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Direct assembly of multiply oxygenated carbon chains by decarbonylative radical–radical coupling reactions

Nature Chemistry volume 9, pages 207–212 (2017)Cite this article

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Abstract

Pentoses and hexoses contain more than three oxygen-bearing stereocentres and are ideal starting materials for the synthesis of multiply oxygenated natural products such as sagittamide D, maitotoxin and hikizimycin. Here we demonstrate new radical–radical homocoupling reactions of sugar derivatives with minimal perturbation of their chiral centres. The radical exchange procedure using Et3B/O2 converted sugar-derived α-alkoxyacyl tellurides into α-alkoxy radicals via decarbonylation and rapidly dimerized the monomeric radicals. The robustness of this process was demonstrated by a single-step preparation of 12 stereochemically diverse dimers with 6–10 secondary hydroxy groups, including the C5–C10 stereohexad of sagittamide D and the enantiomer of the C51–C60 stereodecad of maitotoxin. Furthermore, the optimally convergent radical–radical cross-coupling reaction achieved a one-step assembly of the protected C1–C11 oxygenated carbon chain of the anthelmintic hikizimycin. These exceptionally efficient homo- and heterocoupling methods together provide a powerful strategy for the expedited total synthesis of contiguously hydroxylated natural products.

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Figure 1: Representative examples of multiply oxygenated natural products and retrosynthetic analysis of hikizimycin.
Figure 2: Radical–radical coupling strategies for the synthesis of contiguously substituted polyol structures.
Figure 3: Structures of the four D-sugars used in this study and their carboxylic acid derivatives 3a–3j, and synthesis of 3k and 3l from 4 and 7.
Figure 4: Presumed conformations of the representative α-alkoxy radicals.
Figure 5: Radical–radical cross-coupling reaction for the synthesis of the hikizimycin carbon chain 9-SS.

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Acknowledgements

This research was financially supported by the Funding Program for a Grant-in-Aid for Scientific Research (A) (JSPS Grant no. 26253003) to M.I., and a Grant-in-Aid for Scientific Research (C) (JSPS Grant no. 16K08156) to M.N. A Fellowship from JSPS to K.M. is gratefully acknowledged. We thank D. Kamimura (Kaken Pharmaceutical) for conducting the preliminary experiments for dimerization reactions. This paper is dedicated to Professor Samuel J. Danishefsky on the occasion of his 80th birthday.

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  1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Kengo Masuda, Masanori Nagatomo & Masayuki Inoue

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  1. Kengo Masuda
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K.M., M.N. and M.I. conceived and designed the study. K.M. and M.N. performed the syntheses and M.N. and M.I. co-wrote the paper.

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Correspondence to Masayuki Inoue.

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Masuda, K., Nagatomo, M. & Inoue, M. Direct assembly of multiply oxygenated carbon chains by decarbonylative radical–radical coupling reactions. Nature Chem 9, 207–212 (2017). https://doi.org/10.1038/nchem.2639

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