Mimicking/Extracting Structure and Functions of Natural Products: Synthetic Approaches that Address Unexplored Needs in Chemical Biology

Natural products are often attractive and challenging targets for synthetic chemists, and many have interesting biological activities. However, synthetic chemists need to be more than simply suppliers of compounds to biologists. Therefore, we have been seeking ways to actively apply organic synthetic methods to chemical biology studies of natural products and their activities. In this personal review, I would like to introduce our work on the development of new biologically active compounds inspired by, or extracted from, the structures of natural products, focusing on enhancement of functional activity and specificity and overcoming various drawbacks of the parent natural products.     

Synthesis of heterocycles using nanomagnetic nickel catalysts

Abstract

Heterocyclic scaffolds are important components in the structure of many drugs and natural products. They are well-known compounds because of their broad spectrum of pharmaceutical and biological activities. In this paper, we provide an overview of the utilization of nickel complexes immobilized on magnetic nanoparticles as attractive and efficient catalytic systems for synthesis of heterocyclic molecules.     

Magnetic nanoparticles supported copper catalysts: Synthesis of heterocyclic scaffolds

Abstract

Heterocyclic scaffolds are important components in the structure of many drugs and natural products. They are well-known compounds because of their broad spectrum of pharmaceutical and biological activities. In this paper, we provide an overview of the utilization of copper complexes immobilized on magnetic nanoparticles as economical and efficient catalytic systems for the synthesis of heterocyclic molecules.     

An Efficient Approach to Regio- and Stereodefined Fully-Substituted Alkenylsilanes by Pd-Catalyzed Allenic C(sp3)−H Oxidation

A highly efficient palladium-catalyzed functionalization of allenylsilanes to give regio- and stereodefined fully-substituted alkenylsilanes has been developed. This oxidative coupling reaction showed good functional group compatibility with exclusive regio- and stereoselectivity. The pending olefin on the silyl group was shown to be an indispensable element for the initial allenic C(sp³)−H bond cleavage, and performs as the directing group to control the overall selectivity. The addition of substoichiometric amounts of Et₃N was found to increase the reaction rate leading to a higher reaction yield. The reaction can be easily scaled up and applied for the late-stage functionalization of natural products and pharmaceutical compounds, including amino acids and steroid derivatives. The newly introduced functional groups include aryl, alkynyl, and boryl groups. The highly strained four-membered ring, silacyclobutene was obtained when B₂pin₂ was employed as the coupling partner. Mechanistic studies, including kinetic isotope effects, showed that the allenic C(sp³)−H bond cleavage is the rate-limiting step.     

Cellular targets of natural products

Natural products have evolved, at least in part, to bind to biological macromolecules, particularly proteins. As a result, natural products are able to interact with many specific targets within the cell. Indeed for many years this has been central in the drug development process. Today, however, natural products are finding increasing use as probes to interrogate biological systems as part of chemical genomics and related research. In order to demonstrate the utility of natural products in these efforts, the biological activities of many of the major classes of natural products is discussed, according to the cellular organelle and localisation of their specific molecular targets. Emphasis is given to newly discovered compounds and activities that either provide interesting insights into a specific biological function, or that form the basis for potentially new therapeutic approaches.     

从炔烃衍生物出发的有机合成方法学

研究了过渡金属催化的炔烃衍生物的异构化反应.从α,β-炔酮、2-炔酸酯和2-炔酸酰胺可以生成相应的(E,E)-共轭双烯酮、双烯酸酯和双烯酸酰胺.首次从2-炔醇异构化为相应的2-烯酮或2-烯醛.这一反应具有简单、高产率和立体选择性的优点.假设反应烯经过连二烯中间体,然后再异构化成产物,这一反应提供了方便而有潜在应用价值的方法以制备天然产物合成时的重要中间体.     

Amine-catalyzed coupling of allenic esters to alpha,beta-unsaturated carbonyls

Nucleophilic amines catalyze the 1,4-addition of allenic esters to alpha,beta-unsaturated carbonyl compounds. The reactions proceed under mild conditions. In addition, Baylis-Hillman products serve as appropriate electrophiles for the process such that a one-pot, three-component coupling of aldehydes, acrylates, and allenic esters may be achieved.     

