Domino Reactions in Library Synthesis

Vincent Eschenbrenner-Lux, Herbert Waldmann, and Kama Kumar 

In this chapter, we present an overview of domino reactions that have been used to construct various types of compound libraries targeting either natural product (NP) structures and privileged scaffolds or diverse ring systems. 

Domino Reactions Concepts for Efficient Organic Synthesis, First Edition. Edited by Lutz F. Tietze. 

Domino Reactions in Natural-Product-Inspired Compound Collection Syntheses 

In contrast to the total synthesis of an NP, which often is a long, multistep, and time-consuming endeavor, generating NP-like compounds should follow easy and efficient synthesis routes to provide a large number of compounds. Domino reaction sequences can play a major role in providing relatively complex and NP-based compound collections. ChiraHty of the product is another important factor that determines the biological effect of a molecule. Therefore, enantioselective and diastereoselective domino reactions are of particular interest in this area. 

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Tietze, L.F. Lieb, M.E. (1998) Domino Reactions for Library Synthesis of Small Molecules in Combinatorial Chemistry. Current Opinion in Chemical Biology, 2, 363-371. 

Scaffold diversity is an important parameter to characterize any compound collection. Organic synthesis is expected to provide efficient approaches to create three-dimensionally complex and structurally diverse small molecules. Branching pathways in DOS is an elegant approach to access scaffold diversity that could lead to small, yet diverse, focused compound libraries. Branching cascades strategy has successfully demonstrated the power and application of cascade or domino reactions in compound collection synthesis to build rapidly complex scaffolds for library synthesis. Further synthesis endeavors toward branching pathways... 

Domino Reactions in the Build-Couple-Pair Approach for Library Synthesis... 

Domino reactions present a modern approach in organic synthesis since they allow the preparation of complex molecules starting from simple substrate in a few steps and in many cases with high stereoselectivity. Moreover, as multi-component transformation they are highly suitable for combinatorial chemistry and give access to libraries of great diversity. 

In the build-couple-pair approach to library synthesis, the building blocks are first synthesized from commercial material (build phase), which are then coupled to form a substrate (couple phase) that can further react under certain conditions and pair itself intramolecularly to form the cyclic products depicting the scaffold framework [24]. It is in the last two steps that the domino reaction can intervene to yield a more complex scaffold and with higher ring diversity. 

Researchers at the University of Tokyo prepared a small (2 X 2) library in a chip microreactor by reacting 3-nitroben-zoyl chloride and 3,5-dinitrobenzoyl chloride, each with dl-1-phenylethylamine and 4-amino-1-benzylpiperidine using a phase-transfer catalyst. GlaxoSmithKline (GSK) generated a 2 x 2 library for a domino reaction, which consisted of a Knoevenagel condensation that gave an intermediate that immediately underwent an intramolecular hetero-Diels-Alder reaction with inverse electron demand. GSK published the synthesis of a 3 x 7 library using... 

The rapid synthesis of heteroaromatic Hantzsch pyridines can be achieved by aromatization of the corresponding 1,4-DHP derivative under microwave-assisted conditions [51]. However, the domino synthesis of these derivatives has been reported in a domestic microwave oven [58,59] using bentonite clay and ammoniiun nitrate, the latter serving as both the source of ammonia and the oxidant, hi spite of some contradictory findings [51,58,59], this approach has been employed in the automated high-throughput parallel synthesis of pyridine libraries in a 96-well plate [59]. In each well, a mixture of an aldehyde, ethyl acetoacetate and a second 1,3-dicarbonyl compound was irradiated for 5 min in the presence of bentonite/ammonium nitrate. For some reactions, depending upon the specific 1,3-dicarbonyl compound used. 

Emetine is the main alkaloid found in the root of Cephadis ipecacuanha [102], which has been used for centuries as an emetic and was subsequently shown to be a potent antiamebic [103], A concise synthesis of this compound as well as a small library of analogues was recently reported by Tietze and co-workers [104], who made use of their powerful three-component domino-Knoevenagel-condensation/ hetero-[4+2] reaction sequence previously described in Section 8.1. 

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