Current Organic Chemistry   Send Orders for Reprints to reprints@benthamscience.net 1078 Current Organic Chemistry, 2019, 23, 1078-1089 REVIEW ARTICLE Trienamines for the Organocatalytic Synthesis of Nitrogen-Containing Heterocycles Jessica R. Gutiérrez Cano a , Julio López a , Miguel A. Vázquez a , David Cruz Cruz a,* and Clarisa Villegas Gómez a,* a Departamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato. Noria Alta S/N, 36050 Guana- juato, Gto. México A R T I C L E H I S T O R Y Received: November 23, 2018 Revised: March 25, 2019 Accepted: May 10, 2019 DOI: 10.2174/1385272823666190617164651 Abstract: Nitrogen-containing heterocycles (NCH), constitute an important group of molecules, which are widely extended in whole chemical space. These compounds are of great interest due to their diverse biological activities. Currently, many compounds derived from NCH are used as powerful drugs for the treatment of diseases ranging from bactericides to anticancer agents. During last decade, the enantioselective synthesis of numerous heterocyclic compounds has been achieved through the use of chiral organocatalysts. The present contribution explores the application of the aminocatalysis towards the synthesis of NCH, particularly through the trienamine catalysis. Keywords: Nitrogen-containing heterocycles, organocatalysis, aminocatalysis, trienamine catalysis, activation mode, cycloaddition reactions. 1. INTRODUCTION The medicinal properties of plants have inspired many scientists and natural product chemist in the laboratory throughout history. The study of the therapeutic behaviour led to the discovery of com- pounds that could be isolated to produce the same effects. These compounds, which now we call natural products, have been the source of inspiration for the discovery and development of new drugs. Among the immense structural diversity of natural products, Nitrogen-Containing Heterocycles (NCH), such as alkaloids, cyclic amino acids, steroidal-alkaloids, etc. have been of great interest due to their attractive properties [1]. NCHs are widely available from natural sources, in fact, a considerable number of them have been isolated from plants, fungi, bacteria, microorganisms and marine species [1, 2]. Numerous studies have demonstrated the ability of these compounds to exert important and powerful biological activi- ties, which is of special interest for the development of new drugs. Given their importance in numerous areas of medicine, a wide range of stereo- and nonestereoselective methodologies are cur- rently available for the synthesis of NCHs. These methods have been applied in both target-oriented synthesis (TOC) and in the diversification of privileged structures (pDOS). Undoubtedly, these strategies have been successful. However, in some cases, these methodologies require long linear syntheses, which result in low overall yields. Additionally, many of these methodologies are not stereocontrolled or they use toxic reagents. During last two decades, organocatalysis has proven to be a powerful tool for accessing a variety of molecular architectures. The ability of small organic *Address correspondence to this author at the Departamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta S/N 36050, Guanajuato, Gto. México; Tel: +52 4737320006 Ext: 1489; E-mails: clarisa.villegas@ugto.mx; david.cruz@ugto.mx molecules to promote several transformations in a simple and effi- cient way with high levels of stereocontrol has allowed for tremen- dous development in the field of asymmetric synthesis. Particularly, aminocatalysis has proven to be a highly robust, efficient and stereoselecitve method for generating complex molecular scaffolds. Its applicability and generality lie in the ability of primary or sec- ondary amines to condense with aldehydes and ketones to form reactive intermediates, which can then participate in a wide variety of transformations. In this regard, the interest in asymmetric or- ganocatalytic reactions has evolved very quickly due to the fact that chiral amines such as proline [3], diarylsilylprolinol derivatives [4], 2,3,5-trisubstituted-4-imidazolidinone [5] and cinchona alkaloids derivatives [6] have been widely used to catalyse important reac- tions, such as Diels-Alder, aldol, Mannich, Michael or ene- reactions. In addition to promoting numerous carbon-carbon and carbon-halogen bond forming reactions, these catalysts are also able to provide high regio and stereocontrol during these transformations [7]. Aminocatalysis is thought to promote reactivity through one of two activation modes. Which pathway is invoked during a reaction depends on the structural and electronic differences in the carbonyl compound. However, all are based on the concept of HOMO-rising and LUMO-lowering. In the HOMO-raising activation mode, the condensation of a primary or secondary chiral amine with an eno- lizable ketone or aldehyde produces an enamine intermediate. In the enamine, the α-carbon of carbonyl acquires a nucleophilic charac- ter, allowing the functionalization at this position. In the LUMO- lowering activation mode, an iminium ion intermediate is formed as a result of the condensation of an aminocatalyst with an α,β- unsaturated carbonyl compound, which means that the β-carbon is then more susceptible to nucleophilic additions [8, 9]. Since the first studies in aminocatalysis, both enamine and iminium ion activation modes have contributed to the development 1875-5348/19 $58.00+.00 © 2019 Bentham Science Publishers