Importance of Baylis-Hillman adducts in modern drug discovery

The Baylis-Hillman (BH) reaction plays a fascinating role in the field of synthetic and medicinal chemistry. BH adducts and their derivatives have been used as crucial synthons for the synthesis of various pharmaceutically useful natural products and compounds with carbocyclic or heterocyclic frameworks. This digest letter aims to discuss some key ideas for the synthesis of biologically active scaffolds using BH reaction and raise the awareness of this emerging research domain in modern drug discovery. In this review, we will present and discuss recent reports of various biologically active scaffolds derived from BH reaction, and their reported biological activities.     

Indole Synthesis Using Silver Catalysis

Indoles are amongst the most important classes of heteroaromatics in organic chemistry, commonly found in biologically active natural products and therapeutically useful compounds. The synthesis of indoles is therefore important and several methods for their synthesis that make use of silver(I) catalysts and reagents have been developed in recent years. This Minireview contains, to the best of our knowledge, a comprehensive coverage of silver‐mediated indole forming reactions since the first reaction of this type was reported in 2004.     

微波辐射下磷酸改性铌酸催化的香豆素修饰吡唑并[3,4-b]吡啶衍生物的高效合成

香豆素和吡唑并[3,4-b]吡啶骨架广泛存在于具有生物活性的天然化合物中,在药物化学中也被广泛用作药物核心单元,具有极其重要的作用.以磷酸改性铌酸作为催化剂,通过微波辐射下醛、香豆素衍生物、5-氨基吡唑的三组分反应一锅法高产率地合成一系列香豆素修饰的吡唑并[3,4-b]吡啶衍生物.该反应一步完成,具有催化剂和溶剂对环境友好,操作简单等优点.产物的结构经红外光谱、核磁共振谱及高分辨质谱予以确定.     

1,3-Cyclohexadien-1-Als: Synthesis,Reactivity and Bioactivities

In synthetic organic chemistry, there are very useful basic compounds known as building blocks. One of the main reactions wherein they are applied for the synthesis of complex molecules is the Diels–Alder cycloaddition. This reaction is between a diene and a dienophile. Among the most important dienes are the cyclic dienes, as they facilitate the reaction. This review considers the synthesis and reactivity of one of these dienes with special characteristics—it is cyclic and has an electron withdrawing group. This building block has been used for the synthesis of biologically active compounds and is present in natural compounds with interesting properties.     

Development of new synthetic reactions for nitrogen-containing compounds and their application

Nitrogen-containing compounds are core parts not only of natural and synthetic medicines but also of biologically active compounds including natural products. This review focuses on the development of new synthetic reactions for nitrogen-containing compounds via three methodologies: the reductive photocycloaddition reaction of enamides, radical addition reaction, and nucleophilic addition reaction. Newly developed reactions were successfully applied to the synthesis of various types of nitrogen-containing compounds including medicines, lead compounds to new drugs, natural alkaloids, and others.     

An Expeditious Synthesis of β-Indolylketones Catalyzed by p-Toluenesulfonic Acid (PTSA) Using Ultrasonic Irradiation

The investigation of the chemistry of indoles has been, and continues to be, one of the most active areas of heterocyclic chemistry.[1] In particular, β-indolylketones have received much attention as important building blocks for the synthesis of many natural products and other biologically active compounds.[2] In continuation of our work in the synthesis of indole derivates,[3] we describe the remarkable catalytic of PTSA as a cheaper catalyst in ultrasound-accelerated Michael reaction of indole with α, β-unsaturated ketones (2), which provide one of the most efficient routes to the synthesis of β-indolyketones. In all cases, the substitution on the indole nucleus occurred exclusively at the 3-position, and N-alkylation products have not been observed. In addition, the structure of 3a was further confirmed by single crystal X-ray crystallography.     

Inverse-Electron-Demand Diels–Alder Reactions of 2-Pyrones: Bridged Lactones and Beyond

Inverse-electron-demand Diels–Alder (IEDDA) reactions of electron-poor 2-pyrones as electrophilic dienes have been extensively studied in the past fifty years. These reactions provide an efficient access to bridged bicyclic lactones and their derivatives, such as densely functionalized 1,3-cyclohexadienes after CO₂ extrusion and polysubstituted aromatic compounds through elimination. This reaction has been used for the synthesis of many biologically active natural products and drug candidates. In this review, the developments of these IEDDA reactions including non-catalytic, Lewis acid-catalyzed and organocatalytic IEDDA reactions, and their applications in total synthesis are discussed in detail.     

