Research towards the synthesis of the furanosteroid class of natural products

Abstract

The goal of this research was to explore new routes for the construction of viridin- and xestoquinone-related classes of natural products along with similar non-natural products. The four main targets being addressed are viridin, wortmannin, xestoquinone and halenaquinone. These compounds possess a wide array of biological activities including inhibition of topoisomerase I and II, phosphatidylinositol 3-kinase (PI 3-kinase), protein tyrosine kinase (PTK), and human epidermal growth factor (EGF) kinase. Various kinases as well as topoisomerases affect disease states involving aberrant cell proliferation. The common furanosteroid backbone of these natural products allows for a unified strategy in their construction. The B,C,D-ring systems will be synthesized by a Diels-Alder approach, and the A,B,E-ring systems will be constructed using transition-metal mediated couplings. The core of each molecule, the B-ring, (amino aldehyde 27) is a known compound and can be synthesized in enantiomerically pure form. In the course of elaborating the core of these natural products, we developed a methodology for the diastereoselective addition of organozincs to beta-amino aldehydes. Other achievements include assembly of the B,C,D-rings in xestoquinone and halenaquinone, and annulation of a furan which can be applied in the synthesis of all four natural products. With regard to stereochemistry, the stereocenter in xestoquinone and halenaquinone has been set, the A and B-ring stereocenters in wortmannin have been correctly synthesized, and all but one stereocenter in viridin has been set correctly. The long term goal is to apply methodologies developed while pursuing the synthesis of one natural product to the other furanosteroids. After this is accomplished we will address the assembly of derivate compounds utilizing the B,C,D-ring system of one molecule, followed by annulation of the A,E-rings of another molecule. This thesis represents the founding work in this area within the Behar group