Multicomponent reactions in the synthesis of nitrogen heterocycles and their application to drug discovery.

摘要

This dissertation comprises two separate projects, relying on the use of multicomponent reactions as a common theme. The introduction (Chapter 1) briefly overviews the utility of multicomponent reactions highlighting their medicinal chemistry applications. The first part (Chapters 2 and 3) describes the development of new practical synthetic methodologies for one-step synthesis of nitrogen heterocycles (isoindolines and dihydroquinolines) using three-component reaction of boronic acids, amines and aldehydes (Petasis reaction) or its variations. The second part (Chapters 4 and 5) deals with the applications of multicomponent reactions to the diversity oriented synthesis of biologically active small molecules.;Chapter 2 reviews the known synthetic approaches to isoindoline derivatives based on [4+2] cycloadditions and describes the development of our own methodology based on tandem Petasis-Diels-Alder reaction, focusing on the expansion of the substrate scope (salicylaldehydes, heterocyclic aldehydes, glyoxylic acid, sugars and sugar ketals) and diastereoselectivity. Some transformations of the reaction products are also investigated.;Chapter 3 briefly overviews the known syntheses of 1,2-dihydroquinolines, discusses a new variation of catalytic version of Petasis reaction (2 H-chromene synthesis, catalyzed by tertiary amines) and development of trifluoroborate-based approach to 1,2-dihydroquinolines. This methodology is further extended onto the novel trifluoroborate-based three-component reaction involving 2-sulfamidobenzaldehydes, simple aromatic and aliphatic aldehydes.;Chapter 4 includes a short review of classical Passerini and Ugi reactions from the mechanistic point, demonstrating the applicability of these reactions to the diversity-oriented synthesis of a wide variety of drug-like molecules. An insight is given into suggested biological mechanism of action of a series of 18 simple propiolamide pseudodipeptides, prepared in one step by Ugi reaction. Structure-activity relationship studies in a series of ∼50 analogs prepared by Ugi reaction with some post-multicomponent step modifications are described, and preparation of fluorescent propiolamide-based tools for the identification of their intracellular targets is outlined. The reactions of propiolamides with biologically relevant nucleophiles are studied by NMR methods.;Chapter 5 describes the dual role of APE1/Ref-1 enzyme and briefly overviews a small number of known small molecule inhibitors. A set of ∼20 diverse molecules aimed at selective targeting either its endonuclease or redox function is prepared using single-step multicomponent and multistep synthetic approaches.