Syntheses of Fumagillin and Ovalicin

This review focuses on the synthetic strategies used for the construction of fumagillin, ovalicin, and other natural products of this family that are known angiogenesis inhibitors. These compounds are comprised of a cyclohexane framework, two epoxides, and five or six contiguous stereogenic centers. The first total syntheses of fumagillin and ovalicin were reported by Corey in 1972 and 1985, respectively. There were numerous studies directed at these natural products in the decades that followed with many reports appearing in the year 2000 or later. Despite the relatively small size of these molecules, their syntheses highlight the efficient construction of stereogenic centers in organic synthesis.     

The role of vanadium bromoperoxidase in the biosynthesis of halogenated marine natural products

Halogenated natural products are frequently reported metabolites in marine seaweeds. These compounds span a range from halogenated indoles, terpenes, acetogenins, phenols, etc., to volatile halogenated hydrocarbons that are produced on a very large scale. In many cases these halogenated marine metabolites possess biological activities of pharmacological interest. Given the abundance of halogenated marine natural products found in marine organisms and their potentially important biological activities, the biogenesis of these compounds has intrigued marine natural product chemists for decades. Over a quarter of a century ago, a possible role for haloperoxidase enzymes was first suggested in the biogenesis of certain halogenated marine natural products, although this was long before haloperoxidases were discovered in marine organisms. Since that time, FeHeme- and Vanadium-haloperoxidases (V-HPO) have been discovered in many marine organisms. The structure and catalytic activity of vanadium haloperoxidases is reviewed herein, including the importance of V-HPO-catalyzed bromination and cyclization of terpene substrates.     

Silver(I)-catalyzed tandem 1,3-acyloxy migration/Mannich-type addition/elimination of the sulfonyl group of N-sulfonylhydrazone-propargylic esters to 5,6-dihydropyridazin-4-one derivatives

The addition of nucleophiles to C=N bonds offers a highly efficient synthetic strategy for accessing nitrogen-containing molecules.1 Among the well-developed addition reactions, such as the highly efficient Mannich reaction, various C-H bond-activated compounds including carboxylic acid derivatives, nitroalkanes, and terminal alkynes have been applied as nucleophiles to achieve different classes of amines.2 However, employing new nucleophiles without activated C-H bonds, such as internal alkynes and allenic esters are limited when using metal catalysts.3 Herein, we wish to report a new addition of allenic esters to C=N bonds initiated by a silver-catalyzed 1,3-migration of propargylic esters.     

An Efficient Synthesis of 4-Halo-5-hydroxyfuran-2(5H)-ones via the Sequential Halolactonization and γ-Hydroxylation of 4-Aryl-2,3-alkadienoic Acids

5-Hydroxyfuran-2(5H)ones are an important class of compounds because they often occur in natural products and exhibit a broad range of biological activities. Recently, much attention has been focused on the efficient and di verse synthesis of these compounds, particularly 4-halo-5-hydroxy-2(5H)-furanones. The typical synthetic strategies include acid catalyzed cyclization of ketonic acids, auto oxidation of corresponding lactone in air, rearrangement reactions of α-phenylsulphinylacrylates, oxidation with chromium trioxide in acetic acid, and bromination-hydrolysis of α ,β-butanolides. Herein, we wish to report that 4-halo-5-hydroxyfuran-2(5H)-ones were synthesized via the efficient sequential halolactonization-hydroxylation reaction of 4-aryl-2,3-allenoic acids with I2 or CuX2 (X = Br or Cl) inmoderate to good yields.     

Efficient synthesis of maleimides and carbazoles via Zn(OTf)(2)-catalyzed tandem annulations of isonitriles and allenic esters

Lewis acid Zn(OTf)(2)-catalyzed tandem annulations of isonitriles and allenic esters which lead to efficient and flexible syntheses of a range of biologically significant maleimides and carbazoles and related compounds are reported. A mechanistic rationale is proposed to account for the observed reactivity.     

Indium-mediated radical cyclization of iodoalkenes and iodoalkynes with and without allylic and propargylic leaving groups

Upon treatment with In and I₂, mono-substituted alkenes having an iodine substituent at the δ-position of the tether gave the corresponding iodinated cyclic compounds, whereas di- and tri-substituted alkenes gave the corresponding hydroxylated cyclic compounds. Alkenes bearing leaving groups at the allylic position were transformed only to the corresponding vinyl substituted cyclic compounds. On the other hand, alkynes bearing good leaving groups at the propargylic position gave allenic products selectively.     

