Studies of stereocontrolled allylation reactions for the total synthesis of phorboxazole A.

نویسندگان

  • David R Williams
  • Andre A Kiryanov
  • Ulrich Emde
  • Michael P Clark
  • Martin A Berliner
  • Jonathan T Reeves
چکیده

A highly convergent total synthesis of the potent anticancer agent (+)-phorboxazole A (1) is accomplished. Four components (3-6) are assembled with considerations for control of absolute and relative stereochemistry. Iterative asymmetric allylation methodology addresses key stereochemical features in the preparation of the 2,6-cis- and 2,6-trans-tetrahydropyranyl rings of the C3-C19 component (3). The stereocontrolled asymmetric allylation process is also used for development of the C28-C41 fragment (4). Novel Barbier coupling reactions of alpha-iodomethyl oxazoles and related thiazoles are described with samarium iodide. The convergent assembly of components 4 and 5 features formation of the fully substituted C22-C26 pyran by intramolecular capture of an allyl cation intermediate with high facial selectivity, and further efforts lead to E-C19/C20 olefination. The synthesis culminates with use of a modified Julia olefination for attachment of the C42-C46 segment and subsequent late-stage macrocyclization by installation of the (Z)-C2/C3 alpha,beta-unsaturated lactone.

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عنوان ژورنال:
  • Proceedings of the National Academy of Sciences of the United States of America

دوره 101 33  شماره 

صفحات  -

تاریخ انتشار 2004