Combined Computational and Experimental Study Reveals Complex Mechanistic Landscape of Brønsted Acid-Catalyzed Silane-Dependent P═O Reduction.

The reaction mechanism of Brønsted acid-catalyzed silane-dependent P═O reduction has been elucidated through combined computational and experimental methods. Due to its remarkable chemo- and stereoselective nature, the Brønsted acid/silane reduction system has been widely employed in organophosphine-catalyzed transformations involving P(V)/P(III) redox cycle. However, the full mechanistic profile of this type of P═O reduction has yet to be clearly established to date. Supported by both DFT and experimental studies, our research reveals that the reaction likely proceeds through mechanisms other than the widely accepted "dual activation mode by silyl ester" or "acid-mediated direct P═O activation" mechanism. We propose that although the reduction mechanisms may vary with the substitution patterns of silane species, Brønsted acid generally activates the silane rather than the P═O group in transition structures. The proposed activation mode differs significantly from that associated with traditional Brønsted acid-catalyzed C═O reduction. The uniqueness of P═O reduction originates from the dominant Si/O═P orbital interactions in transition structures rather than the P/H-Si interactions. The comprehensive mechanistic landscape provided by us will serve as a guidance for the rational design and development of more efficient P═O reduction systems as well as novel organophosphine-catalyzed reactions involving P(V)/P(III) redox cycle.

Chiral Bisphosphine-Catalyzed Asymmetric Staudinger/aza-Wittig Reaction: An Enantioselective Desymmetrizing Approach to Crinine-Type Amaryllidaceae Alkaloids.

An unprecedented chiral bisphosphine-catalyzed asymmetric Staudinger/aza-Wittig reaction of 2,2-disubstituted cyclohexane-1,3-diones is reported, enabling the facile access of a broad range of cis-3a-arylhydroindoles in high yields with excellent enantioselectivities. The key to the success of this work relies on the first application of chiral bisphosphine DuanPhos to the asymmetric Staudinger/aza-Wittig reaction. An effective reductive system has been established to address the challenging PV═O/PIII redox cycle associated with the chiral bisphosphine catalyst. In addition, comprehensive experimental and computational investigations were carried out to elucidate the mechanism of the asymmetric reaction. Leveraging the newly developed chemistry, the enantioselective total syntheses of several crinine-type Amaryllidaceae alkaloids, including (+)-powelline, (+)-buphanamine, (+)-vittatine, and (+)-crinane, have been accomplished with remarkable conciseness and efficiency.

Orthogonal genome-wide screens of bat cells identify MTHFD1 as a target of broad antiviral therapy.

Bats are responsible for the zoonotic transmission of several major viral diseases, including those leading to the 2003 SARS outbreak and likely the ongoing COVID-19 pandemic. While comparative genomics studies have revealed characteristic adaptations of the bat innate immune system, functional genomic studies are urgently needed to provide a foundation for the molecular dissection of the viral tolerance in bats. Here we report the establishment of genome-wide RNA interference (RNAi) and CRISPR libraries for the screening of the model megabat, Pteropus alecto. We used the complementary RNAi and CRISPR libraries to interrogate P. alecto cells for infection with two different viruses: mumps virus and influenza A virus, respectively. Independent screening results converged on the endocytosis pathway and the protein secretory pathway as required for both viral infections. Additionally, we revealed a general dependence of the C1-tetrahydrofolate synthase gene, MTHFD1, for viral replication in bat cells and human cells. The MTHFD1 inhibitor, carolacton, potently blocked replication of several RNA viruses, including SARS-CoV-2. We also discovered that bats have lower expression levels of MTHFD1 than humans. Our studies provide a resource for systematic inquiry into the genetic underpinnings of bat biology and a potential target for developing broad-spectrum antiviral therapy.

Natural Product-Oriented Photo-Induced Denitrogenative Annulations of 1-Alkenylbenzotriazoles.

