Chiral Z-olefin molecules are much more challenging targets in organic synthesis due to their thermodynamically unfavorable nature compared with that of their corresponding E-olefin counterparts. Particularly, the transformations toward advanced chiral Z-olefin products from readily available E-olefin precursors are faced with huge difficulties associated with the energetic uphill process. A possible solution to this issue is taking advantage of the different kinetic behaviors between Z- and E-olefins. However, recognizing the different reactivities between Z- and E-olefins poses great challenges for molecular catalysis. Herein, we report an Ir-catalyzed Z-selective asymmetric allylic substitution using oxindoles as nucleophiles via the kinetic resolution of Z/E olefin mixtures. The higher reactivity of Z-allylic carbonates than their E-counterparts in this reaction manifold originates from the faster oxidative addition of Z-allylic carbonates to the Ir(I) catalyst and the faster nucleophilic attack to anti-pi-allyl-Ir intermediates than that to syn-pi-allyl-Ir intermediates by external nucleophiles. When coupled with photoinduced olefin E/Z isomerization, the same products are accessed from E-allylic carbonates in up to 97% yield with 96% ee and >19:1 Z/E ratio. The results reported in this study represent an unprecedented pattern in asymmetric Tsuji-Trost-type reactions, a class of fundamental transformations in organic synthesis, and provide a unique approach to advanced chiral Z-olefins.

Steroid natural products (SNPs) play an indispensable role in drug discovery owing to their remarkable structural features and biological activities. However, the inadequate amounts of steroid samples derived from natural sources has limited thorough assessment of SNP bioactivities. Accordingly, chemical synthesis of these compounds has become an important, practical way to obtain them in sufficient quantities. Chemists have been focusing on efficient synthesis of SNPs since the 1930s, and significant breakthroughs have been achieved in the past few decades. This review presents advances in this field over the past 20 years, highlighting key C-C bond formation and reorganization reactions in the construction of steroidal skeletons, as well as redox-relay events for the installation of complex oxidation states. We hope this review will serve as a timely reference to allow researchers to quickly learn about state-of-the-art achievements in SNP synthesis and will inspire the development of more powerful strategies for natural product synthesis.

Room-temperature organic afterglow materials hold great promise for the development of advanced anticounterfeiting technologies, making it crucial to create scalable materials suitable for diverse applications. In this study, we successfully combined biomass-based materials with phosphorescence dopants to synthesize a novel biomass-based organic afterglow adhesive. When applied to plastic substrates, this adhesive not only exhibited a yellow-green afterglow lasting over 30 s but also demonstrated exceptional adhesive performance. The synergistic interaction between the adhesive and plastic substrates enabled the manifestation of roomtemperature phosphorescence. By simulating various application scenarios, we further validated the adhesive's significant potential in anti-counterfeiting applications. Importantly, the synthesis process employed costeffective, readily available, and environmentally friendly materials, laying a solid foundation for industrial-scale production.

Organometallic compounds can undergo intramolecular C-H activation to form cyclometallic species, which can then undergo selective ring-opening to enable a through space migration of the metal atom within the molecule. Compared to the widely studied heteroatom-directed C-H activation reactions, this process is more complex and difficult to control. Over the past decade, significant progress has been made in this area, providing powerful new tools for the functionalization of remote C-H bonds. The aryl-to-vinylic 1,4-palladium migration represents one of the most significant research area in this field. Although it faces challenges, including the migration of palladium to the thermodynamically less stable vinyl position and the inherent diverse reactivity of alkenes, it provides a novel strategy for the highly stereoselective synthesis of polysubstituted alkenes. Owing to its considerable academic and practical significance, this method has garnered widespread attention. This review summarizes the key mechanisms of aryl-to-vinylic 1,4-palladium migration, various transformation reactions, and potential synthetic applications. Finally, the challenges encountered in this field and prospects for future development are discussed.

