Frank Roschangar

Chemical Biology of Epothilones

Only a few months after the disclosure of the absolute configuration of epothilones A (R=H, see picture on the right) and B (R=Me) the first total syntheses of these natural products were reported. Interest intensified with the realization of their potential as anticancer agents with a taxol-like mechanism of action. In addition to describing the most important total syntheses and biological properties of the naturally occurring epothilones A-E, this review also provides a systematic overview of numerous epothilone analogues that have been modified in the A-D regions in order to obtain information about structure-activity relationships.

Total synthesis of Epothilone E and related side-chain modified analogues via a stille coupling based strategy

A Stille coupling strategy has been utilized to complete a total synthesis of epothilone E from vinyl iodide 7 and thiazole-stannane 8h. The central core fragment 7 and its trans-isomer 11 were prepared from triene 15 using ring-closing metathesis (RCM), and were subsequently coupled to a variety of alternative stannanes to provide a library of epothilone analogues 18a-o and 19a-o. The Stille coupling approach was then used to prepare epothilone B analogues from the key macrolactone intermediate 24 which was itself synthesized by a macrolactonization based strategy.

Totalsynthese von Epothilon E und seitenkettenmodifizierten Epothilon-Analoga durch Stille-Kupplung

Ringschlus durch Olefinmetathese (siehe unten, a), Abspaltung der Schutzgruppe (b), Stille-Kupplung (c) und die abschliesende Epoxidierung (d) sind die wesentlichen Schritte der ersten Totalsynthese des naturlich vorkommenden Epothilons E 1. Ausgehend von dem Produkt der Olefinmetathese, einer sehr fortgeschrittenen Zwischenstufe, ist eine Fulle von Epothilon-E-Analoga mit unterschiedlichen aromatischen Resten in der Seitenkette zuganglich. TBS = tBuMe2Si.