Nickel-Catalyzed Antibody Bioconjugation.

New biocompatible methods for post-translational protein modification are challenging to develop but crucial to create improved chemical probes and optimize next-generation biologic therapies such as antibody-drug conjugates (ADCs). Herein, we describe the bottom-up construction of an aqueous nickel-catalyzed cross-coupling for the chemospecific arylation of cysteine residues on peptides and proteins and its use for the preparation of ADCs. A variety of arene linkages are exemplified, enabling the incorporation of small molecules, probes, and cytotoxic payloads. The utility of this new bioconjugation platform in a drug discovery setting is highlighted by the construction of novel ADCs with target-mediated in vitro cytotoxic activity.

A General One-Pot Protocol for Hindered N-Alkyl Azaheterocycles from Tertiary Carboxylic Acids.

In this letter, we report a general one-pot strategy that utilizes three elementary steps (decarboxylative hydrazination, Boc deprotection, and heterocycle condensation) to regioselectively prepare hindered C(sp3) substituted pyrazoles and triazoles. The operational simplicity of this sequence and ubiquity of tertiary carboxylic acids allow rapid access to hindered N-alkyl azaheterocycles that will be useful to practitioners of medicinal chemistry and agro-chemistry.

Open-Air Alkylation Reactions in Photoredox-Catalyzed DNA-Encoded Library Synthesis.

DNA-encoded library (DEL) technology is a powerful tool commonly used by the pharmaceutical industry for the identification of compounds with affinity to biomolecular targets. Success in this endeavor lies in sampling diverse chemical libraries. However, current DELs tend to be deficient in C(sp3) carbon counts. We report unique solutions to the challenge of increasing both the chemical diversity of these libraries and their C(sp3) carbon counts by merging Ni/photoredox dual catalytic C(sp2)-C(sp3) cross-coupling as well as photoredox-catalyzed radical/polar crossover alkylation protocols with DELs. The successful integration of multiple classes of radical sources enables the rapid incorporation of a diverse set of alkyl fragments.

Photoinduced Kochi Decarboxylative Elimination for the Synthesis of Enamides and Enecarbamates from N-Acyl Amino Acids.

Decarboxylative elimination of easily accessible N-acyl amino acids to provide enamide and enecarbamate building blocks has been realized through the combination of an organophotoredox catalyst and copper acetate as the terminal oxidant. This operationally simple process utilizes inexpensive and readily available reagents without preactivation of the carboxylic acid. Enamides and enecarbamates are now accessible directly from N-acyl amino acids consequently improving upon the utility of Kochi's oxidative decarboxylation of carboxylic acids.

Correction: Rapid access to diverse, trifluoromethyl-substituted alkenes using complementary strategies.

[This corrects the article DOI: 10.1039/C7SC05420C.].

Redox-Neutral Photocatalytic Cyclopropanation via Radical/Polar Crossover.

A benchtop stable, bifunctional reagent for the redox-neutral cyclopropanation of olefins has been developed. Triethylammonium bis(catecholato)iodomethylsilicate can be readily prepared on multigram scale. Using this reagent in combination with an organic photocatalyst and visible light, cyclopropanation of an array of olefins, including trifluoromethyl- and pinacolatoboryl-substituted alkenes, can be accomplished in a matter of hours. The reaction is highly tolerant of traditionally reactive functional groups (carboxylic acids, basic heterocycles, alkyl halides, etc.) and permits the chemoselective cyclopropanation of polyolefinated compounds. Mechanistic interrogation revealed that the reaction proceeds via a rapid anionic 3- exo- tet ring closure, a pathway consistent with experimental and computational data.

Engaging sulfinate salts via Ni/photoredox dual catalysis enables facile Csp2 -SO2R coupling.

This report details the development and implementation of a strategy to construct aryl- and heteroaryl sulfones via Ni/photoredox dual catalysis. Using aryl sulfinate salts, the C-S bond can be forged at room temperature under base-free conditions. An array of aryl- and heteroaryl halides are compatible with this approach. The broad tolerance and mild nature of the described reaction could potentially be employed to prepare sulfones with biological relevance (e.g., in bioconjugation, drug substance synthesis, etc.) as demonstrated in the synthesis of drug-like compounds or their precursors. When paired with existing Ni/photoredox chemistry for Csp3 -Csp2 cross-coupling, an array of diverse sulfone scaffolds can be readily assembled from bifunctional electrophiles. A mechanistic manifold consistent with experimental and computational data is presented.

Rapid access to diverse, trifluoromethyl-substituted alkenes using complementary strategies.

Two synergistic approaches to the facile assembly of complex α-trifluoromethyl alkenes are described. Using α-trifluoromethyl-ß-silyl alcohols as masked trifluoromethyl alkenes, cross-coupling or related functionalization processes at distal electrophilic sites can be executed without inducing Peterson elimination. Subsequent Lewis acidic activation affords functionalized α-trifluoromethyl alkenes. Likewise, the development of a novel α-trifluoromethylvinyl trifluoroborate reagent complements this approach and allows a one-step cross-coupling of (hetero)aryl halides to access a broad array of complex α-trifluoromethyl alkenes.

Photoredox Generation of Carbon-Centered Radicals Enables the Construction of 1,1-Difluoroalkene Carbonyl Mimics.

