocatalyst using LED-NMR. The data-rich output of this experiment is suitable for same-excess and variable time normalization analyses (VTNA). Together, these identified an unexpected change in mechanism between reactions conducted at ambient and cryogenic temperatures. At -78 °C, the kinetic data are consistent with the triplet rebound mechanism we previously proposed for this reaction, involving sensitization of maleimide and rapid reaction with a hydrogen-bound quinoline within the solvent cage. At room temperature, the cycloaddition instead proceeds through intracomplex energy transfer to the hydrogen-bound quinolone. These results highlight the potential sensitivity of photocatalytic reaction mechanisms to the precise reaction conditions and the further utility of LED-NMR as a fast, data-rich tool for their interrogation that compares favorably to conventional ex situ kinetic analyses.

Cooperative Stereoinduction in Asymmetric Photocatalysis.

Stereoinduction in complex organic reactions often involves the influence of multiple stereocontrol elements. The interaction among these can often result in the observation of significant cooperative effects that afford different rates and selectivities between the matched and mismatched sets of stereodifferentiating chiral elements. The elucidation of matched/mismatched effects in ground-state chemical reactions was a critically important theme in the maturation of modern stereocontrolled synthesis. The development of robust methods for the control of photochemical reactions, however, is a relatively recent development, and similar cooperative stereocontrolling effects in excited-state enantioselective photoreactions have not previously been documented. Herein, we describe a tandem chiral photocatalyst/Brønsted acid strategy for highly enantioselective [2 + 2] photocycloadditions of vinylpyridines. Importantly, the matched and mismatched chiral catalyst pairs exhibit different reaction rates and enantioselectivities across a range of coupling partners. We observe no evidence of ground-state interactions between the catalysts and conclude that these effects arise from their cooperative behavior in a transient excited-state assembly. These results suggest that similar matched/mismatched effects might be important in other classes of enantioselective dual-catalytic photochemical reactions.

Decarboxylative cross-nucleophile coupling via ligand-to-metal charge transfer photoexcitation of Cu(II) carboxylates.

Reactions that enable carbon-nitrogen, carbon-oxygen and carbon-carbon bond formation lie at the heart of synthetic chemistry. However, substrate prefunctionalization is often needed to effect such transformations without forcing reaction conditions. The development of direct coupling methods for abundant feedstock chemicals is therefore highly desirable for the rapid construction of complex molecular scaffolds. Here we report a copper-mediated, net-oxidative decarboxylative coupling of carboxylic acids with diverse nucleophiles under visible-light irradiation. Preliminary mechanistic studies suggest that the relevant chromophore in this reaction is a Cu(II) carboxylate species assembled in situ. We propose that visible-light excitation to a ligand-to-metal charge transfer (LMCT) state results in a radical decarboxylation process that initiates the oxidative cross-coupling. The reaction is applicable to a wide variety of coupling partners, including complex drug molecules, suggesting that this strategy for cross-nucleophile coupling would facilitate rapid compound library synthesis for the discovery of new pharmaceutical agents.

Chiral Photocatalyst Structures in Asymmetric Photochemical Synthesis.

Asymmetric catalysis is a major theme of research in contemporary synthetic organic chemistry. The discovery of general strategies for highly enantioselective photochemical reactions, however, has been a relatively recent development, and the variety of photoreactions that can be conducted in a stereocontrolled manner is consequently somewhat limited. Asymmetric photocatalysis is complicated by the short lifetimes and high reactivities characteristic of photogenerated reactive intermediates; the design of catalyst architectures that can provide effective enantiodifferentiating environments for these intermediates while minimizing the participation of uncontrolled racemic background processes has proven to be a key challenge for progress in this field. This review provides a summary of the chiral catalyst structures that have been studied for solution-phase asymmetric photochemistry, including chiral organic sensitizers, inorganic chromophores, and soluble macromolecules. While some of these photocatalysts are derived from privileged catalyst structures that are effective for both ground-state and photochemical transformations, others are structural designs unique to photocatalysis and offer insight into the logic required for highly effective stereocontrolled photocatalysis.

Chiral Brønsted acid-controlled intermolecular asymmetric [2 + 2] photocycloadditions.

