The major goal of this research program is to develop catalytic enantioselective transformations based on the concept of chiral anion phase transfer catalysis that will be broadly applicable to the preparation of therapeutically relevant organic molecules. Towards this end, several new enantioselective reactions of carbon-carbon pi-bonds are proposed, with a major emphasis placed on the development of enantioselective sp3-C-F bond construction. We will develop reactions that involve activation of pi-bonds as electrophiles towards heteroatom and carbon-based nucleophiles, by coordination phosphate-derived chiral anions in the presence of cationic electrophiles. We will also demonstrate that this reactivity manifold is applicable to other reaction classes, such as direct enantioselective fluorination reactions and fluorinated dearomatization. These methods will be exploited in the enantioselective construction of fluorinated building blocks, heterocycles and natural product analogs. Thus, we anticipate that the proposed air and moisture tolerant transformations will provide synthetic chemists and biomedical researchers with additional tools for single enantiomer synthesis.

Public Health Relevance

The proposed program aims to develop new methods for the preparation of structures and compounds of potential importance to medicinal chemistry. To this end, the enantioselective formation of fluorinated carbocyclic and heterocyclic structures using chiral anion phase transfer catalysis is proposed.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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University of California Berkeley
Schools of Arts and Sciences
United States
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Neel, Andrew J; Milo, Anat; Sigman, Matthew S et al. (2016) Enantiodivergent Fluorination of Allylic Alcohols: Data Set Design Reveals Structural Interplay between Achiral Directing Group and Chiral Anion. J Am Chem Soc 138:3863-75
Yang, Xiaoyu; Toste, F Dean (2016) Asymmetric addition of ?-branched cyclic ketones to allenamides catalyzed by a chiral phosphoric acid. Chem Sci 7:2653-2656
Brantley, Johnathan N; Samant, Andrew V; Toste, F Dean (2016) Isolation and Reactivity of Trifluoromethyl Iodonium Salts. ACS Cent Sci 2:341-50
Yang, Xiaoyu; Wu, Tao; Phipps, Robert J et al. (2015) Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions. Chem Rev 115:826-70
Miles, Dillon H; Guasch, Joan; Toste, F Dean (2015) A Nucleophilic Strategy for Enantioselective Intermolecular ?-Amination: Access to Enantioenriched ?-Arylamino Ketones. J Am Chem Soc 137:7632-5
Nelson, Hosea M; Williams, Brett D; MirĂ³, Javier et al. (2015) Enantioselective 1,1-arylborylation of alkenes: merging chiral anion phase transfer with Pd catalysis. J Am Chem Soc 137:3213-3216
Yang, Xiaoyu; Toste, F Dean (2015) Direct asymmetric amination of ?-branched cyclic ketones catalyzed by a chiral phosphoric acid. J Am Chem Soc 137:3205-8
Hiramatsu, Kenichi; Honjo, Takashi; Rauniyar, Vivek et al. (2015) Enantioselective Synthesis of Fluoro-Dihydroquinazolones and -Benzooxazinones by Fluorination-Initiated Asymmetric Cyclization Reactions. ACS Catal 6:151-154
Nelson, H M; Patel, J S; Shunatona, H P et al. (2015) Enantioselective ?-Amination Enabled by a BINAM-Derived Phase-Transfer Catalyst. Chem Sci 6:170-173
Milo, Anat; Neel, Andrew J; Toste, F Dean et al. (2015) Organic chemistry. A data-intensive approach to mechanistic elucidation applied to chiral anion catalysis. Science 347:737-43

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