The investigation of new chemical reactions that perform asymmetric transformations is a valuable exercise. The benefits of research in asymmetric synthesis are largely practical: the development of new methods leads to efficient and resourceful production of complex molecules of value. When this research effort is directed to the preparation of bioactive molecules, the exercise becomes acutely relevant to biomedical sciences and can directly impact human health. This proposal describes a unified research plan for the preparation of three important medicinally privileged structural motifs: [2.2.2]-diazabicyclic, 2-pyridone, and epipolythiodioxopiperazine (ETP) alkaloids. More than 70 distinct fungal metabolites (including the brevianamides, notoamides, and stephacidins) are now known to share in common the [2.2.2]-diazabicyclic core. Diverse biological activities including antihelmintic, antitumor, neuroprotective, calmodulin (CaM)-inhibition and insecticidal properties are observed across this natural product family. 2-pyridones are a ubiquitous functionality that has found widespread application in drug development and medicine. Camptothecin, one of the most well known natural products containing a 2-pyridone, is an important chemotherapeutic agent in the toolbox for the treatment of colorectal cancer. Synthetic research on camptothecin has delivered semi-synthetic derivatives (irinotecan and topotecan), which exhibit reduced toxicity and have replaced the natural product in the clinic. ETP alkaloids show varied and impressive bioactivities (most notably tumor selective, subnanomolar cytotoxicity) and have promising therapeutic potential. Current methods to prepare the polysulfide bridge require strongly acidic or basic conditions. We propose the direct entry to the ETP core (under neutral reaction conditions) by formal cycloaddition with diatomic sulfur. The research plan described in this proposal will enable new methods to prepare [2.2.2]- diazabicyclic, 2-pyridone, and ETP structures from a common intermediate, a 2,5-diketopiperazine azadiene (pyrazinone) precursor. Additionally, we are pursuing domino or """"""""one- pot"""""""" reaction methodology for the preparation of these structures, an effort that is economical with regard to our time as researchers, but also resource and cost efficient and has the greatest opportunity to streamline research into both known bioactive molecules and new chemical space. Our research efforts will also contribute broadly to fundamental chemical understanding of the reactivity and selectivity of underexplored reactions. The College of William &Mary does not offer a doctoral degree in chemistry (BS/MS only);accordingly, my research group is composed of undergraduate researchers (and one MS candidate). My current research program creates a rigorous environment for discovery-based learning and enforces teaching and training in the one-on-one research experience. The proposed research would continue within this climate. Support from the NIH would enable the research of 4 undergraduates and one Master's candidate for each year of the award.
[2.2.2]-diazabicyclic alkaloids, 2-pyridone, and epipolythiodioxopiperazine (ETP) structures are medicinally privileged scaffolds. New and efficient methods to prepare these structural motifs will streamline biomedical research into these molecules and aid in the preparation of new biologically active entities as well as contribute broadly to fundamental chemical understanding and reactivity of these molecules.