Described is a facile, scalable route to access functional-group-rich gem-difluoroalkenes. Using visible-light-activated catalysts in conjunction with an arsenal of carbon-radical precursors, an array of trifluoromethyl-substituted alkenes undergoes radical defluorinative alkylation. Nonstabilized primary, secondary, and tertiary radicals can be used to install functional groups in a convergent manner, which would otherwise be challenging by two-electron pathways. The process readily extends to other perfluoroalkyl-substituted alkenes. In addition, we report the development of an organotrifluoroborate reagent to expedite the synthesis of the requisite trifluoromethyl-substituted alkene starting materials.

Photoredox-Mediated Routes to Radicals: The Value of Catalytic Radical Generation in Synthetic Methods Development.

Photoredox catalysis has experienced a revitalized interest from the synthesis community during the past decade. For example, photoredox/Ni dual catalysis protocols have been developed to overcome several inherent limitations of palladium-catalyzed cross-couplings by invoking a single-electron transmetalation pathway. This Perspective highlights advances made by our laboratory since the inception of the photoredox/Ni cross-coupling of benzyltrifluoroborates with aryl bromides. In addition to broadening the scope of trifluoroborate coupling partners, research using readily oxidized hypervalent silicates as radical precursors that demonstrate functional group compatibility is highlighted. The pursuit of electrophilic coupling partners beyond (hetero)aryl bromides has also led to the incorporation of several new classes of C(sp2)-hybridized substrates into light-mediated cross-coupling. Advances to expand the radical toolbox by utilizing feedstock chemicals (e.g., aldehydes) to access radicals that were previously inaccessible from trifluoroborates and silicates are also emphasized. Additionally, several organic photocatalysts have been investigated as replacements for their expensive iridium- and ruthenium-based counterparts. Lastly, the net C-H functionalization of the radical partner in an effort to improve atom economy is presented. An underlying theme in all of these studies is the value of generating radicals in a catalytic manner, rather than stoichiometrically.

Photocatalytic Aminodecarboxylation of Carboxylic Acids.

Aminodecarboxylation of unactivated alkyl carboxylic acids has been accomplished utilizing an organic photocatalyst. This operationally simple reaction utilizes readily available carboxylic acids to chemoselectively generate reactive alkyl intermediates that are not accessible via conventional two-electron pathways. The organic radical intermediates are efficiently trapped with electrophilic diazo compounds to provide aminated alkanes.

Dual Catalytic Decarboxylative Allylations of α-Amino Acids and Their Divergent Mechanisms.

The room temperature radical decarboxylative allylation of N-protected α-amino acids and esters has been accomplished via a combination of palladium and photoredox catalysis to provide homoallylic amines. Mechanistic investigations revealed that the stability of the α-amino radical, which is formed by decarboxylation, dictates the predominant reaction pathway between competing mechanisms.

Decarboxylative allylation of amino alkanoic acids and esters via dual catalysis.

A combination of photoredox and palladium catalysis has been employed to facilitate the room temperature decarboxylative allylation of recalcitrant α-amino and phenylacetic allyl esters. This operationally simple process produces CO2 as the only byproduct and provides direct access to allylated alkanes. After photochemical oxidation, the carboxylate undergoes radical decarboxylation to site-specifically generate radical intermediates which undergo allylation. A radical dual catalysis mechanism is proposed. Free phenylacetic acids were also allylated utilizing similar reactions conditions.

Activation of alcohols with carbon dioxide: intermolecular allylation of weakly acidic pronucleophiles.

The direct coupling of allyl alcohols with nitroalkanes, nitriles, and aldehydes using catalytic Pd(PPh3)4 has been accomplished via activation of C-OH bonds with CO2. The in situ formation of carbonates from alcohols and CO2 facilitates oxidative addition to Pd to form reactive π-allylpalladium intermediates. In addition, the formation of a strong base activates nucleophiles toward the reaction with the π-allylpalladium electrophile. Overall, this atom economical reaction provides a new C-C bond without the use of an external base and generates water as the only byproduct.

Crystal structure of (1S,2R,6R,7R,8S,12S)-4,10,17-triphenyl-15-thia-4,10-diaza-penta-cyclo[5.5.5.0(1,16).0(2,6).0(8,12)]hepta-deca-13,16-diene-3,5,9,11-tetrone p-xylene hemisolvate.

The title tetrone compound, C32H22N2O4S· 0.5C8H10, is the major product (50% yield) of an attempted Diels-Alder reaction of 2-(α-styr-yl)thio-phene with N-phenyl-male-imide (2 equivalents) in toluene. Recrystallization of the resulting powder from p-xylene gave the title hemisolvate; the p-xylene mol-ecule is located about an inversion center. In the crystal, the primary tetrone contacts are between a carbonyl O atom and the four flagpole H atoms of the bi-cyclo-[2.2.2]octene core, forming chains along [001].

Development of asymmetric deacylative allylation.

Herein we present the development of asymmetric deacylative allylation of ketone enolates. The reaction directly couples readily available ketone pronucleophiles with allylic alcohols using facile retro-Claisen cleavage to form reactive intermediates in situ. The simplicity and robustness of the reaction conditions is demonstrated by the preparation of >6 g of an allylated tetralone from commercially available materials. Furthermore, use of nonracemic PHOX ligands allows intermolecular formation of quaternary stereocenters directly from allylic alcohols.