In this era of '-omics' and structural biology there is an ever-increasing need for novel small molecules that can modulate biological processes. For this, combinatorial synthesis is undisputed as an enabling tool to access the required small-molecule based compound collections. Although, the benefit for efficient biological evaluation and ultimately successful drug discovery seems obvious, the actual hit rates for new drug candidates have decreased steadily over the past decade. Structural diversity and complexity are essential to address 'drug likeliness' in the design and synthesis of compound libraries. So far only a very limited number of molecules that cover the enormous potential of the chemical space have been actually made by Man and explored for potential useful properties, like their biological relevance. This continues to drive synthetic chemists to develop novel reactions that can efficiently access unexplored regions of chemical space.Rapid generation of diverse sets of complex molecules can be achieved by employing diversity-oriented synthetic strategies in combination with so-called complexity-generating reactions. Multicomponent reactions (MCRs), which combine in one-pot at least three simple building blocks, provide a most powerful platform to access diversity as well as complexity in a limited number of reaction steps. Here we describe novel modular reaction sequences based on our previously reported MCR chemistry in combination with other common organic reactions or even with a second MCR. Combination of our MCRs with, e.g., cycloadditions, transition-metal mediated cross-coupling reactions or with more traditional MCRs like Biginelli-3CR, Ugi-4CR and the Passerini-3CR will be shown. Examples in which the synthetic methodology was applied for the easy generation of focused libraries for the synthesis of medicinally relevant ligands will be discussed.

Multicomponent reactions as useful tools for efficient diversity oriented synthesis

243rd National Meeting (2012)

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