Regioselective aliphatic C-H functionalization using frustrated radical pairs.

Frustrated Lewis pairs (FLPs) are well documented for the activation of small molecules such as dihydrogen and carbon dioxide1-4. Although canonical FLP chemistry is heterolytic in nature, recent work has shown that certain FLPs can undergo single-electron transfer to afford radical pairs5. Owing to steric encumbrance and/or weak bonding association, these radicals do not annihilate one another, and they have thus been named frustrated radical pairs (FRPs). Notable preliminary results suggest that FRPs may be useful reagents in chemical synthesis6-8, although their applications remain limited. Here we demonstrate that the functionalization of C(sp3)-H bonds can be accomplished using a class of FRPs generated from disilazide donors and an N-oxoammonium acceptor. Together, these species undergo single-electron transfer to generate a transient and persistent radical pair capable of cleaving unactivated C-H bonds to furnish aminoxylated products. By tuning the structure of the donor, it is possible to control regioselectivity and tailor reactivity towards tertiary, secondary or primary C-H bonds. Mechanistic studies lend strong support for the formation and involvement of radical pairs in the target reaction.

Exploring Electrochemical C(sp3)-H Oxidation for the Late-Stage Methylation of Complex Molecules.

The "magic methyl" effect, a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group, provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp3)-H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C-C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the "magic methyl" effect. This synthesis strategy thus circumvents multistep de novo synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.

Switching on elusive organometallic mechanisms with photoredox catalysis.

Transition-metal-catalysed cross-coupling reactions have become one of the most used carbon-carbon and carbon-heteroatom bond-forming reactions in chemical synthesis. Recently, nickel catalysis has been shown to participate in a wide variety of C-C bond-forming reactions, most notably Negishi, Suzuki-Miyaura, Stille, Kumada and Hiyama couplings. Despite the tremendous advances in C-C fragment couplings, the ability to forge C-O bonds in a general fashion via nickel catalysis has been largely unsuccessful. The challenge for nickel-mediated alcohol couplings has been the mechanistic requirement for the critical C-O bond-forming step (formally known as the reductive elimination step) to occur via a Ni(III) alkoxide intermediate. Here we demonstrate that visible-light-excited photoredox catalysts can modulate the preferred oxidation states of nickel alkoxides in an operative catalytic cycle, thereby providing transient access to Ni(III) species that readily participate in reductive elimination. Using this synergistic merger of photoredox and nickel catalysis, we have developed a highly efficient and general carbon-oxygen coupling reaction using abundant alcohols and aryl bromides. More notably, we have developed a general strategy to 'switch on' important yet elusive organometallic mechanisms via oxidation state modulations using only weak light and single-electron-transfer catalysts.

Direct ß-alkylation of aldehydes via photoredox organocatalysis.

Direct ß-alkylation of saturated aldehydes has been accomplished by synergistically combining photoredox catalysis and organocatalysis. Photon-induced enamine oxidation provides an activated ß-enaminyl radical intermediate, which readily combines with a wide range of Michael acceptors to produce ß-alkyl aldehydes in a highly efficient manner. Furthermore, this redox-neutral, atom-economical C-H functionalization protocol can be achieved both inter- and intramolecularly. Mechanistic studies by various spectroscopic methods suggest that a reductive quenching pathway is operable.

Discovery of TRPA1 Antagonist GDC-6599: Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease.

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as a polymodal sensor for exogenous and endogenous stimuli, and has been implicated in neuropathic pain and respiratory disease. Herein, we describe the optimization of potent, selective, and orally bioavailable TRPA1 small molecule antagonists with strong in vivo target engagement in rodent models. Several lead molecules in preclinical single- and short-term repeat-dose toxicity studies exhibited profound prolongation of coagulation parameters. Based on a thorough investigative toxicology and clinical pathology analysis, anticoagulation effects in vivo are hypothesized to be manifested by a metabolite─generated by aldehyde oxidase (AO)─possessing a similar pharmacophore to known anticoagulants (i.e., coumarins, indandiones). Further optimization to block AO-mediated metabolism yielded compounds that ameliorated coagulation effects in vivo, resulting in the discovery and advancement of clinical candidate GDC-6599, currently in Phase II clinical trials for respiratory indications.

