Accelerated photochemical reactions at oil-water interface exploiting melting point depression.

Water can accelerate a variety of organic reactions far beyond the rates observed in classical organic solvents. However, using pure water as a solvent introduces solubility constraints that have limited the applicability of efficient photochemistry in particular. We report here the formation of aggregates between pairs of arenes, heteroarenes, enamines, or esters with different electron affinities in an aqueous medium, leading to an oil-water phase boundary through substrate melting point depression. The active hydrogen atoms in the reactants engage in hydrogen bonds with water, thereby accelerating photochemical reactions. This methodology realizes appealingly simple conditions for aqueous coupling reactions of complex solid molecules, including complex drug molecules that are poorly soluble in water.

Reactivity of Superbasic Carbanions Generated via Reductive Radical-Polar Crossover in the Context of Photoredox Catalysis.

Photocatalytic reactions involving a reductive radical-polar crossover (RRPCO) generate intermediates with carbanionic reactivity. Many of these proposed intermediates resemble highly reactive organometallic compounds. However, conditions of their formation are generally not tolerated by their isolated organometallic versions and often a different reactivity is observed. Our investigations on their nature and reactivity under commonly used photocatalytic conditions demonstrate that these intermediates are indeed best described as free, superbasic carbanions capable of deprotonating common polar solvents usually assumed to be inert such as acetonitrile, dimethylformamide, and dimethylsulfoxide. Their basicity not only towards solvents but also towards electrophiles, such as aldehydes, ketones, and esters, is comparable to the reactivity of isolated carbanions in the gas-phase. Previously unsuccessful transformations thought to result from a lack of reactivity are explained by their high reactivity towards the solvent and weakly acidic protons of reaction partners. An intuitive explanation for the mode of action of photocatalytically generated carbanions is provided, which enables methods to verify reaction mechanisms proposed to involve an RRPCO step and to identify the reasons for the limitations of current methods.

Reversible Radical Addition Guides Selective Photocatalytic Intermolecular Thiol-Yne-Ene Molecular Assembly.

In modern organic chemistry, harnessing the power of multicomponent radical reactions presents both significant challenges and extraordinary potential. This article delves into this scientific frontier by addressing the critical issue of controlling selectivity in such complex processes. We introduce a novel approach that revolves around the reversible addition of thiyl radicals to multiple bonds, reshaping the landscape of multicomponent radical reactions. The key to selectivity lies in the intricate interplay between reversibility and the energy landscapes governing C-C bond formation in thiol-yne-ene reactions. The developed approach not only allows to prioritize the thiol-yne-ene cascade, dominating over alternative reactions, but also extends the scope of coupling products obtained from alkenes and alkynes of various structures and electron density distributions, regardless of their relative polarity difference, opening doors to more versatile synthetic possibilities. In the present study, we provide a powerful tool for atom-economical C-S and C-C bond formation, paving the way for the efficient synthesis of complex molecules. Carrying out our experimental and computational studies, we elucidated the fundamental mechanisms underlying radical cascades, a knowledge that can be broadly applied in the field of organic chemistry.

Visible-Light-Induced Synthesis of 1,2-Dicarboxyl Compounds from Carbon Dioxide, Carbamoyl-dihydropyridine, and Styrene.

ß-Amidated carboxylic acids, or succinamic acid derivatives, constitute a valuable chemical scaffold with broad applications in pharmaceuticals, agrochemicals, and polymer sciences. Herein, we report a redox-neutral multicomponent reaction for the synthesis of succinamic acid derivatives in good yields. This protocol involves styrene, CO2 and 1,4-carbamoyl-dihydropyridine as radical precursors. The method exhibits a broad substrate scope under mild reaction conditions, including late-stage functionalization. Moreover, by employing 13CO2, the method enables the synthesis of labeled 1,2-dicarboxylic compounds.

Towards a General Access to 1-Azaspirocyclic Systems via Photoinduced, Reductive Decarboxylative Radical Cyclizations.

