This project focuses on the development and synthetic applications of stereoselective iminium bis-(silane) cyclization and vanadium promoted free radical methylenecyclopentane annulations. Recent discoveries in the principal investigator's laboratory indicate that chiral and achiral 2-propylidene-1,3-bis(silane) bearing imines undergo efficient cyclization with superb levels of substrate directed stereocontrol in the presence of TiCl4. This project will continue the investigation of 2-propylidene-1,3-bis(silane) by studying the stereoselective bond forming reactions between 2-propylidene-1,3-bis(silane) and carbon based electrophiles. Once developed, such a methodology will be employed to synthesize structurally intricate isotropanes and their derivatives. The development of free radical methylenecyclopentane annulations promoted by the novel and highly economical vanadium reagent (CF3CH2O)VOCl2 is another objective of the project.
With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor Tom Livinghouse, of the Department of Chemistry at Montana State University. Professor Livinghouse's research efforts revolve around the discovery, development, and exploitation of novel reactions for the synthesis of challenging natural products. Professor Livinghouse's bis(silane) cyclization strategy allows the efficient construction of complex molecules. The project is of considerable significance to the chemical and pharmaceutical industry, as it could impact how organic molecules are prepared.
PROJECT DESCRIPTION The development of new processes by which the efficiency of pharmaceutical synthesis can be improved is a central goal of biomedical research. The elucidation of novel reaction types that enable selective organic transformations remains fundamental to this endeavor. Over the years, various discoveries in this area have enabled the efficient preparation of a wide variety of important medicinals that have benefited humanity. The research conducted under this NSF award has shown that a variety of stereochemically diverse heterocycles can be prepared with excellent selectivity by an unusually efficient class of iminium ion initiated cyclizations, specifically with respect to the synthesis of bioactive substances. Our NSF funded research program has shown that this new reaction type will permit rapid access to important classes of synthetic intermediates for pharmacological design and development. The research conducted under this NSF grant has also led to a new synthetic method in the area of organozinc(II)-promoted heterocycle synthesis. We believe that this method will receive considerable utilization as a vehicle for the stereocontrolled synthesis of small molecules having known biomedical significance. As specific medicinals, the research conducted under this NSF award has enabled preparative routes to the rare antitumor agents (+) -stemofoline and (+)-asparagamine A, as well as the synthesis of prospective isotropane muscarine agonists for the treatment of Alzheimer’s disease.
