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Jeffrey N. Johnston

Title and Contact Information

Stevenson Professor of Chemistry
Office: 12435-H MRBIV
Phone: (615) 322-7376
EmailWebsite

Education

Ph. D., The Ohio State University, 1997

Specialties

VICB
Organometallic Chemistry
Organic Chemistry
Natural Products
Medicinal Chemistry
Chemical Biology
Bioorganic Chemistry
Asymmetric Catalysis

In the News

VICC-VU Joins Effort To Develop New Cancer
AAAS-Professor Johnston elected as 2010 Fellow Award
Chemistry World-New synthesis for chiral anticancer compound
ACS-National Committee on Professional Training
Reporter-Lepesheva-Waterman-Villalta collaboration(Chemistry/Biochemistry/Meharry Medical College) yields cure for chronic Chagas disease

Johnston

Research

Our programs are tied by the common theme of organic synthesis. We are interested in the development of new reactions and reagents for natural product total synthesis, and we have contributed a variety of new reactions to the chemist's arsenal, including free radical-mediated aryl and vinyl amination, the Brønsted acid-catalyzed aza-Darzens reaction, and a new acid catalyzed olefin aminoacyloxylation reaction. We also apply these reactions to the targets that inspired them. For example, our synthesis of mitomycin C uses the acid-catalyzed aza-Darzens reaction, in addition to a regioselective enamine-quinone coupling. And in our approach to (+)-zwittermicin A, we deploy a variation of our Brønsted acid catalyzed azide-olefin addition. As a result, we are able to synthesize highly functionalized, stereochemically dense advanced intermediates with considerable brevity. We reported the first total synthesis of (+)-serratezomine A using the free radical-mediated vinyl amination reaction, which provided this challenging target in a mere 15 steps (longest linear sequence).

We have also advanced the concept and first embodiment of chiral proton catalysis – polar ionic hydrogen bond catalysis. Reagents known as BAM-protic acid complexes are bifunctional, containing both a polar ionic hydrogen bond (a Brønsted acid) and a Brønsted base. These catalysts synchronize the activation of two substrates while orienting the electrophile for stereoselective addition. The net result is the ability to make a variety of products in enantioenriched form through carbon-carbon bond-forming reactions. From this perspective, these catalysts function in a chemically similar manner to enzymes. An underlying goal of our program is to understand how biological catalysts achieve substrate activation, and determine how this can be translated to small molecule catalysts.

A recent addition to our repertoire is Umpolung Amide Synthesis (UmAS), and its use to prepare α-amino acids, and their polymers – peptides – using fully enantioselective means. This expands our ability to prepare non-natural amino acids considerably, as we have developed methods previously to prepare indoline α-amino acids, constrained proline derivatives, α,β-diamino acids, and α-amino phosphonic acids. Based on these unique skills, we find ourselves drawn further to problems in bioorganic chemistry.

We have ongoing internal and collaborative projects in organometallic catalysis that target reactions not amenable to protic acid catalysis. Our contributions in this area include the development of the first axially chiral b-diketiminate (IAN amines), and the study of their coordination chemistry with group IV metals.

Finally, we have established several new collaborative projects with Vanderbilt investigators in the broad area of medicinal chemistry. These are based on our use of chiral proton catalysis to prepare chiral nonracemic secondary amines, and their conversion to promising therapeutics for Chagas disease, and investigational new drugs like (–)-Nutlin-3 (Hoffmann-La Roche).

Through these studies, the student is trained how to think about problems in organic chemistry from an approach that involves extensive laboratory experimentation. Germane to this training is the routine use of spectroscopic (NMR, IR, mass spectroscopy, X-ray diffraction) and analytical (chiral stationary phase HPLC) techniques. Many of these projects require the student to draw knowledge from an extensive body of literature in organic chemistry while developing truly novel reactions and the reagents (catalysts) that promote them with high levels of stereocontrol. Furthermore, our approach to the development of new chemistry follows a highly synergistic combination of informed design, mechanistic organic chemistry, empiricism, and at times, a touch of luck.

 

 

 

Selected Publications

Davis, T. A.; Vilgelm, A. E.; Richmond, A.; Johnston, J. N. Preparation of (-)-Nutlin-3 Using Enantioselective Organocatalysis at Decagram Scale. Journal of Organic Chemistry. 2013, 78: 10605-10616.

Villalta, F.; Dobish, M. C.; Nde, P. N.; Kleshchenko, Y. Y.; Hargrove, T. Y.; Johnson, C. A.; Waterman, M. R.; Johnston, J. N.; Lepesheva, G. I. VNI Cures Acute and Chronic Experimental Chagas Disease. Journal of Infectious Diseases. 2013, 208: 504-511.