A convenient and versatile approach to important 1-azaspirocyclic systems relevant to medicinal chemistry and natural products is reported herein. The main strategy relies on a reductive decarboxylative cyclization of redox-active esters which can be rapidly assembled from abundant cyclic azaacids and tailored acceptor sidechains, with a focus on alkyne acceptors enabling the generation of useful exo-alkene moieties. Diastereoconvergent variants were studied and could be achieved either through remote stereocontrol or conformational restriction in bicyclic carbamate substrates. Two sets of metal-free photocatalytic conditions employing inexpensive eosin Y were disclosed and studied experimentally to highlight key mechanistic divergences.

Side-Selective Solid-Phase Metallaphotoredox N(in)-Arylation of Peptides.

Postsynthetic diversification of peptides through selective modification of endogenous amino acid side chains has enabled significant advances in peptide drug discovery while expanding the biological and medical chemistry space. However, current tools have been focused on the modification of reactive polar and ionizable side chains, whereas the decoration of aromatic systems (e.g., the N(in) of the tryptophan) has been a long-standing challenge. Here, we introduce metallaphotocatalysis in solid-phase peptide synthesis for the on-resin orthogonal N-arylation of relevant tryptophan-containing peptides. The protocol allows the chemoselective introduction of a new C(sp2)-N bond at the N(in) of tryptophan in biologically active protected peptide sequences in the presence of native redox-sensitive side chains. The fusion of metallaphotocatalysis with solid-phase peptide synthesis opens new perspectives in diversifying native amino acid side chains.

Development of Photoswitchable Tethered Ligands that Target the µ-Opioid Receptor.

Converting known ligands into photoswitchable derivatives offers the opportunity to modulate compound structure with light and hence, biological activity. In doing so, these probes provide unique control when evaluating G-protein-coupled receptor (GPCR) mechanism and function. Further conversion of such compounds into covalent probes, known as photoswitchable tethered ligands (PTLs), offers additional advantages. These include localization of the PTLs to the receptor binding pocket. Covalent localization increases local ligand concentration, improves site selectivity and may improve the biological differences between the respective isomers. This work describes chemical, photophysical and biochemical characterizations of a variety of PTLs designed to target the µ-opioid receptor (µOR). These PTLs were modeled on fentanyl, with the lead disulfide-containing agonist found to covalently interact with a cysteine-enriched mutant of this medically-relevant receptor.

Photoswitchable Probes of Oxytocin and Vasopressin.

Oxytocin (OT) and vasopressin (VP) are related neuropeptides that regulate many biological processes. In humans, OT and VP act via four G protein-coupled receptors, OTR, V1aR, V1bR, and V2R (VPRs), which are associated with several disorders. To investigate the therapeutic potential of these receptors, particularly in the receptor-dense areas of the brain, molecular probes with a high temporal and spatial resolution are required. Such a spatiotemporal resolution can be achieved by incorporating photochromic moieties into OT and VP. Here, we report the design, synthesis, and (photo)pharmacological characterization of 12 OT- and VP-derived photoprobes using different modification strategies. Despite OT's and VP's sensitivity toward structural changes, we identified two photoprobes with good potency and photoswitch window for investigating the OTR and V1bR. These photoprobes should be of high value for producing cutting-edge photocontrollable peptide probes for the study of dynamic and kinetic receptor activation processes in specific regions of the brain.

Photogenerated donor-donor diazo compounds enable facile access to spirocyclopropanes.

Prompted by the increasing interest in strained hydrocarbons as potential drug candidates, we developed a simple and efficient photochemical protocol for (spiro)cyclopropanes from bench stable tosylhydrazones and electron poor olefins. This two-step one-pot transformation proceeds by (3+2)-cycloaddition of in situ formed donor-donor diazo compounds, followed by nitrogen extrusion of the Δ1-pyrazoline intermediates. Notably, kinetic analysis enabled the isolation of intermediary spiro-heterocycles.

