Formal synthesis of (+)-discodermolide and epothilone A

Subash C Jonnalagadda, Purdue University

Abstract

Since the discovery of paclitaxel (Taxol™) from Taxus brevifolia and its clinical success as an anti-cancer drug, there have been extensive efforts to find compounds with similar action. Epothilone, and discodermolide, are two such the compounds that bind and stabilize the microtubules leading to the arrest of mitosis at the G2M phase with a mode of action similar to that of Taxol. This highly encouraging biological profile makes discodermolide a promising candidate for the synergistic cancer treatment therapy and for clinical development as a chemotherapeutic agent for Taxol-resistant carcinoma. Epothilone is currently under Phase II clinical trials and is 10 folds more effective against multi-drug resistant tumor cells than Taxol. We undertook the synthesis of two microtubule stabilizing agents, discodermolide and epothilone A. "Allyl"boration with a novel aryloxyallylborane based on α-pinene and ring closing metathesis were utilized as the key steps for the synthesis of goniodiol, epigoniodiol and deoxygoniopypyrone. A practical procedure was developed for the large scale preparation of γ-γdimethylallyldiisopinocampheylborane and was utilized for the preparation of C1-C7 subunit of epothilone A. A novel protocol for the synthesis of β-hydroxy-δ-lactones was developed via diastereoselective dihydroxylation and regioselective deoxygenation of α-pyrones and this protocol was applied for the synthesis of C1-C8 and C15-C 21 subunits of discodermolide as well as the C1-C6 subunit of epothilone A. An improved methodology based on the bromination of the vinylboronates was developed for the stereoselective synthesis of trisubstituted (Z)-bromoalkenes. This protocol was utilized as a key step for the synthesis of C9-C14 subunit of discodermolide. In conclusion, we have synthesized three cytotoxic natural products goniodiol, epigoniodiol, deoxygoniopypyrone, the C1-C8, C 9-C14 and C15-C21 subunits of (+)-discodermolide, and the C1-C6 and C7-C21 subunits of epothilone A. Formal syntheses of both epothilone A and discodermolide were achieved via the synthesis of all the required subunits.

Degree

Ph.D.

Advisors

Ramachandran, Purdue University.

Subject Area

Organic chemistry

COinS