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Chalcogenide motifs are present as principal moieties in a vast array of natural products and complex molecules. Till date, the construction of these chalcogen motifs has been restricted to either the use of directing groups or the employment of a large excess of electronically activated arenes, typically employed as a cosolvent. Despite being highly effective, these methods have their own limitations in the step economy and the deployment of an excess amount of arenes. Herein, we report the evolution of a catalytic system employing arene-limited, nondirected thioarylation of arenes and heteroarenes using a complimentary dual-ligand approach. The reaction is controlled by a combination of steric and electronic factors, and the utilization of a suitable ligand enables the generation of products on a complimentary spectrum to that generated by classical methods. The combination of ligands remains imperative in the reaction protocol with theoretical calculations pointing towards a monoprotected amino acid ligand being crucial in the concerted metalation deprotonation (CMD) mechanism by a characteristic [5,6]-palladacyclic transition state, while the pyridine moiety assists in the active catalyst species formation and product release. Combined experimental and computational mechanistic investigations point toward the C-H activation step being both regio- and rate-determining. Interestingly, oxidative addition of the diphenyl disulfide substrate is found to be unlikely, and an alternative transmetalation-like mechanism involving the Pd-Ag heterometallic complex is proposed to be operative.

A carbene-catalyzed sulfonylation reaction between enone aryl aldehydes and sulfonyl chlorides is disclosed. The reaction effectively installs sulfone moieties in a highly enantioselective manner to afford sulfone-containing bicyclic lactones. The sulfonyl chloride behaves both as an oxidant and a nucleophilic substrate (via its reduced form) in this N-heterocyclic carbene (NHC)-catalyzed process. The NHC catalyst provides both activation and stereoselectivity control on a very remote site of enone aryl aldehyde substrates. Water plays an important role in modulating catalyst deactivation and reactivation routes that involve reactions between NHC and sulfonyl chloride. Experimental studies and DFT calculations suggest that an unprecedented intermediate and a new oxidation mode of the NHC-derived Breslow intermediate are involved in the new asymmetric sulfonylation reaction. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Nanyang Technological University National Research Foundation (NRF) Submitted/Accepted version We acknowledge funding supports from the National Natural Science Foundation of China (22061007 and 22071036); Frontiers Science Center for Asymmetric Synthesis and Medicinal Molecules, Department of Education, Guizhou Province [Qianjiaohe KY number (2020)004]; The 10 Talent Plan (Shicengci) of Guizhou Province ([2016] 5649); Science and Technology Department of Guizhou Province ([2018]2802, [2019]1020); Program of Introducing Talents of Discipline to Universities of China (111 Program, D20023) at Guizhou University; Singapore National Research Foundation under its NRF Investigatorship (NRF-NRFI2016- 06) and Competitive Research Program (NRF-CRP22-2019- 0002); Ministry of Education, Singapore, under its MOE AcRF Tier 1 Award (RG7/20, RG5/19), MOE AcRF Tier 2 (MOE2019-T2-2-117), and MOE AcRF Tier 3 Award (MOE2018-T3-1-003); a Nanyang Research Award Grant; and a Chair Professorship Grant, Nanyang Technological University. X.Z. acknowledges the support from the IHPC, A*STAR, and thanks the Deputy Chief Executive Research Office (DCERO), A*STAR, for a Career Development Fund (CDF Project Number C210812008) for this work

Summary C-Alkyl glycosides occur widely in nature and are indispensable in drug development programs, owing to their diverse range of medicinal properties. Previous synthetic efforts often utilize stoichiometric reagents, and catalytic methods that afford such glycosides exhibit limited scope. Here, we describe a stereoselective Ti-catalyzed regime that efficiently merges a vast array of readily available glycosyl chlorides with activated olefins, through stereocontrolled glycosyl radical addition to deliver an assortment of C-alkyl glycosides. By employing alkynes as radical acceptors, the present strategy is amenable to the synthesis of C-alkenyl glycosides bearing a Z olefin appendage. The unexpected greater reactivity of glycosyl chlorides (compared with simple tertiary chloroalkanes) in the presence of an organotitanium complex is elucidated through mechanistic and computational studies. Utility of the protocol is underscored by the concise preparation of therapeutically important carbohydrates and glycopeptide conjugates, which are difficult to access using alternative approaches.

