A supramolecular docking strategy has been developed for the SCXRD determination of flexible alkyl-chain-containing molecules. By incorporating pillar[5]arene-based recognition units into MOFs, EtP5-MOF-2 was constructed as a supramolecular dock capable of selectively capturing and organizing alkyl-bearing guests. Through cooperative host–guest interactions, this platform reduces conformational motion and promotes molecular ordering, enabling the structural determination of 48 challenging molecules, including natural products, approved drugs, and synthetic compounds. Furthermore, supramolecular docking allows direct structural analysis of alkyl-chain-containing products derived from crude reaction mixtures without purification and enables unknown compound identification through blind experiments. This strategy also provides opportunities for reactive species stabilization and absolute configuration determination, offering a versatile platform for crystallization-assisted structural elucidation.
The selective hydrogenolysis of furfural (FUR) to 2-methylfuran (2-MF) has attracted substantial attention as a representative biomass-upgrading approach. Despite the development of numerous catalytic systems, the factors governing high 2-MF selectivity remain insufficiently understood. This review summarizes recent advances in FUR hydrogenolysis from the perspective of synergistic hydrogenation and C–O bond cleavage. Efficient 2-MF production generally relies on the cooperation of metallic sites for H2 activation and carbonyl hydrogenation and oxidized metal species (Lewis acid sites) that facilitate C–O bond activation and cleavage. On this basis, four core factors governing catalytic performance are systematically discussed: metal composition, thermal treatment, synthetic method, and support effects. Particular attention is devoted to how these factors regulate the electronic structure of metal sites, adsorption configuration, metal dispersion, interfacial interactions, and surface acidity. Finally, current challenges and future opportunities are highlighted. This review provides mechanistic insights into the fundamental determinants of 2-MF selectivity and offers guidance for the rational design of highly selective catalysts for FUR upgrading.
We detail the concept, implementation, and illustrative applications of the "control from root design"(CRD) strategy for developing safe, environmentally benign, simple, health-protective, quality-assured, and cost-efficient (six CRD criteria) manufacturing processes for active pharmaceutical ingredients (APIs). Unlike conventional approaches, in which synthetic routes are typically established first, and sustainability is optimized retrospectively, CRD integrates synthetic route design and sustainability evaluation from project inception. Drawing on both the principles of green and sustainable chemistry and practical experience from industrial innovation and implementation, CRD embeds a “green gene” foundation into the core technology before regulatory lock-in occurs, thereby resolving the API industry’s persistent process lock-in problem. While established green metrics provide some quantitative guidance, CRD offers a structured, case-specific decision approach that incorporates these metrics into early-stage route design and evaluation. We demonstrate the efficacy and versatility of the CRD strategy through several API R&D case studies, including VV116, molnupiravir, and tecovirimat. By aligning regulatory requirements and sustainability objectives from the outset, CRD streamlines API process research and development and reduces both post-approval modifications and overall lifecycle costs.
The synthesis of complex nonbiaryl atropisomers with multiple stereogenic elements remains a significant challenge due to their flexible conformations and rotational freedom. Here, we report an ene-reductase-catalyzed asymmetric reduction strategy that enables control over both central and axial chirality, yielding structurally diverse maleimide atropisomers containing tertiary carbon stereocenters with yields up to 70% yield and outstanding enantioselectivities. Two ene-reductases 12-Oxophytodienoate reductase 1 (OPR1) and Nicotinamide-dependent cyclohexenone reductase (NCR), respectively, demonstrated exceptional stereoselectivity towards halogenated and bulky substrates. Mechanistic studies on OPR1 revealed 22 active-site residues critical for stereocontrol, with saturation mutagenesis identifying key positions that reshape the active site and influence catalytic enantioselectivity. This work highlights the potential of biocatalysis for the efficient synthesis of complex axially chiral molecules and underscores future opportunities in enzyme engineering to expand substrate scope and optimize catalytic efficiency.
Sugar acids, as carbohydrate derivatives, are widely used in pharmaceuticals, food, and materials. Traditional chemical catalytic production methods can no longer meet the requirements for economic feasibility, safety, and atom economy, whereas biocatalysis has emerged as a promising alternative due to its environmental friendliness, safety, and sustainability. This review summarizes the recent advances in the biocatalytic production of three high-value sugar acids, namely glucaric acid, galactaric acid, and xylonic acid. Key strategies are critically discussed, including strain screening and engineering, enzyme engineering, enzyme immobilization, and fermentation process optimization. The advantages and disadvantages of different technological routes are compared in terms of yield, stability, and industrial applicability. Unlike existing reviews that primarily focus on chemical or biological production pathways, this review offers a new perspective by highlighting the challenges related to catalysts and reaction processes in sugar acid biosynthesis and the corresponding strategies to address them, aiming to provide insights for the development of sugar acid biosynthesis.
