| Geldanamycin (1) is an antitumor antibiotic known to disrupt cellular signaling pathways by inhibition of the chaperone heat shock protein 90 (Hsp90). The cellular substrates of Hsp90 (e.g. HER2, steroid hormone receptors, EGF) have been implicated in a wide variety of cancers. Thus 1 provides a valuable tool for further probing the effects of signal transduction disruption in the development and treatment of cancer.; Geldanamycin (1) is a member of the rather complex benzoquinoid ansamycin family along with the herbimycins and macbecins. This complexity offers a considerable challenge from a total synthetic standpoint, but it provides the opportunity to develop new synthetic methodologies. To date, a total synthesis of 1 has not been reported but would play a critical role in further exploiting its biological activity.; Our progress toward 1 begins with the application of the Evans' alkylation in order to establish the C14 methyl stereocenter. To address the two sets of vicinal oxygenated stereocenters at C11-C12 and C6-C7, we have applied novel anti and a syn-selective glycolate aldol reactions. The anti aldol reaction uses our recently developed 5,6-bis-(4-methoxyphenyl)-[1,4]-dioxan-2-one chiral auxiliary while the syn relies upon a Masamune norephedrine glycolate ester.; The C10 methyl stereocenter is provided via a substrate controlled diastereoselective hydroboration of a 2,2-disubstituted olefin. The diene portion of 1 is established by a combination of Horner-Emmons and Still-Gennarri olefinations. Finally, macrolactamization is accomplished with BOP-Cl.; The oxidative demethylation approach at the benzoquinone portion of 1 failed to give the desired product and instead formed the C17-C20 benzoquinone imine. All attempts to alter the outcome of the oxidation failed to provide 1. However, the synthetic methods developed and applied herein will allow for the completion of 1 and further biological evaluation. |
