Synthesis Of Natural Products Research Articles

Recent Advances in Xanthine Oxidase Inhibitors.

Uric acid is a product of purine nucleotide metabolism, and high concentrations of uric acid can lead to hyperuricemia, gout and other related diseases. Xanthine oxidase, the only enzyme that catalyzes xanthine and hypoxanthine into uric acid, has become a target for drug development against hyperuricemia and gout. Inhibition of xanthine oxidase can reduce the production of uric acid, so xanthine oxidase inhibitors are used to treat hyperuricemia and related diseases, including gout. In recent years, researchers have obtained new xanthine oxidase inhibitors through drug design, synthesis, or separation of natural products. This paper summarizes the research on xanthine oxidase inhibitors since 2015, mainly including natural products, pyrimidine derivatives, triazole derivatives, isonicotinamide derivatives, chalcone derivatives, furan derivatives, coumarin derivatives, pyrazole derivatives, and imidazole derivatives, hoping to provide valuable information for the research and development of novel xanthine oxidase inhibitors.

Filamentous morphology: a new frontier for genetic modification of filamentous fungal cell factories

Filamentous fungi are a group of eukaryotic microorganisms widely found in nature. Some filamentous fungi have been developed as "cell factories" and extensively used for the production of recombinant proteins, organic acids, and secondary metabolites due to their strong protein secretion capabilities or effective synthesis of many natural products. The growth morphology of filamentous fungi significantly influences the quality and quantity of fermented products. Previous research conducted by the authors' group revealed that an increase in hyphal branches leads to enhanced protein secretion during liquid fermentation. With the development of morphological engineering of filamentous fungi, an increasing number of studies have focused on modifying fungal mycelium morphology to improve the yield of target metabolites during fermentation. While there have been a few reviews on the relationship between fungal fermentation morphology and productivity, research in this area is rapidly developing and requires updates. The paper presents a comprehensive review of domestic and international research reports, along with the authors' own research findings, to systematically review the morphological patterns of filamentous fungi, the impact of fungal morphology on industrial fermentation, as well as methods and strategies for regulating mycelial morphology. The aim of this review is to enhance the understanding of relevant domestic scholars regarding the morphological development of filamentous fungi and provide ideas for the rational engineering of fungal strains suitable for industrial fermentation.

Construction of Hydroindole Skeleton by Photocatalytic Oxidative Dearomatization and Cyclization Sequence, and a Concise Synthesis of Melodamide A and (±)-Toussaintine C.

A method of synthesizing hydroindole skeletons has been developed by using photocatalytic oxidative dearomatization and an aza-Michael addition sequence. Using this method, optically active hydroindoles, which are often used in natural product synthesis as chiral building blocks, can be easily prepared with >99% ee. Furthermore, the synthesis of melodamide A and (±)-toussaintine C was achieved using this method as a key step.

Development of a Divergent Synthesis of Pleurotinoid Natural Products.

Herein, we describe the evolution of our syntheses of the pleurotinoid natural products pleurotin (1), pleurogrisein (3), and 4-hydroxypleurogrisein (4). An approach based on a proximity-induced intramolecular Diels-Alder cycloaddition of a transient ortho-quinone dimethide (e.g., 6, Scheme 1) was inferior to an alternative construction featuring Gao's titanium(IV)-mediated photoenolization Diels-Alder coupling of ortho-tolualdehyde 20 with functionalized hydrindenone 22. While this pairing exhibited the desired stereoface selectivity and produced cis-fused hydrindanone 23, the successful realization of our syntheses of 1, 3, and 4 required a post-Diels-Alder epimerization of the unactivated stereocenter at C-5 in compound 23. Ultimately, it was possible to generate a reactive oxygen-centered radical via a reductive homolytic cleavage of the N-O bond in 23 and capitalize on its ability to break the C5-H bond in an intramolecular 1,5-hydrogen atom transfer (HAT). The carbon radical arising from this pivotal 1,5-HAT was subsequently trapped in situ by an exogenous thiol in a kinetically controlled HAT reaction to establish the natural configuration at C-5. The successful flipping of the cis-hydrindane in 23 to the challenging trans configuration in 24 provided a firm foundation for a formal synthesis of pleurotin (1), as well as syntheses of pleurogrisein (3) and 4-hydroxypleurogrisein (4).

