Yonggui Robin Chi

Thiamine diphosphate (ThDP)-dependent enzymes are versatile biocatalysts for carbon–carbon bond formation, yet their catalytic repertoire has been largely confined to linear homologation and intramolecular cyclizations that rely on single-site reactive intermediates such as the Breslow or ketyl radical species. Intermolecular annulation─a powerful strategy for constructing cyclic architectures─has remained elusive within this enzyme class. Here, we report the first intermolecular [3 + 2] annulation catalyzed by a ThDP-dependent enzyme, achieved through a homoenolate-mediated nucleophilic addition pathway. A phylogeny-guided enzyme mining identified a previously uncharacterized enzyme from Variovorax boronicumulans(ThDP-5), and subsequent protein engineering yielded the F484S variant, which exhibits markedly enhanced activity and exquisite stereocontrol. This biocatalytic system exhibits a broad substrate scope (30 examples), accommodating diverse substituted cinnamaldehydes and isatins to afford chiral spirooxindole lactones with excellent stereoselectivity (up to > 20:1 dr and 99% ee). Preparative-scale reactions (2 mmol) validate its synthetic utility. This work expands ThDP-dependent biocatalysis to intermolecular annulations, providing a robust and selective platform for the construction of pharmaceutically relevant spirocyclic architectures.

The direct activation of C–H bonds remains a central challenge in synthetic chemistry, with photochemical hydrogen atom transfer (HAT) offering a mild and powerful strategy. Aldehydes represent an attractive, readily available class of potential HAT photocatalysts, yet their short-lived excited states often result in inefficient catalyst turnover dominated by competing pathways. Herein, we report an unexplored merging of aldehyde and triazolium photocatalytic systems that overcomes these intrinsic limitations and enables aldehydes to function as effective and regenerable HAT photocatalysts. In this electron-shuttle manifold, triazolium salts rapidly intercept α-hydroxybenzyl radicals formed via excited aldehyde-mediated HAT, facilitating efficient catalyst turnover while generating reducing radicals that convert benzylic radicals into carbanions. This strategy activates a broad range of C(sp3)–H bonds and enables a broad range of three-component coupling with alkenes and electrophiles, including alkyl-deuteration, alkylative cyclization, aryl-alkylation, and alkylative carboxylation transformations. Furthermore, the functionalized products exhibit potent antimicrobial activity against various fungi, underscoring their potential as fungicidal agrochemical leads. The merger of simple benzaldehyde with a triazolium as a mechanistically distinct electron-shuttle catalyst establishes a practical HAT platform that expands the synthetic potential of aldehyde photocatalysis for direct C–H functionalization.

Protecting-group-free glycosides, which serve as fundamental scaffolds for numerous therapeutic agents, present significant synthetic challenges due to the difficulties in stereocontrol and the reliance on multistep protection-deprotection sequences. Herein, we report a unified and concise strategy that enables the highly stereoselective synthesis of diverse protecting-group-free glycosides─including alkenyl C-glycosides with multiple stereocenters, alkyl C-glycosides, aryl thioglycosides, and aryl selenoglycosides─that were previously difficult to access from unprotected glycosyl donors. The process involves generating glycosyl radicals from readily accessible glycosylsulfonohydrazides under copper/ligand/base mediation, which then undergo addition to various radicals or unsaturated bonds with high stereoselectivity. Notably, nitrogen-containing ligands are key to achieving highly stereoselective alkenyl glycosides and alkyl thioglycosides. The utility of this approach is demonstrated by the concise synthesis of an anti-inflammatory drug, highlighting its potential to accelerate the development of glycoside-based therapeutics.

Monosaccharides are ubiquitous motifs in natural and synthetic molecules, yet methods for their selective structure editing remain limited due to the multiple hydroxy groups for differentiation and their structural complexity. Among possible strategies for stereoinversion and functional group swapping of saccharides, the classical S_N2 substitution of alcohols via sulfonate esters offers a potentially robust approach. A central challenge, however, is the selective functionalization of sulfonyl groups on specific hydroxyl moiety. Here we report an organocatalytic approach to enable site-selective sulfonylation of minimally protected saccharides by exploiting an underexplored N-heterocyclic carbene (NHC)-derived sulfonyl-azolium intermediate. Distinct NHC scaffolds govern regioselectivity for the sulfonyl group transfer, overcoming the challenge of differentiating multiple hydroxyl units in complex sugar substrates. The installed sulfonates serve as versatile leaving groups for subsequent nucleophilic substitution, constituting a "sulfonylation-swapping" strategy that transforms abundant sugars into diverse high-value rare sugars, including pharmaceutically relevant structures such as dapagliflozin analogues. Furthermore, the readily accessed rare sugars exhibit intriguing antimicrobial activity against various plant pathogens, demonstrating significant potential for the development of potent fungicide agents.

