Synthesis Of Natural Products Research Articles

Facile Construction of Quaternary Carbon Centers via Dinuclear Titanium(III)‐Catalyzed Reductive Coupling of Tertiary Chlorides and Activated Olefins

AbstractThe establishment of all‐carbon quaternary carbon centers represents a pivotal aspect in the synthesis of numerous natural products and pharmaceutical compounds, underscoring its paramount significance in synthetic organic chemistry. Herein, we present a novel synthetic strategy for the generation of quaternary carbon centers through the reductive coupling of tertiary halides, catalyzed by dinuclear (salen)titanium catalysts. This catalytic framework demonstrates notable reactivity towards tertiary chlorides while maintaining inertness towards secondary and primary chlorides, thereby facilitating exceptional chemoselectivity for C−C bond formation. The reaction proceeds with remarkable efficiency across a diverse range of substrates under mild reaction conditions.

Development of Organocatalytic Reactions for the Synthesis of Natural Products and Pharmaceuticals

This review describes novel organocatalytic methods for the enantioselective construction of spiroindans and spirochromans and the application of the methods to the total synthesis of natural products. We developed an intramolecular Friedel-Craftstype 1,4-addition in which the substrates were a resorcinol derivative and 2-cyclohexenone linked by an alkyl chain. The reaction proceeded smoothly in the presence of a cinchonidine-based primary amine (30 mol%) with water and p-bromophenol as additives. A variety of spiroindanes were obtained with high enantioselectivity under these conditions. The reaction was applied in the first total synthesis of the unusual proaporphine alkaloid (-)-misramine, which included the key steps of enantioselective spirocyclization and double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. The total synthesis of misrametine was achieved by selective demethylation of the methoxy group from the precursor to misramine. Next, a method for highly enantioselective organocatalytic construction of spirochromans containing a tetrasubstituted stereocenter was developed. An intramolecular oxy-Michael addition was catalyzed by a bifunctional cinchona alkaloid thiourea catalyst. A variety of spirochroman compounds containing a tetrasubstituted stereocenter were obtained with excellent enantioselectivity of up to 99% enantiomeric excess. The reaction was applied to the asymmetric formal synthesis of (-)-(R)-cordiachromene.

Total synthesis of Comfreyn A and structural analogues via two photochemical key steps.

In this work the influence of o-fluorine substituents on the photo-dehydro-Diels-Alder (PDDA) reaction was investigated and the findings of this study were applied to the total synthesis of natural products. The reactant molecules consisted of two alkyl arylpropiolates, connected by a suberic acid tether and bearing fluorine substituents in each of the o-positions. While quantum chemical calculations suggested that a fluorine substituent prevents an attack of the adjacent carbon atom in the second C-C bond forming step of the PDDA reaction, this attack took place nevertheless. The subsequent fluoride elimination, assisted by protic solvents or trialkylsilanes, resulted in an "Umpolung" of the 4-position of the cycloallene intermediate enabling the introduction of nucleophiles at this position. The nucleophilic replacement of the second fluorine substituent could also be triggered photochemically. After removal of the tether, the two arene moieties stand nearly perpendicular to each other and a selective excitation of the naphthalene moiety was possible. This led to an intramolecular photoinduced electron transfer (PET) followed by a nucleophilic replacement of the fluoride according to a SR+N1Ar* mechanism. The formed phenolic hydroxyl group underwent spontaneous lactonization with the adjacent ester group. Based on these results, the first total synthesis of the lignan Comfreyn A and some structural analogues were developed.

Carbohydrate Derived α,β-Unsaturated Enals (Perlin’s Aldehyde) as Chiral Synthon for the Synthesis of Privileged Scaffolds

Perlin’s aldehyde is an α,β-unsaturated carbonyl compound with two well-defined chiral centres and a free hydroxy group. Since its discovery and synthesis by A. S. Perlin in 1975, it has been used as a flexible chiral synthon for synthesising natural products, its scaffolds and biologically significant compounds. Perlin’s aldehydes serve as useful starting materials in diversity-oriented synthesis (DOS) and chiral building blocks in organic synthesis. Currently, synthesising frameworks based on carbohydrates is at the forefront of organic synthesis. Inspired by the reactivity of Perlin’s aldehyde, various research groups worldwide used this molecule as a chiral synthon and published a number of research papers and a review article covering literature until 2012. This review covers recent advances in the synthesis of natural products, their scaffolds and other molecules, starting from perlin aldehyde, covering the literature from 2013 till date.

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.