Gold-Catalyzed Oxidative Rearrangement Strategy to Yield 2-Hydroxycyclohepta-1,3-diene-1-carbonyl Compounds.

A gold-catalyzed oxidative rearrangement of propargyl alcohols, derived from commercially available cyclohex-2-en-1-ones and alkynes, was successfully developed for the efficient synthesis of seven-membered rings. Thorough investigations were conducted to optimize the reaction conditions and evaluate its compatibility with various functional groups. Additionally, this methodology was applied to the formal total synthesis of guanacastepene A, demonstrating its practical utility in complex natural product synthesis. This versatile and efficient approach opens up new possibilities for the construction of diverse seven-membered ring systems, providing valuable building blocks for further exploration in drug discovery and the synthesis of intricate molecules.

Photochemical dearomative skeletal modifications of heteroaromatics.

Dearomatization has emerged as a powerful tool for rapid construction of 3D molecular architectures from simple, abundant, and planar (hetero)arenes. The field has evolved beyond simple dearomatization driven by new synthetic technology development. With the renaissance of photocatalysis and expansion of the activation mode, the last few years have witnessed impressive developments in innovative photochemical dearomatization methodologies, enabling skeletal modifications of dearomatized structures. They offer truly efficient and useful tools for facile construction of highly complex structures, which are viable for natural product synthesis and drug discovery. In this review, we aim to provide a mechanistically insightful overview on these innovations based on the degree of skeletal alteration, categorized into dearomative functionalization and skeletal editing, and to highlight their synthetic utilities.

Sustainable Synthesis through Catalyst-Free Photoinduced Cascaded Bond Formation.

The beginning of photochemical reactions revolutionized synthetic chemistry through sustainable practices. This review explores cutting-edge developments in leveraging light-induced processes for generating cascaded C-C and C-hetero bonds without catalysts. Significantly, catalyst-free photoinduced methodologies have garnered considerable attention, especially in the creation of varied heterocyclic frameworks for drug design and the synthesis of natural products. The article delves into underlying mechanisms, addresses limitations, and evaluates various methodologies, emphasizing the potential of photocatalyst and transition metal-free photochemical reactions to enhance sustainability. Divided into two sections, it covers recent strides in C-C and C-heteroatom and multiple C-heteroatom bond formation reactions.

Profiling expression strategies for a type III polyketide synthase in a lysate-based, cell-free system

Some of the most metabolically diverse species of bacteria (e.g., Actinobacteria) have higher GC content in their DNA, differ substantially in codon usage, and have distinct protein folding environments compared to tractable expression hosts like Escherichia coli. Consequentially, expressing biosynthetic gene clusters (BGCs) from these bacteria in E. coli often results in a myriad of unpredictable issues with regard to protein expression and folding, delaying the biochemical characterization of new natural products. Current strategies to achieve soluble, active expression of these enzymes in tractable hosts can be a lengthy trial-and-error process. Cell-free expression (CFE) has emerged as a valuable expression platform as a testbed for rapid prototyping expression parameters. Here, we use a type III polyketide synthase from Streptomyces griseus, RppA, which catalyzes the formation of the red pigment flaviolin, as a reporter to investigate BGC refactoring techniques. We applied a library of constructs with different combinations of promoters and rppA coding sequences to investigate the synergies between promoter and codon usage. Subsequently, we assess the utility of cell-free systems for prototyping these refactoring tactics prior to their implementation in cells. Overall, codon harmonization improves natural product synthesis more than traditional codon optimization across cell-free and cellular environments. More importantly, the choice of coding sequences and promoters impact protein expression synergistically, which should be considered for future efforts to use CFE for high-yield protein expression. The promoter strategy when applied to RppA was not completely correlated with that observed with GFP, indicating that different promoter strategies should be applied for different proteins. In vivo experiments suggest that there is correlation, but not complete alignment between expressing in cell free and in vivo. Refactoring promoters and/or coding sequences via CFE can be a valuable strategy to rapidly screen for catalytically functional production of enzymes from BCGs, which advances CFE as a tool for natural product research.

