An efficient synthesis of okadaic acid: Synthesis of the C16-C27 central core and analogs of the natural product to study protein phosphatase regulation

The basis for this thesis is the development and execution of a versatile, efficient synthesis of the marine natural product okadaic acid. This synthesis will then be modified to produce structural analogs of the natural product to study its phosphatase inhibition properties. Okadaic acid, a polyether natural product, consists of a 38-carbon backbone and contains 17 stereocenters, so it poses a great challenge for the synthetic chemist.;The first part of the thesis gives the details of the total synthesis of this complex natural product, focusing on the synthesis of the central core and elaboration into the fragment representing carbons 15-38 of the natural product. The synthesis was convergent, in that the natural product was dissected into three fragments of approximately equal complexity. These fragments incorporated a maximal degree of functionality to minimize the number of post-coupling transformations. The highlights of the chemistry used to synthesize the C15-C38 fragment are: the synthesis of the C16-C27 central core in 14 linear steps and in ca. 13% overall yield from a known altropyranoside; and the use of an unstabilized organocerium reagent at C28 to couple with a very sensitive, highly functionalized ;The second part of the thesis describes the design and synthesis of some analogs of okadaic acid that will be used to probe the mechanistic basis of its binding and inhibition of the protein phosphatases 1 and 2A. In the course of this analog development some modifications to the original synthetic effort were made to better streamline entry into analogs of the okadaic acid architecture. Namely, an improved synthesis of an alkyne representing C9-C14 and the synthesis of a modified central core of the natural product is reported.