Control over the stereochemistry of excited-state photoreactions remains a significant challenge in organic synthesis. Recently, it has become recognized that the photophysical properties of simple organic substrates can be altered upon coordination to Lewis acid catalysts, and that these changes can be exploited in the design of highly enantioselective catalytic photoreactions. Chromophore activation strategies, wherein simple organic substrates are activated towards photoexcitation upon binding to a Lewis acid catalyst, rank among the most successful asymmetric photoreactions. Herein, we show that chiral Brønsted acids can also catalyze asymmetric excited-state photoreactions by chromophore activation. This principle is demonstrated in the context of a highly enantio- and diastereoselective [2+2] photocycloaddition catalyzed by a chiral phosphoramide organocatalyst. Notably, the cyclobutane products arising from this method feature a trans-cis stereochemistry that is complementary to other enantioselective catalytic [2+2] photocycloadditions reported to date.

Enantioselective Synthesis of γ-Oxycarbonyl Motifs by Conjugate Addition of Photogenerated α-Alkoxy Radicals.

Enantioselective catalytic Giese addition of photogenerated α-alkoxy radicals to acyl pyrazolidinones can be accomplished using a tandem Sc(III) Lewis acid/photoredox catalyst system. Surprisingly, the excited-state oxidation potential was not the only important variable, and the optimal photocatalyst was not the strongest oxidant screened. Our results show that both the oxidation and reduction potentials of the photocatalyst can be important for the reaction outcome, highlighting the importance of holistic considerations in designing photochemical reactions.

Copper-Mediated Radical-Polar Crossover Enables Photocatalytic Oxidative Functionalization of Sterically Bulky Alkenes.

Oxidative heterofunctionalization reactions are among the most attractive methods for the conversion of alkenes and heteroatomic nucleophiles into complex saturated heterocycles. However, the state-of-the-art transition-metal-catalyzed methods to effect oxidative heterofunctionalizations are typically limited to unhindered olefins, and different nucleophilic partners generally require quite different reaction conditions. Herein, we show that Cu(II)-mediated radical-polar crossover allows for highly efficient and exceptionally mild photocatalytic oxidative heterofunctionalization reactions between bulky tri- and tetrasubstituted alkenes and a wide variety of nucleophilic partners. Moreover, we demonstrate that the broad scope of this transformation arises from photocatalytic alkene activation and thus complements existing transition-metal-catalyzed methods for oxidative heterofunctionalization. More broadly, these results further demonstrate that Cu(II) salts are ideal terminal oxidants for photoredox applications and that the combination of photocatalytic substrate activation and Cu(II)-mediated radical oxidation can address long-standing challenges in catalytic oxidation chemistry.

Construction of Complex Cyclobutane Building Blocks by Photosensitized [2 + 2] Cycloaddition of Vinyl Boronate Esters.

Cyclobutyl moieties in drug molecules are rare, and in general, they are minimally substituted and stereochemically simple. Methods to assemble structurally complex cyclobutane building blocks suitable for rapid diversification are thus highly desirable. We report herein a photosensitized [2 + 2] cycloaddition with vinyl boronate esters affording straightforward access to complex, densely functionalized cyclobutane scaffolds. Mechanistic studies suggest an activation mode involving energy transfer to the styrenyl alkene rather than the vinyl boronate ester.

Oxidase reactions in photoredox catalysis.

The nature of the terminal oxidant in oxidation reactions is an important reaction variable that can profoundly impact the mechanism, efficiency, and practicality of a synthetic protocol. One might reasonably categorize catalytic oxidation reactions into either "oxygenase" type reactions, in which the oxidant serves as an atom- or group-transfer reagent, or "oxidase" type reactions, where the oxidant is involved in catalyst turnover but does not become structurally incorporated into the product. As the field of photoredox catalysis has matured over the past decade, many successful oxygenase-type photoreactions have been reported. The development of photocatalytic oxidase reactions, on the other hand, has been somewhat slower. This tutorial review presents selected examples of some of the key classes of terminal oxidants that have been used in the design of photoredox oxidase transformations, along with the mechanistic features and benefits of each.

Olefin-Supported Cationic Copper Catalysts for Photochemical Synthesis of Structurally Complex Cyclobutanes.

The sole method available for the photocycloaddition of unconjugated aliphatic alkenes is the Cu-catalyzed Salomon-Kochi reaction. The [Cu(OTf)]2 ⋅benzene catalyst that has been standard in this reaction for many decades, however, is air-sensitive, prone to photodecomposition, and poorly reactive towards sterically bulky alkene substrates. Using bench-stable precursors, an improved catalyst system with superior reactivity and photostability has been designed, and it offers significantly expanded substrate scope. The utility of this new catalyst for the preparation of sterically crowded cyclobutane structures is highlighted through the preparation of the cores of the natural products sulcatine G and perforatol.