In Situ Triflation‐Tandem Cross‐Coupling Enables Synthesis and Photophysical Studies of Indenones and Benzofulvenes

Indan‐1,3‐diones stand as versatile precursors to a plethora of complex molecules with wide applications; however, their direct cross‐coupling methodologies remain largely unexplored. Herein, we unveil an in situ triflation‐tandem cross‐coupling strategy to synthesize a diverse variety of indenones and benzofulvenes from indan‐1,3‐diones. The successful synthesis of a neolignan natural product and the key intermediate of Indatraline (antidepressant) showcased the synthetic utility of the methodology. The strategy enabled tuning the electronic characteristics of indenones and benzofulvenes, modulating the HOMO‐LUMO gaps. The photophysical properties of these molecules were studied, and the experimental results were compared with the predictions obtained from the DFT studies.

Cyclization by metal-catalyzed hydrogen atom transfer/radical-polar crossover

Catalytic transformation of alkenes via the metal-hydride hydrogen atom transfer (MHAT) mechanism has notably advanced synthetic organic chemistry. This review focuses on MHAT/radical-polar crossover (MHAT/RPC) conditions, offering a novel perspective on generating electrophilic intermediates and facilitating various intramolecular reactions. Upon using cobalt hydrides, the MHAT mechanism displayed exceptional chemoselectivity and functional group tolerance, making it invaluable for the construction of complex biologically relevant molecules under mild conditions. Recent developments have enhanced regioselectivity and expanded the scope of MHAT-type reactions, enabling the formation of cyclic molecules via hydroalkoxylation, hydroacyloxylation, and hydroamination. Notably, the addition of an oxidant to traditional MHAT systems enables the synthesis of rare cationic alkylcobalt(IV) complexes, bridging radical mechanisms to ionic reaction systems. This review culminates with examples of natural product syntheses and exploration of asymmetric intramolecular hydroalkoxylation, highlighting the ongoing challenges and opportunities for future research to achieve higher enantioselectivity. This comprehensive study revisits the historical evolution of the MHAT mechanism and provides the groundwork for further innovations in the synthesis of structurally diverse and complex natural products. 1 Introduction 2 Intramolecular hydroalkoxylation and hydroacyloxylation reactions 3 Intramolecular hydroamination reactions 4 Intramolecular hydroarylation reactions 5 Deprotective cyclization 6 Asymmetric intramolecular hydroalkoxylation

Evaluation of a cascade cyclization approach toward harringtonolide

An account of synthetic work directed toward the total synthesis of the cytotoxic cephalotaxus norditerpenoid, harringtonolide, is disclosed. An initial Lewis Acid-catalyzed Diels-Alder/Ene cascade was designed to construct a key 6,6,5-fused tricyclic building block in a single step. While this process could not be realized in a single pot, a three-step cycloaddition/Barbier-type sequence afforded this motif, and after subsequent ring-closing metathesis, the entire 7,6,6,5-fused core of the natural product was generated. This strategy could be of use in the synthesis of various cephalotane natural products containing 7-membered rings.

Organic Electrosynthesis: A Promising Green Tool in Solving Key Steps for the Total Synthesis of Complex Natural Products

Abstract: Electro-organic synthesis, an atom-efficient, sustainable, mild process, permits an ecofriendly and elegant green path to synthesize structurally complex, still valuable molecules, avoiding the use of conventional harsh oxidizing and reducing agents and long-route reaction protocols. Being one of the oldest forms of reaction setups in a laboratory, it deals with fundamental redox chemistry through the direct application of electrical potential. Here flow of electrons acts as an oxidizing agent at the anode at the same time reducing agent at the cathode, depending upon the requirement of the reaction. Simultaneously, it minimizes the generation of reagent waste during the reaction. However, electrifying organic synthesis plays more than preventing the waste footprint. This technology provides an alternative roadmap through nonclassical bond disconnections to access desired target molecules by cutting down a number of steps with the formation of apparently looking difficult bonds with excellent regio-, chemo-and stereoselectivity. Hence, it emerges as an alternative and attractive technique for the contemporary synthetic communities. Consequently, in recent years, multiple milestones have been achieved in the electro-organic synthesis of fascinating natural products through oxidative C-C bond formation, C-H/N-H functionalization, very rare oxidative N-N dimerization, RCDA dimerization, etc. Thus, synthesis of extremely complex natural products through finding new electro-synthetic route as a key methodology have become one of the alluring synthetic targets to synthetic chemists because of their versatile utilities in medicine, agriculture, food, and cosmetic industry. This review presents advances in electrochemistry in the total synthesis of 20 complex natural products reported since 2013. Enabling synthetic steps are analyzed alongside innate advantages as well as future prospects are speculated.

