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A convergent total synthesis of the kedarcidin chromophore: 20-years in the making

The Journal of Antibiotics volume 72, pages 350–363 (2019)Cite this article

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Abstract

The kedarcidin chromophore is a formidible target for total synthesis. Herein, we describe a viable synthesis of this highly unstable natural product. This entailed the early introduction and gram-scale synthesis of 2-deoxysugar conjugates of both l-mycarose and l-kedarosamine. Key advances include: (1) stereoselective allenylzinc keto-addition to form an epoxyalkyne; (2) α-selective glycosylations with 2-deoxy thioglycosides (AgPF6/DTBMP) and Schmidt donors (TiCl4); (3) Mitsunobu aryl etherification to install a hindered 1,2-cis-configuration; (4) atropselective and convergent Sonogashira-Shiina cyclization sequence; (5) Ohfune-based amidation protocol for naphthoic acid; (6) Ce(III)-mediated nine-membered enediyne cyclization and ester/mesylate derivatisation; (7) SmI2-based reductive olefination and global HF-deprotection end-game. The longest linear sequence from gram-scale intermediates is 17-steps, and HRMS data of the synthetic natural product was obtained for the first time.

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Acknowledgements

This work represents over 20-years of collective effort (1997–2017) and was latterly supported by a Grant-in-Aid for Specially Promoted Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), SORST (Japan), as well as the Science and Technology Agency (JST), Japanese Society for the Promotion of Science, Fellowship and Multidimensional Materials Science Leaders Program (to MJL). We are especially grateful to Dr. John E. Leet at Bristol-Myers Squibb for kindly providing original chromoprotein material and the 1H NMR spectra of the natural kedarcidin chromophore.

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  1. Masahiro Hirama

    Present address: Acro-Scale, Inc., 3-8-1-F7 Kokubuncho, Sendai, 980-0803, Japan

Authors and Affiliations

  1. School of Chemistry, University of Lincoln, Brayford Pool, Lincoln, Lincolnshire, LN6 7TS, UK

    Martin J. Lear

  2. Department of Chemistry, Graduate School of Science, Tohoku University, Aza Aramaki, Aoba-ku, Sendai, 980-8578, Japan

    Martin J. Lear, Keiichiro Hirai, Kouki Ogawa, Shuji Yamashita & Masahiro Hirama

  3. Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai, 980-8578, Japan

    Masahiro Hirama

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Dedication: Dedicated to Professor Samuel J. Danishefsky for his outstanding contributions to the total synthesis of highly complex and biologically important natural products.

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Lear, M.J., Hirai, K., Ogawa, K. et al. A convergent total synthesis of the kedarcidin chromophore: 20-years in the making. J Antibiot 72, 350–363 (2019). https://doi.org/10.1038/s41429-019-0175-y

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