Stereoselective Halogenation in Natural Product Synthesis

At last count, nearly 5000 halogenated natural products have been discovered. In approximately half of these compounds, the carbon atom to which the halogen is bound is sp³‐hybridized; therefore, there are an enormous number of natural products for which stereocontrolled halogenation must be a critical component of any synthesis strategy. In this Review, we critically discuss the methods and strategies used for stereoselective introduction of halogen atoms in the context of natural product synthesis. Using the successes of the past, we also attempt to identify gaps in our synthesis technology that would aid the synthesis of halogenated natural products, as well as existing methods that have not yet seen application in complex molecule synthesis. The chemistry described herein demonstrates yet again how natural products continue to provide the inspiration for critical advances in chemical synthesis.     

Recent advances on the synthesis of flavans,isoflavans, and neoflavans

Heterocyclic compounds are the omnipresent structural cores comprising many natural and pharmaceutical products of biological significance. Significantly, heterocyclic compounds are widely distributed in nature, and also have applications in agrochemicals, sanitizers, as dyestuff, as copolymers, etc. Among heterocyles, flavonoids are a class of compounds that are highly interesting and constitute many natural products. In general, all flavanoids contains a basic core of C₆-C₃-C₆ of phenyl-benzopyran backbone. The relative placement of the phenyl group on to the benzopyran core makes further classification into flavanoids, isoflavanoids and neoflavanoids. Flavans (2-aryl chroman) are subclass of anthoxanthanes exhibits a broad spectrum of biological properties such as anti-inflammatory, anti-oxidant, and anti-malarial properties. Some representative naturally occurring products possessing flavan core are apigenin, luteolin, tangeretin, scutellarein, etc. On the other hand, some of the notable isoflavan-based natural products are glabridin and (S)-(−)-equol. Glabridin is isolated from Licorice roots, which regulates paraoxonase (PON₂) levels. While the simple isoflavan (S)-(−)-equol, is produced from soy isoflavone intake. Also, natural products such as dalbergichromene, centchroman, and (+)-myristinin A possess neoflavan (4-aryl-3,4-dihydro-2H-chromenes) core structure. Owing to their broad biological and pharmacological properties, synthetic chemists are fascinated in developing new routes toward their synthesis. As a result, a decent number of reports have been established in the literature. Thus, for the past 5 years of time frame, many new methodologies have been witnessed, for the synthesis of various flavan systems. This review emphasizes most of the significant methods on accomplishing flavans, isoflavans and neoflavans and also focused on their applications to the synthesis of relevant natural as well as biologically active products.     

ortho-Quinols in (Bio)Synthesis of Natural Products

6-Alkyl-6-hydroxycyclohexa-2,4-dienone derivatives, commonly referred to as ortho-quinols, and their simple ester and ether variants constitute a class of organic compounds that aroused much interest amongst chemists over the past 70 years for several reasons related to organic synthesis, natural product chemistry and biochemistry. It was very early on that organic chemists understood the potential of the unique yet versatile chemical reactivity of such compounds to synthesize more complex structures, and it soon emerged that ortho-quinols could constitute key intermediates in the biosynthesis of certain natural products of various origins. This minireview discusses the chemistry of ortho-quinols from the point of view of their role in the synthesis and biosynthesis of natural products. Examples of completed syntheses of natural products mostly taken in the literature of the last 20 years or so, together with some chosen pieces from older but pioneering and most remarkable works, are highlighted to illustrate this discussion.     

Enantioselective Reactions of N‐Acyliminium Ions Using Chiral Organocatalysts

N‐acyliminium ions are reactive intermediates that can act as electron‐deficient electrophiles toward weak or soft nucleophiles, thereby providing useful methods for both intermolecular‐ and intramolecular carbon–carbon and carbon–heteroatom bond formation. Nucleophilic additions to N‐acyliminium ions constitute an important method for providing α‐functionalized amino compounds and many other biologically active nitrogen‐containing heterocycles. The development of efficient catalytic asymmetric reactions is a key objective in modern organic chemistry and is very important for the synthesis of natural products, pharmaceuticals, and agrochemicals. Various methods are available for this purpose and mostly rely on the use of chiral catalysts for enantioselective synthesis. This review deals with one aspect of such catalysis, which has emerged only in the past few years, and its applications in enantioselective reactions of N‐acyliminium ions to provide various nitrogen‐containing heterocycles.     

Highly Diastereoselective Synthesis of Syn‐1,3‐Dihydroxyketone Motifs from Propargylic Alcohols via Spiroepoxide Intermediates

Syn dihydroxyketone motifs are embedded in a wide range of biologically active natural products, however the development of stereoselective synthetic methods to assemble these structures has proven a challenging task. We report a highly diastereoselective method for the synthesis of syn dihydroxyketones from propargylic alcohols, with wide scope for application in natural product synthesis. The reaction sequence involves regioselective cyclisation of propargylic alcohols with incorporation of a triketone to give enol dioxolanes that are then diastereoselectively epoxidised to form unusual spiroepoxide intermediates. Hydrolysis affords syn dihydroxyketones as essentially single diastereisomers. The reaction sequence is operationally simple, of wide substrate scope, and remarkably can be efficiently carried out as a one‐pot process with no loss of overall yield or diastereoselectivity.     

