The Smith Group focuses on three principal research areas: (A) development of innovative synthetic methods having wide application; (B) demonstration of the utility of these synthetic tactics for the rapid construction of architecturally complex natural and unnatural products having significant bio-regulatory properties, and (C) novel bioorganic/medicinal chemistry programs, including non-peptide peptidomimetics (i.e., early examples of foldemers) in collaboration with the late Professor Ralph Hirschmann, programs relating to neurodegenerate diseases including Alzhemer’s and tauopathologies, in collaboration with Professors Virginia Lee and John Trojanowski (University of Pennsylvania School of Medicine), studies to inhibit HIV cellular entry (an NIH funded Program Project, involving colleagues at Harvard, Columbia, Bryn Mawr, Drexel, and Johns Hopkins), and projects on peptide/protein folding with Professor Robin Hochstrasser (Penn Chemistry). In each of the collaborative programs, Smith and his students exploit the power of “state-of-the-art” organic synthesis to provide solutions to biomedical programs of importance for the improvement of human health.

In the area of complex molecule synthesis, a principal goal has been the development of efficient fragment union tactics, a prerequisite of most complex molecule synthetic campaigns. For example, the syntheses of phorboxazole A, spongistatin 1 and discodermolide (the latter two on gram scale) inspired the development of new methods such as the Petasis-Ferrier Union/Rearrangement, now widely applicable to natural products containing cis-tetrahydropyran rings, and multicomponent Anion Relay Chemistry (ARC), a new tactic that now permits the “one-pot” union of multiple fragments by controlling, in precise fashion, the migration of negative charge in a molecular array as the structural complexity increases in a highly convergent manner. The ARC tactic is a process not dissimilar to “living polymerization!” This tactic recently proved highly effective in the construction of both nitrogen containing natural products and diversity-oriented libraries comprising natural “product-like” molecules.

The synthetic expertise available in the Smith laboratory has and continues to benefit diverse collaborative projects, by providing access to the design and synthesis of novel analogs and molecular probes. Pleasingly, completed and on-going collaborations have contributed to the development of small-molecule probes for neurodegenerative diseases, bioavailable HIV-1 protease inhibitors, small molecule inhibitors of the HIV cell entry process, and ultra-fast photofragmentation reactions based on s-tertrazene chemistry to serve as phototriggers to initiate conformational changes in peptides on the sub-nanosecond timescale.