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2,5-Bis(tert-butyldimethylsilyloxy)thiophenes are introduced as bench-stable Diels-Alder dienes for reaction with arynes as dienophiles. Ring-opening of the cycloadducts can be achieved via TBAF-promoted desilylation, providing convergent redox-neutral access to a library of substituted naphthoquinones. Strategically, this two-step sequence represents the application of stable vicinal bisketene equivalents as Diels-Alder dienes. Extension to anthraquinone is also demonstrated, in this case via mild autoxidation of a readily accessible cyclohexenyl-fused derivative.

We herein report the use of ethyl but-3-ynoate as a C2 building block for asymmetric (4+2)-heterocycloadditions with various Michael acceptors. Upon using chiral isochalcogenoureas as Lewis base catalysts, these reactions can be carried out with good to excellent control of the regioselectivity, diastereoselectivity, and enantioselectivity.

Cross-coupling and nucleophilic aromatic substitution reactions of 2,4-dihalopyrimidines generally favor reaction at the C4 site, especially in the absence of other substituents on the pyrimidine ring. Here we review our recent discovery of reaction conditions that enable C2-selective Pd-catalyzed C-S coupling of unsubstituted 2,4-dichloropyrimidines, as well as some substituted derivatives. The unusual C2-selectivity complements previously established cross-coupling methods and raises interesting mechanistic questions about oxidative addition in cross-coupling catalytic cycles.

Activity-based protein profiling (ABPP) technology has served as a powerful platform for studying proteins for more than two decades. However, the further growth of this field depends on the development of new probe structures to expand the proportion of the proteome that can be studied using these methods. Inspired by previous reports of succinimide-containing covalent inhibitors for proteases, we synthesized a panel of potential probe structures with a succinimide reactive group and a terminal alkyne tag suitable for subsequent azide-alkyne click chemistry. Members of this panel with an N-arylsulfonyl linker produce labeling of both purified serine proteases as well as proteins in complex cellular lysates. We found that one of these probes labels the human rhomboid protease RHBDL2 at low micromolar concentrations and can be competed with active-site inhibitors. Our studies establish succinimide as a new reactive group for the development of activity-based probes and offer a new chemical tool for studying a class of enzymes with limited functional characterization.

Bioreversible protein esterification is a simple, customizable, and traceless strategy for the exogenous delivery of proteins into mammalian cells. Enabling this protein delivery strategy are α-aryl-α-diazoamides bearing a tolyl moiety. The aqueous solubility of the ensuing esterified protein is, however, often compromised, which can result in the loss of soluble esterified protein for downstream applications. Here, we undertook a structure-activity relationship campaign to generate hydrophilic diazoamides for use as protein esterification and cellular delivery agents. We find that the careful adjustment of the hydrogen-bond basicity of α-aryl-α-diazoamides is sufficient to engender soluble esterified proteins, as high hydrogen-bond basicity correlates with high aqueous solubility. Importantly, enhancing aqueous solubility of diazoamides should proceed pari passu with preserving their lipophilicity and reactivity towards esterification of carboxylic acids, as the best-performing diazoamide from our study contains an N-acetyl piperazine while retaining the tolyl moiety. Our efforts can inspire new generations of esterified proteins with better solubility.

The sodium activated potassium channel known as SLACK (K_Na1.1 or Slo2.2) is widely expressed in the central nervous system and represents a potential target for the treatment of several neurological disorders. While much recent progress has been made toward the discovery of small molecule inhibitors of these channels, reports regarding small molecule activators have been scant. Having identified such compounds via a high-throughput screen, we were interested in establishing structure-activity relationships that could serve as the foundation for the design of potent activators of SLACK channels. In this Letter, we describe the implementation of an efficient synthetic approach to the regioselective synthesis of a series of benzimidazole and azabenzimidazoles based on one of our hit compounds. The key step utilizes a one-pot reduction/formylation/condensation reaction of 2-nitro-arylamines. Also presented herein is functional activity for 15 new analogs prepared by this approach and obtained via a thallium-flux assay in cells stably expressing human wild-type SLACK channels. Many of these new analogs demonstrated substantially improved potency relative to the initial hit compound and provide valuable new data that can be utilized in the design of additional derivatives.

This account highlights an iron-catalyzed exclusively 1,2-cis-selective glycosylation method for aminoglycoside synthesis. This selective nitrogen atom transfer reaction is effective for a broad range of glycosyl donors and acceptors, and it can be operated in a reiterative fashion and scaled up to the multi-gram scale. Mechanistic studies revealed a unique yet generally applicable glycosylation mechanism in which the iron catalyst activates a glycosyl acceptor and an oxidant when it facilitates the cooperative atom transfer of both moieties to a glycosyl donor in an exclusively cis-selective manner.

The addition of alkyllithium reagents to heterocyclic aldimines is described. This method is a straightforward two-step procedure from the starting aldehyde and amine with one purification. The ability to use unprotected indole carboxaldehydes as substrates is a key feature of this method that make it an attractive way to synthesize the corresponding amine products.

Due to the relative instability and low electrophilicity of enolizable alicyclic imines, their functionalization commonly requires cryogenic temperatures and highly reactive nucleophiles such as organolithium compounds. Stable BF₃ adducts of these imines streamline the synthesis of functionalized amines and obviate the need for cryogenic temperatures. In favorable cases, these adducts can be stored for over a year. The compatibility of cyclic imine-BF₃ complexes with organometallic and radical-centered nucleophiles makes them ideal building blocks for functionalized azacycles.

Protein macrocyclization is a pivotal process in the stabilization of protein structures, significantly enhancing their proteolytic stability and thermostability. While nature elegantly accomplishes this through a diverse family of ligases, laboratory methods typically rely on recombinant proteins engineered with unnatural amino acids and cysteine crosslinkers. Herein, we present a biological metabolite 4-hydroxynonenal (4-HNE) to selectively modify nucleophilic amino acids, cysteine (Cys), histidine (His), and lysine (Lys) into electrophilic hemiacetals followed by cyclization via oxime chemistry. This reaction demonstrates a broad substrate scope, enabling the modification and cyclization of proteins with a wide range of three-dimensional structures and molecular weights, from 8 to 60 kilodaltons. The resulting cyclized proteins exhibit greater proteolytic stability and enhanced thermal stability at elevated temperatures compared to their uncyclized counterparts. This clearly underscores the critical role of cyclization in preserving the intricate 3D structures of proteins and opens new avenues for advanced protein engineering.