There exists a continuing need for new routes to nitrogen heterocycles--a source of important new drugs. This project continues support for the study of 2-aminopyrroles as precursors for novel nitrogen heterocycles. The 2-aminopyrrole-ring system is electron rich and can act as a dienophile in inverse-electron demand Diels-Alder reactions with electron poor azadienes. Reactions that will lead to a pyrrole ring annulated to a six-membered ring containing one or two nitrogen atoms. The 1,3-dipolar cycloaddition reaction of 2-aminopyrroles has never been reported. Reactions of 2-aminopyrroles with phenyl azides and nitrilimines would lead to interesting heterocyclic systems in which a pyrrole ring is annulated to a five-membered ring containing 2 or 3 nitrogen atoms--heterocyclic compounds that are poorly known, with potential biological activity, and not readily available by other methods. Studies will be carried out to determine if the 1,3-dipolar cycloaddition reaction is concerted or a step-wise process.
With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor Michael De Rosa of the Department of Chemistry at Penn State Brandywine. Professor De Rosa's research efforts focus on the chemistry of simple 2-aminopyrroles without further substitution on the ring. Compounds first prepared in Professor De Rosa's research group. Previous studies have discovered several new reactions of 2-aminopyrroles. The proposed work should lead to novel reaction pathways to interesting, and in some cases, previously unknown heterocyclic systems. Undergraduates will carry out experimental work during the summer. It is expected that this project will support the work of 10-12 undergraduates.
The search for privileged structures is an on-going goal of organic chemists. Privileged structures are molecules that can bind to cell receptors or enzymes. As such they are useful for identifying potential new drug targets. Many of them are nitrogen heterocyclic compounds—rings made up of carbon atoms and containing one or more nitrogen atoms. Pyrrole and its derivatives are examples of such compounds. Our group is working on the synthesis and reactions of aminopyrroles. The presence of the amino group makes these compounds extremely reactive. One result is that they can be expected to react with many other molecules with the incorporation of the pyrrole ring in the new compound. But their high reactivity also makes them very unstable. Before the start of our work 3-aminopyrrole (A), the simplest 3-amino derivative, had never been made because of its instability. We found that 3-aminopyrrole could be trapped as a stable salt, and then released as needed in a chemical reaction. In this way its chemical reactivity could be harnessed and used for the synthesis of new and interesting heterocyclic compounds containing a pyrrole ring and other nitrogen atoms that might be expected to interact with cell receptors or enzymes. One of the ways in which we accomplished this was by a process known as cycloaddition. Through cycloaddition two molecules combine to form a new compound containing two or more rings fused together (B). The resulting molecules are often flat which makes any potential biological interactions easier. Another route to new compounds is by a process known as nucleophilic substitution: the amino group replaced (substituted for) another group with the formation of a linear array of two or three rings (C). Rearrangements are reactions in which the atoms making up the molecule end up in new positions. During the course of a cycloaddition study we discovered an unprecedented rearrangement in which one ring contracted at the same time as another ring expanded giving compounds that are difficult to prepare in one-step (D). This NSF grant funded the summer research of seven undergraduate students over the course of three summers. They worked for up to 40 hours a week for 10-12 weeks. Some of them have been co-authors of publications, and of conference presentations in the US and shortly, in Korea. Students that participated in our summer research program have gone on to graduate school, pharmacy school, and careers in industry.