Copper Catalyzed [3 + 2] Annulation Reaction of Exocyclic Sulfonyl Enamides for the Synthesis of N,O-Spiroketal and Spiroketal.

A copper-catalyzed [3 + 2] annulation reaction of exocyclic enamines/enol ethers with 1,4-benzoquinone esters has been developed, providing facile access to N,O- spiroketals and spiroketals under mild conditions with broad substrate scope (26 examples, 71-94% yields). Gram scale synthesis and chemical transformations demonstrated that this method is potentially useful in the synthesis of natural products and drugs containing a N,O- spiroketal moiety. The chiral N,O-spiroketal could be obtained with 98% ee after recrystallization, when a chiral SaBOX ligand was employed.

Who is Who in the Carbene Chemistry of N‐Sulfonyl Hydrazones

Comprehensive SummaryOver the past few decades, N‐sulfonyl hydrazones have been recognized as alternative precursors for hazardous diazo compounds in organic synthesis, allowing for diverse innovative and original chemical transformations that were otherwise difficult to achieve. This critical review summarizes the major advancements in the carbene chemistry of N‐sulfonyl hydrazones. The contents of this review are organized based on research conducted by leading scientists who have made significant contributions to this field. The individual carbene transfer reactions and their mechanisms, as well as the potential applications in the synthesis of natural products and complex bioactive molecules, are thoroughly discussed.

Heterologous synthesis of ginsenoside F1 and its precursors in Nicotiana benthamiana

Ginsenoside F1 has high medicinal values, which is a kind of rare triterpene saponin isolated from Panax plants. The extremely low content of ginsenoside F1 in herbs has limited its research and application in medical field. In this work, we constructed a pathway in tobacco for the biosynthesis of ginsenoside F1 by metabolic engineering. Four enzyme genes (PnDDS, CYP716A47, CYP716S1 and UGT71A56) isolated from Panax notoginseng were introduced into tobacco. Thus, a biosynthetic pathway for ginsenoside F1 synthesis was artificially constructed in tobacco cells; moreover, the four exogenous genes could be expressed in the roots, stems and leaves of transgenic plants. Consequently, ginsenoside F1 and its precursors were successfully synthesized in the transgenic tobacco, compared with Panax plants, the content of ginsenoside F1 in transgenic tobacco was doubled. In addition, accumulation of ginsenoside F1 and its precursors in transgenic tobacco shows organ specificity. Based on these results, a new approach was established to produce rare ginsenoside F1; meanwhile, such strategy could also be employed in plant hosts for the heterologous synthesis of other important or rare natural products.

Late-stage benzenoid-to-troponoid skeletal modification of the cephalotanes exemplified by the total synthesis of harringtonolide

Skeletal modifications enable elegant and rapid access to various derivatives of a compound that would otherwise be difficult to prepare. They are therefore a powerful tool, especially in the synthesis of natural products or drug discovery, to explore different natural products or to improve the properties of a drug candidate starting from a common intermediate. Inspired by the biosynthesis of the cephalotane natural products, we report here a single-atom insertion into the framework of the benzenoid subfamily, providing access to the troponoid congeners — representing the reverse of the proposed biosynthesis (i.e., a contra-biosynthesis approach). Computational evaluation of our designed transformation prompted us to investigate a Büchner–Curtius–Schlotterbeck reaction of a p-quinol methylether, which ultimately results in the synthesis of harringtonolide in two steps from cephanolide A, which we had previously prepared. Additional computational studies reveal that unconventional selectivity outcomes are driven by the choice of a Lewis acid and the nucleophile, which should inform further developments of these types of reactions.

