AmericanChemicalSociety.com

Summary. Although modern organic chemistry offers the power to make or manipulate most any molecule, there are a number of gaps in our capabilities to efficiently, or even effectively, install certain functionality. For example, no general method exists for the asymmetric halogenation of one of the simplest of all functional groups: an alkene. Starter Grant Funding (Type G) from the American Chemical Society Petroleum Research Fund provided the stimulus needed for my research group to develop methods and reagents capable of solving this problem for selected substrate classes, secure substantial federal and private funding for continued study, and provide an opportunity to train 7 students at various educational levels through their work on a research problem of both significance and challenge. Approach and Key Research Findings. Using the structures of several halogenated natural products as our sources of inspiration, we have devoted our attention to the development of methods for the chemo- and/or enantioselective halogenation of alkenes within complex frameworks, with a particular eye towards developing asymmetric, halonium-induced cation-pi cyclizations of polyene substrates. This latter process, though utilized by Nature to fashion hundreds of natural products via the action of heme- or vanadium-based haloperoxidases, has yet to be replicated in the laboratory with simple chemical surrogates. During the course of the funding period of our ACS PRF grant, we were able to develop a unique substrate-based approach that permitted the first effective asymmetric chlorination and bromination of a simple olefin to occur; the chlorine form of that reaction is highlighted in the table of contents graphic, and proved to be the critical step that would ultimately enable us to complete the first asymmetric total synthesis of (–)-napyradiomycin A1. Critical in the design of this operation was a stoichiometric blocking group which shielded the same face of every olefin molecule in the reaction flask, thereby preventing any loss of initial chirality through the well documented process of halonium transfer to unreacted alkenes. We are now attempting to extend this blocking concept to other substrate classes, particularly acyclic cases; we are also studying the established transformation on theoretical terms in collaboration with Prof. Travis Dudding (Brock University, St. Catherines, Canada) to ensure that we understand it as fully as possible to assist in that design process towards greater substrate scope. In addition, we were able to make inroads on the challenging process of initiating halonium-induced cation-pi cyclization, developing a two-step asymmetric mimic for the reaction using stoichiometric amounts of certain chiral metal salts. We also discovered the first class of simple reagents, all of general form Et2SX•SbCl5X, that can effect direct, racemic iodonium- and bromonium-induced polyene cyclizations for every standard terpene class; more standard electrophilic halogen sources afford modest yields of products alongside several inseparable by-products. Current efforts are attempting to extend the lessons learned from this new reagent class to the analogous chlorine-based reactions as well as generate asymmetric variants; we are also trying to develop asymmetric, metal-free, proton-induced, cation-pi cyclizations as well based on the design of these unique reagents. Career Impact and Student Training. As a young investigator, the ACS PRF Type G grant was the first competitive, peer-reviewed source of funding I received. Success in this application provided confidence in the importance of the problem being addressed, as well as enhanced the focus of our research to ensure that all of the broad objectives outlined were met. Consequently, the results garnered through the program became the backbone of a successful NSF CAREER proposal which was funded this past May and will extend funding for this project through mid-2014. The results have also been the subject of many of the 40 invited lectures I have had the opportunity to present in both academic and industrial settings here and abroad.

Equally significant, if not more so, I was able to utilize the funding from this project to train 7 students at various levels (1 postdoctoral researcher, 4 graduate students, and 2 undergraduates) through their efforts to meet these project aims. That support included summer stipends for 3 students and minor equipment and reagent purchases essential in our making critical proof-of-concept discoveries. Of these students, one was able to use this project as the basis for his successful application to receive a prestigious NSF Predoctoral Fellowship and another was able to use it secure summer funding through Pfizer, Inc. Some of these students have also had the chance to present their work at poster sessions during two ACS National meetings as well as serve as co-authors on 3 publications (1 published, 1 in press, and 1 in preparation) in leading scientific journals. Finally, the efforts of the undergraduate students in this project, in particular, helped me to forge a series of educational concepts and goals within my laboratory for the study of organic chemistry by early students that served as the basis for my successful application to receive one of 10 Cottrell Scholarships nationwide as administered by the Research Corporation for Science Advancement. I will have the opportunity to share those ideas next June in a public forum on science education at the University of Arizona. In short, my students and I will always be grateful for the PRF support it received, and I hope in the future that we will be able to tackle other critical problems through