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. These investigations are categorized based on the specific ring formations they engender, accentuating the prevailing gold-catalyzed methodologies applied to surmount intricate challenges in natural products synthesis.

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 (MgBr2·Et2O) 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. Eventually, a new and scalable synthetic route toward (-)-vinigrol was developed and provided over 600 mg materials, manifesting the power of macrocyclic stereocontrol and TADA reaction.

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. Our study indicates that targeting the PDI-ADAM17 signaling module to regulate the shedding of cytokine receptors by the chemical approach constitutes a promising strategy for alleviating RA.

Enantioselective Total Synthesis of (-)-Zygadenine.

The Veratrum 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. Subsequently, a meticulously designed sequence of redox manipulations was optimized to achieve the de novo synthesis of this highly oxidized Veratrum alkaloid.

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. Our in vitro studies show that lepadins E and H exhibit significant cytotoxicity, promote p53 expression, increase ROS production and lipid peroxides, reduce SLC7A11 and GPX4 levels, and upregulate ACSL4 expression, all of which consistently support induction of ferroptosis through the classical p53-SLC7A11-GPX4 pathway. Our animal model study of lepadin H confirms its in vivo antitumor efficacy with negligible toxicity to normal organs. This work elucidates the mode of action of lepadins (E and H) and verifies their in vivo efficacy as a new class of ferroptosis inducers for anticancer therapy with translational potential.

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-endo-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. Extensive studies of late-stage functional group manipulation were performed to forge the C1 stereogenic center, during which a photoexcited intramolecular hydrogen atom transfer reaction was discovered and the mechanism was further studied through density functional theory (DFT) calculations. The biomimetic 1,2-rearrangement from the grayanoid skeleton provided a 5/8/5/5 tetracyclic framework and resulted in the first total synthesis of (+)-kalmanol.

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.

A small-molecule approach towards the Fountain of Youth: chemically induced pluripotent stem cells.

Generation and regeneration as an answer to disease treatment has been around for some time. Yet never have we come so close to reaching such 'life-altering' capabilities. Today, the field of regenerative medicine research focuses on replacing non-functional or dead cells with healthy ones, in order to repair or regenerate tissues and organs to restore normal functions. Pluripotent stem cells have the ability of long-term self-renewal and possess the potential to differentiate to all kinds of functional cells in humans. Therefore, how to directly obtain a large number of pluripotent stem cells from patients in vitro, to be grown into differentiated specific tissues and organs, has become one of the most important topics. Six decades ago, Gurdon's group discovered that cell differentiation is a reversible process [1], laying down the foundation for cell reprogramming research. Commonly there are biological and chemical methods for the acquisition of pluripotent stem cells in vitro, which also aim to produce further differentiated specific tissues and organs. Fifteen years ago, Yamanaka's group first reported the acquisition of induced pluripotent stem cells (iPSCs) via overexpression of four transcription factors OSKM to the somatic cells [2]. Chemical reprogramming-using cell permeable small molecules to manipulate the cell fates-has also progressed significantly. Hongkui Deng at Peking University and his co-workers reported that a combination of small molecule compounds could induce pluripotent stem cells from mouse somatic cells with an induction efficiency as high as 0.2% in 2013 [3]. After long-term persistence and unremitting efforts, Deng's group announced the acquisition of chemically induced pluripotent stem cells (CiPSCs) from human fibroblasts through a step-wised chemical reprogramming strategy in 2022. This technology for preparing human CiPSCs solves the underlying technical bottleneck for the development of stem cells and regenerative medicine, and advances the application of cell reprogramming towards a new stage [4]. As the progress in human cell reprogramming led to sufficient resources of CiPSCs, chemically induced cell fate trans differentiation research also brought us surprises. Deng and colleagues not only demonstrated that small molecules can reprogram astrocytes into neurons in the adult mouse brain, which provides a potential approach for developing neuronal replacement therapies [5], but also constructed a bio-artificial liver device through directed differentiation of human pluripotent stem cells to hepatic cells [6]. Recently, Deng and colleagues established an efficient method for producing islet cells from human CiPSCs and demonstrated that these cells were able to ameliorate diabetes in non-human primates [7]. CiPSCs might be considered to have potential in the fields of cell therapy, drug screening and disease modeling, and are the most critical 'seed cells' in the field of regenerative medicine. Emerging as important regulators of cell fate, natural product small molecules and their derivatives have played an important role in Deng's work. NSR spoke to Hongkui Deng about the highlights and possibilities of the field.

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. Evidence is provided that the salivaricins exert immunomodulatory effects in inhibiting T follicular helper (Tfh) cell differentiation and interleukin-21 (IL-21) production. Mechanically, salivaricins directly bind to and induce conformational changes of IL-6 and IL-21 receptors, thereby inhibiting the bindings of IL-6 and IL-21 to their receptors and suppressing the downstream signaling pathway. Finally, salivaricin administration exerts both prophylactic and therapeutic effects against experimental arthritis in a murine model of RA. Together, these results provide a mechanism link of microbial peptides-mediated immunomodulation.

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-endo-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(sp3)-C(sp2) 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(sp3)-C(sp2) 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. Accordingly, late-stage diversification provides an opportunity to rapidly access various derivatives for modifying lead compounds, identifying cellular targets, probing protein-protein interactions, and elucidating natural product biosynthetic relationships.

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. However, its structure and mechanism remain elusive since its discovery. Here, we report the structure of human SOAT1 (hSOAT1) determined by cryo-EM. hSOAT1 is a tetramer consisted of a dimer of dimer. The structure of hSOAT1 dimer at 3.5 Å resolution reveals that a small molecule inhibitor CI-976 binds inside the catalytic chamber and blocks the accessibility of the active site residues H460, N421 and W420. Our results pave the way for future mechanistic study and rational drug design targeting hSOAT1 and other mammalian MBOAT family members.

Elimination of senescent cells by ß-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. Herein, we developed a prodrug strategy to design a new compound based on the increased activity of lysosomal ß-galactosidase (ß-gal), a primary characteristic of senescent cells. Our prodrug SSK1 is specifically activated by ß-gal and eliminates mouse and human senescent cells independently of senescence inducers and cell types. In aged mice, our compound effectively cleared senescent cells in different tissues, decreased the senescence- and age-associated gene signatures, attenuated low-grade local and systemic inflammation, and restored physical function. Our results demonstrate that lysosomal ß-gal can be effectively leveraged to selectively eliminate senescent cells, providing a novel strategy to develop anti-aging interventions.

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.

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[3.2.0]hept-3-ene as the substrate. We utilized this methodology as the key reaction to synthesize 17-deacetoxyl chromodorolide B.