Euphorbiaceae-derived highly strained tetracyclic diterpenoids represented by Pepluanols A–D and Euphorikanin A are a class of natural products with novel skeletons, complex stereostructures, and prominent biological activities, which have become a research hotspot in the fields of organic synthesis and medicinal chemistry. Their unique ring–fusion modes, densely arranged contiguous chiral centers, highly sterically congested molecular frameworks, and scarce natural abundance pose tremendous challenges to chemical synthesis. Meanwhile, their specific inhibitory effects on ion channels and selective cytotoxicity against cancer cells endow them with significant pharmaceutical development potential. This review systematically summarizes the latest research progress in the total synthesis of Pepluanols and Euphorikanin A in recent years, elaborates in detail the design ideas, key reactions, stereocontrol strategies, and synthetic innovations of different synthetic routes for these target molecules, and analyzes the advantages and limitations of various synthetic methods. The core synthetic challenges of this class of diterpenoids are summarized from the aspects of polycyclic framework construction, chiral center control, unconventional ring system assembly, and oxidation-state modulation. Furthermore, the unresolved scientific issues in the current synthetic research are discussed, and the future research directions are prospected in combination with the development trends of modern organic synthetic chemistry, such as photocatalysis/transition-metal synergistic catalysis, biomimetic synthesis, and modular synthesis. This review provides a comprehensive reference for the synthesis of complex Euphorbiaceae diterpenoids (Pepluanols and Euphorikanin A) and lays a foundation for their structural modification and drug development.
Positional selectivity control in the C–H bond functionalization of aniline derivatives remains a formidable challenge in synthetic organic chemistry. Owing to the broad utility of these compounds across pharmaceuticals, agrochemicals, and materials science, synthetic tactics enabling para-selective C–H bond functionalization of aniline scaffolds have attracted substantial research interest. This review systematically summarizes and dissects recent advances in para-selective C–H bond functionalization methodologies applicable to primary, secondary, and tertiary anilines, encompassing transformations including alkylation, arylation, alkenylation, borylation, acylation, and allylation. The comprehensive analysis presented herein aims to offer valuable insights and practical guidance for the efficient para C–H bond functionalization of aniline derivatives.
Here, we report a mild, metal-free, and highly efficient catalytic strategy using B(C6F5)3 for both hydroxyl protection and direct O-glycosylation. This method enables the facile installation of tetrahydropyranyl (THP) protecting groups under exceptionally mild conditions (30°C) and, in a key advancement, directly facilitates O-glycosylation with high efficiency. The protocol exhibits broad functional-group tolerance and substrate generality across a wide range of aliphatic alcohols, phenols, and complex molecular scaffolds, including serine derivatives and natural products such as cholesterol. Its synthetic utility is further demonstrated through a concise, gram-scale preparation of salidroside. By operating under mild and metal-free conditions, this B(C6F5)3-catalyzed approach provides a powerful and sustainable tool for glycosyl-conjugate synthesis, bridging protective group chemistry with glycosidic bond formation.
This study describes a strategy for selecting metal hydrides to achieve efficient and highly selective cross- and branched hydroalkenylation. By combining 2,6-lutidinium tetrafluoroborate with manganese as a mild reductant, cobalt hydride is selectively generated under nickel catalysis, leading to cross-selective alkene–alkene coupling and furnishing valuable branched products with exceptional selectivity.
Mycolicibacterium phytosterol degradation is a cornerstone industrial strategy for the production of steroidal pharmaceuticals; however, the metabolic pathways governing C17 side-chain cleavage remain incompletely characterized. In this study, we identified and characterized a family of 14 acyl-CoA thioesterases (MnTE1–14) from Mycolicibacterium neoaurum that operate at a critical metabolic node within the C22 steroid branch. In vitro biochemical assays confirmed that these MnTEs possess broad substrate specificity and robust hydrolytic activity toward both steroidal, fatty acyl, and aromatic acyl-CoAs. By overexpressing these MnTEs in a M. neoaurum mutant strain (ΔchsE1-E2/ΔchsH1-H2/ΔkstD), we significantly enhanced the titers of high-value C22 steroidal carboxylates—specifically 3-oxo-4-pregnene-20-carboxylic acid (3-OPC) and 3-oxo-4,17-pregnadiene-20-carboxylic acid (3-OPDC). Our findings elucidate a previously elusive step in the phytosterol catabolic network and establish an efficient, sustainable, green biocatalytic platform for the synthesis of key steroidal drug intermediates.