The Direct Decarboxylative N-Alkylation of Azoles, Sulfonamides, Ureas, and Carbamates with Carboxylic Acids via Photoredox Catalysis.

Herein, we describe a method for the direct decarboxylative C-N coupling of carboxylic acids with a range of nitrogen nucleophiles. This platform employs visible-light-mediated photoredox catalysis and an iodine(III) reagent to generate carbocation intermediates directly from aliphatic carboxylic acids via a radical-polar crossover mechanism. A variety of C-N bond-containing products are constructed from a diverse array of nitrogen heterocycles, including pyrazoles, imidazoles, indazoles, and purine bases. Furthermore, sulfonamides, ureas, and carbamates can also be utilized as the nucleophile to generate a selection of N-alkylated products. Notably, a two-step approach to construct free amines directly from carboxylic acids is accomplished using Cbz-protected amine as the nucleophile.

A Retrospective Look at the Impact of Binding Site Environment on the Optimization of TRPA1 Antagonists.

Transient receptor potential ankyrin 1 (TRPA1) antagonists have generated broad interest in the pharmaceutical industry for the treatment of both pain and asthma. Over the past decade, multiple antagonist classes have been reported in the literature with a wide range of structural diversity. Our own work has focused on the development of proline sulfonamide and hypoxanthine-based antagonists, two antagonist classes with distinct physicochemical properties and pharmacokinetic (PK) trends. Late in our discovery program, cryogenic electron microscopy (cryoEM) studies revealed two different antagonist binding sites: a membrane-exposed proline sulfonamide transmembrane site and an intracellular hypoxanthine site near the membrane interface. A retrospective look at the discovery program reveals how the different binding sites, and their location relative to the cell membrane, influenced the optimization trajectories and overall drug profiles of each antagonist class.

Tetrahydrofuran-Based Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists: Ligand-Based Discovery, Activity in a Rodent Asthma Model, and Mechanism-of-Action via Cryogenic Electron Microscopy.

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as a polymodal sensor for exogenous and endogenous stimuli and has generated widespread interest as a target for inhibition due to its implication in neuropathic pain and respiratory disease. Herein, we describe the optimization of a series of potent, selective, and orally bioavailable TRPA1 small molecule antagonists, leading to the discovery of a novel tetrahydrofuran-based linker. Given the balance of physicochemical properties and strong in vivo target engagement in a rat AITC-induced pain assay, compound 20 was progressed into a guinea pig ovalbumin asthma model where it exhibited significant dose-dependent reduction of inflammatory response. Furthermore, the structure of the TRPA1 channel bound to compound 21 was determined via cryogenic electron microscopy to a resolution of 3 Å, revealing the binding site and mechanism of action for this class of antagonists.

Transient receptor potential ankyrin 1 (TRPA1) antagonists: a patent review (2015-2019).

INTRODUCTION: TRPA1 is a non-selective cation channel predominantly expressed in sensory neurons, and functions as an irritant sensor for a plethora of noxious external stimuli and endogenous ligands. Due to its involvement in pain, itch, and respiratory syndromes, TRPA1 has been pursued as a promising drug target. AREAS COVERED: In this review, the small molecule patent literature of TRPA1 antagonists from 2015-2019 was surveyed. The patent applications are described with a focus on chemical structures, biochemical/pharmacological activities, and potential clinical applications. The development of TRPA1 antagonists in clinical trials has been highlighted. EXPERT OPINION: During 2015-2019, significant progress was made toward the discovery of new TRPA1 antagonists. A total of 14 organizations published 28 patent applications disclosing several distinct classes of chemical matter and potential uses. During this period, three new molecules entered the clinic (ODM-108, HX-100, and GDC-0334) bringing the total number of TRPA1 antagonists to reach clinical trials to five (including earlier molecules CB-625 and GRC 17536); however, to our knowledge, development of all five molecules have been discontinued. Further clinical trials of recent TRPA1 antagonists with good pharmacokinetics would be needed to help understand TRPA1 involvement in human diseases and its potential as a therapeutic target.

