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Hydrogenation catalyst generates cyclic peptide stereocentres in sequence

Abstract

Molecular recognition plays a key role in enzyme-substrate specificity, the regulation of genes, and the treatment of diseases. Inspired by the power of molecular recognition in enzymatic processes, we sought to exploit its use in organic synthesis. Here we demonstrate how a synthetic rhodium-based catalyst can selectively bind a dehydroamino acid residue to initiate a sequential and stereoselective synthesis of cyclic peptides. Our combined experimental and theoretical study reveals the underpinnings of a cascade reduction that occurs with high stereocontrol and in one direction around a macrocyclic ring. As the catalyst can dissociate from the peptide, the C to N directionality of the hydrogenation reactions is controlled by catalyst–substrate recognition rather than a processive mechanism in which the catalyst remains bound to the macrocycle. This mechanistic insight provides a foundation for the use of cascade hydrogenations.

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Fig. 1: Unidirectional peptide synthesis is catalysed by enzymes and synthetic catalysts.
Fig. 2: Synthesizing cyclic dehydropeptides using dehydroamino acids.
Fig. 3: Examining the hydrogenation of cyclic dehydropeptide 5a′ gives mechanistic insight.
Fig. 4: Mechanistic experiments support a unidirectional hydrogenation.
Fig. 5: Computational support for a sequential and unidirectional cascade reduction.
Fig. 6: Cascade hydrogenation of cyclic dehydropeptides 5a and 8 using chiral Rh catalysis yields a different result.

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Acknowledgements

Funding was provided by the National Science Foundation (NSF) (CHE-1465263 to V.M.D. and CHE-1565669 to O.W.). D.N.L. is grateful for an NSF Graduate Fellowship. We acknowledge Y. Zhu (Shanghai Jiao Tong University) for help with substrate synthesis and the Nowick lab for use of HPLC instrumentation.

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Contributions

D.N.L., H.A.K. and B.K. performed the chemical reactions. E.H. conducted the computational experiments. All the authors contributed to the writing and editing of the manuscript.

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Correspondence to Olaf Wiest or Vy M. Dong.

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The authors declare no competing interests.

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Supplementary information

Supplementary information

Supplementary experimental details and compound characterization data

Computational data

Supplementary tables 3–31 outlining the coordinates, energies and frequencies from the quantum mechanical calculations performed in this study

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Le, D.N., Hansen, E., Khan, H.A. et al. Hydrogenation catalyst generates cyclic peptide stereocentres in sequence. Nature Chem 10, 968–973 (2018). https://doi.org/10.1038/s41557-018-0089-5

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