The photo-induced denitrogenative annulations of a variety of 1-alkenylbenzotriazoles were investigated. By judiciously manipulating the structural variations of 1-alkenylbenzotriazoles, two characteristic polycyclic skeletons associated with monoterpene indole alkaloids were constructed through a diverted and controllable manner. The present work not only enriches the photochemistry of 1-alkenylbenzotriazoles, but also offers a unified approach to access skeletally diverse indole alkaloid scaffolds.

Enantioselective Total Synthesis of Dysiherbols A, C, and D.

Herein, we report the enantioselective total synthesis of dysiherbols A, C, and D, a unique group of 6/6/5/6/6 pentacyclic quinone/hydroquinone sesquiterpenes, featuring a photo-induced quinone-alkene [2 + 2] cycloaddition and a tandem [1,2]-anionic rearrangement/cyclopropane fragmentation as key elements. Based on our total synthesis, the originally proposed structures of dysiherbols C and D have been revised. Detailed computational studies were carried out to gain deep insight into the unprecedented [1,2]-anionic rearrangement, which revealed that the transformation, albeit a symmetry-forbidden process, proceeded through a concerted manner owing to the release of high ring-strain energy and the evolution of local aromaticity in the transition state. Taking all, the present work offers a mechanistically interesting and synthetically useful approach to accessing dysiherbols and related congeners.

Biomimetic Synthesis of Natural Products: A Journey To Learn, To Mimic, and To Be Better.

Total synthesis of natural products has been one of the most exciting and dynamic areas in synthetic organic chemistry. Nowadays, the major challenge in this field is not whether a given target of interest can be synthesized but how to make it with commendable efficiency and practicality. To meet this grand challenge, a wise way is to learn from Mother Nature who is recognized for her superb capability of forging complicated and sometimes beyond-imagination molecules in her own delicate way. Indeed, since Sir Robert Robinson published his groundbreaking synthesis of tropinone in 1917, biomimetic synthesis of natural products, a process of imitating nature's way to make molecules, has evolved into one of the most popular research directions in organic synthesis.Our group has been engaging in biomimetic synthesis of natural products in the past decade. During this time, we have come to realize that the successful implementation of a biomimetic synthesis entails the orchestrated combination of bioinspiration and rational design. On the one hand, we prefer to utilize some elegant bioinspired transformations (e.g., Diels-Alder dimerization, 6π-electrocyclization, and [2 + 2]-photocycloaddition) as the key steps of our synthesis, which enable rapid construction of the core skeletons of the chased targets with high efficiency; on the other hand, various powerful reactions (e.g., dyotropic rearrangement of ß-lactone, tandem aldol condensation/Grob fragmentation reaction, and organocatalytic asymmetric Mukaiyama-Michael addition) are rationally designed by us, which allow for facile access to the requisite precursors for attempting biomimetic transformations. In some cases, the proposed biomimetic transformation may fail to give a satisfactory result in practice, and thus we opt to develop creative tactics (e.g., hydrogen atom transfer-triggered vinyl cyclobutane ring opening/oxygen insertion/cyclization cascade) that can meet the challenge. Guided by this synthesis concept, we have achieved the total syntheses of multiple families of natural products of great importance in both chemistry and biology, representatives of which include xanthanolides, cytochalasans, and plakortin-type polyketides. Of note, most of these targets could be accessed in a concise, efficient, and scalable manner, which paves the way for further exploration of their biological functions and medicinal potential. Moreover, owing to their biomimetic nature, our syntheses provide valuable information for deciphering the underlying biosynthetic pathways of the chased targets, which could not be attained by other synthetic modes.

A Yeast-Based Drug Discovery Platform To Identify Plasmodium falciparum Type II NADH Dehydrogenase Inhibitors.

