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Understanding organic reaction mechanisms is crucial for interpreting the formation of products at the atomic and electronic level, but still remains as a domain of knowledgeable experts. The lack of a large-scale dataset with chemically reasonable mechanistic sequences also hinders the development of reliable machine learning models to predict organic reactions based on mechanisms as human chemists do. Here, we present a high-quality and the first large-scale reaction dataset, denoted as mech-USPTO-31K, with chemically reasonable arrow-pushing diagrams validated by synthetic chemists, encompassing a wide spectrum of polar organic reaction mechanisms. We envision this dataset curated by applying a simple and flexible method that automatically generates reaction mechanisms using autonomously extracted reaction templates and expert-coded mechanistic templates to become an invaluable tool to develop future reaction outcome prediction models and discover new reactions.
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Chemical synthesis plays a crucial role in confirming and revising the structures of natural products. Through meticulous synthetic efforts, NMR spectroscopic and single-crystal X-ray diffraction analyses, DFT calculations, and mass spectrometric investigations, we revised the structure of securingine E. The revised structure of securingine E was unambiguously confirmed by its chemical synthesis.
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The isolation of a natural product conventionally precedes its chemical synthesis. Often, the isolation and structure determination of a natural product present in minute quantities in its natural source pose formidable challenges, akin to finding "a needle in a haystack." On the other hand, leveraging plausible biosynthetic insights and biomimetic synthetic expertise would allow for the prior synthesis of presumed natural products, followed by their verification in natural sources. In this study, we unveil two novel securinega alkaloids, securingines H and I, employing the natural product anticipation through synthesis approach. Structural analysis of securingines H and I suggests that they are biosynthetic derivatives of secu'amamine E and securinol A, respectively. We posit that this "synthesis first" strategy represents a valuable approach to the discovery of new natural products.
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The generation of radical intermediates via SET-mediated deoxygenation of activated alcohol derivatives is desirable, as alcohols can be utilized in various radical-mediated reactions. Herein, we introduce α-N-phthalimido-oxy isobutyrate (NPIB) as a novel activating group for alcohols. Essentially, it is a more chemically robust alternative to Overman's N-phthalimidoyl oxalate group. The utility of the NPIB group is showcased in the conversion of tertiary alcohols to nitriles under Ir/Cu dual catalysts and in the presence of TMSCN upon blue LED irradiation. With our newly developed NPIB handle, the reactivities of N-hydroxyphthalimide esters derived from carboxylic acids would be achievable with naturally and commercially more abundant alcohol substrates.
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In this study, we present the first total synthesis of (-)-securingine G. Diverging from the proposed biosynthetic pathway, our approach involves the addition of nucleophilic pyridine anion species to the electrophilic menisdaurilide congener. Crucially, incorporating a weakly basic yet nucleophilic tri(2-pyridinyl)lanthanum complex proved essential to circumvent undesired base-mediated pathways during the key coupling reaction. Notably, we introduce n-Bu3La·5LiCl as a new exchange reagent, facilitating efficient halide/lanthanum exchange of (hetero)aryl halides.
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Securinega alkaloids have intrigued chemists since the isolation of securinine in 1956. This family of natural products comprises a securinane subfamily with a piperidine substructure and norsecurinane alkaloids featuring a pyrrolidine core. From a biosynthetic perspective, the piperidine moiety in securinane alkaloids derives from lysine, whereas the pyrrolidine moiety in norsecurinane natural products originates from ornithine, marking an early biogenetic divergence. Herein, we introduce a single-atom deletion strategy that enables the late-stage conversion of securinane to norsecurinane alkaloids. Notably, for the first time, this method enabled the transformation of piperidine-based (allo)securinine into pyrrolidine-based (allo)norsecurinine. Straightforward access to norsecurinine from securinine, which can be readily extracted from the plant Flueggea suffruticosa, abundant across the Korean peninsula, holds promise for synthetic studies of norsecurinine-based oligomeric securinega alkaloids.
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Efficiently generating intricate molecular complexity is a coveted goal in organic synthesis. This can be realized through the implementation of inventive and audacious strategies coupled with the exploration and advancement of novel molecular reactivity pathways. Herein, we present a concise two-step synthesis of a high-oxidation state heterotrimeric securinega alkaloid, suffranidine B, from 2,3-dehydroallosecurinine and the vinylogous ketoaldehyde compound derived from kojic acid. Key to the success was the astute selection of appropriate acids during both the heterotrimerization and the desymmetrizing cyclization steps. This study underscores the value of biomimicry in the synthesis of complex natural products.
