Synthesis Of Natural Products Research Articles

Palladium-catalyzed γ-C-H Arylation of Unsaturated Carbonyl Compounds: An Emerging Remote Buchwald–Hartwig–Miura Arylation

As an important complement to Buchwald-Hartwig-Miura arylation, Pd-catalyzed -C-H including -C(sp3)-H and -C(sp2)-H arylations provide a more direct way to install an aryl group on less reactive -site of the unsaturated carbonyls, attracting considerable interests from chemistry community in recent years. The review summarizes the applications of this method in both cyclic and linear unsaturated carbonyls (aldehydes, ketones, esters, amide, and nitriles), as well as in the total synthesis of natural products, natural products skeletons, and bioactive analogues.

Zirconium Hydride Catalysis Initiated by Tetrabutylammonium Fluoride.

In our drug discovery campaigns to target the oncogenic drivers of cancers, the demand for a chemoselective, stereoselective and economical synthesis of chiral benzylamines drove the development of a catalytic zirconium hydride reduction. This methodology uses the inexpensive, bench stable zirconocene dichloride, and a novel tetrabutylammonium fluoride activation tactic to catalytically generate a metal hydride under ambient conditions. The diastereo- and chemoselectivity of this reaction was tested with the preparation of key intermediates from our discovery programs and in the scope of sulfinyl ketimines and carbonyls relevant to medicinal chemistry and natural product synthesis. A preliminary mechanistic investigation conducted into the role of tetrabutylammonium fluoride indicates that formation of a zirconocene fluoride occurs to initiate catalysis. The implications of this convenient activation approach may provide expanded roles for zirconium hydrides in catalytic transformations.

Copper and Photocatalytic Synergistic Strategies for Radical Cyclization Reactions

The rapid development of photo‐synergistic transition metal catalytic systems has provided a green paradigm to complement thermal transition metal catalytic methods. However, the most commonly used iridium or ruthenium complexes involve expensive in nature, in contrast to the abundant copper elements in the earth's crust, which are highly valued for their unique electronic structure and light‐absorbing properties. Recently, the application of copper and photocatalytic synergistic strategies in radical cyclization reactions has progressed considerably, leading to a renaissance in the synthesis of functional natural products, drugs and their analogues, but summary work addressing this aspect has not been reported. In this review, we briefly analyze the effect of ligand choice on copper complexes and some inorganic copper salts and even on light sources. We then summarize the copper and photocatalytic synergistic strategies in radical cyclization reactions and classify them into three categories, C, N and O radicals, according to the class of the central atom of the radical in each work, and in each category will be elaborated in turn from coordination cyclization via Cu catalysts, direct radical cyclization and other cyclization mode. For individual more complex reactions, the mechanisms are explored and briefly discussed.

Concise Total Syntheses of (-)-Crinipellins A and B Enabled by a Controlled Cargill Rearrangement.

Herein, we report concise total syntheses of diterpene natural products (-)-crinipellins A and B with a tetraquinane skeleton, three adjacent all-carbon quaternary centers, and multiple oxygenated and labile functional groups. Our synthesis features a convergent Kozikowski β-alkylation to unite two readily available building blocks with all the required carbon atoms, an intramolecular photochemical [2 + 2] cycloaddition to install three challenging and adjacent all-carbon quaternary centers and a 5-6-4-5 tetracyclic skeleton, and a controlled Cargill rearrangement to rearrange the 5-6-4-5 tetracyclic skeleton to the desired tetraquinane skeleton. These strategically enabling transformations allowed us to complete total syntheses of (-)-crinipellins A and B in 12 and 13 steps, respectively. The results of quantum chemical computations revealed that the Bronsted acid-catalyzed Cargill rearrangements likely involve stepwise paths to products and the AlR3-catalyzed Cargill rearrangements likely involve a concerted path with asynchronous alkyl shifting events to form the desired product.

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations.

A steadily increasing number of reports have been published on chemo-enzymatic synthesis methods that integrate biosynthetic enzymatic transformations with chemical conversions. This review focuses on the total synthesis of natural products and classifies the enzymatic reactions into three categories. The total synthesis of five natural products: cotylenol, trichodimerol, chalcomoracin, tylactone, and saframycin A, as well as their analogs, is outlined with an emphasis on comparing these chemo-enzymatic syntheses with the corresponding natural biosynthetic pathways.

