The goal of this proposal is to develop new selective chemical methods for achieving selective dihalogenation, halofunctionalization, and dihalide derivatization reactions that can be used for the synthesis of complex, biologically active small molecules. Nearly 2,000 compounds containing either a chlorine- or bromine-bearing stereogenic center have been characterized, and while biological activity has been demonstrated in areas of pressing medical need (e.g. anticancer, antibiotic), further investigation into the therapeutic potential and physical basis for bioactivity has been hindered by an unreliable supply from natural sources as well as by a lack of selective methods for systematic chiral organohalogen synthesis. Preliminary findings indicate that the modular combination of metal Lewis acid, electrophilic halogenating agent, and ligand is capable of effecting selective dibromination, bromochlorination, dichlorination, and haloetherification on a variety of alcohol-containing alkene substrates.
The first aim of this research is the full development of this strategy to catalyst-controlled chemo-, regio-, diastereo-, and enantioselective dihalogenation and halofunctionalization reactions.
The second aim of this research is the extension of this strategy for the synthesis of halogenated bioactive small molecules.
The third aim of this research involves identifying conditions that will allow for the derivatization of enriched dihalides for the selective synthesis of bioactive small molecules through stereospecific carbon-heteroatom and carbon-carbon bond-forming reactions. This contribution is significant because it will enable the selective preparation of numerous classes of chiral halogenated and non-halogenated compounds for further biological evaluation. Innovation stems from developing a general, tunable, methodological platform to enable the predictable and selective preparation of numerous classes of chiral halogenated small molecules.

Public Health Relevance

The proposed research is relevant to public health because it will allow efficient access to a large area of chemical space that cannot be reached with present technology. The current lack of methods for constructing chiral organohalogens has precluded follow-up studies to promising biological activities and initial preclinical interest. The goal of his proposal is to develop a general platform that enables the selective assembly of motifs that are found within a host of such molecules and the subsequent use of these motifs for the synthesis of bioactive small molecules.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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Stanford University
Schools of Arts and Sciences
United States
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Seidl, Frederick J; Burns, Noah Z (2016) Selective bromochlorination of a homoallylic alcohol for the total synthesis of (-)-anverene. Beilstein J Org Chem 12:1361-5
Landry, Matthew L; Hu, Dennis X; McKenna, Grace M et al. (2016) Catalytic Enantioselective Dihalogenation and the Selective Synthesis of (-)-Deschloromytilipin A and (-)-Danicalipin A. J Am Chem Soc 138:5150-8
Gál, Bálint; Bucher, Cyril; Burns, Noah Z (2016) Chiral Alkyl Halides: Underexplored Motifs in Medicine. Mar Drugs 14:
Burckle, Alexander J; Vasilev, Vasil H; Burns, Noah Z (2016) A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Sesquiterpenes. Angew Chem Int Ed Engl 55:11476-9
Bucher, Cyril; Deans, Richard M; Burns, Noah Z (2015) Highly Selective Synthesis of Halomon, Plocamenone, and Isoplocamenone. J Am Chem Soc 137:12784-7