Here we report the conceptualization and design of a general, redox switchable organophosphorus alkyl radical trap enabling the synthesis of a broad range of C(sp3)–P(V) modalities. This plug-and-play approach relies upon an in-situ activation of alcohols and dialkyl phosphites, two broadly available sources of molecular complexity. The mild, photocatalytic deoxygenative strategy employed here allows for the direct transformation of sugars, nucleosides, and complex pharmaceutical architectures to their organophosphorus analogs, including medicinally relevant phosphonate ester prodrugs.

The kinetics of halide exchange in cyclopentadienylruthenium bis(triarylphosphine) halide complexes CpRu (PAr3)(2)X (1a X = Cl, 1b X = Br, 1c X = I; X'= Cl, Br, Ar = C6H5, 2 Ar = p-CH3OC6H4, X = Cl, X' = Br and 3 Ar = p-FC6H4, X = Cl, X' = Br) have been measured and the results interpreted with respect to two possible mechanisms: halide dissociation vs phosphine dissociation. Halide exchange between nBu4NX ' and 1-3 in fluorobenzene under pseudo-first order conditions is found to be first order in 1-3. Relative rates of halide exchange follow the order: 1a > 1b > 1c > 2 approximate to 3 with activation parameters Delta H-dagger= 117 +/- 6 kJ/mol and Delta S-dagger = 44 +/- 18 J/mol-K (1a, X' = Br) and Delta H-dagger = 120 +/- 14 kJ/mol Delta S-dagger= 50 +/- 45 J/mol-K (1b, X' = Cl). Plots of k(obs) vs [X'-] for 1 and 2 are consistent with a two-term rate law where k(obs) = (k(1) + k(2)[X'(-)]) while reactions of 3 are independent of the halide concentration. The rate data are consistent with phosphine dissociation as the rate determining step followed by a slightly faster reaction with halide ions where the dissociated phosphine competes effectively with halide for the open coordination site in a CpRu(PAr3)X intermediate.

Kinetic measurements of the reaction between CpRu(PPh3)2Cl (1a) and 1-bromobutane reveal a nearly first order dependence on the concentration of haloalkane and a negative entropy of activation, ΔS† < 0.

The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.

Modern proximity labeling techniques have enabled significant advances in understanding biomolecular interactions. However, current tools primarily utilize activation modes that are incompatible with complex biological environments, limiting our ability to interrogate cell- and tissue-level microenvironments in animal models. Here, we report μMap-Red, a proximity labeling platform that uses a red-light-excited SnIV chlorin e6 catalyst to activate a phenyl azide biotin probe. We validate μMap-Red by demonstrating photonically controlled protein labeling in vitro through several layers of tissue, and we then apply our platform in cellulo to label EGFR microenvironments and validate performance with STED microscopy and quantitative proteomics. Finally, to demonstrate labeling in a complex biological sample, we deploy μMap-Red in whole mouse blood to profile erythrocyte cell-surface proteins. This work represents a significant methodological advance toward light-based proximity labeling in complex tissue environments and animal models.

Light-powered catalysis has found broad utility as a chemical transformation strategy, with widespread impact on energy, environment, drug discovery and human health. A noteworthy application impacting human health is light-induced sensitization of cofactors for photodynamic therapy in cancer treatment. The clinical adoption of this photosensitization approach has inspired the search for other photochemical methods, such as photoredox catalysis, to influence biological discovery. Over the past decade, light-mediated catalysis has enabled the discovery of valuable synthetic transformations, propelling it to become a highly utilized chemical synthesis strategy. The reaction components required to achieve a photoredox reaction are identical to photosensitization (catalyst, light source and substrate), making it ideally suited for probing biological environments. In this Review, we discuss the therapeutic application of photosensitization and advancements made in developing next-generation catalysts. We then highlight emerging uses of photoredox catalytic methods for protein bioconjugation and probing complex cellular environments in living cells.

Here we report the direct conversion of strong, aliphatic C(sp3)-H bonds into the corresponding alkyl sulfinic acids via decatungstate photocatalysis. This transformation has been applied to a diverse range of C(sp3)-rich scaffolds, including natural products and approved pharmaceuticals, providing efficient access to complex sulfur-containing products. To demonstrate the broad potential of this methodology for the divergent synthesis of pharmaceutically relevant molecules, procedures for the diversification of the sulfinic acid products into a range of medicinally relevant functional groups have been developed.

Despite the growing utilization of visible light photochemistry in both chemistry and biology, a general low-heat photoreactor for use across these different disciplines does not exist. Herein, we describe the design and utilization of a standardized photoreactor for visible light driven activation and photocatalytic chemical transformations. Using this single benchtop photoreactor, we perform photoredox reactions across multiple visible light wavelengths, a high throughput photocatalytic cross coupling reaction, and in vitro labeling of proteins and live cells. Given the success of this reactor in all tested applications, we envision that this multi-use photoreactor will be widely used in biology, chemical biology, and medicinal chemistry settings.

This work describes an expedient access to sp3-rich nitrogen heterocycles via mild photoredox cleavage of 4-alkyl-1,4-dihydropyridines followed by cyclization of the resultant carbon-centered radicals with tethered imines.

C-H functionalization of electron-deficient heteroarenes using commercial unactivated alkyl halides through reductive quenching photoredox catalysis was developed. Mainstream approaches rely on the use of an excess of strong acids that result in regioselectivities dictated by the innate effect of the protonated heteroarene, leaving the functionalization of other carbons unexplored. We report a mild method under basic conditions that allows access to previously underexplored regioselectivities by relying on a combination of conjugate and halogen ortho-directing effects. Overall, this methodology gives quick access to a variety of alkylated heteroarenes that will be of interest to medicinal chemistry programs.