Synthesis of (+)-Saxitoxin Facilitated by a Chiral Auxiliary for Photocycloadditions Involving Alkenylboronate Esters.

(+)-Saxitoxin, a potent neurotoxin and Na blocker, poses significant synthetic challenges due to its compact tricyclic framework and guanidinium moieties. We report a concise and asymmetric total synthesis featuring an intramolecular [2 + 2] photocycloaddition of an alkenylboronate ester equipped with a new chiral auxiliary. This auxiliary, compatible with UV light and easily exchangeable on B(pin) derivatives, enabled high stereocontrol through hydrogen-bond-mediated transition-state stabilization.

Enantioselective Total Syntheses of (+)-Kobusine, (+)-Spirasine IX and the Purported Structure of (+)-Orgetine: Strategic Use of C-H Bonds.

Enantioselective total syntheses of (+)-kobusine, (+)-spirasine IX and the proposed structure of (+)-orgetine were achieved. A unique approach was developed to construct a cage-like hexacyclic ring system that underwent an HAT-initiated radical rearrangement to forge the hetisine-type scaffold. Subsequent late-stage redox manipulations, including an intramolecular hydride shift, were deployed to provide different C20-diterpenoid alkaloids.

Divergent syntheses of complex Veratrum alkaloids.

The Veratrum alkaloids are a class of highly intricate natural products renowned for their complex structural and stereochemical characteristics, which underlie a diverse array of pharmacological activities ranging from anti-hypertensive properties to antimicrobial effects. These properties have generated substantial interest among both synthetic chemists and biologists. While numerous advancements have been made in the synthesis of jervanine and veratramine subtypes over the past 50 years, the total synthesis of highly oxidized cevanine subtypes has remained relatively scarce.

Global profiling of functional histidines in live cells using small-molecule photosensitizer and chemical probe relay labelling.

Recent advances in chemical proteomics have focused on developing chemical probes that react with nucleophilic amino acid residues. Although histidine is an attractive candidate due to its importance in enzymatic catalysis, metal binding and protein-protein interaction, its moderate nucleophilicity poses challenges. Its modification is frequently influenced by cysteine and lysine, which results in poor selectivity and narrow proteome coverage.

Gold-catalyzed cyclization and cycloaddition in natural product synthesis.

Covering: 2016 to mid 2023Transition metal catalysis, known for its remarkable capacity to expedite the assembly of molecular complexity from readily available starting materials in a single operation, occupies a central position in contemporary chemical synthesis. Within this landscape, gold-catalyzed reactions present a novel and versatile paradigm, offering robust frameworks for accessing diverse structural motifs. In this review, we highlighted a curated selection of publications in the past 8 years, focusing on the deployment of homogeneous gold catalysis in the ring-forming step for the total synthesis of natural products.

Enantioselective Total Synthesis of (-)-Vinigrol: The Evolution of a Transannular Diels-Alder Strategy.

Vinigrol is a structurally and stereochemically complex diterpenoid that displays various potent pharmacological activities. Two generations of synthetic routes were designed and pursued based on a transannular Diels-Alder (TADA) cycloaddition strategy. An intramolecular [2 + 2]photocycloaddition in the presence of the chelating Lewis acid (MgBr·EtO) was first discovered to enable the reaction of sterically challenging substrates, which was followed by [2 + 2]cycloreversion to provide α-pyrones fused with a 10-membered ring.

Photoaffinity labeling coupled with proteomics identify PDI-ADAM17 module is targeted by (-)-vinigrol to induce TNFR1 shedding and ameliorate rheumatoid arthritis in mice.

Various biological agents have been developed to target tumor necrosis factor alpha (TNF-α) and its receptor TNFR1 for the rheumatoid arthritis (RA) treatment, whereas small molecules modulating such cytokine receptors are rarely reported in comparison to the biologicals. Here, by revealing the mechanism of action of vinigrol, a diterpenoid natural product, we show that inhibition of the protein disulfide isomerase (PDI, PDIA1) by small molecules activates A disintegrin and metalloprotease 17 (ADAM17) and then leads to the TNFR1 shedding on mouse and human cell membranes. This small-molecule-induced receptor shedding not only effectively blocks the inflammatory response caused by TNF-α in cells, but also reduces the arthritic score and joint damage in the collagen-induced arthritis mouse model.

