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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM110525-04
Application #
9279153
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
2014-05-01
Project End
2019-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Michigan State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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