Chemical biology--identification of small molecule modulators of cellular activity by natural product inspired synthesis

The aim of this tutorial review is to introduce the reader to the concept, synthesis and application of natural product-inspired compound collections as an important field in chemical biology. This review will discuss how potentially interesting scaffolds can be identified (structural classification of natural products), synthesized in an appropriate manner (including stereoselective transformations for solid phase-bound compounds) and tested in biological assays (cell-based screening as well as biochemical in vitro assays). These approaches will provide the opportunity to identify new and interesting compounds as well as new targets for chemical biology and medicinal chemistry research.     

Review on asymmetric synthetic methodologies for chiral isoquinuclidines; 2008 to date

Isoquinuclidines constitute the central structural nucleus of numerous biologically active natural products, for example, iboga alkaloids such as ibogamine and catharanthine as well as non-indole-containing alkaloids such as the dioscorine and the cannivonines. Furthermore, in medicinal and pharmaceutical chemistry, the isoquinuclidine core is commonly employed as a rigid azabicyclic scaffold, thus providing significant precursors in the synthesis of numerous valuable alkaloids. Summarizing well-organized approaches to access the chiral isoquinuclidine structural centerpiece signifies a significant endeavor not only for developing biologically active natural products but also enhancing biological researches that can lead to possible drug discovery. Over time, the values and methodologies for the asymmetric synthesis of chiral isoquinuclidines are increasing; hence to advance asymmetric synthesis, this review combines and discusses the pros and cons of each synthesis techniques from 2008. This review should be helpful for promoting further developments of asymmetric synthetic methodologies and for medicinal chemistry.     

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.     

Recent advances in the iron-catalysed multicomponent reactions

Iron-catalysed reactions are widely used in organic synthesis owing to its benefits over other metals. Among the important organic reactions, multicomponent reactions play a significant role due to its greener aspects like high atom economy, minimal amount of by-product, economic feasibility etc. For the past few years, iron-catalysed multicomponent reactions have attracted the attention of several chemists which lead to the invention of some fine chemistry. The majority of iron-catalysed multicomponent reactions results in the synthesis of heterocyclic compounds having biologically active natural products, pharmaceutical etc. These developments in the iron-catalysed multicomponent reactions are the focus of this review. This is the first review in this topic which covers the literature up to 2020, and it encompasses the different methods for the synthesis of acyclic, carbocyclic and heterocyclic compounds.     

Recent Advances in the Synthesis of Coumarin Derivatives via Knoevenagel Condensation: A Review

The synthesis of coumarins through Knoevenagel condensation is one of the most important processes in synthetic organic chemistry and medicinal chemistry. Compounds including a coumarin (2-oxo-2H-1-benzopyran) backbone have a wide range of application in the pharmaceutical field. Thus, many methodologies have been developed for the synthesis of this important class of compounds. However, some methods are always associated with toxic and corrosive catalysts, longer reaction time, poor yield, less purity, and by-products along with the desired product. Furthermore, some of these processes are not efficient and environmentally friendly. Therefore, mild, efficient, and environmentally friendly protocols have been developed recently by many scientists for the synthesis of coumarin derivatives via Knoevenagel condensation with good yield and purity. In this review, we have summarized various methods for the synthesis of coumarins via Knoevenagel condensation.     

The thriving chemistry of ketenimines

Ketenimines are an important class of reactive species and useful synthetic intermediates. During the last two decades several practical and versatile approaches to ketenimines have been developed, leading to exhaustive investigations on ketenimine chemistry and the discovery of a variety of highly efficient reactions. Five types of reactions for ketenimines have been reported, including nucleophilic additions (ketenimines can be used as both electrophiles and nucleophiles), radical additions, cycloaddition reactions, electrocyclic ring closure reactions, and σ rearrangements. Furthermore, numerous complex organic compounds, particularly the biologically interesting heterocycles, have been constructed using these methodologies. The review of these accomplishments is presented here.     

Carboxylic acid catalyzed three-component aza-Friedel-Crafts reactions in water for the synthesis of 3-substituted indoles

[reaction: see text] The carboxylic acid catalyzed three-component aza-Friedel-Crafts reactions of aldehydes, primary amines, and indoles in water have been developed. The aza-Friedel-Crafts products could be easily transformed to various 3-substituted indoles including biologically active compounds. This system offers a novel efficient method for the synthesis of 3-substituted indoles.     

