The total synthesis of bromophycolide A is a goal worthy of great effort because the macrolide shows a very high potential as an anticancer agent, yet it is currently unavailable to the scientific community at large;as far as we know, it is only available to Kubanek and coworkers. Once a synthetic method is available, the full potential of bromophycolide A as an anticancer drug can be investigated. Its synthesis poses several unique challenges to the synthetic chemist. Its tri-brominated, 15-member ring possesses both diterpene and benzoate skeletons, which come together in a new and interesting type of macrolide structure. These factors necessitate novel methods overcome the difficulties inherent to such a structure. We have proposed new key methods which have the very real potential not only to make the total, asymmetric synthesis of bromophycolide A a reality, but to enhance the synthetic repertoire of natural products chemistry. As a highlight of this proposal, two new methods for asymmetric bromination are proposed, which use a chiral electrophilic brominating agent to promote: 1) the enantioselective and regioselective 1-bromination of ketones;and 2) the enantioselective and regioselective bromination of olefins with tandem cyclizations of potentially vast scope. Both new methods will have widespread utility as they will provide the most efficient route to highly useful synthetic intermediates.
The total synthesis of bromophycolide A is a goal worthy of great effort because the marine natural product shows a very high potential as an anticancer agent, yet it has not been synthesized and is currently unavailable to the scientific community at large. Once a synthetic method is available, and by the proposed synthetic route we believe we can provide this method, the full potential of bromophycolide A as an anticancer drug can be investigated. Additionally, our proposal includes development of new methods that will be highly useful to organic chemists, particularly in the area of marine natural product synthesis.
|Shanahan, Charles S; Fang, Chao; Paull, Daniel H et al. (2013) Asymmetric Formal Total Synthesis of the Stemofoline Alkaloids: The Evolution, Development and Application of a Catalytic Dipolar Cycloaddition Cascade. Tetrahedron 69:7592-7607|
|Fang, Chao; Paull, Daniel H; Hethcox, J Caleb et al. (2012) Enantioselective iodolactonization of disubstituted olefinic acids using a bifunctional catalyst. Org Lett 14:6290-3|
|Paull, Daniel H; Fang, Chao; Donald, James R et al. (2012) Bifunctional catalyst promotes highly enantioselective bromolactonizations to generate stereogenic C-Br bonds. J Am Chem Soc 134:11128-31|
|Fang, Chao; Shanahan, Charles S; Paull, Daniel H et al. (2012) Enantioselective formal total syntheses of didehydrostemofoline and isodidehydrostemofoline through a catalytic dipolar cycloaddition cascade. Angew Chem Int Ed Engl 51:10596-9|