Many disease pathologies can be understood through the elucidation of localized biomolecular networks, or microenvironments. To this end, enzymatic proximity labeling platforms are broadly applied for mapping the wider spatial relationships in subcellular architectures. However, technologies that can map microenvironments with higher precision have long been sought. Here, we describe a microenvironment-mapping platform that exploits photocatalytic carbene generation to selectively identify protein-protein interactions on cell membranes, an approach we term MicroMap (μMap). By using a photocatalyst-antibody conjugate to spatially localize carbene generation, we demonstrate selective labeling of antibody binding targets and their microenvironment protein neighbors. This technique identified the constituent proteins of the programmed-death ligand 1 (PD-L1) microenvironment in live lymphocytes and selectively labeled within an immunosynaptic junction.

Decarboxylative cross-coupling of alkyl carboxylic acids with vinyl halides has been accomplished through the synergistic merger of photoredox and nickel catalysis. This new methodology has been successfully applied to a variety of α-oxy and α-amino acids, as well as simple hydrocarbon-substituted acids. Diverse vinyl iodides and bromides give rise to vinylation products in high efficiency under mild, operationally simple reaction conditions.

Multicomponent reactions (MCRs) have become a mainstay in both academic and industrial synthetic organic chemistry due to their step- and atom-economy advantages over traditional synthetic sequences 1 . Recently, bicyclo[1.1.1]pentane (BCP) motifs have come to the fore as valuable pharmaceutical bioisosteres of benzene rings, and, in particular, 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para -phenyl ring replacements 2 . Often these structures are generated from [1.1.1]propellane via opening of the internal C─C bond, either through the addition of radicals or metal-based nucleophiles 3 - 13 . The resulting propellane-addition adducts are subsequently transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. While this approach has been effective to date, it is clear that a multicomponent reaction that enables single-step access to complex and diverse polysubstituted BCP products would be synthetically advantageous over the current stepwise approaches. Herein we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicycles using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. The reaction operates on short time scales (five minutes to one hour) across multiple (>10) nucleophile classes and can accommodate a diverse array of radical precursors, including those which generate alkyl, α-acyl, trifluoromethyl, and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which has substantially different pharmacokinetic properties to those of its commercial progenitor.

Herein we report a highly efficient method for nickel-catalyzed C–N bond formation between sulfonamides and aryl electrophiles. This technology provides generic access to a broad range of N-aryl and N-heteroaryl sulfonamide motifs, which are widely represented in drug discovery. Initial mechanistic studies suggest an energy-transfer mechanism wherein C–N bond reductive elimination occurs from a triplet excited NiII complex. Late-stage sulfonamidation in the synthesis of a pharmacologically relevant structure is also demonstrated.

A method for the decarboxylative macrocyclization of peptides bearing N-terminal Michael acceptors has been developed. This synthetic protocol enables the efficient synthesis of γ-amino acid-containing cyclic peptides and is tolerant of functionality present in both natural and non-proteinogenic amino acids. Linear precursors ranging from 3 to 15 amino acids cyclize effectively under this photoredox protocol. To demonstrate the preparative utility of this method in the context of bioactive molecules, we have generated COR-005, a somatostatin analog currently in clinical trials.

An advanced intermediate in a projected synthesis of pactamycin has been prepared. Early installation of the C1-dimethylurea functionality allows for its participation in a diastereoselective, chelation-controlled addition of organometal nucleophiles to the C5 prochiral ketone. Four of the molecule’s six stereocenters are set with a ketone functional handle provided for subsequent manipulation.

Amethod for the decarboxylative macrocyclization of peptides bearing N-terminal Michael acceptors has been developed. This synthetic method enables the efficient synthesis of cyclic peptides containing g-amino acids and is tolerant of functionalities present in both natural and non-proteinogenic amino acids.L inear precursors ranging from 3t o1 5a mino acids cyclize effectively under this photoredoxm ethod. To demonstrate the preparative utility of this method in the context of bioactive molecules,wesynthesized COR-005, asomatostatin analogue that is currently in clinical trials.Cyclic peptides have recently received significant attention from ab road range of scientists in both academic and pharmaceutical settings. [1] At the heart of this focus is the remarkable finding that this class of peptide structure delivers unprecedented and selective therapeutic benefit for al arge range of disease areas that include oncology,a lgiatry,a nd neurology.While many naturally occurring macrocycles have found medicinal applications over the last century,the use of non-natural cyclic peptides has become prominent due mainly to the advent of synthetic biology techniques that allow large numbers of these macrocyclic rings to be rapidly assembled and tested on micro scale. [2]

Herein we report a highly efficient method for nickel-catalyzed C-N bond formation between sulfonamides and aryl electrophiles. This technology provides generic access to a broad range of N-aryl and N-heteroaryl sulfonamide motifs, which are widely represented in drug discovery. Initial mechanistic studies suggest an energy-transfer mechanism wherein C-N bond reductive elimination occurs from a triplet excited Ni II complex. Late-stage sulfonamidation in the synthesis of a pharmacologically relevant structure is also demonstrated.