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Securinega alkaloids, composed of more than 100 members characterized by the compact tetracyclic scaffold, have fascinated the synthetic community with their structural diversity and notable bioactivities. On the basis of the structural phenotype, oligomerizations and oxidations are major biosynthetic diversification modes of the basic Securinega framework. Despite the rich history of synthesis of basic monomeric Securinega alkaloids, the synthesis of oligomeric Securinega alkaloids, as well as oxidized derivatives, has remained relatively unexplored because of their extra structural complexity. In the first half of this Account, our synthetic studies toward high-order Securinega alkaloids are described. We aimed to establish a reliable synthetic method to form C14-C15' and C12-C15' bonds, which are prevalent connection modes between monomers. During our total synthesis of flueggenine C (9), we have invented an accelerated Rauhut-Currier reaction capable of forming the C14-C15' bond stereoselectively. Installation of the nucleophilic functionality to the Michael acceptor, which ushers the C-C bond forming conjugate addition to follow the intramolecular pathway, was the key to success. The C12-C15' linkage, which was inaccessible via an accelerated Rauhut-Currier reaction, was established by devising a complementary cross-coupling/conjugate reduction-based dimerization strategy that enabled the total synthesis of flueggenines D (11) and I (14). In this approach, the C12-C15' linkage was established via a Stille cross-coupling, and the stereochemistry of the C15' position was controlled during the following conjugate reduction step. In the later half of this Account, our achievements in the field of high-oxidation state Securinega alkaloids synthesis are depicted. We have developed oxidative transformations at the N1 and C2-C4 positions, where the biosynthetic oxidation event occurs most frequently. The discovery of a VO(acac)2-mediated regioselective Polonovski reaction allowed us to access the key 2,3-dehydroallosecurinine (112). Divergent synthesis of secu'amamine A (62) and fluvirosaones A (60) and B (61) was accomplished by exploiting the versatile reactivities of the C2/C3 enamine moiety in 112. We have also employed a fragment-coupling strategy between menisdaurilide and piperidine units, which allowed the installation of various oxygen-containing functionality on the piperidine ring. Combined with the late-stage, light-mediated epimerization and well-orchestrated oxidative modifications, collective total synthesis of seven C4-oxygenated securinine-type natural products was achieved. Lastly, the synthesis of flueggeacosine B (70) via two synthetic routes from allosecurinine (103) was illustrated. The first-generation synthesis (seven overall steps) employing Pd-catalyzed cross-coupling between stannane and thioester to form the key C3-C15' bond enabled the structural revision of the natural product. In the second-generation synthesis, we have invented visible-light-mediated, Cu-catalyzed cross-dehydrogenative coupling (CDC) between an aldehyde and electron-deficient olefin, which streamlined the synthetic pathway into four overall steps. Organisms frequently utilize dimerization (oligomerization) and oxidations during the biosynthesis as a means to expand the chemical space of their secondary metabolites. Therefore, methods and strategies for dimerizations and oxidations that we have developed using the Securinega alkaloids as a platform would be broadly applicable to other alkaloids. It is our sincere hope that lessons we have learned during our synthetic journey would benefit other chemists working on organic synthesis.
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Alcaloides , Securinega , Estereoisomerismo , PiperidinasRESUMEN
Securinega alkaloids have fascinated the synthetic chemical community for over six decades. Historically, major research foci in securinega alkaloid synthesis have been on the efficient construction of the fused tetracyclic framework that bears a butenolide moiety and tertiary amine-based heterocycles. These "basic" securinega alkaloids have evolved to undergo biosynthetic oxidative diversifications, especially on the piperidine core. However, a general synthetic solution to access these high-oxidation state securinega alkaloids is lacking. In this study, we have completed the total synthesis of various C4-oxygenated securinine-type alkaloids including securingines A, C, D, securitinine, secu'amamine D, phyllanthine, and 4-epi-phyllanthine. Our synthetic strategy features stereocontrolled oxidation, rearrangement, and epimerization at N1 and C2-C4 positions of the piperidine core within (neo)securinane scaffolds. Our discoveries provide a fundamental synthetic solution to all known securinine-type natural products with various oxidative and stereochemical variations around the central piperidine ring.
