Journal
JOURNAL OF ANTIBIOTICS
Volume 72, Issue 6, Pages 350-363Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41429-019-0175-y
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology (MEXT), SORST (Japan)
- Science and Technology Agency (JST)
- Japanese Society for the Promotion of Science
- Fellowship and Multidimensional Materials Science Leaders Program
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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) alpha-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 endgame. 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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