Efficient Oxidation with Singlet Oxygen from 5,10,15,20-Tetraphenylporphyrin under Blue LED Irradiation and Air Atmosphere: Simplified Preparation of Key Building Blocks for Natural Product Synthesis

AbstractA method for preparing important building blocks for natural product synthesis has been developed using singlet oxygen generated from 5,10,15,20-tetraphenylporphyrin under blue LED irradiation. Using this method, the allylic oxidation of dicyclopentadiene proceeded smoothly in air atmosphere with an 87% yield. The conditions, using TPP under blue LED irradiation, were expanded to include the oxidation of cyclopentadiene. The approach offers a simple and cost-effective method of synthesizing important building blocks for natural product synthesis.

Baeyer-Villiger oxidation: a promising tool for the synthesis of natural products: a review.

Baeyer-Villiger oxidation is a well-known reaction utilized for the synthesis of lactones and ester functionalities from ketones. Chiral lactones can be synthesized from chiral or racemic ketones by employing asymmetric Baeyer-Villiger oxidation. These lactones act as key intermediates in the synthesis of most of the biologically active natural products, their analogues, and derivatives. Various monooxygenases and oxidizing agents facilitate BV oxidation, providing a broad range of synthetic applications in organic chemistry. The variety of enzymatic and chemoselective Baeyer-Villiger oxidations and their substantial role in the synthesis of natural products i.e., alkaloids, polyketides, fatty acids, terpenoids, etc. (reported since 2018) have been summarized in this review article.

Natural hypoglycaemic bioactives: Newer avenues and newer possibilities.

The incidences of endocrine and metabolic disorders like diabetes have increased worldwide. Several proposed molecular pathways mechanisms for the management of diabetes have been identified, but glycaemic control is still a challenging task in the drug discovery process. Most of the drug discovery processes lead to numerous scaffolds that are prominent in natural products. The review deals with the natural bioactives as an α-amylase inhibitors, α-glucosidase inhibitors, protein tyrosine phosphatase-1B inhibitors, dipeptidyl peptidase-IV inhibitors, G-protein coupled receptors-40 agonists, PPAR-γ agonists and the activators of 5'-adenosine monophosphate-activated protein kinase and glucokinase. So, in this review, we focused on the hypoglycaemic bioactives, which will assist scientific developers, traditional medicinal practitioners, and readers to discover some potent antidiabetic molecules. Strategies like chemometric approaches, scaffold hopping, and total synthesis of natural products by group modification or ring opening/closing mechanism could be useful for the development of novel hit/lead antidiabetic molecules. The study concludes that each phyto molecule inherits a potential to get explored by repurposing techniques for various antidiabetic targets and offer an alternative antidiabetic therapeutic medicinal potential.

Recent Progress in Synthetic and Biological Application of Diorganyl Diselenides.

Diorganyl diselenides have emerged as privileged structures because they are easy to prepare, have distinct reactivity, and have broad biological activity. They have also been used in the synthesis of natural products as an electrophile in the organoselenylation of aromatic systems and peptides, reductions of alkenes, and nucleophilic substitution. This review summarizes the advancements in methods for the transformations promoted by diorganyl diselenides in the main functions of organic chemistry. Parallel, it will also describe the main findings on pharmacology and toxicology of diorganyl diselenides, emphasizing anti-inflammatory, hypoglycemic, chemotherapeutic, and antimicrobial activities. Therefore, an examination detailing the reactivity and biological characteristics of diorganyl diselenides provides valuable insights for academic researchers and industrial professionals.

Recent Progress in Synthetic and Biological Application of Diorganyl Diselenides.

Diorganyl diselenides have emerged as privileged structures because they are easy to prepare, have distinct reactivity, and have broad biological activity. They have also been used in the synthesis of natural products as an electrophile in the organoselenylation of aromatic systems and peptides, reductions of alkenes, and nucleophilic substitution. This review summarizes the advancements in methods for the transformations promoted by diorganyl diselenides in the main functions of organic chemistry. Parallel, it will also describe the main findings on pharmacology and toxicology of diorganyl diselenides, emphasizing anti-inflammatory, hypoglycemic, chemotherapeutic, and antimicrobial activities. Therefore, an examination detailing the reactivity and biological characteristics of diorganyl diselenides provides valuable insights for academic researchers and industrial professionals.

The Chemistry of Angucyclines.

