Studies Toward the Completion of the C29-C51 Segment of Spongistatin 1
Spongistatin 1 (Altohyrtin A) is a marine natural product, which was isolated in 1993 from a species of Spongia in the Eastern Indian Ocean by Pettit and co-workers, and also from Hyrtios altum collected off the coast of Okinawa by Kobayashi and Kitagawa. This large macrocycle with 24 stereocenters boasts two spiroketals (AB and CD) in the C1-C28 segment, two highly functionalized tetrahydropyran rings (E and F), and a sensitive chlorodiene side chain in the C29-C51 segment, which is the focus of this dissertation. The biological activity of spongistatin 1 extends beyond the initially reported potent cytotoxicity in that it also aggressively inhibits cell growth in many cancer cell lines with IC50 values in the pico- to nanomolar range, and has been shown to inhibit the growth of various fungi and yeasts. These results are attributed to spongistatin 1 binding to tubulin in a manner that inihibits microtubule formation.
Our efforts toward a concise synthesis of the C29-C51 segment of spongistatin 1 have resulted in an approach wherein three highly advanced intermediates are joined in two very convergent steps. One key intermediate, the vinyl iodide side chain, comprises the C45-C51 portion of our target; the second is the fully functionalized C38-C44 F ring methyl ester; and the third, the C29-C37 E segment sulfone, which later forms the E ring. In the first convergent step, the C44-C45 bond was formed via a B-alkyl Suzuki coupling to join the side chain and F ring. This was followed immediately by an ?-sulfonyl anion addition to form the C37-C38 bond, which completes the carbon skelton of the C29-C51 segment. Further transformations cyclized the E ring and installed the stereocenter at C38. Future work focuses on installing the double bond at C48-C49 to complete the side chain functionalization, followed by formation of the Wittig salt at C29 to join this segment with the C1-C28 unit and complete the total synthesis of spongistatin 1.
School:The Ohio State University
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:marine macrolides total synthesis spongistatin 1 coupling reactions
Date of Publication:01/01/2008