Improvement and application of vacuum-infiltration system in tomato.

The Agrobacterium-mediated transient expression system has been developed and applied to various plants as an alternative to stable transformation. However, its application in tomatoes is still limited due to low expression efficiency. In this study, we describe an improved vacuum-infiltration system that can be used in both tomato fruits and leaves. Notably, this study is the first report of vacuum infiltration in attached tomato fruits. The feasibility of the improved vacuum-infiltration system in Micro-Tom tomato was confirmed by various assays, including multiple fluorescent protein expression analysis, β-glucuronidase activity analysis, and RUBY reporter visualization. Subsequently, the improved vacuum-infiltration system was successfully applied to tomato biotechnology research. Herein, a trichome-specific promoter in tomato was identified that can drive the directional synthesis of specific plant natural products (PNPs). Additionally, based on the assessment results of the improved vacuum-infiltration system, we obtained a flavonoid-rich tomato variety through the stable transformation of AmRosea and AmDelila. In a significant practical application, we successfully synthesized the high-value scutellarin in tomato, which provides an alternative route for the production of PNPs from plants. In addition, the improved vacuum-infiltration system has been demonstrated to be suitable for commercial tomato varieties ('Emerald' and 'Provence') as well. The improved vacuum-infiltration system not only speeds up fundamental and applied research in tomato but also offers an additional powerful tool for advancing tomato synthetic biology research.

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.

Enantioselective Allylboration of Acetylene: A Versatile Tool for the Stereodivergent Synthesis of Natural Products

AbstractEfficient catalytic methods that allow the use of simple and abundant chemical feedstocks for the preparation of synthetically versatile compounds are central to modern synthetic chemistry. Acetylene is a basic feedstock with a remarkable production over one million tons per year, although it is underutilized in the stereoselective synthesis of fine chemicals. Here we report a facile catalytic multicomponent reaction that allows for the enantio‐ and diastereoselective allylboration of acetylene gas. This process is catalyzed by a chiral copper catalyst, operates without specialized equipment or pressurization, and provides chiral skipped dienes bearing stereodefined and orthogonally functionalized olefins with excellent levels of chemo‐, regio‐, enantio‐ and diastereoselectivity. The combined stereochemical features and orthogonal functionalization make the products privileged structural scaffolds to access the complete set of stereoisomers of the chiral skipped diene core through simple enantio‐ and diastereodivergent pathways. The utility of the method is demonstrated with the enantioselective synthesis of three bioactive natural skipped diene products, namely (+)‐Nyasol, (+)‐Hinokiresinol and Phorbasin C, and other related synthetically relevant chiral molecules.

Enantioselective Allylboration of Acetylene: A Versatile Tool for the Stereodivergent Synthesis of Natural Products.

Efficient catalytic methods that allow the use of simple and abundant chemical feedstocks for the preparation of synthetically versatile compounds are central to modern synthetic chemistry. Acetylene is a basic feedstock with a remarkable production over one million tons per year, although it is underutilized in the stereoselective synthesis of fine chemicals. Here we report a facile catalytic multicomponent reaction that allows for the enantio- and diastereoselective allylboration of acetylene gas. This process is catalyzed by a chiral copper catalyst, operates without specialized equipment or pressurization, and provides chiral skipped dienes bearing stereodefined and orthogonally functionalized olefins with excellent levels of chemo-, regio-, enantio- and diastereoselectivity. The combined stereochemical features and orthogonal functionalization make the products privileged structural scaffolds to access the complete set of stereoisomers of the chiral skipped diene core through simple enantio- and diastereodivergent pathways. The utility of the method is demonstrated with the enantioselective synthesis of three bioactive natural skipped diene products, namely (+)-Nyasol, (+)-Hinokiresinol and Phorbasin C, and other related synthetically relevant chiral molecules.

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.

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

AbstractIndan‐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.

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.

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.

Recent Advance in the β‐Stereoselective Synthesis of 2‐Deoxy Glycosides

AbstractCompounds containing a 2‐deoxy β‐glycoside linkage play important roles in carbohydrate chemistry, serving as potential therapies with significant biological properties. From the viewpoint of synthesis, many strategies developed in recent years targeted the stereoselective construction of 2‐deoxy glycosides. This review aims to summarise recent advances in the synthetic routes toward 2‐deoxy β‐glycosides developed over the last decade. Where associated, practical applications of these strategies in the total synthesis of natural products are highlighted.

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 solutions (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.

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.

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 angucycline and angucyclinone natural products.

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.

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.