Multicomponent reaction design in the quest for molecular complexity and diversity.

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.

Scope and limitations of an efficient four-component reaction for dihydropyridin-2-ones.

A broad range of isonitrile-functionalized 3,4-dihydropyridin-2-ones could be prepared using a four-component reaction between phosphonates, nitriles, aldehydes, and isocyanoacetates. The reaction involves initial formation of a 1-azadiene intermediate which is trapped in situ by an isocyanoacetate to give the desired heterocyclic scaffold through cyclocondensation. The full scope and limitations of this four-component reaction are described. Variation of the nitrile and aldehyde inputs proved to be extensively possible, but variation of the phosphonate input remains limited. Regarding the isocyanoacetate, alpha-aryl isocyanoacetates give moderate to high yields and result in a complete diastereoselectivity for the 3,4-cis isomer. Alpha-alkyl isocyanoacetates gave the corresponding dihydropyridin-2-ones in moderate yields, most of them as mixtures of diastereomers. Elevated temperatures during cyclocondensation generally increased the yield and resulted in a change of the diastereomeric ratio in favor of the cis-diastereomer. In addition to isocyanoacetates, a limited number of other alpha-acidic esters resulted in the formation of dihydropyridin-2-ones, albeit in much lower yield. Computational studies show that the observed difference in yield cannot be simply correlated to specific physical properties (including acidity) of the different alpha-acidic esters.

A novel three-component reaction toward dihydrooxazolopyridines.

Isocyano dihydropyridones accessible via a recently reported multicomponent reaction react with aldehydes and amines to afford dihydrooxazolopyridines in high yield. The scope and limitations of this novel multicomponent reaction were investigated. The efficient combination of two highly variable multicomponent reactions allows the construction of a very broad range of dihydrooxazolopyridines, an unexplored class of bicyclic compounds. The implications of the observed reactivity profile for the mechanism of this multicomponent reaction are discussed.

Synthesis of conformationally constrained peptidomimetics using multicomponent reactions.

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.

A flexible six-component reaction to access constrained depsipeptides based on a dihydropyridinone core.

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.

Diastereoselective multicomponent synthesis of dihydropyridones with an isocyanide functionality.

[Structure: see text] 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.