Synthesis of Biologically Important Furanosteroids

Dartmouth College, Hanover NH

Investigators

Abstract

The furanosteroids are a class of novel fungal metabolites, several of which are potent inhibitors of phosphatidylinositol 3-kinase (PI-3 kinase), an enzyme that plays a key role in the life cycle of cells. However, the known members of this class are far too toxic and non-selective for development as anti-tumor agents. Because of this, there is intense interest in developing new synthetic pathways to both the naturally occurring compounds, and simpler analogs. This project addresses the development of a concise synthetic approach to the furanosteroids that should be equally applicable to the biologically important natural products as well as structural analogs. The methodology proposed takes advantage of a sequence of reactions, leading from readily available starting materials to the final target compounds without isolation of intermediate structures. More specifically, synthetic approaches will be explored for the preparation of viridian, demethoxyviridin, viridiol, demethoxyviridiol, wortmannin and desacetoxywortmannin. The key step in the synthesis of all of these compounds is an intramolecular Diels-Alder/retro-Diels-Alder reaction of an alkyne with an oxazole to give a bridged intermediate that, without isolation, immediately undergoes a retro-Diels-Alder reaction to produce a furan ring. This strategy allows for remarkably short synthetic schemes given the complexity of the final compounds. With the support of this award from the Organic and Macromolecular Chemistry Program, Professor Peter A. Jacobi, of the Department of Chemistry at Dartmouth College, is developing new methods for the efficient synthesis of representatives of a unique class of molecules, produced naturally by fungi, known as the furanosteroids. Some of these compounds are potent inhibitors of an enzyme that plays a key role in the life cycle of cells. As such, they hold promise as a new class of therapeutic agents for diseases characterized by rapid cell proliferation, as is the case in cancer. However, the known members of this class are far too toxic and non-selective for development as anti-tumor agents. Thus, there is intense interest in developing new synthetic pathways to both the naturally occurring compounds, and simpler analogs, but progress in this area has been slow because of the great difficulties associated with synthesizing these compounds. Professor Jacobi and his students are developing a concise synthetic approach to the furanosteroids, that should be equally applicable to the biologically important natural products as well as structural analogs. Ultimately, these studies could lead to the discovery of simpler analogs of the natural products that have enhanced biological activity but are significantly less toxic and more site specific.