Transition‐Metal‐Mediated Cleavage of C−C Bonds in Aromatic Rings

Metal‐mediated cleavage of aromatic C?C bonds has a range of potential synthetic applications: from direct coal liquefaction to synthesis of natural products. However, in contrast to the activation of aromatic C?H bonds, which has already been widely studied and exploited in diverse set of functionalization reactions, cleavage of aromatic C?C bonds remains Terra incognita. This Minireview summarizes the recent progress in this field and outlines key challenges to be overcome to develop synthetic methods based on this fundamental organometallic transformation.     

Total Synthesis of Camptothecin and Related Natural Products by a Flexible Strategy

A flexible strategy for constructing natural products containing indolizinone or quinolizinone scaffolds and their analogues was developed, which was based on a cascade exo hydroamination followed by spontaneous lactamization. This method was applied in the total synthesis of camptothecin in nine steps in a new ring‐forming approach. It was also used to efficiently prepare five biogenetically or structurally related natural alkaloids, including 22‐hydroxyacuminatine, oxypalmatine, norketoyobyrine, naucleficine, and nauclefine, as well as 35 natural‐product‐like molecules. We believe that this method and the small‐molecule library prepared with it can open new avenues for studying the bioactivity of camptothecin and Nauclea natural products.     

(2E)-4,4-Dimethoxy-2-butenal in the Synthesis of Conjugated Dienes and Dienals

Using (2E)-4,4-dimethoxy-2-butenal as starting compound, methods were developed for synthesis of (2E,4E)- and (2E,4Z)-dimethoxyalkadienes. Deacetalization of the latter gives with high yield the corresponding dienals which are naturally occurring compounds and also synthons for preparation of conjugated dienes as key compounds for building up other natural products.     

Intramolecular C−H Amination of N-Alkylsulfamides by tert-Butyl Hypoiodite or N-Iodosuccinimide

1,3-Diamines are an important class of compounds that are broadly found in natural products and are also widely used as building blocks in organic synthesis. Although the intramolecular C−H amination of N-alkylsulfamide derivatives is a reliable method for the construction of 1,3-diamine structures, the majority of these methods involve the use of a transition-metal catalyst. We herein report on a new transition-metal-free method using tert-butyl hypoiodite (t-BuOI) or N-iodosuccinimide (NIS), enabling secondary non-benzylic and tertiary C−H amination reactions to proceed. The cyclic sulfamide products can be easily transformed into 1,3-diamines. Mechanistic investigations revealed that amination reactions using t-BuOI or NIS each proceed via different pathways.     

New Approach to the Synthesis of the Natural Product Aripuanin

Abstract

Aripuanin is a megastigmane that exists in the leaves of Ficus aripuanensis C.C. Berg (Moraceae). The present study describes a new approach to the total synthesis of this natural product starting from the readily available β-ionone. The proposed synthetic route provided racemic aripuanin in moderate yields (~31%). This route can be applied to the synthesis of other natural products bearing the megastigmane moiety, as well as to the enantioselective synthesis of aripuanin derivatives.     

Synthesis,characterisation and antibacterial studies of carbon nanoparticle and carbon nanoparticle encapsulated in functionally modified β-cyclodextrin with {5-[4-(dimethylamino) benzylidene]-4-oxo-2-thioxo-1, 3-thiazolidin-3-yl} acetic acid

This paper describes the synthesis of carbon nanoparticle (CNP) from natural sources such as kitchen soot, synthesis of a chromophoric system {5-[4-(dimethylamino) benzylidene]-4-oxo-2-thioxo1, 3-thiazolidin-3-yl} acetic acid and its incorporation into β-cyclodextrin (β-CD) through the esterification of the hydroxyl group with the free carboxyl function of the chromophoric system by DCC coupling. Encapsulation of CNP into functionally modified β-CD system was achieved. Characterisation of the products was undertaken by UV–visible, FT-IR, NMR, fluorescence spectroscopic methods, SEM, TEM and X-ray diffraction methods. Their antibacterial activities were addressed. The antibacterial activity of CNP and functionally modified β-CD-CNP products were tested against various pathogenic bacterial strains such as Streptcoccus haemoliticus (+ve), Staphylococcus aureus (+ve), Klebsiella pneumonia (?ve) and E. coli (MTCC1687) (?ve) by disc diffusion method. The results showed that the CNPs and functionally modified products have good antibacterial activity against selected pathogenic bacterial strains.     