Natural‐Product Sugar Biosynthesis and Enzymatic Glycodiversification

Many biologically active small‐molecule natural products produced by microorganisms derive their activities from sugar substituents. Changing the structures of these sugars can have a profound impact on the biological properties of the parent compounds. This realization has inspired attempts to derivatize the sugar moieties of these natural products through exploitation of the sugar biosynthetic machinery. This approach requires an understanding of the biosynthetic pathway of each target sugar and detailed mechanistic knowledge of the key enzymes. Scientists have begun to unravel the biosynthetic logic behind the assembly of many glycosylated natural products and have found that a core set of enzyme activities is mixed and matched to synthesize the diverse sugar structures observed in nature. Remarkably, many of these sugar biosynthetic enzymes and glycosyltransferases also exhibit relaxed substrate specificity. The promiscuity of these enzymes has prompted efforts to modify the sugar structures and alter the glycosylation patterns of natural products through metabolic pathway engineering and enzymatic glycodiversification. In applied biomedical research, these studies will enable the development of new glycosylation tools and generate novel glycoforms of secondary metabolites with useful biological activity.     

4-羟基-2-吡啶酮类天然生物碱的研究进展

4-羟基-2-吡啶酮类生物碱是从植物和昆虫等内生真菌发酵液中提取分离得到的一类新型天然生物碱, 具有抗真菌、抗菌和抗肿瘤等多种生物活性. 对近年来4-羟基-2-吡啶酮类天然生物碱的分离、结构确证和全合成等进行了总结和概述, 重点介绍了Ilicilolin H, Tenellin和Sambutaxin等的全合成.     

Gold-catalyzed hydroarylation of allenes: a highly regioselective carbon-carbon bond formation producing six-membered rings

Gold-catalyzed intramolecular hydroarylation of allenic anilines and phenols offers an efficient route to dihydroquinoline and chromene derivatives under mild reaction conditions. The hydroarylation takes place at the terminal or central allenic carbon depending on the substrate structure, leading to a highly selective formation of six-membered rings.     

4-羟基-2-吡啶酮类化合物的合成研究进展

4-羟基-2-吡啶酮是天然生物碱结构母核,同时也是一类重要的医药中间体,该类衍生物具有抗真菌、抗菌和抗肿瘤等多种生物活性.因此,其合成得到了广泛的研究和关注.综述了近年来4-羟基-2-吡啶酮类化合物的合成方法及其研究进展.     

Chemical Diversity and Biological Activity of Secondary Metabolites Isolated from Indonesian Marine Invertebrates

Marine invertebrates have been reported to be an excellent resource of many novel bioactive compounds. Studies reported that Indonesia has remarkable yet underexplored marine natural products, with a high chemical diversity and a broad spectrum of biological activities. This review discusses recent updates on the exploration of marine natural products from Indonesian marine invertebrates (i.e., sponges, tunicates, and soft corals) throughout 2007–2020. This paper summarizes the structural diversity and biological function of the bioactive compounds isolated from Indonesian marine invertebrates as antimicrobial, antifungal, anticancer, and antiviral, while also presenting the opportunity for further investigation of novel compounds derived from Indonesian marine invertebrates.     

Chiral allylic and allenic metal reagents for organic synthesis

This account traces the evolution of our work on the synthesis of chiral allylic and allenic organometal compounds of tin, silicon, zinc, and indium and their application to natural product synthesis over the past quarter century.     

Bi(OTf)3-catalysed prenylation of electron-rich aryl ethers and phenols with isoprene: a direct route to prenylated derivatives

Electron-rich aryl ethers and phenols react with isoprene (2-methylbuta-1,3-diene) in the presence of catalytic Bi(OTf)(3) at 40 °C to afford the corresponding prenylated or 2,2-dimethylchroman products, respectively, in moderate to good yields. This transformation offers a convenient and expedient entry to prenylated derivatives of electron-rich aromatics that often display enhanced biological activities. The methodology has been employed in the efficient synthesis of a biologically active natural product and related compounds.