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Total synthesis of the marine toxin phorboxazole A using palladium(II)-mediated intramolecular alkoxycarbonylation for tetrahydropyran synthesis

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  • The potent antitumor agent phorboxazole A was synthesized from six subunits comprising C1-C2 (115), C3-C8 (98), C9-C19 (74), C20-C32 (52), C33-C41 (84) and C42-C46 (85). Tetrahydropyrans B and C containing cis-2,6-disubstitution were fabricated via palladium(II)-mediated intramolecular alkoxycarbonylation which, in the case of tetrahydropyran C, was carried out with catalytic palladium(II) and p-benzoquinone as the stoichiometric re-oxidant. Tetrahydropyran D was obtained by a stereoselective tin(IV)-catalyzed coupling of a C9 aldehyde with an allylsilane, and the C19-C20 connection was made using a completely stereoselective Wittig-Schlosser (E) olefination. Coupling of the oxazole C32 methyl substituent with the intact C33-C46 δ-lactone 3 was accompanied by elimination of the vinyl bromide to a terminal alkyne, but the C32-C33 linkage was implemented successfully with 83 and C33-C41 lactone 84. The C42-C46 segment of the side chain was then appended via Julia-Kocienski olefination. The macrolide portion of phorboxazole A was completed by means of an Ando-Still-Gennari intramolecular (Z)-selective olefination at C2-C3 which required placement of a (dimethoxyphosphinyl)acetate moiety at C24. Final deprotection led to phorboxazole A via a route in which the longest linear sequence is 37 steps and the overall yield is 0.36%.
  • This is the author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the Royal Society of Chemistry and can be found at: http://pubs.rsc.org/en/journals/journalissues/ob.
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  • Kuntiyong, P., Lee, T. H., Kranemann, C. L., & White, J. D. (2012). Total synthesis of the marine toxin phorboxazole A using palladium(II)-mediated intramolecular alkoxycarbonylation for tetrahydropyran synthesis. Organic & Biomolecular Chemistry, 10(39), 7884-7899. doi: 10.1039/c2ob25766a
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  • 10
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  • 39
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  • We are grateful to the Ministry of Science and Technology of the Royal Thai Government for a predoctoral scholarship to P.K. and to the Deutsche Forschungsgemeinschaft for a postdoctoral fellowship to C.L.K. Financial support was provided by the National Institute of General Medical Sciences (GM50574 and GM58889).
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