Enantioselective Total Synthesis of (-)-Zygadenine.

The alkaloids are highly complex steroidal alkaloids characterized by their intricate structural and stereochemical features and exhibit a diverse range of pharmacological activities. A new synthetic pathway has been developed to access this family of natural products, which enabled the first total synthesis of (-)-zygadenine. This synthetic route entails the construction of a hexacyclic carbon skeleton through a stereoselective intramolecular Diels-Alder reaction, followed by a radical cyclization.

Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy.

Induction of ferroptosis emerges as an effective method for cancer treatment. With massive efforts to elucidate the ferroptosis mechanism, the development of new ferroptosis inducers proceeds rather slowly, with only a few small molecules identified. Herein, we report our discovery of marine alkaloid lepadins E and H as a new class of ferroptosis inducers.

Enantioselective Total Syntheses of Grayanane Diterpenoids and (+)-Kalmanol: Evolution of the Bridgehead Carbocation-Based Cyclization and Late-Stage Functional Group Manipulation Strategies.

Grayanane diterpenoids contain over 300 highly oxidized and structurally complex members, many of which possess important biological activities. Full details are provided for the development of the concise, enantioselective and divergent total syntheses of grayanane diterpenoids and (+)-kalmanol. The unique 7--trig cyclization based on a bridgehead carbocation was designed and implemented to construct the 5/7/6/5 tetracyclic skeleton, demonstrating the practical value of the bridgehead carbocation-based cyclization strategy.

Pro-aromaticity Enabled Dealkenylative Functionalizations via Photo-Excitation and Oxidation.

A general and practical approach for diverse dealkenylative functionalization of olefin-containing substrates has been developed through the one-pot formation and utilization of pro-aromatic 1,4-dihydropyridazines using tetrazine as the key cycloaddition reagent. Triggered by either excitation or oxidation, the targeted C-C bonds in the 1,4-dihydropyridazine intermediates could be readily cleaved to generate alkyl radicals for subsequent transformations. Diverse carbon-carbon and carbon-hetero bond forming protocols, including Giese-type addition, hydrazination, borylation, Minisci-type alkylation, copper-catalyzed NH alkylation, acylation, alkynylation, cyanation, and azidation, are achieved in a highly modular fashion.

Total Synthesis of (+)-Mutilin: A Transannular [2+2] Cycloaddition/Fragmentation Approach.

A new and enantioselective total synthesis of the diterpenoid (+)-mutilin is described. Following a Claisen rearrangement approach to construct the 6,9-bicycle, a transannular [2+2] photocycloaddition and the ensuing ring-opening reaction were implemented to forge the characteristic 5-6-8 propellane-like skeleton. Subsequent late-stage alkylations and reduction completed the synthesis.

Tonsillar Microbiome-Derived Lantibiotics Induce Structural Changes of IL-6 and IL-21 Receptors and Modulate Host Immunity.

Emerging evidence emphasizes the functional impacts of host microbiome on the etiopathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). However, there are limited mechanistic insights into the contribution of microbial biomolecules especially microbial peptides toward modulating immune homeostasis. Here, by mining the metagenomics data of tonsillar microbiome, a deficiency of the encoding genes of lantibiotic peptides salivaricins in RA patients is identified, which shows strong correlation with circulating immune cells.

Enantioselective Total Syntheses of Grayanane Diterpenoids: (-)-Grayanotoxin III, (+)-Principinol E, and (-)-Rhodomollein XX.

