New opportunities for the Cope rearrangement: methods, modular synthesis, and applications in drug discovery

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Research Summary/Abstract: The overall goal of the Grenning research lab is to develop programable and highly diversifiable platforms for accessing complex chemical space of interest to drug discovery. Summarized herein is an overview of work and future directions aimed at transforming the classic Cope rearrangement into a versatile synthetic transformation of high value for complex molecule synthesis. While variants of the Cope rearrangement (e.g. the oxy-Cope rearrangement, aza-Cope rearrangement, and divinylcyclopropane Cope rearrangement) have found extensive use and value in modern chemical synthesis, the classic Cope has not. This transformation is a diamond in the rough that, post-MIRA funding, will have clear and diverse value to chemical synthesis and drug discovery. In our published and unpublished works, we have addressed (or are addressing) fundamental challenges related to thermodynamics and kinetics and proposed potential applications of this transformation in modular complex molecule synthesis. Our current and future directions will involve continuing to improve our understanding of this transformation, develop unique, complexity generating transformations and/or sequences where this transformation plays a key role, introduce a variety of catalytic-asymmetric methods for accessing enantioenriched building blocks, and prepare molecules of modern interest to drug discovery; a well-rounded and diverse research program focusing both on fundamental and applied chemical discoveries. Regarding the latter goal, we currently have on going collaborations with many medicinal chemistry and chemical biology groups and will continue to make new connections allowing for the most impactful discoveries related to synthesis and medicine. Funding of this proposal will result in new and general transformations of value beyond the scope of the proposal and new leads for drug discovery. For example, we have already established a highly modular route to Vorinostat analogs and collaboratively (with the Pflum lab at Wayne State University) will examine their bioactivity as HDAC inhibitors. Beyond or chemistry products (methods, syntheses, and molecules), we are requesting significant funding for the training of students and postdocs to professional synthetic chemists which will be of critical value to a knowledgeable, scientific workforce of value to a variety of technical industries. For example, Ph.D. graduates from my lab are currently continuing their studies as post docs (e.g. Primali Navaratne; Stoltz Lab) or have gone directly into industry (Ehsan Fereyduni; Research Scientist at Intel). ! 1!