Rigid peptide analogs. While constrained peptide mimics can serve as valuable chemical probes for determining the biologically active conformation of peptides, the difficulties associated with their synthesis often limit their utility. In order to address this problem, we have been developing new tools for constructing peptide mimics that allow for the rapid insertion of conformational constraints into pre-selected sites within a peptide. This chemistry capitalizes on the use of electroauxiliaries that allow for the selective oxidation of a single nitrogen within the peptide backbone. The oxidation reactions can be conducted using either anodic electrochemistry or chemical oxidants. Once the constrained peptide mimics are constructed, they are used to “map” the conformational requirements of peptide receptors for which there is limited structural data available.

Oxidative Cyclization Reactions. The formation of new carbon-carbon bonds and the generation of new ring compounds lies at the heart of synthetic organic chemistry. New reactions that can generate the cyclic framework that provides the three-dimensional structure of a molecule can change not only particular steps within a synthesis but also the entire synthetic route being examined. Recently, we discovered that anodic electrochemistry could be used to efficiently generate and study highly reactive radical cation intermediates. The radical cation intermediates were used to initiate a variety of new cyclization reactions that accomplished the net coupling of two electron-rich nucleophiles. These reactions are currently being used to construct a variety of biologically interesting natural products.

Chips. How does one generate a library of 10,000 or more molecules in a 1 cm2 area so that each of the molecules is located in a unique, individually addressable location? The generation of such a library would be useful for screening the gene products generated by a cell. In an effort to answer this question, we are currently exploring the scope of the synthetic chemistry that can be performed at specific, pre-selected locations on a chip.

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