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A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling

Abstract

A prerequisite for successful screening campaigns in drug discovery or chemical genetics is the availability of structurally and thus functionally diverse compound libraries. Diversity-oriented synthesis (DOS) provides strategies for the generation of such libraries, of which the build/couple/pair (B/C/P) algorithm is the most frequently used. We have developed an advanced B/C/P strategy that incorporates multidimensional coupling. In this approach, structural diversity is not only defined by the nature of the building blocks employed, but also by the linking motif installed during the coupling reaction. We applied this step-efficient approach in a DOS of a library that consisted of 73 macrocyclic compounds based around 59 discrete scaffolds. The macrocycles prepared cover a broad range of different molecular shapes, as illustrated by principal moment-of-inertia analysis. This demonstrates the capability of the advanced B/C/P strategy using multidimensional coupling for the preparation of structurally diverse compound collections.

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Figure 1: Comparison of the couple phase in a classical B/C/P strategy with the multidimensional coupling phase introduced in our work.
Figure 2: Outline of the synthetic strategy used for the construction of the macrocyclic DOS library.
Figure 3: Multidimensional coupling exemplified for azido building block 3.
Figure 4: Illustrative macrocyclizations of the pair phase.
Figure 5: Illustrative members of the DOS library.
Figure 6: Principle moment of inertia plot.

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Acknowledgements

This work was supported by the European Union, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council, Frances and Augustus Newman Foundation, Wellcome Trust and Isaac Newton Trust. H.S.G.B. acknowledges a fellowship within the Postdoctoral Programme of the German Academic Exchange Service. F.N. thanks the Gates Cambridge Trust and acknowledges a Krishnan-Ang Studentship. Y.S.T. thanks the Agency for Science, Technology and Research and D.W. thanks the German Research Foundation for a postdoctoral fellowship (WI 4198/1-1).

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H.S.G.B., D.W. and D.R.S. conceived and supervised the project. H.S.G.B., F.N., C.E.H., H.J. and D.W. planned, performed and evaluated the experiments. Y.S.T. performed the molecular informatics studies. H.S.G.B., F.N., D.W. and D.R.S. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to David R. Spring.

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Beckmann, H., Nie, F., Hagerman, C. et al. A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling. Nature Chem 5, 861–867 (2013). https://doi.org/10.1038/nchem.1729

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