Securinega alkaloids constitute a structurally diverse class of natural products with intriguing architectures and biological activities. Herein, we report the discovery of four new Securinega alkaloids, flueggeacosines D-F and securingine J, from Flueggea suffruticosa. Flueggeacosines D and E possess dimeric frameworks incorporating a benzoquinolizidine motif derived from allosecurinine backbone. A concise synthetic strategy combining TBADT-catalyzed radical hydroacylation and Mo(CO)6-mediated reductive rearrangement enables efficient access to these complex alkaloids. Our synthetic approach also realizes a synthesis-based natural product anticipation predicting and confirming the existence of flueggeacosine F and securingine J in F. suffruticosa. Furthermore, oxidative rearrangements of flueggeacosine A furnish flueggeacosines D and F, supporting a plausible biosynthetic linkage. These findings establish a unified route to oxidized dimeric Securinega alkaloids and demonstrate the synergy of synthesis and biosynthetic reasoning in natural product discovery.

Securinega alkaloids possess a distinctive tetracyclic scaffold and are pharmaceutically relevant, yet their biosynthesis in Flueggea suffruticosa remains unresolved. Here, we combine chemical logic with stable-isotope-labeled feeding experiments and single-cell transcriptomics to elucidate the core biosynthetic pathway. We identify a reductase, FsMS, that reduces premenisdaurilide to menisdaurilide, which then conjugates with 1-piperideine to generate the [2.2.2]-bicyclic neosecurinanes, (–)-virosine A and (–)-virosine B. We also identify two sulfotransferases, FsNSST1 and FsNSST2, that O-sulfate these neosecurinanes; the resulting sulfate esters undergo a spontaneous 1,2-amine shift to yield the [3.2.1]-bicyclic securinanes, allosecurinine and securinine. This transformation reveals an unexpected biosynthetic role of sulfotransferases, not as conventional tailoring enzymes, but as key mediators of scaffold remodeling. The newly identified biosynthetic genes are co-expressed within a specific vasculature-associated cell type, enabling prioritization of additional pathway candidates. These findings highlight the power of chemically guided single-cell transcriptomics in unraveling complex biosynthetic pathways. Securinega alkaloids, comprising a distinctive tetracyclic scaffold, have long been studied, but their biosynthesis has remained largely unknown. Here, the authors employ chemical insights with single-cell transcriptomics to reveal key biosynthetic steps of securinega alkaloids in Flueggea suffruticosa.

Biomimicry has long been a valuable approach for designing efficient synthetic strategies in complex natural product synthesis. However, abiotic yet powerful transforms can significantly streamline the synthesis by introducing greater convergence to the synthetic route. Herein, we delineate a convergent total synthesis of elodeoidins A and B, enabled by a cross-dehydrogenative coupling (CDC) reaction between an aldehyde and an electron-deficient olefin. The CDC reaction operating under the newly discovered reaction conditions proceeds via distinct concerted deprotonation within the formal Cu(III) catalytic complex. Furthermore, the total synthesis of both structural candidates of elodeoidin B revealed that the natural product exists as a mixture of epimers at the C8 stereocenter.

In general, natural products exist in their most thermodynamically stable form. Therefore, final stage-reaction conditions leading to thermodynamic equilibrium often facilitate the production of the desired natural products. On the other hand, syntheses of contra-thermodynamic natural products pose greater challenges, as the thermodynamic bias should be overcome. Herein, we present the synthesis of contra-thermodynamic securinega alkaloid securingine B, derived from the more thermodynamically stable isomer secu’amamine D. Harnessing the disparity in triplet energy between two natural products, we have established a photochemical equilibrium favoring securingine B. Conversely, secu’amamine D was reformed from securingine B under thermodynamic equilibrium conditions. Inspired by these observations, we devised a novel type of photoswitching platform by introducing a push-pull system to the securinega framework. By leveraging this new photoswitching scaffold, we have developed a securingine B-inspired photochromic material and, subsequently, exploited it as a photoresponsive chiral dopant.

Over the past century, biomimetic synthesis has significantly enhanced our understanding of the biosynthetic pathways involved in the formation of natural products. In this article, we present a two-step biomimetic synthesis of fluvirosaone A from 2,3-dehydroallosecurinine, featuring a Nazarov-type cyclization as the key step. Based on our synthetic results and computational analysis, we propose an alternative biosynthetic route for fluvirosaone A, identifying pyruvaldehyde as the likely source of the extraneous three carbons incorporated into the securinega skeleton.

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.

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.

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.

Organic redox‐active molecules are a promising platform for designing sustainable, cheap, and safe charge carriers for redox flow batteries. However, radical formation during the electron‐transfer process causes severe side reactions and reduces cyclability. This problem is mitigated by using naphthalene diimide (NDI) molecules and regulating their π–π interactions. The long‐range π‐stacking of NDI molecules, which leads to precipitation, is disrupted by tethering four ammonium functionalities, and the solubility approaches 1.5 m in water. The gentle π–π interactions induce clustering and disassembling of the NDI molecules during the two‐electron transfer processes. When the radical anion forms, the antiferromagnetic coupling develops tetramer and dimer and nullifies the radical character. In addition, short‐range‐order NDI clusters at 1 m concentration are not precipitated but inhibit crossover. They are disassembled in the subsequent electron‐transfer process, and the negatively charged NDI core strongly interacts with ammonium groups. These behaviors afford excellent RFB performance, demonstrating 98% capacity retention for 500 cycles at 25 mA cm‐2 and 99.5% Coulombic efficiency with 2 m electron storage capacity.