We disclose herein an atroposelective synthesis of novel bridged biaryls containing medium-sized rings via N-heterocyclic carbene organocatalysis. The reaction starts with addition of the carbene catalyst to the aminophenol-derived aldimine substrate. Subsequent oxidation and intramolecular desymmetrization lead to the formation of 1,3-oxazepine-containing bridged biaryls in good yields and excellent enantioselectivities. These novel bridged biaryl products can be readily transformed into chiral phosphite ligands. Preliminary density function theory calculations suggest that the origin of enantioselectivity arises from the more favorable frontier molecular orbital interactions in the transition state leading to the major product. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Nanyang Technological University National Research Foundation (NRF) Submitted/Accepted version We acknowledge financial supports of the starting-up funding from Hunan Normal University, the National Natural Science Foundation of China (21901233, 22201071), Singapore National Research Foundation under its NRF Investigatorship (NRF-NRFI2016-06) and Competitive Research Program (NRF-CRP22-2019-0002); the Ministry of Education, Singapore, under its MOE AcRF Tier1 Award (RG108/16, RG5/19, RG1/18), MOE AcRF Tier 2 (MOE2019-T2-2-117), MOE AcRF Tier 3 Award (MOE2018-T3-103); the Agency for Science, Technology and Research (A*STAR) under its A*STAR AMEIRG Award (A1783c0008, A1783c0010); GSK-EDB Trust Fund; Nanyang Research Award Grant, Nanyang Technological University; X.Z. acknowledges the support from IHPC, A*STAR, and thanks the Deputy Chief Executive Research Office (DCERO), A*STAR, for a Career Development Fund (CDF Project Number C210812008) for this work.

Hand-foot-and-mouth disease (HFMD) is an infectious disease of children caused by more than 20 types of enteroviruses, with most cases recovering spontaneously within approximately one week. Severe HFMD in individual children develops rapidly, leading to death, and is associated with other complications such as viral myocarditis and type I diabetes mellitus. The approval and marketing of three inactivated EV-A71 vaccines in China in 2016 have provided a powerful tool to curb the HFMD epidemic but are limited in cross-protecting against other HFMD-associated enteroviruses. This review focuses on the epidemiological analysis of HFMD-associated enteroviruses since the inactivated EV-A71 vaccine has been marketed, collates the progress in the development of multivalent enteroviruses vaccines in different technical routes reported in recent studies, and discusses issues that need to be investigated for safe and effective HFMD multivalent vaccines.

Fabrication of multifunctional catalysts has always been the pursuit of synthetic chemists due to their efficiency, cost-effectiveness, and environmental friendliness. However, it is difficult to control multi-step reactions in one-pot, especially the spatial compartmentalization of incompatible active sites. Herein, we constructed metal-organic framework (MOF) composites which regulate the location distribution of metal nanoparticles according to the reaction path and coupled with the diffusion of substrates to achieve tandem reaction. The designed UiO-66-Pt-Au catalyst showed good activity and selectivity in hydrosilylation-hydrogenation tandem reaction, because the uniform microporous structures can control the diffusion path of reactants and intermediates, and Pt and Au nanoparticles were arranged in core-shell spatial distribution in UiO-66. By contrast, the low selectivity of catalysts with random deposition and physical mixture demonstrated the significance of artificial control to the spatial compartmentalization of active sites in tandem catalytic reactions, which provides a powerful approach for designing high-performance and multifunctional heterogeneous catalysts.