In the past decade, visible-light-mediated photocatalysis has emerged as an applicable strategy for the generation of diverse radical species via single electron transfer (SET) and energy transfer (EnT) processes. Within this context, visible-light-mediated hydrogen atom transfer (HAT) has attracted major interest due to its mild and environmentally benign conditions applied in the selective activation of C-H bonds. Strategies employing C- and heteroatom-centered radical species to selectively activate C-H bonds have become versatile tools due to their mildness and good functional group compatibility for synthesizing value-added products. In this regard, a review on C-centered radical-promoted HAT processes was reported by Gevorgyan's group (Chem. Sci. 2020, 11, 12974, DOI: 10.1039/d0sc04881j), and a review on visible-light-promoted remote C-H functionalization via 1,5-HAT was recently reported by Zhu's group (Chem. Soc. Rev. 2021, DOI: 10.1039/d0cs00774a). Compared to N- and O-centered radical-promoted HAT processes, C(sp(3))-centered radical-promoted HAT is more challenging and less explored due to the small differences in C-H bond dissociation energies. Additionally, in the realm of C-centered radical-promoted HAT, the generation of C-centered radicals has mostly involved SET processes, while the EnT-mediated C-centered radical-promoted HAT process has been less discussed because of the considerable scarcity of related reports. As a result of the rapid advancement of EnT catalysis in synthetic chemistry, C-C-centered biradical species can be readily generated from C=C double bonds via the EnT process using a photocatalyst under visible-light irradiation. An array of transformations (such as cycloaddition and isomerization) involving these C-C-centered biradical species have been reported. Our group recognized these C-C-centered biradicals as practical initiators of the HAT process in C-H functionalization reactions and devoted considerable effort to this field. Initially, we used a triplet excited allene moiety to realize remote sp(3) C-H bond activation successfully. Later, a visible-light-induced triplet biradical HAT reaction of diarylethylenes was disclosed by our group. To further enhance its synthetic applicability, we applied simple styrene derivatives to realize such a novel EnT-mediated HAT process. Detailed control experiments combined with comprehensive density functional theory calculations elucidated the reaction mechanisms of these biradical-mediated HAT reactions along with the subsequent transformations of the obtained products.In addition to the advancements achieved in our group, Bach, Petersen, and others also reported such EnT-mediated HAT processes utilizing aryl acrylamide or aryl acrylate derivatives. Given the rapid progress over the past 5 years and the lack of focused discussion in this area, it is necessary to highlight these reports as a complement to the area of visible-light-mediated HAT via carbon-to-carbon processes. We anticipate that this Account will offer worthwhile insights and serve as guidance for future related research.

Acospectoside A (1) and acovenoside B (2), two cytotoxic cardenolides extracted from the venomous South African bush Acokanthera oppositifolia, are distinguished by their unique structural motifs of the l-acovenose moiety at C-3 and a 1 beta-O-acetylated cardenolide aglycone. Here, we report the synthesis of these cardiac glycosides featuring delicate introductions of the 1-O-acetyl group under acid-catalyzed conditions, 14 beta-OH by Mukaiyama hydration, and a C17-butenolide moiety by Stille coupling.

Covering: 2013-2024Benefiting significantly from recent advances in genome mining, ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products have emerged as a source of chemical inspiration to drive the discovery of therapeutic agents and the development of new biological tools for addressing challenges to synthetic approaches. Despite being confined to twenty proteinogenic amino acid building blocks, the structural complexity and diversity of RiPPs that arise from enzymatic posttranslational modifications (PTMs) surpass expectations and are now believed to be comparable to those produced by non-ribosomal peptide synthetases. Here, we highlight the PTM enzymes characterized over the past decade that engage the -(NH-C alpha-CO)n- repeating units in transformations, particularly those leading to structural rearrangements by peptide backbone remodeling. Unveiling the catalytic mechanisms of these unusual PTM enzymes deepens the understanding in RiPP biosynthesis and, eventually, will enhance our capability of rational design, development and production of functional peptide agents using synthetic biology strategies.

Supramolecular stereocomplexation is an important tool to advance sustainable polymers, and oxygen-containing polymers represent the most widely studied materials for stereocomplexation. However, the sulfur-containing analogues, a newly emerged class of sustainable polymers, remain essentially unexplored because of a significant challenge encountered in the synthesis of stereoregular polymers and relatively low supramolecular interaction. In this contribution, by the utilization of [Et3O]+[B(C6F5)4]- as a metal-free cationic initiator, controlled isomerization-driven ring-opening polymerizations (IROPs) of nine examples of chiral five-membered thionolactones have been achieved with free or suppressed racemization via unique monomer-stabilized SN2 propagation mechanism, which allows an unprecedented access to a library of new stereoregular polythioesters with high isotacticities (80.0%-99.5%). The investigations into structure-stereocomplexation relationship led to the disclosure of two new polythioester stereocomplexes with high melting temperatures (117.0-161.0 degrees C). The fundamental aspects of stereocomplex formation mechanism and critical factors that affect stereocomplexed ability have also been revealed.

An air-stable P-chiral bisoxaphospholane ligand (2S,2 ' S,3R,3 ' R)-BIOP is designed and developed. Ligand BIOP has shown high efficiency in rhodium-catalyzed asymmetric hydroformylation of various allylic-type terminal olefins, providing chiral 2-methyl-3-arylpropan-1-ols, 2-methyl-3-aryloxypropan-1-ols, and 4-hydroxy-3-methyl-N-arylbutanamides in excellent enantioselectivities (up to 97% ee) and good b/l ratios (up to 11.9:1).