Visible-Light Photocatalysis as an Enabling Technology for Drug Discovery: A Paradigm Shift for Chemical Reactivity.

Visible light-mediated photocatalysis, which relies on the ability of photocatalysts to absorb low-energy visible light and engage in single-electron transfer (SET) or energy transfer (ET) processes with organic substrates, has emerged as one of the fastest growing fields in organic synthesis. This catalytic platform enables a highly selective approach to promote radical-based organic transformations which unlocks unique reaction pathways. Due to the extremely mild conditions of these transformations and compatibility in aqueous environments, photocatalysis has emerged as an enabling technology in drug discovery. Photocatalysis is uniquely positioned for application in pharmaceutical development because of its demonstrated potential for broad functional group tolerance, biocompatibility, site-specific selectivity, and operational simplicity. This review will highlight the recent advances of visible-light photocatalysis through its application in peptide functionalization, protein bioconjugation, Csp 3-Csp 2 cross-coupling, late-stage functionalization, isotopic labeling, DNA-encoded library technology (DELT), and microenvironment mapping (µMap).

Native functionality in triple catalytic cross-coupling: sp³ C-H bonds as latent nucleophiles.

The use of sp(3) C-H bonds--which are ubiquitous in organic molecules--as latent nucleophile equivalents for transition metal-catalyzed cross-coupling reactions has the potential to substantially streamline synthetic efforts in organic chemistry while bypassing substrate activation steps. Through the combination of photoredox-mediated hydrogen atom transfer (HAT) and nickel catalysis, we have developed a highly selective and general C-H arylation protocol that activates a wide array of C-H bonds as native functional handles for cross-coupling. This mild approach takes advantage of a tunable HAT catalyst that exhibits predictable reactivity patterns based on enthalpic and bond polarity considerations to selectively functionalize α-amino and α-oxy sp(3) C-H bonds in both cyclic and acyclic systems.

O-H hydrogen bonding promotes H-atom transfer from α C-H bonds for C-alkylation of alcohols.

The efficiency and selectivity of hydrogen atom transfer from organic molecules are often difficult to control in the presence of multiple potential hydrogen atom donors and acceptors. Here, we describe the mechanistic evaluation of a mode of catalytic activation that accomplishes the highly selective photoredox α-alkylation/lactonization of alcohols with methyl acrylate via a hydrogen atom transfer mechanism. Our studies indicate a particular role of tetra-n-butylammonium phosphate in enhancing the selectivity for α C-H bonds in alcohols in the presence of allylic, benzylic, α-C=O, and α-ether C-H bonds.

Dual catalysis. Merging photoredox with nickel catalysis: coupling of α-carboxyl sp³-carbons with aryl halides.

Over the past 40 years, transition metal catalysis has enabled bond formation between aryl and olefinic (sp(2)) carbons in a selective and predictable manner with high functional group tolerance. Couplings involving alkyl (sp(3)) carbons have proven more challenging. Here, we demonstrate that the synergistic combination of photoredox catalysis and nickel catalysis provides an alternative cross-coupling paradigm, in which simple and readily available organic molecules can be systematically used as coupling partners. By using this photoredox-metal catalysis approach, we have achieved a direct decarboxylative sp(3)-sp(2) cross-coupling of amino acids, as well as α-O- or phenyl-substituted carboxylic acids, with aryl halides. Moreover, this mode of catalysis can be applied to direct cross-coupling of C(sp³)-H in dimethylaniline with aryl halides via C-H functionalization.