Conventional methods utilizing in vitro protein activity assay or in vivo parasite survival to screen for malaria inhibitors suffer from high experimental background and/or inconvenience. Here, we introduce a yeast-based system to facilitate chemical screening for specific protein or pathway inhibitors. The platform comprises several isogeneic Pichia strains that differ only in the target of interest, so that a compound which inhibits one strain but not the other is implicated in working specifically against the target. We used Plasmodium falciparum NDH2 (PfNDH2), a type II NADH dehydrogenase, as a proof of principle to show how well this works. Three isogenic Pichia strains harboring, respectively, exogeneously introduced PfNDH2, its own complex I (a type I NADH dehydrogenase), and PfNDH2 with its own complex I, were constructed. In a pilot screen of more than 2,000 compounds, we identified a highly specific inhibitor that acts on PfNDH2. This compound poorly inhibits the parasites at the asexual blood stage; however, is highly effective in repressing oocyst maturation in the mosquito stage. Our results demonstrate that the yeast cell-based screen platform is feasible, efficient, economical, and has very low background noise. Similar strategies could be extended to the functional screen for interacting molecules of other targets.

Chemical trigger-enabled bioconjugation reaction.

Development of conceptually novel and practically useful bioconjugation reactions has been an intense pursuit of chemical biology research. Herein, we report an unprecedented bioconjugation reaction that hinges on a chemical trigger-enabled inverse-electron-demand Diels-Alder (IEDDA) cycloaddition of trans-cycloheptene (TCH) with tetrazine. Unlike the conventional strain-promoted bioconjugation reactions that utilize built-in strained alkenes as reactants, the current one features a "trigger-release-conjugate" reaction model, in which a highly strained TCH species is released from a bench-stable bicyclic N-nitrosourea (BNU) derivative upon treatment with an external stimulus. It is noteworthy that the reactivity-stability balance of BNU derivatives could be tuned by manipulating their N-1 substituents. As a proof-of-concept case, this new chemical trigger-enabled IEDDA reaction has been applied to in vitro protein labeling and pretargeted cell imaging. This work opens a new avenue to utilize BNU derivatives as a new class of chemical reporters in bioconjugate chemistry.

A Global Review on Short Peptides: Frontiers and Perspectives.

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. Peptide "drugs" initially played only the role of hormone analogs to balance disorders. Nowadays, they achieve numerous biomedical tasks, can cross membranes, or reach intracellular targets. The role of peptides in bio-processes can hardly be mimicked by other chemical substances. The article is divided into independent sections, which are related to either the progress in short peptide-based theranostics or the problems posing challenge to bio-medicine. In particular, the SWOT analysis of short peptides, their relevance in therapies of diverse diseases, improvements in (bio)synthesis platforms, advanced nano-supramolecular technologies, aptamers, altered peptide ligands and in silico methodologies to overcome peptide limitations, modern smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems are discussed.

Tailored Synthesis of Skeletally Diverse Stemona Alkaloids through Chemoselective Dyotropic Rearrangements of ß-Lactones.

The collective synthesis of skeletally diverse Stemona alkaloids featuring tailored dyotropic rearrangements of ß-lactones as key elements is described. Specifically, three typical 5/7/5 tricyclic skeletons associated with stemoamide, tuberostemospiroline and parvistemonine were first accessed through chemoselective dyotropic rearrangements of ß-lactones involving alkyl, hydrogen, and aryl migration, respectively. By the rational manipulation of substrate structures and reaction conditions, these dyotropic rearrangements proceeded with excellent efficiency, good chemoselectivity and high stereospecificity. Furthermore, several polycyclic Stemona alkaloids, including saxorumamide, isosaxorumamide, stemonine and bisdehydroneostemoninine, were obtained from the aforementioned tricyclic skeletons through late-stage derivatizations. A novel visible-light photoredox-catalyzed formal [3+2] cycloaddition was also developed, which offers a valuable tool for accessing oxaspirobutenolide and related scaffolds.

Strain-Driven Dyotropic Rearrangement: A Unified Ring-Expansion Approach to α-Methylene-γ-butyrolactones.