Synthesis and Biological Activity of α-Methylene-γ-butyrolactones

α-Methylene-γ-butyrolactones [dihydro-3-methylene-2(3H)furanones] constitute an important group of natural products and possess wide-ranging biological activities. Progress in the synthesis of the heterocycle and the classification of the synthetic methods are not only of practical interest, but also fundamentally important as a current example for the construction of an unusual 1,4-functionality distance and an α-substituted acrylic ester moiety which is susceptible to nucleophilic attack.     

Total Synthesis of Suberitines A–D Featuring Tunable Biomimetic Late-Stage Oxidative Dearomatization and Acetalization

Aaptaminoids are a unique family of marine alkaloids bearing a benzo[de][1,6]-naphthyridine core. This work describes the first total synthesis of suberitines A–D ( 1 – 4 ), four typical dimeric natural aaptaminoids, employing a step-saving bidirectional strategy. Key methods applied in the total synthesis include a cationic cascade to construct the bis-isoquinoline(s) with Hendrickson reagent-mediated Friedel-Crafts-type cyclization and eliminative aromatization, and a Bronsted acid-promoted Vilsmeier cyclization to generate the naphthyridine(s). The conditionally tunable PIDA-mediated oxidative dearomatization and subsequent methanolysis or hydrolysis successfully served as a powerful biomimetic tool to elaborate the essential oxygenated functionalities of suberitines A–D ( 1 – 4 ) in proper solvent-combinations at the final stage of total synthesis. The biomimetic proposal employed in the late-stage redox interchanges of related natural products was eventually supported by the isolation of synthetic intermediate 23 a as a natural product from the same natural source. Biological screening revealed that five of the synthetic samples including two natural suberitines and three full-skeleton natural product-like intermediates exhibited low micromolar inhibitory activities against the growth of cancer cell line K562.     

The role of Lawesson's reagent in the total synthesis of macrocyclic natural products

This review, including 111 references, describes the applications of Lawesson's reagent (LR) [2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione] for the total synthesis of macrocyclic natural products. LR is a versatile reagent and shows excellent regioselectivity, chemoselectivity, and offers the products in high yield. The thionation of carbonyl moieties present in macrocyclic natural products, and cyclization to construct key heterocyclic fragments is described. Moreover, this review highlights the medicinal significance of the natural products.     

Asymmetric synthesis of chiral oxindoles using isatin as starting material

Asymmetric synthesis plays an important role in the synthesis of therapeutics and natural products. Asymmetric oxindoles with a stereogenic quaternary carbon center are extensively present in various natural products and biologically active compounds. Several methods such as employing chiral auxiliaries or chiral catalysts were developed for asymmetric synthesis of spirooxindoles or 3,3-disubtituted oxindoles. In this review, we make a detailed overview of the latest developments in the use of isatin as starting material for the asymmetric synthesis of spirooxindoles and 3,3-disubstituted oxindoles during the period from 2015 to 2017.     

The Plakotenins: Biomimetic Diels–Alder Reactions,Total Synthesis,Structural Investigations,and Chemical Biology

The total synthesis of plakotenin, a cytotoxic marine natural product, using a biomimetic Diels–Alder reaction is described in detail. Two approaches were used, whereby the Diels–Alder reaction occurs at different stages of the synthesis. Homo‐ and nor‐plakotenin, related natural products, were also prepared, as well as iso‐plakotenin, a diastereoisomer of plakotenin. The syntheses prove the relative and absolute stereochemistry of the latter. The chemical biology of the plakotenins was investigated on selected compounds.     

芳香类化合物异戊烯基化的研究进展

结构多样的芳香类化合物一直被用作新药发现的线索或主要来源。通过对类药物天然产物进行异戊烯基化结构修饰,能有效提高芳香类化合物生物活性及生物利用度,为新药研究与开发提供简便高效的方法。本文综述了近年来芳香类化合物异戊烯基化的各种方法,以为今后研究提供参考。     

Several Enantiopure Chiral Building Blocks Derived from D‐Mannose and a Formal Synthesis of Dubiusamine C

Several multi‐functional chiral building blocks derived from D‐mannose are developed, which may find diverse utilities as sources of 1‐hydroxy‐3‐methyl structural units in enantioselective synthesis of many natural products. A formal synthesis of natural dubiusamine‐C is also presented.     

Highly Enantioselective Iridium‐Catalyzed Hydrogenation of α,β‐Unsaturated Esters

α,β‐Unsaturated esters have been employed as substrates in iridium‐catalyzed asymmetric hydrogenation. Full conversions and good to excellent enantioselectivities (up to 99 % ee) were obtained for a broad range of substrates with both aromatic‐ and aliphatic substituents on the prochiral carbon. The hydrogenated products are highly useful as building blocks in the synthesis of a variety of natural products and pharmaceuticals.