Part I. Stereospecific Synthesis of Vinyl Iodides: Iododesilylation of Homoallylic Alcohol Derivatives Part II. Model Studies, A Formal Synthesis of (-)-Englerin A, and the Total Synthesis and Biological Evaluation of New Englerin Analogs.

摘要

Part I. Vinyl iodides with defined geometry are important chemical building blocks. Their preparation by iododesilylation of the corresponding vinyl silane is an attractive method. Kishi et al. have shown that if iododesilylation is carried out with N-iodosuccinimide (NIS) in an acetonitrile/chloroacetonitrile mixture, one obtains vinyl iodides in which the geometry of the olefin is highly retained. By carrying out iododesilylation with NIS in hexafluoroisopropanol, Zakarian et al. have shown that the olefin geometry is also retained, but to a larger degree. Previously, the Parker group has applied this methodology to a synthetic study of trisubstituted vinyl iodides. Therein, they found that if iododesilylation was carried out with NIS in DMSO, one obtains products in which the geometry of the olefin had been highly inverted. To obtain a more thorough understanding of the scope and limitations of the methodology, we extended this study to disubstituted homoallylic alcohol derivatives. The results obtained should be useful for the synthesis of polypropionates containing a disubstituted homoallylic alcohol moiety.;Part II. In 2008 Beutler et al. isolated the guaiane sesquiterpene (-)-englerin A (EA) from the stem bark of Phyllanthus engleri, a species indigenous to east Africa. In an NCI 60 cell panel, EA displayed selective and potent activity against human renal cancer cell lines. This fact, combined with the limited response that kidney cancers display to standard chemotherapy, has made EA an important new drug lead. Although there have now been EA syntheses published by 11 research laboratories, little work has been done in the area of analog synthesis. The majority of EA analogs synthesized for structure activity relationship studies have been those in which the ester side chains have been altered. There has been little synthetic work revealing the necessity of the EA core structure for cytotoxicity. By utilizing chemistry that has been developed in our laboratories, we have completed a second-generation formal synthesis of EA. In addition, a late stage synthetic intermediate that permits the synthesis of analogs with core modifications was synthesized. By way of this intermediate, we have completed the total synthesis of two new analogs with modification at C4.