Guang-Xun Li

Poly‐substituted pyridines fused with cyclic imide represent a privileged class of core structural motifs widely found in pharmaceuticals and agrochemicals. In this study, we report a simple and practical strategy for the efficient synthesis of such compounds, achieving up to 97% yield. The reaction employs readily available starting materials derived from commercial amines. The key transformation involves a tandem process comprising selective dehydrogenative aromatization followed by amide formation via the intramolecular aminolysis of ester. This protocol is amenable to gram‐scale synthesis and enables the preparation of a range of useful derivatives. Furthermore, preliminary biological activity screening revealed micromolar‐range anticancer potency toward U937 cell line.

Sulfur(VI) fluoride exchange (SuFEx) has emerged as a powerful click chemistry platform for covalent bond formation, with broad applications in drug discovery, polymer science, and bioconjugation. Among the diverse SuFEx linkers developed in recent years, sulfonimidoyl fluorides (RN=S(O)F) have gained prominence due to their tunable electrophilicity, multifunctional modifiable sites, and the presence of chiral sulfur(VI) centers. This reagent exhibits exceptional reactivity in stereospecific SuFEx transformations, offering not only an efficient strategy for the synthesis of enantioenriched sulfur compounds but also a versatile foundation for covalent drug discovery and chemical probe development. This review systematically summarizes recent advances in sulfonimidoyl fluoride chemistry, with an emphasis on the construction of chiral S(VI) centers and stereocontrolled SuFEx reactions. Despite the limited literature in this nascent field, key breakthroughs and discuss future research directions, is consolidated providing forward‐looking perspectives to stimulate further progress in stereospecific SuFEx chemistry.

Chiral sulfilimines represent a type of chiral S(IV) compound that is versatile as pharmacophores and chiral building blocks for chiral S(VI) compounds. Herein, we report an efficient method of preparing chiral sulfilimines (up to 90% yield and up to 96% enantiomeric excess) from commercially available diaryliodonium salts and prochiral sulfenamides. The reaction was enlarged to the gram scale for the preparation of chiral sulfilimines and allowed for the derivatization of chiral sulfoximines and sulfondiimines with complete retention of stereochemistry.

Phosphoranyl radical-mediated fragmentation has emerged as a powerful strategy for generating diverse radicals that would initiate multiple interesting conversions. However, we have learned from most of these conversions that the P-containing fragments were wasted as a side product. Herein, wasted phosphine oxide was utilized by functionalizing readily available aromatic olefins. A series of substituted tertiary phosphine oxides were obtained in moderate to good yields.

The fundamentally significant halogenation processes in organic synthesis heavily depend on the use of hazardous and toxic elemental halogens directly or indirectly, inevitably increasing environmental burden and leading to various production problems. Flavin-dependent halogenases (FDHs) in nature produce organic halides under benign conditions, yet their practical application remained elusive and difficult to scale up. Inspired by FDHs, here we develop a mild and eco-friendly biomimetic aerobic oxidative halogenation strategy that utilizes O₂ from the air to oxidize non-toxic halide salts as a safer alternative. Using simple alloxan as catalyst and low-cost ascorbic acid as reductant, we successfully emulate the challenging flavoenzymatic aerobic halogenation cycle without requiring light activation. This approach yields various important monobromide and iodide products with high efficiency, excellent selectivity, and good functional group tolerance. Moreover, its successful application in late-stage bromination of complex bioactive molecules, operational ease at the gram scale, and use of cost-effective, unpurified primary raw materials all indicate significant potential for green industrial production.

Chiral phosphoramidates characterized by at least a P-N bond without a P-C bond demonstrate a significant applicative value within nucleoside phosphoramidate prodrugs. Despite the availability of methodologies for the selective construction of diverse chiral organophosphorus entities, achieving P-stereocenters solely substituted by heteroatoms often relies on diastereomeric synthesis. Here, we present a catalytic enantioselective desymmetrization strategy using an electrophilic phosphorus reagent with three leaving groups as a substrate, enabling a three-phase nucleophilic attack with various alcohols and amines. By generating a broad range of possible substituent combinations around phosphorus atoms, this synthetic strategy may expedite the synthesis and screening of biologically active phosphoramidates.

Sulfonimidamides, featuring a hexavalent sulfur structure, are a class of key compounds with broad application prospects in the fields of pharmaceuticals and agrochemicals. However, their applications have been limited due to the lack of economically effective synthetic methods. Utilizing the cost-effective and readily accessible sulfonyl chloride as the initial reagent, this method involves the sequential formation of intermediates, including sulfinamide and sulfonimidoyl chloride, culminating in the synthesis of the sulfonylimidamide compounds. This approach yields sulfonimidamides in moderate to good yields, thereby offering a viable synthetic route for the expanded application of these important compounds.

Sulfur‐centered electrophilic ‘warheads’ have emerged as key components for chemical proteomic probes through sulfur‐exchange chemistry (SuFEx) with protein nucleophiles. Among these functional groups, sulfonimidoyl fluorides (SIFs) stand out for their modifiable sites, tunable electrophilicities, and chiral sulfur‐center, presenting exciting possibilities for new covalent chemical probes. However, the synthetic access to chiral SIFs has been a challenge, limiting their exploration and applications. In this study, we describe a convenient route to obtain chiral SIFs from readily available sulfenamides via a series of one‐pot tandem reactions with high enantiomeric excess (ees). The resulting chiral SIFs were further converted into a diverse array of chiral S(VI) derivatives under mild conditions or in buffer solutions. Most significantly, the specificity of the chiral SIFs in protein ligation experiments underscored the critical role of sulfur‐center chirality in the design and screening of more‐selective covalent probes and therapeutics.

Sulfur‐centered electrophilic ‘warheads’ have emerged as key components for chemical proteomic probes through sulfur‐exchange chemistry (SuFEx) with protein nucleophiles. Among these functional groups, sulfonimidoyl fluorides (SIFs) stand out for their modifiable sites, tunable electrophilicities, and chiral sulfur‐center, presenting exciting possibilities for new covalent chemical probes. However, the synthetic access to chiral SIFs has been a challenge, limiting their exploration and applications. In this study, we describe a convenient route to obtain chiral SIFs from readily available sulfenamides via a series of one‐pot tandem reactions with high enantiomeric excess (ees). The resulting chiral SIFs were further converted into a diverse array of chiral S(VI) derivatives under mild conditions or in buffer solutions. Most significantly, the specificity of the chiral SIFs in protein ligation experiments underscored the critical role of sulfur‐center chirality in the design and screening of more‐selective covalent probes and therapeutics.