Two questions will be addressed: What is a 'natural macrocycle'? And how can similar macrocycles be synthesized more efficiently, ideally in one-pot?Natural products incl. macrocycles are selected by evolution for biological activity. For synthetic libraries, claims of natural-product likeness are commonly made without proof. Many compounds do not fulfill this claim!To clarify this for macrocycles, we conducted chemoinformatic analyses. Over 120.000 secondary metabolites were screened for naturally occurring macrocycles and analyzed for ring size, molecular weight, and the frequency of common substructural motifs. The underlying principles of chemical diversity are reviewed in terms of biosynthetic origin and nature's strategies for diversity/complexity generation. As a result it is suggested that synthetic chemists should not only use nature's molecules, but also nature's strategies as a source of inspiration.1,2)In order to boost the access to macrocycles, we devised a concept combining designed bifunctional starting materials with multi component reaction (MCR) procedures (see sketch).3)Complex macrocycles with non-identical subunits become available in an extremely efficient fashion from six or more building blocks in one pot in infinite number and quantity with almost unlimited size, shape, and functionality, thus opening the door to cyclopeptide mimetics, protein-protein interaction studies, host-guest chemistry, organocatalysis and artificial enzymes, or geometric structures.Mol. Divers. 2005  , 9, 171-186.Topics Curr. Chem. 2005,  243, 137-184.Chem. Rev. 2009  , 109, 796-814

From chemoinformatic analyses to rapid syntheses: What can we learn from nature's macrocycles?

248th National Meeting (2014)

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