Methanol, as a low-cost, abundant, and sustainable C1 feedstock, has garnered considerable attention for methylation reactions via the borrowing hydrogen (BH) process. Herein, we designed and synthesized two-dimensional (2D) N-heterocyclic carbene–iridium (NHC–Ir) coordination assemblies, which act as self-supporting solid molecular catalysts and exhibit excellent activity and exclusive chemoselectivity in two methylation reactions, including β-methylation of primary alcohols and selective mono-N-methylation of arylamines. The protocol delivers up to 98% yield with quantitative mono-selectivity and a turnover number (TON) up to 4940 under basic conditions. A wide range of structurally diverse primary alcohols and anilines is well tolerated, highlighting the capability of this methodology for late-stage methylation of pharmaceutical molecules bearing methyl groups. Moreover, the solid catalyst demonstrates exceptional stability and recyclability; no obvious loss in activity and selectivity was observed even after seven consecutive runs.
Oxiranes are among the most valuable reagents in the chemical sciences, with applications that span pharmaceuticals, agrochemicals, and functional materials. Although remarkable progress has been achieved for the construction of oxiranes, the site-selective epoxidation of non-activated C(sp3)–H bonds remains under-explored. Herein, we present a photoinitiated, metal-free method for the site-specific epoxidation of remote non-activated C(sp3)–H bonds of amides facilitated by amidyl radical-mediated 1,5-hydrogen atom transfer (HAT). The use of a photochemical, radical-mediated approach allows functionalised C(sp3)–H bonds to undergo epoxidation under exceptionally mild conditions and circumvents the previously required pre-functionalized alkenes or ketones at specific sites. Notably, direct photoexcitation of available amides allows these reactions to occur at specific locations through intramolecular HAT, therefore representing the first example of highly site-selective epoxidation of non-activated C(sp3)–H bonds in molecules, in contrast to all previously reported routes. Furthermore, the follow-up ring-opening transformations and agrochemical activity studies underscore the significant potential application of this approach and products.
The selective catalytic strategies for C–O bond activation in saccharides have predominantly centered on predictable and straightforward synthetic logic, as these approaches enable the exclusive formation of new bonds at the original C–O bond sites. Herein, we report a configuration-matched adaptive migratory cross-electrophile coupling (XEC) protocol for D-glucose. This strategy features a tandem in situ conversion of both free and protected hydroxyl groups to bromides, followed by transition-metal-catalyzed cross-electrophile coupling. Notably, a series of alternative product isomers was obtained, distinct from those derived from the cleavage of C–O bonds at the original hydroxyl-bearing positions of glucose. Preliminary mechanistic investigations indicate that the inherent configuration of glucose and the flexible protecting groups facilitate the migratory process. Importantly, the addition of POP, TBAB, and BTMG plays a pivotal role in promoting this XEC transformation.
The hetero-bicyclo[3.2.1]octane scaffold is a prevalent structural motif in bioactive natural products and pharmaceuticals, yet general synthetic methods for its construction remain limited. Herein, we report a Lewis acid-catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[2.1.0]pentanes (BCPs) with nitrones, providing efficient access to densely functionalized 2-oxa-3-azabicyclo[3.2.1]octanes. Generally, this reaction proceeds under mild conditions, features high atom-economy and good step-economy. It also exhibits broad substrate scope and good functional group tolerance, yielding products with high efficiency (up to 95% yield, up to >19:1 dr). The reliability and practicality of this methodology are further successfully demonstrated by scale-up synthesis and diverse synthetic transformations.
Electrocatalytic nitrate reduction to ammonia (NRA) offers a sustainable solution for simultaneously remediating wastewater and producing valuable ammonia; however, its practical application hinges on the development of efficient, stable, and cost-effective electrocatalysts. Among non-precious transition metals, cobalt-based catalysts are particularly promising due to their tunable d-electron configurations. Compared to iron or copper, cobalt species exhibit more favorable adsorption energies for key nitrogenous intermediates, resulting in superior NH3 selectivity and Faraday efficiency (FE). This review systematically summarizes recent advances in cobalt-based single-atom catalysts, compounds, alloys, MOF-derived materials, oxides and molecular electrocatalysts for NRA. Furthermore, we analyze design strategies and performance modulation techniques across these material categories, identify key technical barriers to large-scale application, and outline future research directions. This work aims to provide a theoretical framework for designing high-performance cobalt-based NRA catalysts.