Light-Controlled Biocatalysis by Unspecific Peroxygenases with Genetically Encoded Photosensitizers.

Fungal unspecific peroxygenases (UPOs) have gained substantial attention for their versatile oxyfunctionalization chemistry paired with impressive catalytic capabilities. A major drawback, however, remains their sensitivity towards their co-substrate hydrogen peroxide, necessitating the use of smart in situ hydrogen peroxide generation methods to enable efficient catalysis setups. Herein, we introduce flavin-containing protein photosensitizers as a new general tool for light-controlled in situ hydrogen peroxide production. By genetically fusing flavin binding fluorescent proteins and UPOs, we have created two virtually self-sufficient photo-enzymes (PhotUPO). Subsequent testing of a versatile substrate panel with the two divergent PhotUPOs revealed two stereoselective conversions. The catalytic performance of the fusion protein was optimized through enzyme and substrate loading variation, enabling up to 24300 turnover numbers (TONs) for the sulfoxidation of methyl phenyl sulfide. The PhotUPO concept was upscaled to a 100 mg substrate preparative scale, enabling the extraction of enantiomerically pure alcohol products.

Decarbonylation of benzaldehydes by dual photoorgano-cobalt catalysis.

We report a mild alternative to thermally-driven noble-metal catalyzed decarbonylation protocols for the defunctionalization of benzaldehydes in short reaction times. Our cooperative photocatalytic system involves thioxanthone as an inexpensive HAT-agent and a cobalt complex required for selective C(sp2)-C(sp2) bond cleavage. The generated acyl and phenyl intermediates are postulated to be stabilized as cobalt complexes.

General cross-coupling reactions with adaptive dynamic homogeneous catalysis.

Cross-coupling reactions are among the most important transformations in modern organic synthesis1-3. Although the range of reported (het)aryl halides and nucleophile coupling partners is very large considering various protocols, the reaction conditions vary considerably between compound classes, necessitating renewed case-by-case optimization of the reaction conditions4. Here we introduce adaptive dynamic homogeneous catalysis (AD-HoC) with nickel under visible-light-driven redox reaction conditions for general C(sp2)-(hetero)atom coupling reactions. The self-adjustive nature of the catalytic system allowed the simple classification of dozens of various classes of nucleophiles in cross-coupling reactions. This is synthetically demonstrated in nine different bond-forming reactions (in this case, C(sp2)-S, Se, N, P, B, O, C(sp3, sp2, sp), Si, Cl) with hundreds of synthetic examples under predictable reaction conditions. The catalytic reaction centre(s) and conditions differ from one another by the added nucleophile, or if required, a commercially available inexpensive amine base.

Riboflavin Photocatalyzed Dearomative Spiro-Etherification of Naphthols.

The dearomative spiro-etherification of naphthols is achieved using catalytic amounts of riboflavin tetracetate (RFTA) as a photosensitizer and molecular oxygen as a terminal oxidizing agent under blue light (440 nm) irradiation in the presence of acid. The presence of acid increases the photooxidation power of RFTA and facilitates the dearomatization reaction.

Hybrid Catalysts for Enantioselective Photo-Phosphoric Acid Catalysis.

The syntheses of two novel, organic, and chiral photocatalysts are presented. By combining donor-acceptor cyanoarene-based photocatalysts with a chiral phosphoric acid, bifunctional catalysts have been designed. In preliminary proof-of-concept reactions, their use in both enantioselective energy transfer and photoredox catalysis is demonstrated.

Monitoring the Reversibility of GPCR Signaling by Combining Photochromic Ligands with Label-free Impedance Analysis.