Angucyclines and angucyclinones represent a class of natural compounds that belong to the group of aromatic polyketides. They exhibit a wide array of biological properties, such as antimicrobial, antiviral, and cytotoxic. Their considerable therapeutic potential and diverse scaffolds have attracted many synthetic chemists to devise novel strategies to construct their intricate molecular architecture. Over 300 class members have been isolated from natural sources, mainly from bacterial strains of Streptomyces species. This review highlights recent advancements in their synthesis, such as oxidative cyclization, photooxidation, and metal-catalyzed [4+2]-cycloaddition, which has facilitated the efficient and practical total syntheses of various angucyclines natural products.

Natural product synthesis by a nanoporous In-MOF Catalyst: Crystallographic insight by incorporating substrate inside its nanopores

Metal-organic frameworks (MOFs) are promising candidates as nanoporous heterogeneous catalysts over other solid catalysts. Herein, utilizing a new tetra-acid ligand and employing high-valent Indium metal source we have strategically developed a 3D robust nanoporous framework, IITKGP-53, which retained its crystallinity over a wide range of pH solution (2–12). Considering the green synthesis approach IITKGP-53 was explored as a heterogeneous catalyst toward one-pot three-component Strecker reaction under solvent-free condition, with low catalyst loading for a broad range of substrates. Considering practical utility, biologically important natural product, Girgensohnine, was synthesized for the first time by using this catalyst with excellent conversion rate. The substrate binding sites inside the nanopores and host–guest interactions were verified crystallographically by obtaining a substrate inside nanopores of this MOF (aniline@IITKGP-53) and computational modeling. An in-depth theoretical investigation unveiled the most plausible transition states for the first time. This study inaugurates the usage of nanoporous MOFs as heterogeneous catalysts for natural product synthesis.

Asymmetric synthesis of ENT-03, the predicted mammalian ortholog of the dog fish shark aminosterol trodusquemine (MSI-1436)

ENT-03 was predicted to be the mammalian equivalent of trodusquemine, based on knowledge of the bile acids produced in mammals, such as 7-HOCA. The individual C-25 isomers of ENT-03 were prepared and both isomers were detected in neonatal mouse brain and liver. Trodusquemine and ENT-03 have both demonstrated dramatic effects in obesity and insulin resistance. (25S)-ENT-03 was selected for development for the treatment of diabetes and obesity. In this paper the first synthesis of this putative natural product is described. Starting with a stereo-defined steroidal intermediate 2, the semi-synthesis involves three stereoselective steps: Horner-Emmons olefination, hydrogenation, and reductive amination. Asymmetric hydrogenation using a ruthenium coordinated Mandyphos ligand was found to be effective in controlling the C25-stereochemistry of both isomers. The syntheses of the ENT-03 isomers and a deuterated reference standard facilitated identification and quantification of this natural product in mouse tissues, and exploration of its therapeutic potential.

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.

Unified chemical synthesis of cephalotaxus diterpenoids: A biosynthetic reversed strategy

In this work, we present the details of the first unified chemical synthesis of cephalotaxus diterpenoids with three distinct carbon skeleton structures. Drawing on our previous synthesis of cephalotane-type C18 dinorditerpenoid and inspired by the proposed biosynthetic synthesis pathway, we formulated a biosynthetic reversed chemical synthetic strategy. This strategy facilitated the conversion of C18 dinorditerpenoid into troponoid-type C19 norditerpenoid and intact cephalotane-type C20 diterpenoid through pivotal one-carbon introduction and ring expansion reactions. In the synthesis of troponoid-type C19 norditerpenoid, we utilized TMSCHN2 as one-carbon unit and meticulously examined the selective regulatory effect of halogen substituents in ring expansion and rearrangement reactions. This endeavor culminated in the successful synthesis of natural product molecules within this subclass, notably including cephinoid H and fortalpinoid C, marking the first chemical total synthesis in this line of research. In the investigation of intact cephalotane-type C20 diterpenoid synthesis, while adhering to the overall synthesis strategy, we initially pursued a ring expansion before carbon introduction approach, which proved unsuccessful. Subsequently, we explored a synthetic route of introducing carbon first and then expanding the ring, leading to a successful outcome and resulting in the first chemical total synthesis of the representative molecule cephanolide E within this subclass. Various challenges such as establishing crucial quaternary carbon stereocenters, selecting appropriate one-carbon units, and controlling ring expansion reactions were effectively addressed throughout this process. Moreover, enantioselective synthesis of natural products within this family was achieved through the development of asymmetric Michael reactions.

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.