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Alcaloides , Euphorbiaceae , Azepinas , Compuestos Heterocíclicos de Anillo en Puente , Lactonas , Piperidinas , EstereoisomerismoRESUMEN
We previously discovered that triterpenoid saponin platycodin D inhibits the SARS-CoV-2 entry to the host cell. Herein, we synthesized various saponin derivatives and established a structure-activity relationship of saponin-based antiviral agents against SARS-CoV-2. We discovered that the C3-glucose, the C28-oligosaccharide moiety that consist of (â3)-ß-d-Xyl-(1 â 4)-α-l-Rham-(1 â 2)-ß-d-Ara-(1 â ) as the last three sugar units, and the C16-hydroxyl group were critical components of saponin-based coronavirus cell entry inhibitors. These findings enabled us to develop minimal saponin-based antiviral agents that are equipotent to the originally discovered platycodin D. We found that our saponin-based antiviral agents inhibited both the endosomal and transmembrane protease serine 2-mediated cell surface viral entries. Cell fusion assay experiment revealed that our newly developed compounds inhibit the SARS-CoV-2 entry by blocking the fusion between the viral and host cell membranes. The effectiveness of the newly developed antiviral agents over various SARS-CoV-2 variants hints at the broad-spectrum antiviral efficacy of saponin-based therapeutics against future coronavirus variants.
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COVID-19 , Saponinas , Antivirales/farmacología , Humanos , Fusión de Membrana , SARS-CoV-2 , Saponinas/farmacología , Relación Estructura-ActividadRESUMEN
We describe a method to generate alkylidene carbenes via tetramethylammonium-fluoride-induced desilylation of silyl vinyl iodides. The reversible carbene generation from an iodovinyl anion enabled us to unearth mechanistic aspects of the trimethylenemethane (TMM) diyl cyclization reaction that could not be explored via previous methods. We observed that a slow diyl-diylophile cycloaddition can induce the reversible formation of an alkylidene carbene from the TMM diyl intermediate via a retro-cyclopropanation at ambient temperature.
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We completed the synthesis of dimeric high-oxidation-state securinega alkaloid flueggeacosine B via two synthetic routes from allosecurinine. The first-generation synthesis (seven overall steps) involved a Liebeskind-Srogl cross-coupling reaction for the union of two functionalized fragments, the organostannane and the thioester. As a means to further streamline the synthetic route, we have developed a visible-light-mediated Cu-catalyzed cross-dehydrogenative coupling (CDC) reaction between an aldehyde and an electron-deficient olefin. This enabled the second-generation synthesis of flueggeacosine B from allosecurinine in four overall steps. The newly developed CDC reaction paves a direct way to a conjugated dicarbonyl moiety, a ubiquitous structural moiety present in various natural products.
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Alcaloides , Cobre/química , Securinega , Alquenos , Catálisis , PaladioRESUMEN
Rhodonoid natural products are found in nature as a scalemic mixture. This interesting phytochemical feature is presumed to originate from a reversible electrocyclic ring opening of the chromene core present in the biogenetic precursors of rhodonoids. Herein, we systematically investigated factors that are responsible for this racemization event. This eventually led us to complete the asymmetric total synthesis of rhodonoids A, C, D, and G.
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Productos Biológicos , BenzopiranosRESUMEN
Herein, we present the synthesis of 1-hydroxyherquline A and describe its reactivity discovered during its attempted conversion to herquline A, a long-sought natural product target in the synthetic chemical community. The strategic installation of the C1 hydroxyl group enabled the key aza-Michael addition-mediated N10-C2 bond formation and eventually access to 1-hydroxyherquline A, the most advanced herquline A congener reported to date. Our attempted reductive transformation of 1-hydroxyherquline A to herquline A was challenged by the extremely strained bowl-shaped pentacyclic structures of key precursors that prevented either radical formation at C1 or protonation (or hydrogenation) from the desired face. These discoveries regarding the innate chemical reactivities of advanced intermediates toward herquline A may prove useful in efforts toward this formidable target.
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Productos BiológicosRESUMEN
Biosynthetic processes often involve reorganization of one family of natural products to another. Chemical emulation of nature's rearrangement-based structural diversification strategy would enable the conversion of readily available natural products to other value-added secondary metabolites. However, the development of a chemical method that can be universally applied to structurally diverse natural products is nontrivial. Key to the successful reorganization of complex molecules is a versatile and mild bond-cleaving method that correctly places desired functionality, facilitating the target synthesis. Here, we report a ring-opening functionalization of a tertiary amine that can introduce desired functionalities in the context of alkaloids reorganization. The semistability of the difluoromethylated ammonium salt, accessed by the reaction of tertiary amine and in situ generated difluorocarbene, enabled the attack at the α-position by various external nucleophiles. The utility and generality of the method is highlighted by its applications in the transformation of securinega, iboga, and sarpagine alkaloids to neosecurinega, chippiine/dippinine, and vobasine-type bisindole alkaloids, respectively. During the course of these biosynthetically inspired reorganizations, we could explore chemical reactivities of biogenetically relevant precursors.