Pigza, J. A.; Han, J. S.; Chandra, A.; Mutnick, D.; Pink, M.; Johnston, J. N. Total Synthesis of the Lycopodium Alkaloid Serratezomine A Using Free Radical-Mediated Vinyl Amination to Prepare a beta-Stannyl Enamine Linchpin. Journal of Organic Chemistry. 2013, 3: 843.

Leighty, M. W.; Shen, B.; Johnston, J. N. Enantioselective Synthesis of alpha-Oxy Amides via Umpolung Amide Synthesis. Journal of The American Chemical Society. 2012, 37: 15236.

Dobish, M. C.; Johnston, J. N. Achiral Counterion Control of Enantioselectivity in a Bronsted Acid-Catalyzed Iodolactonization. Journal of The American Chemical Society. 2012, 14: 6071.

Shackleford, J. P.; Shen, B.; Johnston, J. N. Catalytic, enantioselective synthesis of stilbene cis-diamines: A concise preparation of (-)-Nutlin-3, a potent p53/MDM2 inhibitor. Proceedings of the National Academy of Sciences of the United States of America. 2012, 109: 46.

Davis, T. A.; Danneman, M. W.; Johnston, J. N. Chiral proton catalysis of secondary nitroalkane additions to azomethine: synthesis of a potent GlyT1 inhibitor. Chemical Communications. 2012, 48: 5580.

Muchalski, H.; Johnston, J. N.  Transformations of Alkenes: Aziridination. Science of Synthesis. 2011, 1: 155.

Chandra, A.; Johnston, J. N. Total Synthesis of the Chlorine-Containing Hapalindoles K, A, G. Angewandte Chemie International Edition. 2011, 50: 7641.

Srinivasan, J. M.; Mathew, P. A.; Williams, A. L.; Huffman, J. C.; Johnston, J. N. Stereoselective synthesis of complex polycyclic aziridines: use of the Bronsted acid-catalyzed aza-Darzens reaction to prepare an orthogonally protected mitomycin C intermediate with maximal convergency. Chemical Communications. 2011, 47: 9377.

Davis, T. A.; Johnston, J. N. Catalytic, enantioselective synthesis of stilbene cis-diamines: A concise preparation of (-)-Nutlin-3, a potent p53/MDM2 inhibitor. Chemical Science. 2011, 2: 1079.

Tomasiak, T. M.; Archuleta, T. L.; Andrell, J.; Luna-Chavez, C.; Davis, T. A.; Sarwar, M.; Ham, A. J.; McDonald, W. H.; Yankovskaya, V.; Stern, H. A.; Johnston, J. N.; Maklashina, E.; Cecchini, G.; Iverson, T. M. Geometric Restraint Drives On- and Off-pathway Catalysis by the Escherichia coli Menaquinol:Fumarate Reductase. Journal of Biological Chemistry. 2011, 286: 3056.

Johnston, J. N. A Chiral N-Phosphinyl Phosphoramide: Another Offspring for the Sage Phosphoric Acid Progenitor. Angew Chem Int Ed Engl. 2011,  50: 2891.

Johnston, J. N.; Hong, K. B.; Troyer, T. L. Origins of Selectivity in Brønsted Acid-Promoted Diazoalkane-Azomethine Reactions (The Aza-Darzens Aziridine Synthesis). Org Lett. 2011, 13: 1792.

Johnston, J. N.; Muchalski, H.; Troyer, T. L. To Protonate or Alkylate? Stereoselective Bronsted Acid Catalysis of C-C Bond Formation Using Diazoalkanes. Angewandte Chemie-International Edition. 2010, 49: 2298.

Shen, B.; Makley, D.M.; Johnston, J.N. Umpolung reactivity in amide and peptide synthesis. Nature. 2010, 465: 1032.

Muchalski, H.; Hong, K.; Johnston, J. N. Brønsted Acid-Promoted Azide-Olefin Cycloadditions for the Preparation of Contiguous Aminopolyols Derived from an anti-1,3-Diol Scaffold: The Importance of Disiloxane Ring Size to Diastereoselection. Beilstein Journal of Organic Chemistry. 2010, 6: 1206.

Dobish, M.; Johnston, J. N. Chiral Brønsted Base-Promoted Nitroalkane Alkylation: Enantioselective Synthesis of Chiral Nonracemic sec-Alkyl-3-Substituted Indoles. Organic Letters. 2010, 12: 5744.

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