CONSPECTUS: 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.

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.

We completed the synthesis of dimeric high-oxidation-state securinega alkaloidflueggeacosine B via two syntheticroutes from allosecurinine. Thefirst-generation synthesis (seven overall steps) involved a Liebeskind-Srogl cross-coupling reactionfor the union of two functionalized fragments, the organostannane and the thioester. As a means to further streamline the syntheticroute, we have developed a visible-light-mediated Cu-catalyzed cross-dehydrogenative coupling (CDC) reaction between analdehyde and an electron-deficient olefin. This enabled the second-generation synthesis offlueggeacosine B from allosecurinine infour overall steps. The newly developed CDC reaction paves a direct way to a conjugated dicarbonyl moiety, a ubiquitous structuralmoiety present in various natural products.

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.

Enhancing the stability and durability of metal-organic frameworks (MOFs) is vital for practical applications because many promising MOF materials suffer from phase transitions and/or structural decompositions with humidity being a particularly damaging condition. In mechanical engineering, the frame of buildings and furniture can be stabilized significantly by installing a truss beam. Employing the same principle, we functionalized the organic component of MOF-5 to contain a carbazole moiety that can act as a molecular truss beam by reaching across the corner and forming a stable π–π interaction with a phenyl group on the edge position of the MOF-skeleton. This structural support enhanced the stability of the MOF substantially, allowing the designed MOF to maintain compositional integrity under steam conditions at 90 °C for ~5 days. The unmodified MOF-5 shows clear signs of structural collapse after ~1 h.

Securinega alkaloids have fascinated the chemical community for over six decades. Among these intriguing secondary metabolites, there are members that are biosynthesized via oxidation(s) of the basic tetracyclic core of securinega natural products. These oxidation processes result in a sub-family of natural products with intriguing structural variations. We have grouped them as "high-oxidation state" securinega alkaloids. In this minireview, we, for the first time, categorize high-oxidation state securinega alkaloids into five groups based on their structural phenotype. We then describe all known syntheses of high-oxidation state securinega alkaloids based on our classification. Plausible biosynthetic origins of securinega alkaloids in each group are described. Notable interplays between chemical synthesis and biosynthesis within this family of natural products are depicted. The updated comprehensive investigation of the chemistry of high-oxidation state securinega alkaloids provides us with an outlook on remaining key challenges related to these fascinating natural products.

Presented here is a plausible structural candidate of securingine A that was not considered thus far. The newly proposed structure of securingine A is consistent with experimental NOESY data. DP4+ probability analysis of computed H-1 and C-13 chemical shifts corroborates the viability of our newly proposed structure. We propose a biosynthetic scenario that interrelates the newly suggested structure of securingine A and securingine B.

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.

We report a Michael-type cyanation reaction of coumarins by using CO2 as a catalyst. The delivery of the nucleophilic cyanide was realized by catalytic amounts of CO2, which forms cyanoformate and bicarbonate in the presence of water. Under ambient conditions, CO2-catalyzed reactions afforded high chemo- and diastereoselectivity of beta-nitrile carbonyls, whereas only low reactivities were observed under argon or N-2. Computational and experimental data suggest the catalytic role of CO2, which functions as a Lewis acid, and a protecting group to mask the reactivity of the product, suppressing byproducts and polymerization. The utility of this convenient method was demonstrated by preparing biologically relevant heterocyclic compounds with ease.

The selective installation of phosphinoyl and carbamoyl moieties on the pyridine scaffold is an important transformation in synthetic and medicinal chemistry. By employing quinolinone as an efficient organic photocatalyst, we developed a catalytic system driven by visible light that forms phosphinoyl and carbamoyl radicals, which react with various heteroarenium derivatives under mild, transition-metal-free conditions. This straightforward and environmentally friendly synthetic method represents a new approach to site-divergent pyridine functionalization that offers considerable advantages in both simplicity and efficiency. Ambient temperature is sufficient for the formation of the reactive radicals, and the site-selectivity can be switched from C2 to C4 by changing the radical coupling sources. Under standard reaction conditions, phosphinoyl radicals give access to C4 products, while carbamoyl radicals selectively give C2 products. We found that the carbamoyl radical overcomes the intrinsic preference for forming the ortho-product by allowing the oxo functionality of the carbamoyl radical to electrostatically engage the nitrogen of the pyridinium substrate, which preferentially gives the ortho-product. The phosphinoyl radical cannot engage in the same interaction, because the phosphorus is too large. This novel synthetic route tolerates a broad range of substrates and provides a convenient and powerful synthetic tool for accessing the core structures of numerous privileged scaffolds.

The development of intermolecular alkene aminopyridylation has great potential for quickly increasing molecular complexity with two valuable groups. Here we report a strategy for the photocatalytic aminopyridylation of alkenes using a variety of N-aminopyridinium salts as both aminating and pyridylating reagents. Using Eosin Y as a photocatalyst, amino and pyridyl groups are simultaneously incorporated into alkenes, affording synthetically useful aminoethyl pyridine derivatives under mild reaction conditions. Remarkably, the C4-regioselectivity in radical trapping with N-aminopyridinium salt can be controlled by electrostatic interaction between the pyridinium nitrogen and sulfonyl group of β-amino radical. This transformation is characterized by a broad substrate scope, good functional group compatibility, and the utility of this transformation was further demonstrated by late-stage functionalization of complex biorelevant molecules. Combining experiments and DFT calculations on the mechanism of the reaction is investigated to propose a complete mechanism and regioselectivity.