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Alcaloides/síntesis química , Aminas/químicaRESUMEN
The highly strained bowl-shaped pentacyclic structure of herquline A has rendered it one of the most difficult problems in organic synthesis yet to be solved. The challenges associated with the synthesis of herquline A have been well documented in four Ph.D. dissertations and in multiple reports regarding syntheses of its structurally simpler congeners. Herein, we report the construction of the pentacyclic core of herquline A that contains both N10-C2 and C3-C3' bonds. The key for success was the development of the tandem aza-Michael addition/enolate capture protocol that set the stage for subsequent palladium catalyzed C3(sp2 )-C3'(sp2 ) coupling reaction. Ensuing oxidative dearomatization of the left aryl ring allowed the formation of the pentacyclic diketone core of herquline A.
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An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to global public health. Herbal medicines and their derived natural products have drawn much attention in the treatment of COVID-19, but the detailed mechanisms by which natural products inhibit SARS-CoV-2 have not been elucidated. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection routes via lysosome- and transmembrane protease serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by the pharmacological inhibition or gene silencing of NPC1, which is mutated in patients with Niemann-Pick type C (NPC) displaying disrupted membrane cholesterol distribution. Finally, readily available local foods or herbal medicines containing PG root show similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that briefly disrupting the distribution of membrane cholesterol is a potential novel therapeutic strategy for SARS-CoV-2 infection.
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Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2/efectos de los fármacos , Saponinas/farmacología , Serina Endopeptidasas/metabolismo , Triterpenos/farmacología , Internalización del Virus/efectos de los fármacos , Antivirales/química , COVID-19/metabolismo , Línea Celular , Humanos , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Modelos Moleculares , Platycodon/química , SARS-CoV-2/fisiología , Saponinas/química , Triterpenos/químicaRESUMEN
We describe the first total synthesis of cinnamodial-based dimer (-)-capsicodendrin. First, we developed a 12-step synthetic route to access (-)-cinnamodial from 1-vinyl-2,6,6-trimethylcyclohexene. We then showed that (-)-cinnamodial can selectively dimerize to (-)-capsicodendrin under kinetically controlled basic conditions. Our observations regarding a facile conversion of (-)-capsicodendrin back to (-)-cinnamodial hint at the possibility that (-)-capsicodendrin is a chemical reservoir of insecticidal (-)-cinnamodial and Cinnamosma genus plants release it upon environmental stresses.
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Insecticidas , Magnoliopsida , Sesquiterpenos , BenzaldehídosRESUMEN
We describe the total synthesis of epoxyquinoid natural products (+)-pestalofone A and (+)-iso-A82775C. The synthesis of (+)-16-oxo-iso-A82775C, the putative biosynthetic precursor of pestalofone C, is also presented. The allene moiety present in (+)-iso-A82775C and (+)-16-oxo-iso-A82775C was constructed from the ketodiene-yne group via a biosynthetically relevant sequence involving a conjugate reduction and a base-catalyzed tautomerization. Attempted Diels-Alder reaction-based dimerizations of (+)-16-oxo-iso-A82775C and (+)-iso-A82775C toward pestalofones B and C are also described.
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Presented here is a concise synthesis of secu'amamine A, and fluvirosaones A and B from readily available allosecurinine and viroallosecurinine. The key C2-enamine derivative of (viro)allosecurinine, the presumed biosynthetic precursors of these natural products, was accessed, for the first time, by a VO(acac)2 -mediated regioselective Polonovski reaction. Formal hydration and 1,2-amine shift of this pluripotent enamine compound afforded secu'amamine A. Formal oxidative [3+2] cycloaddition reaction between this enamine and TMS-substituted methallyl iodide reagent paved the way to the precursors of fluvirosaones A and B. The relative stereochemistry at the C2 position of these advanced intermediates governs the fate of 1,2-amine shift leading to fluvirosaones A and B. The syntheses of potential biosynthetic precursors and investigations of their chemical reactivities have provided insights regarding the biogenesis of these natural products.