My group develops and applies tools for precision engineering of molecules.  We are committed to identify and harness useful patterns of reactivity in biological molecules and transition metals.
    Proteins are arguably the most interesting molecules in living cells because of their ability to catalyze highly selective transformations.  However, the most modern studies of proteins have centered around enzymatic activity rather than the chemical reactivity of proteins and protein functional groups.  For this reason, we were drawn to study the chemistry of amino acids in the context of proteins.  From a reactivity standpoint, tryptophan is the most interesting of the amino acids because it is pre-disposed to form carbon-carbon bonds.  The tendency to form ill-defined cross-links and fluorescent species led us to elucidate the mechanisms and products of these reactions.  We demonstrated, for the first time, that tryptophan could form highly fluorescent ditryptophan crosslinks, analagous to disulfides and dityrosines.  Ditryptophan crosslinks enforce various elements of local peptide structure: beta turns, gamma turns, and beta sheets. 

    Tryptophan dimers produced through acid-catalyzed reactions proved to be ready receptors of non-enzymatic glycation.  These patterns of reactivity led directly to first total syntheses of a number of indolocarbazole glycoside natural products with potent biological activity.  Oxidative cyclization of tryptophan residues generates 3-hydroxypyrrolidinoindolines which mimic proline yet can directly generate both ditryptophan and tryptathionine crosslinks.  Our studies of these reactions led us to complete syntheses of phakellistatins 3 and 13 and madindoline.


    It is clear that peptide sequence influences the propensity for tryptophan crosslinking.  We have a continued interest in the relationship between peptide sequence and reactivity.  Using one bead-one peptide libraries we identified fluorogenic peptide sequences that generate fluorophores through surprisingly complex mechanisms.  Our current efforts are directed toward the identification of peptide tags that react selectively with fluorogenic reagents. 

    Fluorescent peptides are promising tools for studying enzymes that normally act on full-length proteins.  Protein kinases are probably the most interesting enzymes from the viewpoint of cell function because they transduce extracellular signals into genetic control of cell function.  In collaboration with the Allbritton and Sims groups at UCI we have been developing selective fluorescent peptide substrates for human MAP kinases.  This project requires the combined powers of synthetic organic chemistry, protein expression, enzymology, analytical chemistry, and cell biology.


    After completing the first synthesis of the peronatins we became interested in powerful strategies for de-aromatization through carbon-carbon bond formation.  We initially focused on base-promoted thia-Sommelet dearomatizations which punch quaternary centers into benzene rings.  Later, we focused on transition metal catalyzed approaches to effect this transformation using diazo compounds as sulfonium ylide precursors.  Iron(II) catalysts proved to be the best catalysts for this reaction.  Ultimately, we realized that palladium catalysts would allow us to effect insertion of carbene subunits into aryl halides and related substrates.  Our current work is centered around the development of palladium-catalyzed carbene insertions.