Enzymes catalyze stereoselective transformations under mild conditions, yet their industrial deployment remains constrained by intrinsic fragility, poor recyclability, and prohibitive cost. While immobilization on solid carriers can circumvent these limitations, conventional methods suffer from enzyme leaching or diffusional barriers. Covalent organic frameworks (COFs) offer an ideal solution by combining high surface area, tunable pore environments, and robust covalent linkages; however, the narrow pore apertures of conventional two-/three-dimensional scaffolds (< 2 nm) preclude efficient loading of enzymes whose hydrodynamic diameters typically exceed 5 nm. Here we demonstrate that a one-dimensional, pyrene–phenanthroline COF (PhenCOF) overcomes this steric mismatch by presenting densely distributed, surface-exposed imine groups that serve as anchoring points for covalent enzyme attachment. Candida antarctica lipase B (CALB) was immobilized via an Ugi-type three-component reaction to afford CALB@PhenCOF. The resultant hybrid exhibits exceptional catalytic performance in the kinetic resolution of racemic 1-phenylethanol, achieving 99% conversion, 2.4-fold higher than free CALB. The 1D architecture and hydrophobic microenvironment facilitate substrate diffusion while stabilizing the enzyme's active conformation, as evidenced by retention high activity under wide pH ranges, extreme organic solvents, and temperatures up to 140°C. Notably, covalent immobilization endows unparalleled recyclability, with 95% efficiency maintained over 10 cycles. This work establishes 1D COFs as a paradigm for promising enzyme carriers, merging atomic precision with industrial robustness to address longstanding challenges in biocatalysis.
This work pioneers a palladium-catalyzed asymmetric tandem process merging intramolecular C–H arylation with intermolecular Buchwald–Hartwig amination. It establishes the first metal-catalyzed asymmetric synthesis of C–N axially chiral diarylamines, concurrently constructing planar chiral ferrocenes in a single step with high efficiency and stereoselectivity (up to 98% ee, >20:1 d.r.). Mechanistic studies support a sequential pathway where asymmetric C–H arylation generates planar chirality, followed by axial chirality construction via asymmetric C–N coupling.
An organocatalytic [4+4] annulation between indole-4-boronic acids and o-hydroxybenzyl alcohols has been developed. This method enables the synthesis of a diverse range of indole-fused oxaborocanes in generally good yields. Moreover, by employing a chiral phosphoric acid catalyst, the corresponding chiral indole-fused oxaborocanes were obtained with high enantioselectivity. This work not only reports the first synthesis of indole-fused oxaborocanes and achieves their enantioselective preparation, but also demonstrates the first use of indole-4-boronic acids as four-atom synthons in annulation reactions. Furthermore, this study offers a novel strategy for constructing chiral indole-fused boron-containing eight-membered rings, thereby contributing valuable insights to the fields of chiral indole chemistry and boron chemistry.
While radical addition to SO2 serves as a fundamental strategy for constructing sulfone frameworks, its application in building sulfonamide skeletons, particularly for the modular installation of an aminosulfonyl moiety across alkene substrates, remains underdeveloped. Herein, we report unprecedented photocatalytic intermolecular 1,2-difluoromethylation/ aminosulfonylation of unactivated alkenes employing commercially available, bench-stable CF2HSO2Na as a bifunctional reagent and O-Ts hydroxylamine as electrophilic aminating reagents. The protocol demonstrates broad substrate scope and exceptional functional group tolerance, enabling the late-stage functionalization of complex pharmaceuticals. Mechanistic investigations support radical-polar crossover processes. This work provides a novel, efficient, and environmentally benign strategy for constructing valuable β-difluoromethylated sulfonamide scaffolds, aligning with core principles of green synthesis.
Atom transfer radical addition (ATRA) of alkenes with thiosulfonates is a powerful strategy to construct valuable thioalkylsulfones. However, these methods employ complex catalytic systems, a high loading of rare-earth- or noble-metal-based catalyst, a stoichiometric oxidant or an extra photocatalyst. Herein, we describe a visible-light-driven Na2CO3-enabled vicinal thio- and selenosulfonylation of unactivated alkenes under photocatalyst-free, metal-free, external oxidant-free and mild conditions. This approach features excellent regio- and stereoselectivities, a simple and convenient procedure, broad substrate scope, 100% atom economy, and late-stage functionalization of complex molecules. Preliminary mechanistic studies reveal that the formation of an electron donor-acceptor (EDA) complex is critical to the success of this transformation.