Enantioselective total syntheses of (-)-grayanotoxin III, (+)-principinol E, and (-)-rhodomollein XX were accomplished based on a convergent strategy. The left- and right-wing fragments were assembled via the diastereoselective Mukaiyama aldol reaction catalyzed by a chiral hydrogen bond donor. The unique 7--trig cyclization based on a bridgehead carbocation forged the 5/7/6/5 tetracyclic skeleton that underwent redox manipulations and 1,2-migration to access different grayanane diterpenoids.

Scalable Total Synthesis of (-)-Triptonide: Serendipitous Discovery of a Visible-Light-Promoted Olefin Coupling Initiated by Metal-Catalyzed Hydrogen Atom Transfer (MHAT).

An efficient and scalable total synthesis of (-)-triptonide is accomplished based on a metal-catalyzed hydrogen atom transfer (MHAT)-initiated radical cyclization. During the optimization of the key step, we discovered that blue LEDs significantly promoted the efficiency of reaction initiated by Co(TPP)-catalyzed MHAT. Further exploration and optimization of this catalytic system led to development of a dehydrogenative MHAT-initiated Giese reaction.

Dealkenylative Ni-Catalyzed Cross-Coupling Enabled by Tetrazine and Photoexcitation.

A new and general method to functionalize the C(sp)-C(sp) bond of alkyl and alkene linkages has been developed, leading to the dealkenylative generation of carbon-centered radicals that can be intercepted to undergo Ni-catalyzed C(sp)-C(sp) cross-coupling. This one-pot protocol leverages the easily procured alkene feedstocks for organic synthesis with excellent functional group compatibility without the need for a photoredox catalyst.

Late-Stage Diversification of Natural Products.

Late-stage diversification of natural products is an efficient way to generate natural product derivatives for drug discovery and chemical biology. Benefiting from the development of site-selective synthetic methodologies, late-stage diversification of natural products has achieved notable success. This outlook will outline selected examples of novel methodologies for site-selective transformations of reactive functional groups and inert C-H bonds that enable late-stage diversification of complex natural products.

Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor.

Sterol O-acyltransferase 1 (SOAT1) is an endoplasmic reticulum (ER) resident, multi-transmembrane enzyme that belongs to the membrane-bound O-acyltransferase (MBOAT) family. It catalyzes the esterification of cholesterol to generate cholesteryl esters for cholesterol storage. SOAT1 is a target to treat several human diseases.

Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice.

Cellular senescence, a persistent state of cell cycle arrest, accumulates in aged organisms, contributes to tissue dysfunction, and drives age-related phenotypes. The clearance of senescent cells is expected to decrease chronic, low-grade inflammation and improve tissue repair capacity, thus attenuating the decline of physical function in aged organisms. However, selective and effective clearance of senescent cells of different cell types has proven challenging.

Synthesis of 17-Deacetoxyl Chromodorolide B Based on a Gold-Catalyzed Alkoxycyclization Reaction.

A novel strategy to construct the highly oxidized 3-oxabicyclo[3.3.0]octane skeleton was developed via a gold-catalyzed cascade cyclization with 2,7-dioxabicyclo[3.

Total Synthesis of (-)-Batrachotoxinin A: A Local-Desymmetrization Approach.

An enantioselective total synthesis of (-)-batrachotoxinin A is accomplished based on a key photoredox coupling reaction and the subsequent local-desymmetrization operation. After the expedient assembly of the highly oxidized steroid skeleton, a delicate sequence of redox manipulations was carried out to deliver a late-stage intermediate on gram scale-and ultimately (-)-batrachotoxinin A in an efficient manner.

Total Synthesis of (-)-Oridonin: An Interrupted Nazarov Approach.

An enantioselective total synthesis of (-)-oridonin is accomplished based on a key interrupted Nazarov reaction. The stereochemistry of the Nazarov/Hosomi-Sakurai cascade was first explored to forge a tetracyclic skeleton with challenging quaternary carbons. A delicate sequence of two ring-rearrangements and late-stage redox manipulations was carried out to achieve the de novo synthesis of this highly oxidized -kauranoid.