Monanchocidin A, characterized in sequential 2010-2011 reports, was the first isolated member in a family of structurally complex alkaloids consisting of five members. Preliminary investigations of natural monanchocidin A isolates have identified potent antileukemic properties; however, the dry yields from sea sponge M. pulchra from which it is isolated, precluded broad biological activity assays and thorough evaluation to understand the mechanism of action and phenotypic origins of their biological activity. Indeed, the absolute and relative stereochemical configuration of the natural product has not been rigorously established due to scant availability of material. The proposed research describes a concise, 13 step enantioselective route to access monanchocidin A. The pentacyclic guanidine framework, known as the vessel, which is also common to many members of the crambescidin alkaloid family, will be prepared in only 8 in the by longest linear sequence. A highly oxidized morpholine ring, comprising what is known as the anchor, is entirely unique to the monanchocidin family. We have developed a concise, 11 step route to the complex subunit, which - at present - has not succumbed to partial synthesis. The route is readily amenable to the synthesis of either enantiomer of natural product, which is critical for such an endeavor. Preliminary investigations have demonstrated a critical cascade reaction proceeds in very high yield. In addition, a novel carbon-carbon bond forming reaction catalyzed by copper(II)-salts has been proposed as a key construct of the synthesis to replace the state-of-the-art methods for ?-alkynylation of carbonyls, which use toxic heavy metals, such as lead, tin and mercury. Further, the classic coinage metal-catalyzed allenol cyclization reaction will be developed with tethered hemiaminals as a method for diastereoselective synthesis of N,O-spirohemiaminals. The long-term objective of the research is to establish the full spectrum of potent biological activity for monanchocidin A and its synthetic precursors. These studies will lay the foundations for future target identification and lead optimization.
Leukemia is the most prominent cancer among adolescents in the United States, and as such, there is a need for new small molecule therapeutics. Preliminary biological assay of the marine alkaloid monanchocidin A, isolated in 2010, indicate promising antileukemic activity against several cancer cell lines. This project will develop concise synthesis of the monanchocidin A to enable effective evaluation of its clinical potential and the scope of its biological activity.
