Tuesday, May 15, 2012

Weisheng Tian's Synthesis of (+)-Cephalostatin 1: The Western Domain

          The potent anticancer activity of the bis-steroidal pyrazine cephalostatin 1 has been discussed here previously. The putative biological target of cephalostatin 1 and the related marine natural product ritterazine B has been identified recently by Matt Shair's laboratory. The synthetic laboratory preparation of cephalostatin 1, for obvious reasons (see structure above), is also a fascinating scientific challenge. Synthetic studies targeting the daunting dimeric pyrazine steroidal spiroketals will be the subject of a forthcoming series of posts at this site. The laboratories of Fuchs, Shair and Tian have completed syntheses of cephalostatin 1. We will begin this series by examining Weisheng Tian's preparation of the western hemispheric substructure of cephalostatin 1 starting from the inexpensive steroidal saponin hecogenin (1). The major challenges associated with this task include a selective oxidation of the unactivated angular C18 methyl group and olefin installation (dehydrogenation) on the steroidal D-ring.
          The authors have developed a very useful and practical method for the degradation of a derivative of hecogenin (2) which provides the highly functionalized tetraol 3. In brief, a Baeyer-Villiger oxidation of 2 with in situ-generated performic acid followed by hydrolysis of the intermediate ester affords 3 on multi-hundred gram scale. The tetraol 3 is then advanced in four steps to 4, the substrate for remote functionalization of the C18 angular methyl group. Meystre's hypoiodite method, developed at Ciba in the 1960's, was utilized to accomplish this challenging oxidative transformation. Exposure of pregnane intermediate 4 to lead tetraacetate, iodine and light initiated a hydrogen transfer from C18 to the 20-hydroxy radical and subsequently the C18-centered radical is captured by an iodine radical (see the abbreviated mechanism below).
          This oxidative process is then repeated, resulting in a second C18-centered radical and this species is eventually converted into the lactol acetate shown above. Jones oxidation of the lactol then provides the requisite lactone 5. The Ciba method of C-H activation/oxidation of the angular C18 position of pregnane derivatives was previously applied to a historic synthesis of batrachotoxin by the laboratory of Heinrich Wehrli (reviewed here).
          Elaboration of the western spiroketal system of cephalostatin 1 entailed a rhodium-mediated regioselective O-alkylation of intermediate 6 followed by an efficient intramolecular Horner-Wadsworth-Emmons reaction to generate 8. Compound 8 was then converted to the western half of cephalostatin 1 by a sequence that included a tandem oxymercuration-ketalization as a key step. Epimerization of the anomeric spiroketal stereogenic position followed by global deprotection then secured the targeted advanced western intermediate (shown above, bottom right structure). Elaboration of the western substructure of cephalostatin 1 into the intact natural product by the Tian laboratory will be the subject of the next post at Modern Steroid Science.

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