Multicomponent reactions have become increasingly popular as tools for the rapid generation of small-molecule libraries. However, to ensure sufficient molecular diversity and complexity, there is a continuous need for novel reactions. Although serendipity has always played an important role in the discovery of novel (multicomponent) reactions, rational design strategies have become much more important over the past decade. In this Review, we present an overview of general strategies that allow the design of novel multicomponent reactions. The challenges and opportunities for the future will be discussed.

In a search for new multicomponent strategies leading to valuable small heterocycles, a new highly diastereoselective four-component reaction (4CR) was found in which a phosphonate, nitriles, aldehydes, and isocyanoacetates combine to afford functionalized 3-isocyano-3,4-dihydro-2-pyridones. In this strategy, initially a 1-azadiene is generated, which is trapped in the same pot by an isocyanoacetate as the fourth component. Multicomponent reactions (MCRs) that lead to heterocycles containing isocyano substituents are unprecedented and offer many possibilities for further differentiation.Multicomponent reactions (MCRs) receive significant attention in synthetic method development 1 because they are wellsuited for the easy construction of diversified arrays of, e.g., valuable heterocyclic scaffolds. 2 Methods that employ a common reactive intermediate in a modular synthetic sequence are particularly appreciated because these allow the quick generation of scaffold diversity. We contributed to this area recently with a novel MCR that combines in situ generated 1-azadienes 4 with electron-poor isocyanates 5 to afford functionalized 3,4-dihydropyrimidine-2-ones 6 (Scheme 1). 3a Reaction of 4 with other cyclization partners gives access to triazinanediones 7, 3a 2-aminothiazines 9, 3b and dihydropyrimidine-2-thiones 10. 4 To further explore the potential of this procedure, we examined the four-component reaction (4CR) among diethyl methylphosphonate 1, benzonitrile 11, p-methoxybenzalde-

A novel modular synthetic approach toward constrained peptidomimetics is reported. The approach involves a highly efficient three-step sequence including two multicomponent reactions, thus allowing unprecedented diversification of both the peptide moieties and the turn-inducing scaffold. The turn-inducing properties of the dihydropyridone scaffold were evaluated by molecular modeling, X-ray crystallography, and NMR studies of a resulting peptidomimetic. Although modeling studies point toward a type IV beta-turn-like structure, the X-ray crystal structure and NMR studies indicate an open turn structure.

Highly functionalized and conformationally constrained depsipeptides based on a dihydropyridin-2-one core are prepared by the combination of a four- and a three-component reaction. The synthesis combines a one-pot Horner-Wadsworth-Emmons/cyclocondensation sequence leading to isonitrile-functionalized DHP-2-ones with an isonitrile-based Passerini multicomponent reaction (MCR). Substituents could be independently varied at six different positions. The two MCRs could also be performed as a one-pot procedure, simplifying the protocol and leading to a new and highly variable six-component process.