The efficient copolymerization of acrylates with ethylene using Ni catalysts remains a challenge. Herein, we report two neutral Ni(II) catalysts (POP-Ni-py (1) and PONap-Ni-py (2)) that exhibit high thermal stability and significantly higher incorporation of polar monomer (for 1) or improved resistance to tert-butylacrylate (tBA)-induced chain transfer (for 2), in comparison to previously reported catalysts. Nickel alkyl complexes generated after tBA insertion, POP-Ni-CCO(py) (3) and PONap-Ni-CCO(py) (4), were isolated and, for the first time, characterized by crystallography. Weakened lutidine vs pyridine coordination in 2-lut facilitated the isolation of a N-donor-free adduct after acrylate insertion PONap-Ni-CCO (5) which represents a novel example of a four-membered chelate relevant to acrylate polymerization catalysis. Experimental kinetic studies of six cases of monomer insertion with aforementioned nickel complexes indicate that pyridine dissociation and monomer coordination are fast relative to monomer migratory insertion and that monomer enchainment after tBA insertion is the rate limiting step of copolymerization. Further evaluation of monomer insertion using density functional theory studies identified a cis–trans isomerization via Berry-pseudorotation involving one of the pendant ether groups as the rate-limiting step for propagation, in the absence of a polar group at the chain end. The energy profiles for ethylene and tBA enchainments are in qualitative agreement with experimental measurements.

A new mode of carbene-catalyzed heteroatom activation and asymmetric reactions is disclosed. The reaction starts with addition of a carbene catalyst to a (benz)imidazole-derived aldimine substrate. Subsequent oxidation and proton transfer lead to the formation of a catalyst-bound triaza-diene as the key intermediate, in which the nitrogen atom at a site remote to the catalyst-substrate bond is activated. This unusual triaza-diene intermediate then undergoes highly enantioselective reactions with activated ketones through a concerted asynchronous pathway, as supported by mechanistic studies and preliminary density function theory calculation. Agency for Science, Technology and Research (A*STAR) National Research Foundation (NRF) Accepted version We acknowledge financial supports from Singapore National Research Foundation under its NRF Investigatorship (NRF-NRFI2016-06) and Competitive Research Program (NRF-CRP22-2019-0002); the Ministry of Education, Singapore, under its MOE AcRF Tier 1 Award (RG108/16, RG5/19, RG1/18), MOE AcRF Tier 2 (MOE2019-T2-2-117), MOE AcRF Tier 3 Award (MOE2018-T3-1-003); the Agency for Science, Technology and Research (A*STAR) under its A*STAR AME IRG Award (A1783c0008, A1783c0010); GSK-EDB Trust Fund; Nanyang Research Award Grant, Nanyang Technological University; the National Natural Science Foundation of China (21772029, 21801051, 21807019, 21961006, 22071036, 22061007, 82360589, 81360589), Frontiers Science Center for Asymmetric Synthesis and Medicinal Molecules, Department of Education, Guizhou Province [Qianjiaohe KY number (2020)004]; The 10 Talent Plan (Shicengci) of Guizhou Province ([2016]5649); the Science and Technology Department of Guizhou Province ([2018]2802, [2019]1020); the Program of Introducing Talents of Discipline to Universities of China (111 Program, D20023) at Guizhou University; the Guizhou Province First-Class Disciplines Project [(Yiliu Xueke Jianshe Xiangmu)-GNYL(2017)008], NSFC Grant (81360589), Guizhou University of Traditional Chinese Medicine (China); and Guizhou University. X.Z. thanks the Institute of High Performance Computing (IHPC), A*STAR for financial support and acknowledges the use of super computers in the A*STAR Computational Resource Centre (ACRC) and the National Supercomputing Centre (NSCC), Singapore (https://www.nscc.sg), for computations performed in this work.