Most conventional alkene synthesis reactions (e.g., elimination et al.) inherently favor the formation of thermodynamically more stable E-isomers, posing a long-standing challenge for direct access to Z-alkenes. Here, we report the reprogramming of a thiamine diphosphate (ThDP)-dependent enzyme to catalyze a formal dehalogenative elimination that overrides this intrinsic thermodynamic bias, enabling the direct and selective synthesis of Z-α,β-unsaturated carboxylic acids. In contrast to classical approaches that rely on substrate control, directing groups, or complex ligand architectures, our strategy harnesses the enzyme’s confined active site to achieve kinetic control exclusively via noncovalent interactions─representing a fundamentally distinct and more sustainable approach to stereochemical programming. This transformation diverts the enzyme from its native function in C–C bond formation by channeling the Breslow intermediate toward a homoenolate-mediated pathway, wherein specific noncovalent interactions stabilize the syn-periplanar geometry required for Z-selective dehalogenative elimination. Through rational active-site engineering, the stereochemical trajectory can be inverted to furnish the complementary E-isomer, enabling stereodivergent synthesis from a common scaffold. This work establishes a biocatalytic platform that addresses a critical gap in Z-alkene synthesis, expands the catalytic repertoire of ThDP-dependent enzymes, and provides a sustainable alternative to conventional methodologies.

A P(III)-based stereoselective substitution of phosphorodiamidites catalyzed by chiral pyridine N-oxide catalysts is disclosed. Unlike acid-promoted systems that suffer from stereorandom products and phosphites via uncontrolled multiple substitutions, this approach enables selective monosubstitution to deliver configurationally defined phosphoramidites (up to 4:96 dr). This enables stereoselective phosphitylation of various bioactive molecules, such as simvastatin, estradiol, uridine, and adenosine. Mechanistic studies supported by DFT calculations reveal a water-assisted covalent catalytic pathway.

Indanone-3-carboxylates are key organic synthetic intermediates for a range of bioactive molecules. However, their efficient synthesis, particularly for structurally complex indanone-3-carboxylates, still faces challenges such as cumbersome steps and harsh conditions. Herein, we report a photocatalytic imidazolium ester- and phosphine-mediated dehydroxylative cyclization/acylation of 2-vinylbenzoic acids. This radical relay strategy enables the efficient preparation of structurally diverse indanone-3-carboxylates from readily available 2-vinylbenzoic acids and nitrogen heterocyclic carbene (NHC)-based azolium salts under mild conditions. The reaction exhibits broad substrate scope and, notably, allows facile access to carbon-cycle-fused indanone-3-carboxylate scaffolds that are challenging to obtain using conventional methods. Preliminary bioactivity assays reveal that several products possess good antifungal activity, demonstrating the potential of this method to advance the development of indanone-3-carboxylate-related bioactive molecules.

BACKGROUND: 1,2,4‐Triazolium salts are a class of stable heterocyclic salts widely used as in situ carbene precursors in organic synthesis, and they have also been reported to exhibit favorable physicochemical properties and diverse biological activities. This study aims to elucidate the potential of 1,2,4‐triazolium salts as antifungal and anti‐oomycete agents. RESULTS: In this study, a series of 1,2,4‐triazolium derivatives were evaluated for their inhibitory activities against phytopathogenic oomycete Phytophthora capsici . Compound 42 displayed the most potent in vitro activity against P. capsici , with a half‐maximal effective concentration (EC ₅₀ ) of 5.38 μg mL ⁻¹ , and demonstrated good protective efficacy in vivo against P. capsici . Scanning electron microscopy (SEM) revealed that treatment of P. capsici with compound 42 at 50 μg mL ⁻¹ caused pronounced morphological abnormalities in the hyphae, characterized by severe collapse and shrinkage. Molecular docking studies revealed favorable binding interactions between compound 42 and uridine phosphorylase (UPase, PDB ID: 6KD3), providing possible mechanistic insights into its inhibitory activity. CONCLUSION: Our results establish 1,2,4‐triazolium compound 42 as a promising scaffold for the future development of anti‐oomycete agents, offering a potential molecular basis for the design of novel crop protectants against P. capsici . © 2026 Society of Chemical Industry.

Sulfur(VI)-stereogenic compounds are of growing importance in medicinal chemistry, agrochemical, and materials science, owing to their favorable physicochemical properties and pronounced biological activities. Despite significant advances in organosulfur chemistry, the catalytic asymmetric construction of configurationally stable sulfur-centered chirality at the S(VI) oxidation state remains a formidable challenge. Herein, we disclose a chiral 4-(dimethylamino)pyridine (DMAP)-type nucleophilic organocatalyst for the direct activation of S(VI) moiety, enabling the enantioselective synthesis of sulfur-stereogenic S(VI) compounds from readily accessible sulfonimidoyl chlorides. Distinct from conventional DMAP activation of acyl groups, the generated covalent S(VI)−DMAP intermediates in this study serve as versatile sulfonimidoyl transfer groups, providing access to a broad array of enantioenriched sulfonimidamides, sulfonimidoyl fluorides, and sulfonimidate esters, through highly enantioselective construction of S(VI)−N, S(VI)−F, and S(VI)−O bonds. Mechanistic investigations reveal that the dynamic kinetic resolution process involves a facile inversion of the S(VI) center of the sulfonimidoyl substrate assisted by the generated chloride anion. The resulting chiral S(VI) compounds are readily diversified and exhibit promising antibacterial activity, highlighting the potential of these compounds for agrochemical development.