Recent applications of ring-closing metathesis in the synthesis of lactams and macrolactams

Lactams are an important class of compounds owing to their presence in numerous biologically active molecules of natural and unnatural nature. They are also highly versatile intermediates that can be elaborated into interesting compounds for potential use in organic and medicinal chemistry endeavors. In this feature article, the reader will be given a background to olefin metathesis followed by concise discussions (with selected examples) to report recent applications of ring-closing metathesis to form lactams and macrolactams from acyclic diene precursors, an area which continues to deposit attractive applications in the chemical literature en route or in the final step to the target molecules.     

BrΦnsted acid-promoted ‘on-water’ C(sp^3)-H functionalization fot the synthesis of isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine derivatives targeting the SKP2-CKS1 interaction

The isoindolinone and biaryl scaffolds are prevalent in natural products and drug molecules,which have showed broad and interesting biological activities.The efficient construction of such hybridized molecules and biological evaluation are of great interest to medicinal chemistry community.In this communication,we report an efficient BrΦnsted acid-promoted C(sp^3)-H functionalization approach that enables the rapid construction of biologically important isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine hybrids from 5-methyl-7-(2,4,6-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine,2-formylbenzoic acid and various anilines.The title compounds were generated in high to excellent yields(up to 96%)regardless of the electronic nature and steric effects of the substituents.In this reaction,an isoindolinone scaffold,one C-C single bond,and two C-N bonds were formed simultaneously with high atom economy.In this work,we have envisioned that the methyl group linked to the electron-deficient Nheterocycles could be used as a new synthetic handle for late-state diversification and may have broad applications in the field of organic and medicinal chemistry.Besides,the title compounds have exhibited promising activity against the SKP2-CKS1 interaction.     

Indole‐N‐Carboxylic Acids and Indole‐N‐Carboxamides in Organic Synthesis

Indoles are ubiquitous structures that are found in natural products and biologically active molecules. The synthesis of indoles and indole‐involved synthetic methodologies in organic chemistry have been receiving considerable attention. Indole‐N‐carboxylic acids and derived indole‐N‐carboxamides are intriguing compounds, which have been widely used in organic synthesis, especially in multicomponent reactions and C?H functionalization of indoles. This Minireview summarizes the advances of reactions involving indole‐N‐carboxylic acids and indole‐N‐carboxamides in organic chemistry, and discusses the synthetic potential and perspective of this field.     

Br?nsted acid-promoted 'on-water' C(sp~3)-H functionalization fot the synthesis of isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine derivatives targeting the SKP2-CKS1 interaction

The isoindolinone and biaryl scaffolds are prevalent in natural products and drug molecules,which have showed broad and interesting biological activities.The efficient construction of such hybridized molecules and biological evaluation are of great interest to medicinal chemistry community.In this communication,we report an efficient Br?nsted acid-promoted C(sp~3)-H functionalization approach that enables the rapid construction of biologically important isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine hybrids from 5-methyl-7-(2,4,6-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine,2-formylbenzoic acid and various anilines.The title compounds were generated in high to excellent yields(up to 96%)regardless of the electronic nature and steric effects of the substituents.In this reaction,an isoindolinone scaffold,one C-C single bond,and two C-N bonds were formed simultaneously with high atom economy.In this work,we have envisioned that the methyl group linked to the electron-deficient Nheterocycles could be used as a new synthetic handle for late-state diversification and may have broad applications in the field of organic and medicinal chemistry.Besides,the title compounds have exhibited promising activity against the SKP2-CKS1 interaction.     

Carbonyl Compounds′ Journey to Amide Bond Formation

The formation of amide bonds is one of the most stimulating emerging areas in organic and medicinal chemistry. Amides are recognized as central building blocks in a plethora of interesting pharmaceuticals, proteins, peptides, polymers, natural products, functional materials, and biologically relevant carbocyclic or heterocyclic molecules, and they are also found in a variety of industrial fields. Therefore, a review of recent developments and challenges in the formation of amide bonds from carbonyl compounds is particularly important. Herein, we have scrutinized a range of metal‐catalyzed and metal‐free approaches for the synthesis of amides from aldehydes, ketones, and oximes. In addition, this Minireview highlights relevant mechanistic studies, as well as the potential applications of these methods in the synthesis of candidate drug molecules. We hope that the data compiled herein will encourage further progress in this notable area of chemistry research.