RESEARCH - ORGANIC/MEDICINAL CHEMISTRY

Current research with undergraduate students involves a) the synthesis heterocyclic based diaryl- and bicyclic sulfones as potential antiviral (CMV, VZV, HHV, HIV, etc.) agents; b) the direct electrophilic fluorination of heterocyclic compounds using N-F reagents; c) the transition metal-catalyzed N-arylation of aminoheterocycles; d) synthesis of dicationic compounds as potential DNA minor-groove binding agents with activity against infectious diseases such as African sleeping sickness, Chagas' disease, Leishmaniasis and malaria; and e) development/introduction of new teaching labs in the organic/advanced organic curriculum. Examples of this chemistry are illustrated below:

A. Synthesis of Sulfone-Based Antivirals

Such bicyclic sulfones have been shown to have potent antiviral activity, particularly against herpes type viruses and CMV. These compounds have also been shown to act by a novel mechanism of action. The antiviral screening is performed by collaborators in Belgium.

B. Fluorination of Heteroaromatics using N-F reagents

The above scheme, involving fluorination of 3,5-diphenylisoxazole, represents an example of such chemistry. As a result of this work, we have found that trifluorination of certain ring systems can be accomplished. Current work is focused on fluorination of other ring systems. As N-F reagents are much easier to handle than elemental fluorine, the development of the chemistry using these reagents is important. The ability to fluorinate aromatics is also important as fluorinated compounds have found widespread use as pharmaceuticals and agrochemicals. Considering that the reactivity of heterocycles can vary so much, conditions need to be developed for efficient fluorination of each ring type.

C. N-Arylation of Aminoheterocycles

Using Buchwald/Hartwig type methodology, we are exploring the transition metal catalyzed N-arylation of some 2-aminoheterocycles. Optimization of the conditions involves changing variables such as the metal catalyst (Pd, Cu, Co, etc.), the ligand (typically a phosphine), the base (typically, Cs₂CO₃, K₃PO₄, NaO-t-Bu, etc) and the solvent. Efforts to convert the N-aryl products into bicyclic and tricyclic systems, such as shown in the example above, are also ongoing.

D. Synthesis of Anti-Protozoal Agents

In collaboration with Dr. David Boykin at Georgia State University, we are continuing to synthesize dicationic compounds (diamidines, diguanidines, etc.) as potential anti-protozoal agents (anti-malarial, anti-trypanosomal, anti-leishmanial, etc.). Examples of these type compounds are shown above.

E. Development of New Organic Teaching Labs

Scheme 1

As illustrated above in Scheme 1, I am interested in developing a multi-step sequence for illustrating important aromatic chemistry (such as nitration, nitro reduction, Sandmeyer reaction, etc.) Depending on the instructor's desires and class time, the sequence could begin with either of the first three steps (using commercial available substrates) and does not need to go to the final step.

Scheme 2

As illustrated above in Scheme 2, I am also interested in developing a sequence that illustrates some modern coupling reactions such as the Stille and Suzuki reactions. Such advanced chemistry will be more suited for an advanced organic course in heterocyclic chemistry than for the introductory organic course.