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Research Statement

The Smith Group focuses on three principal research areas: (A) development of innovative synthetic methods having wide application; (B) validation of the synthetic tactics for the rapid construction of architecturally complex natural and unnatural products possession significant bio-regulatory properties, and (C) novel bioorganic/medicinal chemistry programs, including programs on neurodegeneration (Alzheimer’s and tauopathologies), in collaboration with Professors Virginia Lee and John Trojanowski (University of Pennsylvania School of Medicine), studies to inhibit both HIV-1 cellular entry and propagation in infected cells (an NIH funded Program Project, involving colleagues at Harvard, Columbia, Drexel, Yale, and Montreal: see Smith News), as well as projects on peptide/protein folding with the late Professor Robin Hochstrasser and now with Feng Gai (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. 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, small molecule inhibitors of both HIV cell entry and HIV infected cell propagation (see Smith News), 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. The latter permits both the stapling and now the unstapling of peptides/protiens.