Pyrazolidinones, as significant analogs of ,B-lactam antibiotics, have garnered substantial interest for their enantioselective synthesis. Azomethine imines, recognized as valuable building blocks for the construction of these nitrogen-containing compounds, underscore the continuous pursuit of novel building blocks and reaction methodologies within the chemical community. In this paper, we present a cascade cyclization between alkenyl azomethine imines and furan-2(5H)-one to generate chiral coronal polyheterocyclic compounds with high yields and enantioselectivities, catalyzed by dipeptide-derived phosphonium salts. In-vitro biological activity assays highlight the potential of these chiral compounds in drug discovery. Additionally, density functional theory (DFT) calculations elucidate the pivotal role of phosphonium salts, demonstrating their cooperative activations via hydrogen bonding and ion-pairing interactions. (c) 2025 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Olefins are fundamental functional groups present in numerous molecules, and the geometrical configuration of the C=C bonds often plays a critical role in determining the properties of these compounds. Alkenyl geometrical isomerization is, in principle, one of the most efficient approaches for accessing stereodefined olefins. While some progress has been made in achieving unidirectional Z -> E or E -> Z conversion via olefin geometrical isomerization, there remains a strong demand for controllable, bidirectional geometrical isomerization of C=C bonds. Herein, we present a method for Z/E mutual isomerization of alkenyl groups by using a Pd/Cu catalytic system. This process involves Pd-mediated pi-sigma-pi interconversion followed by selective trapping of the pi-allyl-Pd intermediates with N-metalated azomethine ylides generated by a chiral Cu-catalyst. The reaction enables the synthesis of chiral non-natural amino acid derivatives bearing Z- and E-alkenyl groups in an enantio- and Z/E-divergent manner, achieving yields of up to 92%, > 20:1 Z/E or E/Z, and >99% ee. Furthermore, the reaction is scalable to gram quantities, and the resulting products can be transformed into valuable molecules adorned with Z- or E-alkenyl groups. Computational studies show that the bimetallic catalytic system better distinguishes among eight stereoisomers of pi-allyl-Pd intermediates than the monometallic system, which results in exceptional Z/E-selectivity of the products. This method offers a robust protocol for synthesizing Z- or E-trisubstituted olefins bearing a chiral motif utilizing a readily available Z/E-mixture of substrates.

The C-H bond functionalization has been widely used in chemical synthesis over the past decade. However, regio- and stereoselectivity still remain a significant challenge, especially for inert aliphatic C-H bonds. Here we report the mechanism of three Fe(II)/alpha-ketoglutarate-dependent dioxygenases in bicyclomycin synthesis, which depicts the natural tactic to sequentially hydroxylate specific C-H bonds of similar substrates (cyclodipeptides). Molecular basis by crystallographic studies, computational simulations, and site-directed mutagenesis reveals the exquisite arrangement of three enzymes using mutually orthogonal strategies to realize three different regio-selectivities. Moreover, this programmable selective hydroxylation can be extended to other cyclodipeptides. This evidence not only provides a naturally occurring showcase corresponding to the widely used methods in chemical catalysis but also expands the toolbox of biocatalysts to address the regioselective functionalization of C-H bonds.

Here, we report a highly efficient rhodium-catalysed enantioselective hydrosilylation of unactivated alkenes, achieving excellent regioselectivity and high enantioselectivity. The use of a commercially available chiral ferrocene-based phosphine-oxazoline ligand was crucial in achieving excellent chiral induction and high reactivity with undirected unactiviated alkenes, delivering Si-stereogenic monohydrosilanes in high yields and excellent enantioselectivities. This protocol represents a robust, scalable method for the enantioselective synthesis of Si-stereogenic monohydrosilanes, featuring a low catalyst loading, a broad substrate scope and exceptional functional group and heterocycle tolerance. Moreover, the late-stage functionalization of complex motifs opens a new avenue for incorporating chiral silicon motifs into pharmaceuticals and bioactive compounds.

Here, we report an effective approach to the synthesis of anticoagulant fondaparinux, utilizing orthogonal one-pot [1+2+2] glycosylation, simultaneous O,N-sulfation and global debenzylation at atmospheric pressure as key steps. The synthetic route was achieved through the longest linear sequence of 12 steps with 19% overall yield from a commercially available disaccharide. The present synthetic route remarkably enhances synthetic efficiency and streamlines the purification process, thereby opening up a new avenue for the large-scale synthesis of fondaparinux and relevant heparin fragments.

Abnormal aggregation of amyloid-beta protein (1-42) (A beta 42) is the primary pathology in Alzheimer's disease (AD). Two types of A beta 42 fibrils have been identified in the insoluble fraction of diseased human brains. Here, we report that the fraction previously deemed 'soluble' during sarkosyl extraction of AD brains actually harbors numerous amyloid fibrils, with a looser bundling than those in the insoluble fraction. Using cryo-electron microscopy (cryo-EM), we discover a third type (type III) of A beta 42 fibril that is occasionally found in the soluble but not insoluble fraction of one AD brain. We also reveal that cryo-EM structures of A beta 42 fibrils complexed with the positron emission tomography tracer AV-45 show a ligand-binding channel within type I but not type III A beta 42 fibrils. In this binding channel, AV-45 engages with a vertical geometry. Through the discovery of this new structural polymorph of ex vivo A beta 42 fibril, our study highlights the notable structural heterogeneity of A beta fibrils among persons with AD.