Natural and Synthetic Biologically Active Heterocycles

We have classified the many reviews dealing with these materials under the following headings  

General Sources and Topics (it is self-subdivided into Biological Functions, Syntheses). 

Antibiotics (General, Antitumor, -Lactam, Macrocyclic, Miscellaneous). 

Drugs (General, Activity Types, Individuals and Groups). 

Miscellaneous (Enzymes, Amino Acids and Peptides, Plant Metabolites, Marine, Cyclodextrins, Other). 

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It is interesting that the retrosynthetic approach to heterocycles is not considered in monographs or review articles on the synthesis of individual classes of heterocyclic compounds. The examples that follow illustrate the retrosynthetic approach to the five- and six-membered heterocyclic structures often encountered in natural or synthetic biologically active compounds. Examples 7.2, 7.3, 7.6, 7.11 and 7.12 demonstrate syntheses of biologically active compounds developed to large-scale production by chemists at PLIVA Co. (Croatia). 

A vast array of piperidine containing cores, both natural and synthetic, are of biological and medicinal interest. These heterocyclic scaffolds have been the subjects of considerable synthetic efforts, especially for the construction of optically active compounds. In this context, Khan et al. reported a catalytic bromodi-methylsulfonium bromide (BDMS) three-component reaction of 1,3-dicarbonyls with aromatic aldehydes and aromatic amines for a facile access to highly functionalized piperidines (Scheme 24) [104]. This strategy is an interesting illustration of... 

This review on heterocyclic / -enamino esters and related compounds is not exhaustive. Instead, it aims to depict synthetic trends and preparative applicabilities of this rather versatile class of compounds. It is hoped that this review might stimulate a broad application of these compounds to the synthesis of novel heterocycles and especially natural products,188 biologically active substances,189 and drugs.190... 

The extraordinary diversity and multiplicity of heterocycles poses a dilemma What is to be included in an introductory book on heterocyclic chemistry which does not aim to be an encyclopaedia This difficulty had to be resolved in a somewhat arbitrary manner. We decided to treat a representative cross section of heterocyclic ring systems in a conventional arrangement. For these heterocycles, structural, physical and spectroscopic features are described, and important chemical properties, reactions and syntheses are discussed. Synthesis is consequently approached as a retrosynthetic problem for each heterocycle, and is followed by selected derivatives, natural products, pharmaceuticals and other biologically active compounds of related structure type, and is concluded by aspects of the use in synthesis and in selected synthetic transformations. The informations given are supported by references to recent primary literature, reviews and books on experimental chemistry. Finally, a section of problems and their solutions - selected in a broad variety and taken mainly from the current literature - intends to deepen and to extend the topics of heterocyclic chemistry presented in this book. 

As we shall find in later chapters, heterocyclic compounds can be synthesized in many ways. Although some of this work is performed to study fundamental properties or establish new synthetic routes, much more is concerned with the practical aspects of heterocyclic chemistry. Thus, many synthetic (as well as natural) compounds are of extreme value as medicinals, agrochemicals, plastics precursors, dyes, photographic chemicals, and so on, and new structures are constantly being sought in research in these areas. These applications are discussed in Chapter 11. Medicinal chemistry especially is associated intimately with heterocyclic compounds, and most of all known chemicals used in medicine are based on heterocyclic frameworks. We shall observe many of the prominent biologically active heterocyclic compounds as this book proceeds to develop the field of heterocyclic chemistry. 

Benzo-annelated nitrogen heterocycles (indoles, quinolines, isoquinolines, etc.) are often found to be a part of biologically active compounds of both natural and synthetic origin. In a considerable body of data on the syntheses of these compounds, which have so far been documented in the literature, the crucial step is vicarious nucleophilic substitution of hydrogen in nitroarenes. Good examples are presented by the synthesis of nordehydrobufotenine [49], eupolauramine [50, 51], damirone [52], and aklavinone [53]. 

The learning set of the Ml model is formed on the basis of 82 natural and synthetic heterocyclic nitrogen-, oxygen- and sulfur-containing biologically active compounds. They are divided into 2 groups with alternative properties class A comprises 43 highly and medium effective antitumor compounds (ICj < 11 pM for one of the abovementioned types of tumor cells) [1-6, 8-10] class B includes 39 compounds with low antitumor activity (IC >16 pM for one of the abovementioned types of tumor cells) [9-14]. 

Addition of Heterocyclic Compounds Stereocontrolled nucleophilic addition of heterocyclic compounds to chiral nitrones is of great synthetic importance in the synthesis of natural and biologically active compounds. In these reactions, the nitrone group serves as an amino group precursor and the heterocycle furnishes the formyl group (from thiazole) (192, 195, 214, 215, 579) or the carboxyl group (fromfuran) (194-196, 580-584) (Scheme 2.149). 

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