Catalytic asymmetric functionalization of alkenes has provided numerous landmark reactions in the field of organic chemistry. These include asymmetric epoxidations, dihydroxylations, hydrogenations and aziridinations to name a few. Nonetheless, asymmetric electrophilic halogenation reactions have witnessed much less success over the years. It is an ongoing pursuit in our group to bring asymmetric alkene halogenation reactions at par with some the more well studied and widely utilized asymmetric alkene functionalization reactions. To this end, we will define and address the numerous challenges associated with this transformation by adopting a multi-faceted approach. We will begin by proposing straightforward theoretical means to predict the ease of alkene halogenation reactions by defining Halenium Affinity (HalA) as an unprecedented parameter. The resulting predictions of chemo- and regioselectivity in alkene halogenations will be verified experimentally and then further applied to the discovery of non-intuitive (yet powerful) transformations precluding the need for trial-and-error approaches. We propose to develop enantioselective routes to valuable chiral heterocycles such as cyclic sulfates, imidazolines, hydropyrimidines, piperidines and oxazine heterocycles via the asymmetric alkene halogenation reactions;halocyclization reactions of alkenes that utilize a variety of C-, O- and N-nucleophiles (aryl ring, alcohols, sulfonamides, guanidines, tertiary amides and acetamidates among many others) will be investigated. Development of novel asymmetric intermolecular variants of halofunctionalization of olefins with a variety of nucleophiles will be pursued. Finally, we will present examples where alkene halogenation reactions will be developed in order to enable the most efficient means yet to access certain scaffolds found in natural products. In this regard, we will draw from both theoretical predictions (HalA values) as well as mechanistically guided reaction optimizations to pursue the total syntheses of obtusin, Napyradiomycin A1 and related analogs, and Calophyline A. These will challenge us to develop the necessary halocyclization reactions to yield efficient syntheses. The overarching goal is to develop asymmetric alkene halogenation chemistry as a tool to enable strategic bond formation reactions that are currently difficult or impractical to construct using other means.

Public Health Relevance

Transformation of carbon-carbon double bonds into other functional groups in an enantioselective manner has been enabling for the tremendous progress of synthetic organic chemistry, yet the halofunctionalization of olefins in a stereoselective manner remains largely untapped. This program will build upon our recent success in this area to develop new methodologies and synthesize complex natural products through enantioselective halogenation of double bonds.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBCB-R (09))
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Lees, Robert G
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Michigan State University
Schools of Arts and Sciences
East Lansing
United States
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Ashtekar, Kumar Dilip; Marzijarani, Nastaran Salehi; Jaganathan, Arvind et al. (2014) A new tool to guide halofunctionalization reactions: the halenium affinity (HalA) scale. J Am Chem Soc 136:13355-62