A carbene-catalyzed method for highly enantioselective modification of sulfonamides is disclosed. The reaction proceeds under mild conditions with broad substrate scope, wide functional group tolerance, and good to excellent yields. When multiple sulfonamides or amines are present in the same molecule, the reaction occurs in a highly chemo-selective manner. Application of our method allows for selective modification of sulfonamide-containing drug molecules to form the corresponding phthalidyl derivatives as potential prodrugs. Experimental observations and DFT calculations suggest that the reaction proceeds via a stepwise addition pathway, assisted by Li+ ions or protons. Non-covalent interactions, such as cation–π interactions, play important roles in enhancing the reactivity and controlling the enantioselectivity of the reaction. Ministry of Education (MOE) National Research Foundation (NRF) Accepted version

Shape-selective catalysis plays a key role in chemical synthesis. Porous nanomaterials with uniform pore structures are ideal supports for metal nanoparticles (MNPs) to generate efficient shape-selective catalysis. However, many commercial irregular porous nanomaterials face the challenge to realize satisfactory shape selectivity due to the lack of molecular sieving structures. Herein, we report a concept of creating shape selectivity in MNPs/porous nanomaterials through intentionally poisoning certain MNPs using suitable modifiers. The remaining MNPs within the substrates can cooperate with the channels to generate selectivity. Such a strategy not only applies to regular porous nanomaterials (such as MOFs, zeolites) but also extended to irregular porous nanomaterials (such as active carbon, P25). Potentially, the matching among different MNPs, corresponding modifiers, and porous nanomaterials makes our strategy promising in selective catalytic systems.

A solvent-assisted strategy was proposed by controlling the coordination equilibrium to fabricate hierarchical-porous metal-organic frameworks (HP-MOFs). The obtained HP-MOFs showed remarkable enhancement in catalytic efficiency in Lewis acid catalysis resulting from the joint efforts of the hierarchical pores and the exposed metal clusters.

Directed C-H functionalization has been realized as a complementary tool to the traditional approaches for a straightforward access of non-proteinogenic amino acids; albeit such a process is restricted mostly up to the γ-position. In the present work, we demonstrate the diversification [(hetero)arylation] of amino acids and analogous aliphatic amines selectively at the remote δ-position by tuning the reactivity controlled by ligands. An organopalladium δ-C(sp3)-H activated intermediate has been isolated and crystallographically characterized. Mechanistic investigations carried out experimentally in conjunction with computational studies shed light on the difference in the mechanistic picture depending on the substrate structure.

Supported metal nanoparticles (MNPs) have exhibited superior catalytic performance in various heterogeneous catalysis applications, which is usually influenced or even determined by the physicochemical properties of their porous supports. It is well acknowledged that understanding the regulation mechanism of supports is an important prerequisite to predict the catalytic performance of supported MNPs as well as the development of advanced catalysts. Here, we demonstrated that different transition-metal clusters (from Group IIIB to Group IIB) within metal-organic frameworks (MOFs) could accurately regulate the surface electronic status of supported platinum nanoparticles (Pt NPs), and the Pt/MOF composites showed a periodic activity trend in hydrogenation of 1-hexene. A strong correlation was found between the catalytic activity of Pt/MOF composites and the number of electrons in their outmost d orbitals of the transition-metal species, suggesting that the latter could play the role of prediction descriptor. Furthermore, this descriptor can be extended to predict the hydrogenation activity of more Pt/MOF composites and provide an important guiding principle for the design of supported MNPs catalysts.

While the icosahedral closo-[B12H12]2– cluster does not display reversible electrochemical behavior, perfunctionalization of this species via substitution of all twelve B–H vertices with alkoxy orbenzyloxy (OR) substituents engenders reversible redox chemistry, providing access to clusters in the dianionic,monoanionic, and neutral forms. Here, we evaluated the electrochemical behavior of the electron-rich B12(O-3-methylbutyl)12 (1) cluster and discovered that a new reversible redox event that gives rise to a fourth electronic state is accessible through one-electron oxidation of the neutral species. Chemical oxidation of 1 with [N(2,4-Br2C6H3)3]•+ afforded the isolable[1] •+ cluster, which is the first example of an open-shell cationic B12 cluster in which the unpaired electron is proposed to be delocalized throughout the boron cluster core. The oxidation of 1 is also chemically reversible, where treatment of [1]•+ with ferrocene resulted in its reduction back to 1. The identity of [1]•+ is supported by EPR, UV-vis, multinuclear NMR (1H, 11B), and X-ray photoelectron spectroscopic characterization.

