Jeffrey N. Johnston
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.