Recent advances in palladium‐catalyzed α‐arylation reactions

The indispensable role of α‐arylated compounds in chemistry can be accounted from its presence in various pharmaceuticals we use in our daily life. Chemists are establishing diverse methods for the synthesis of various α‐arylated compounds by considering their applications in different fields including biology, medicine, agrochemicals, material science, etc. Diverse pharmacologically active compounds, natural products, and drugs contain α‐arylated carbonyl groups in their structure. The impact of transition metal catalysis in chemistry is overwhelming, among which palladium is the predominant due to its high reactivity as well as catalytic potential. α‐Arylation reactions with palladium catalysts have been successful in producing a variety of desired chemicals. The formation of active pharmaceutical ingredients and total synthesis of natural products can now be achieved by the development of novel pathways through the α‐arylation of carbonyl compounds, catalyzed by palladium. Wide variety of simple arylating agents could be used under the condition of palladium catalysis. Syntheses that utilize α‐arylation methods often offer advanced ways that improve overall yields, expand the scope of the synthesis, and reduce the steps. One of the synthetic achievements is the increased selectivity obtained with lower amounts of the catalyst. Gentle reaction conditions were employed, and broad substrate scope was accomplished. Recent advances in the α‐arylation reactions of various compounds, catalyzed by palladium, is discussed in this review covering literature from 2016 to 2022.

Decennary Update on Oxidative-Rearrangement Involving 1,2-Aryl C-C Migration Around Alkenes: Synthetic and Mechanistic Insights.

In recent years, numerous methodologies on oxidative rearrangements of alkenes have been investigated, that produce multipurpose synthons and heterocyclic scaffolds of potential applications. The present review focused on recently established methodologies for oxidative transformation via 1,2-aryl migration in alkenes (2013-2023). Special emphasis has been placed on mechanistic pathways to understand the reactivity pattern of different substrates, challenges to enhance selectivity, the key role of different reagents, and effect of different substituents, and how they affect the rearrangement process. Moreover, synthetic limitations and future direction also have been discussed. We believe, this review offers new synthetic and mechanistic insight to develop elegant precursors and approaches to explore the utilization of alkene-based compounds for natural product synthesis and functional materials.

Recent Advances in Manganese(III)-Assisted Radical Cyclization for the Synthesis of Natural Products: A Comprehensive Review.

Natural products play an important part in synthetic chemistry since they have many pharmacological properties and are used as active drug compounds in pharmaceutical chemistry. However, synthesis of these complex molecules is difficult due to the requirement of various synthetic steps, which include highly regio- and stereoselectivity. Therefore, oxidative radical cyclization assisted by manganese(III) acetate serves as an important step in obtaining spiro-, tricyclic, tetracyclic, and polycyclic derivatives of these compounds. Manganese(III)-based reactions offer a single-step regio- and stereoselective cyclizations and α-acetoxidations, reducing the number of synthetic steps. Also, the manganese(III)-mediated oxidative free radical cyclization method has been successfully applied for the synthesis of cyclic structures found in many natural products. This article presents a broad overview of manganese(III)-based radical reactions of natural products as a key step in overall synthesis. The authors have classified natural product synthesis processes assisted by manganese(III) acetate as intermolecular, intramolecular, oxidation, acetoxidation, aromatization, and polymerization reactions, respectively.

Short Formal Syntheses of Lycorine and Congeners Using a 5-Endo-Trig/6-Endo-Trig Radical Cyclization Sequence.

Here, we report a practical route to medicinally interesting lycorine congeners alongside formal syntheses of various lycorine-type natural products, including lycorine itself. The efficiency of our strategy derives from a back-to-back 5-endo-trig/6-endo-trig radical cyclization sequence, which we systematically studied both experimentally and computationally. The results of our work will facilitate future development of urgently needed antiviral therapeutics based on lycorine.