G protein-coupled cell surface receptors (GPCR) trigger complex intracellular signaling cascades upon agonist binding. Classic pharmacological assays provide information about binding affinities, activation or blockade at different stages of the signaling cascade, but real time dynamics and reversibility of these processes remain often disguised. We show that combining photochromic NPY receptor ligands, which can be toggled in their receptor activation ability by irradiation with light of different wavelengths, with whole cell label-free impedance assays allows observing the cell response to receptor activation and its reversibility over time. The concept demonstrated on NPY receptors may be well applicable to many other GPCRs providing a deeper insight into the time course of intracellular signaling processes.

Novel green production of natural-like vanilla extract from curcuminoids.

The demand for natural vanilla extract, and vanillin in particular, by far exceeds the current production, as both the cultivation of vanilla beans and the extraction of vanillin are laborious. For this purpose, most vanillin used today is produced synthetically, contrary to the general trend toward bio-based products. The present study deals with the synthesis of nature-based vanillin, starting with the more accessible rhizomes of the plant Curcuma longa. Besides vanillin, vanillic acid and p-hydroxybenzaldehyde are synthesized that way, which are also found in the natural vanilla bean. The extraction of the curcuminoids and, finally, their conversion to the flavors are performed using visible light and food-grade chemicals only. A binary mixture of ethanol and triacetin, as well as a surfactant-free microemulsion consisting of water, ethanol, and triacetin, are investigated in this context. The results exceed the literature values for Soxhlet extraction of vanilla beans by a factor > 7.

Enforced Electronic-Donor-Acceptor Complex Formation in Water for Photochemical Cross-Coupling.

The amino alcohol meglumine solubilizes organic compounds in water and enforces the formation of electron donor acceptor (EDA) complexes of haloarenes with indoles, anilines, anisoles or thiols, which are not observed in organic solvents. UV-A photoinduced electron transfer within the EDA complexes induces the mesolytic cleavage of the halide ion and radical recombination of the arenes leading, after rearomatization and proton loss to C-C or C-S coupling products. Depending on the substitution pattern selective and unique cross-couplings are observed. UV and NMR measurements reveal the importance of the assembly for the photoinduced reaction. Enforced EDA aggregate formation in water allows new activation modes for organic photochemical synthesis.

A dinuclear copper(II) complex with photoswitchable catechol oxidation activity.

In this study, we report the first example of a photoswitchable copper complex with catechol oxidase activity. The distance between the two copper centres is optimal for catalytic catechol oxidation in the Z-configuration. Thus, the activity of the catalyst is increased compared to its E-configuration.

Divergent Functionalization of Styrenes via Radical/Polar Crossover with CO2 and Sodium Sulfinates.

Sulfones and carboxylic acids are prominent motifs widely present in the chemical structure of agrochemicals, pharmaceuticals and many other highly valuable compounds. Herein, we describe a conjunctive strategy for the precise installation of these functionalities onto styrenes using sodium sulfinates and CO2 as coupling partners. The protocol allowed the preparation of carboxy-sulfonylated compounds in good yields and broad functional group tolerance. Additionally, taking advantage of the leaving group ability of the sulfone moiety, a one-pot photocatalytic carboxy-sulfonylation-elimination strategy was developed for the synthesis of α-aryl-acrylates.

Tuning the Photocatalytic Performance of Ruthenium(II) Polypyridine Complexes Via Ligand Modification for Visible-Light-Induced Phosphorylation of Tertiary Aliphatic Amines.

Tuning the redox potential of commonly available photocatalyst to improve the catalytic performance or expand its scope for challenging synthetic conversions is an ongoing demand in synthetic chemistry. Herein, the excited state properties and redox potential of commercially available [Ru(bpy)3 ]2+ photocatalyst were tuned by modifying the structure of the bipyridine ligands with electron-donating/withdrawing units. The visible-light-mediated photoredox phosphorylation of tertiary aliphatic amines was demonstrated under mild conditions. A series of cross-dehydrogenative coupling reactions were performed employing the RuII complexes as photocatalyst giving the corresponding α-aminophosphinoxides and α-aminophosphonates via carbon-phosphorus (C-P) bond formation.