Noble metal-based catalysts have been proven to be active for catalytic organic reactions. The selectivity and conversion can be improved by integration with proper carrier materials, and further modulated by tuning the composition as well as the electronic structure of the active noble metals. Compared with unsupported monometallic catalysts, the synergistic interactions between neighboring metals and the combined effects between the carrier materials and the active components often give rise to positive influences on the enhancement of the catalytic efficiency and selectivity. In this work, we report a facile process for the fabrication of nitrogen-doped carbon black (NCB) supported PdAu bimetallic nanoparticles (NPs) with a uniform dispersion and narrow size distribution. The PdAu/NCB catalyst with a Pd/Au mole ratio of 1/1 shows the highest activity towards both Ullmann coupling reactions of aryl halides and the hydrogenation reaction of nitrophenols. Moreover, this bimetallic catalyst also exhibits a superior recycling durability to that of monometallic Pd/NCB and Au/NCB catalysts. The enhanced catalytic performance of the bimetallic catalyst is mainly due to the large BET specific surface area (125.45 m2 g−1) and the synergy between the individual components of the catalyst.

The late-stage functionalization (LSF) of pharmaceutical and agrochemical compounds by the site-selective activation of C-H bonds offers immediate access to diverse structural analogs and expands the accessible chemical space. We report an C-H functionalization LSF strategy that hinges on the use of an alkyne linchpin to assemble conjugates of sp2-rich marketed pharmaceuticals and agrochemicals with sp3-rich 3D-fragments and natural products. This is accomplished through a template-assisted inverse Sonogashira reaction that displays high levels of selectivity for the meta-position. This protocol is also amenable to distal structural modifications of a-amino acids. The transformation of alkyne functionality to other functional groups further highlights the applicative potential. Computational and experimental mechanistic studies shed light on the detailed mechanism. Turnover-limiting 1,2-migratory insertion of the bromoalkyne coupling partner occurs after relatively fast C-H activation. While this insertion occurs unselectively, regioconvergence results from one of the adducts undergoing a 1,2-trialkylsilyl migration to form the alkynylated product. A heterobimetallic Pd–Ag TS, which is essential for product formation, is explicitly implicated in the β-bromide elimination step.

Palladium(II)-catalyzed meta-selective C-H allylation of arenes has been developed utilizing synthetically inert unactivated acyclic internal olefins as allylic surrogates. The strong σ-donating and π-accepting ability of pyrimidine-based directing group facilitates the olefin insertion by overcoming inertness of the typical unactivated internal olefins. Exclusive allyl over styrenyl product selectivity as well as E stereoselectivity were achieved with broad substrate scope, wide functional-group tolerance, and good to excellent yields. Late-stage functionalisations of pharmaceuticals were demonstrated. Experimental and computational studies shed light on the mechanism and point to key steric control in the palladacycle, thus determining product selectivities.

Noble metal-based catalysts with rationally designed nanostructures have attracted considerable attention due to their excellent catalytic activity for important chemical reactions. It is highly desired to develop efficient nanostructured noble metal based catalysts and to understand the mechanism underlying their catalytic activities. Here, highly efficient nitrophenol reduction was achieved on Pd and Au nanoparticles decorated nitrogen-doped carbon black (NCB). Pd/NCB nanohybrids showed a better performance in the catalytic reduction reaction of 4-nitrophenol compared to Au/NCB catalysts. The improved performance of catalyst can be ascribed to the size of metal nanoparticles, good dispersity and interactions between noble metal nanoparticles and the support. Density functional theory (DFT) calculations reveal that stronger binding energy and greater charge transfer exist between Pd and NCB, implying that N dopant can boost the activity and stability of the hybrid catalysts through enhanced binding energy, more efficient electron transfer and rich active catalytic sites.