Total synthesis of (+)-phorboxazole A

This dissertation describes synthetic studies culminating in the total synthesis of the potent antiproliferative agent phorboxazole A. The synthetic approach to this architecturally complex sponge metabolite exploited the Petasis-Ferrier rearrangement as the cornerstone for this successful strategy. Retrosynthetic disconnection of phorboxazole A suggested three major subtargets, oxazole triflate 104, aldehyde 105, and Wittig salt 106.* In the course of this synthetic venture several interesting discoveries were made with respect to the Petasis-Ferrier rearrangement. The Lewis acid of choice for the construction of the C(11-15) and the C(22-26) cis -tetrahydropyran was found to be Me2AlCl. The inherent symmetry, namely the ability to transpose the enol ether functionality within Petasis-Ferrier substrates, proved crucial in the use of this method in the assembly of subtarget 106.* Macrolide formation entailed Wittig olefination for construction of the C(19-20) E-olefin, Stille cross coupling for assemble of the key C(28-29) bond, and cyclization employing the Still modified Horner-Emmons reaction completed the preparation of the carbon skeleton of phorboxazole A.* Final elaboration of the terminal alkyne (+)-245 to the requisite E-vinyl bromide required a three step sequence employing the alkynyl bromide. Final deprotection completed the total synthesis of (+)-phorboxazole A (1) in 27 linear steps and in an overall yield of 3.5%.* *Please refer to dissertation for diagrams