Tunable heteroaromatic azoline thioethers (HATs) for cysteine profiling.

Here we report a new series of hydrolytically stable chemotype heteroaromatic azoline thioethers (HATs) to achieve highly selective, rapid, and efficient covalent labeling of cysteine under physiological conditions. Although the resulting cysteine-azoline conjugate is stable, we highlight traceless decoupling of the conjugate to afford unmodified starting components in response to reducing conditions. We demonstrated that HAT probes reverse the reactivity of nucleophilic cysteine to electrophilic dehydroalanine (Dha) under mild basic conditions. We demonstrated the umpolung capability of HAT probes for the modification of cysteine on peptides and proteins with various nucleophiles. We demonstrated that HAT probes increase the mass sensitivity of the modified peptides and proteins by 100 fold as compared to the classical methods. Finally, we extended the application of HAT probes for specific modification of cysteines in a complex cell lysate mixture.

Catalyst-Controlled Regioselective Chlorination of Phenols and Anilines through a Lewis Basic Selenoether Catalyst.

We report a highly efficient ortho-selective electrophilic chlorination of phenols utilizing a Lewis basic selenoether catalyst. The selenoether catalyst resulted in comparable selectivities to our previously reported bis-thiourea ortho-selective catalyst, with a catalyst loading as low as 1%. The new catalytic system also allowed us to extend this chemistry to obtain excellent ortho-selectivities for unprotected anilines. The selectivities of this reaction are up to >20:1 ortho/para, while the innate selectivities for phenols and anilines are approximately 1:4 ortho/para. A series of preliminary studies revealed that the substrates require a hydrogen-bonding moiety for selectivity.

Catalytic Atroposelective Synthesis of N-Aryl Quinoid Compounds.

Diarylamines and related scaffolds are among the most common chemotypes in modern drug discovery. While they can potentially possess two chiral axes, there are no studies on their enantioselective synthesis, as these axes typically possess lower stereochemical stabilities. Herein, we report a chiral phosphoric acid catalyzed atroposelective electrophilic halogenation of N-aryl quinoids, a class of compounds that are analogous to diarylamines. This chemistry yields a large range of stereochemically stable N-aryl quinoids in excellent yields and atroposelectivity. This work represents the first example of the atroposelective synthesis of a diarylamine-like scaffold and will serve as a gateway to fundamental and applied studies on the scarcely studied chirality of these ubiquitous chiral scaffolds.

Leveraging Atropisomerism to Obtain a Selective Inhibitor of RET Kinase with Secondary Activities toward EGFR Mutants.

Unstable atropisomerism is innate in many common scaffolds in drug discovery, commonly existing as freely rotating aryl-aryl bonds. Such compounds can access the majority of dihedral conformations around the bond axis; however, most small molecules bind their target within a narrow range of these available conformations. The remaining accessible conformations can interact with other proteins leading to compound promiscuity. Herein, we leverage atropisomerism to restrict the accessible low-energy dihedral conformations available to a promiscuous kinase inhibitor and achieve highly selective and potent inhibitors of the oncogenic target rearranged during transfection (RET) kinase. We then evaluate our lead inhibitor against kinases that were predicted to bind compounds in a similar conformational window to RET, discovering a potent inhibitor of drug-resistant epidermal growth factor receptor (EGFR) mutants including L858R/T790M/C797S EGFR. Leveraging atropisomerism to restrict accessible conformational space should be a generally applicable strategy due to the prevalence of unstable atropisomerism in drug discovery.

Opportunities and challenges for the development of covalent chemical immunomodulators.

Compounds that react irreversibly with cysteines have reemerged as potent and selective tools for altering protein function, serving as chemical probes and even clinically approved drugs. The exquisite sensitivity of human immune cell signaling pathways to oxidative stress indicates the likely, yet still underexploited, general utility of covalent probes for selective chemical immunomodulation. Here, we provide an overview of immunomodulatory cysteines, including identification of electrophilic compounds available to label these residues. We focus our discussion on three protein classes essential for cell signaling, which span the 'druggability' spectrum from amenable to chemical probes (kinases), somewhat druggable (proteases), to inaccessible (phosphatases). Using existing inhibitors as a guide, we identify general strategies to guide the development of covalent probes for selected undruggable classes of proteins and propose the application of such compounds to alter immune cell functions.

Enantioselective Synthesis of Biaryl Atropisomers via the Addition of Thiophenols into Aryl-Naphthoquinones.

We report a cinchona alkaloid catalyzed addition of thiophenol into rapidly interconverting aryl-naphthoquinones, resulting in stable biaryl atropisomers upon reductive methylation. An array of thiophenols and naphthoquinone substrates were evaluated, and we observed selectivities up to 98.5:1.5 e.r. Control of the quinone redox properties allowed us to study the stereochemical stabilities of each oxidation state of the substrates. The resulting enantioenriched products can also be moved on via an SNAr-like reaction sequence to arrive at stable derivatives with excellent enantioretention.

Towards a Catalytic Atroposelective Synthesis of Diaryl Ethers via C(sp 2)-H Alkylation Using Nitroalkanes.

Herein we report studies towards a small molecule catalytic approach to access atropisomeric diaryl ethers that proceeds via a C(sp 2)-H alkylation using nitroalkanes as the alkyl source. A quaternary ammonium salt derived from quinine containing a sterically hindered urea at the C-9 position was found to effect atroposelective C(sp 2)-H alkylation with moderate to good enantioselectivities across several naphthoquinone-containing diaryl ethers. Products can then be isolated in greater than 95:5 er after one round of trituration. For several substrates that were evaluated we observed a 'nitroethylated' product in similar yields and selectivities.

The Catalyst-Controlled Regiodivergent Chlorination of Phenols.

Different catalysts are demonstrated to overcome or augment a substrate's innate regioselectivity. Nagasawa's bis-thiourea catalyst was found to overcome the innate para-selectivity of electrophilic phenol chlorination, yielding ortho-chlorinated phenols that are not readily obtainable via canonical electrophilic chlorinations. Conversely, a phosphine sulfide derived from 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) was found to enhance the innate para-preference of phenol chlorination.

A practical Lewis base catalyzed electrophilic chlorination of arenes and heterocycles.

A mild phosphine sulfide catalyzed electrophilic halogenation of arenes and heterocycles that utilizes inexpensive and readily available N-halosuccinimides is disclosed. This methodology is shown to efficiently chlorinate diverse aromatics, including simple arenes such as anthracene, and heterocycles such as indoles, pyrrolopyrimidines, and imidazoles. Arenes with Lewis acidic moieties also proved amenable, underscoring the mild nature of this chemistry. Lewis base catalysis was also found to improve several diverse aromatic brominations and iodinations.