Amos Brittain Smith
My Laboratory at the University of Pennsylvania has advanced the science of synthetic and bioorganic/medicinal chemistry. A transformative contribution from my group has been the conceptualization and implementation of through-space Anion-Relay Chemistry ARC (i.e., negative charge migration across space) that permits both alkylations or cross-coupling reactions. Powerful multi-component couplings are thereby possible that enable efficient, rapid and completely stereocontrolled elaboration of structurally intricate scaffolds. With this tactic the assembly of many scaffolds having biomedical importance can now be assembled in a single reaction in a process not dissimilar to “living polymerization.” Equally fundamental is our recent development of small molecule and polymer supported, fully recoverable siloxane transfer agents that permit “green” Negishi cross-coupling reactions (i.e., without ZnCl2).
Another important contribution is our creative strategy for the construction of tetrahydropyran ring systems, ubiquitous structural elements of natural products having a range of bioactivities. These and other novel concepts led to the completion of more than 90 total syntheses of architecturally complex natural products including milbemycin b3, FK506, rapamycin, calyculin, okilactomycin, penitrem D, sorangicin A, and most notably discodermolide, phorboxazole A and the spongistatins, that hold promise for clinical development as cancer therapeutics.
With the late Professor Hirschmann, we early on made pioneering contributions to the design and synthesis of what are now termed foldamers, nonpeptide peptidomimetics capable of existing in b-strand/b-turn like conformations that serve as agonists and antagonists of peptide hormones and HIV-1 protease inhibitors.
More recently, we have achieved: (A) the design and synthesis of potent small molecule HIV-1 entry antagonists; (B) brain-penetrant orally bioavailable microtubule-stabilizing agents as drug candidates for Alzheimer’s disease; and with the late Professor Hochstrasser, (C) the introduction of S,S-tetrazine subunit, both as an ultrafast photochemical trigger to probe peptide/protein folding and as a agent that permits peptide/protein stapling, and now for the first time the unstapling of peptides and proteins.
Complete List of Published Work in MyBibliography (>700 peer reviewed publications):