An unprecedented strain-driven dyotropic rearrangement of α-methylene-ß-lactones has been realized, which enables the efficient access of a wide range of α-methylene-γ-butyrolactones displaying remarkable structural diversity. Several appealing features of the reaction, including excellent efficiency, high stereospecificity, predictable chemoselectivity and broad substrate scope, render it a powerful tool for the synthesis of MBL-containing molecules of either natural or synthetic origin. Both experimental and computational evidences suggest that the new variant of dyotropic rearrangements proceed in a dualistic pattern: while an asynchronous concerted mechanism most likely accounts for the reactions featuring hydrogen migration, a stepwise process involving a phenonium ion intermediate is favored in the cases of aryl migration. The great synthetic potential of the title reaction is exemplified by its application to the efficient construction of several natural products and relevant scaffolds.

Renaissance of Ring-Opening Chemistry of Benzotriazoles: New Wine in an Old Bottle.

1,2,3-Benzotriazoles could undergo ring cleavage to form ortho-amino arenediazonium or α-diazo-imine species via a Dimroth-type equilibrium. Historically, the synthetic potential of this unique reactivity had remained underdeveloped. Recently, some new strategies have been developed to effect the ring-opening chemistry of benzotriazoles in more practical manners. A wide range of conceptually novel and synthetically useful reactions have been developed, which enable the access to diverse valuable heterocycles and ortho-amino arene derivatives. As one of the players in this field, our group has also contributed a series of intriguing transition-metal-catalyzed denitrogenative functionalizations of benzotriazoles. In this account, we aim to provide an overview of the ring-opening chemistry of benzotriazoles, with a focus on relevant works published in the past decade. In order to show a whole picture of the research field, some pioneering works in its developing history will also be discussed briefly.

Recent advances in the synthesis of plakortin-type polyketides.

Plakortin-type polyketides represent a growing family of sponge-derived marine natural products that display notable structural and biological diversity. In particular, a series of polycyclic plakortin polyketides, namely hippolachnin A and gracilioethers, have been identified in recent years, which attract immense interest from the synthetic community owing to their unique molecular architectures and promising biomedical potential. A number of elegant total syntheses of these targets and some synthetic studies have been performed through either bio-inspired or rationally designed strategies. This focused review aims to provide an up-to-date summary of the progress in the chemical synthesis of plakortin polyketides, with an emphasis on the key synthetic elements enabling the rapid assembly of their core skeletons.

Enantioselective Total Syntheses of (+)-Hippolachnin A, (+)-Gracilioether A, (-)-Gracilioether E, and (-)-Gracilioether F.

The Plakortin polyketides represent a structurally and biologically fascinating class of marine natural products. Herein, we report a unified strategy that enables the divergent syntheses of various Plakortin polyketides with high step-economy and overall efficiency. As proof-of-concept cases, the enantioselective total syntheses of (+)-hippolachnin A, (+)-gracilioether A, (-)-gracilioether E, and (-)-gracilioether F have been accomplished based on a series of bio-inspired, rationally designed, or serendipitously discovered transformations, which include (1) an organocatalytic asymmetric 1,4-conjugate addition to assemble the common chiral γ-butenolide intermediate enroute to all of the aforementioned targets, (2) a challenging biomimetic [2+2] photocycloaddition to forge the oxacyclobutapentalene core of (+)-hippolachnin A, (3) a [2+2] photocycloaddition followed by one-pot oxidative cleavage of methyl ether/Baeyer-Villiger rearrangement to access (-)-gracilioether F, and (4) an unprecedented hydrogen-atom-transfer-triggered oxygenation of vinylcyclobutane to afford (+)-gracilioether A and (-)-gracilioether E in one pot.

Nature-Inspired Bioorthogonal Reaction: Development of ß-Caryophyllene as a Chemical Reporter in Tetrazine Ligation.

A nature-inspired bioorthogonal reaction has been developed, hinging on an inverse-electron-demand Diels-Alder reaction of tetrazine with ß-caryophyllene. Readily accessible from the cheap starting material through a scalable synthesis, the newly developed ß-caryophyllene chemical reporter displays appealing reaction kinetics and excellent biocompatibility, which renders it applicable to both in vitro protein labeling and live cell imaging. Moreover, it can be used orthogonally to the strain-promoted alkyne-azide cycloaddition for dual protein labeling. This work not only provides an alternative to the existing bioorthogonal reaction toolbox, but also opens a new avenue to utilize naturally occurring scaffolds as bioorthogonal chemical reporters.

Total Syntheses of Asperchalasines†A-E.

The first total syntheses of asperchalasines A-E, a collection of unprecedented merocytochalasans, are reported. Aspochalasin B, a key tricyclic cytochalasan monomer, was first synthesized through a unified approach that hinges on a Diels-Alder reaction and a ring-closing metathesis reaction. The bioinspired Diels-Alder reactions of aspochalasin B with different epicoccine precursors were then explored, which enabled the divergent access of the heterodimers asperchalasines B-E as well as related congeners. Furthermore, the heterotrimer asperchalasine A was obtained from one epicoccine unit and two aspochalasin B units through a biomimetic Diels-Alder reaction followed by an oxidative [5+2]-cycloaddition.

Total Synthesis of Homodimericin†A.

We report the concise total synthesis of homodimericin A (1), a recently identified fungal metabolite bearing an unprecedented molecular architecture. The success of the approach hinges on a series of rationally designed and bioinspired transformations, including a Moore rearrangement to assemble the monomeric hydroquinone precursor, homodimerization through double Michael addition to construct the planar A/B/C tricyclic framework, and a tandem Diels-Alder reaction/carbonyl-ene cyclization to forge the congested D/E/F tricyclic cage motif. Unequivocal evidence for the elucidated structure of homodimericin A was also provided by this study.

Enantioselective and Collective Total Syntheses of Xanthanolides.

An enantioselective synthesis of (+)-8-epi-xanthatin hinging on a chiral phosphoric acid catalyzed tandem allylboration/lactonization reaction is reported. With (+)-8-epi-xanthatin as the precursor, the collective synthesis of a series of synthetically challenging xanthanolides was also accomplished. Among them, xanthipungolide, one of the most complex xanthanolide monomers, was accessed through a bioinspired tandem double-bond isomerization/6π electronic cyclization/intramolecular Diels-Alder reaction, and pungiolides A, B, D, E, and L-N, a group of xanthanolide dimers, were assembled through a bioinspired Diels-Alder dimerization followed by late-stage diversification.

Total synthesis and preliminary SAR study of (±)-merochlorins A and B.

A modular synthesis of merochlorins A and B, two naturally occurring antibiotics, has been achieved concisely from readily available building blocks in 4-6 steps. The key steps include the bio-inspired tandem phenol oxidative dearomatization/[5 + 2] and [3 + 2] cycloadditions to construct the tricyclic cores of the targets, and the intermolecular Diels-Alder reaction followed by dehydrogenative aromatization to assemble the remaining aromatic units. The antibacterial activities of merochlorins A, B and some advanced synthetic intermediates were also evaluated, which provided valuable information on the structure-activity relationship (SAR) of this class of new antibiotics.

Total Syntheses of Periconiasins†A-E.

The first and collective total syntheses of periconiasins A-E, a group of naturally occurring cytochalasans, were achieved by a series of rationally designed or bioinspired transformations. Salient features of the syntheses include a tandem aldol condensation/Grob fragmentation to assemble the linear polyketide-amino acid hybrid precursor, a Diels-Alder macrocylization to construct the 9/6/5 tricyclic core of periconiasins A-C, and a transannular carbonyl-ene reaction to forge the polycyclic framework of periconiasins D and E.