Research

What are the "tools" that allow us to construct molecules, and are these "tools" capable of building the structures we need in a timely and efficient manner? These two questions provide the motivation for our group's exploration of electrochemistry. Because electrochemistry allows one to selectively manipulate the oxidation state of molecules, create reactive intermediates, and reverse the polarity of known functional groups, it provides and ideal method for discovering and exploring many new, synthetically useful reactions.

For example, we have found that the anodic oxidation of electron-rich olefins leads to the formation of radical cations that efficiently trap nucleophiles. In this way, normally nucleophilic enolate equivalents can be used as electrophiles. Current efforts to exploit this unique umpolung reaction are focusing on the construction of natural products like 1-5 in Scheme 1.

In a similar fashion, we are taking advantage electrochemistry's ability to reverse the normal polarity of N-acyliminium ion formation in order to develop new approaches to diversity-oriented synthesis that allow for systematic variations within a core scaffold (6), to synthesize receptor-targeted molecular libraries that contain conformational probes for rapidly gathering information about the three dimensional requirements of the receptor, and to construct new peptide-based bioconjugates (7).

Electrochemistry can also be used to synthesize reactive reagents. For example, in collaboration with scientists at Combimatrix we are currently using electrochemistry as a tool for isolating transition metal based reactions to specific, preselected locations on a chip. In the experiment illustrated in Figure 1, an olefin was converted into a ketone at every other electrode on a chip containing a micro array of 1,000 electrodes in a one cm² area. This was done by using the selected electrodes to generate a Pd (II) reagent and trigger a Wacker oxidation. The bright spots in the checkerboard pattern indicate locations where the olefin was converted to a ketone (and imaged via its 2,4-DNP derivative using an fluoroscene tagged antibody). Current efforts are exploring the fundamental reaction chemistry that can be performed on these chips in order to determine the nature of the molecules that can be synthesized and hence the nature of the biological problems that can be probed using the chips.

Because of the diversity of projects on going in the group, students gain a solid background in organic synthesis, learn about advances that are occurring on the chemistry-biology interface, and acquire experience with much of the advanced instrumentation needed to rapidly make progress in these important areas.

Selected Publications

• Ceng Chen; Gabriella Nagy; Amy V. Walker; Karl Maurer; Andy McShea; Kevin D. Moeller, “Building addressable libraries: The use of a mass spectrometry cleavable linker for monitoring reactions on a microelectrode array,” J. Am. Chem. Soc., 128, 16020 (2006)
• Haizhou Sun; Connor Martin; David Kesselring; Rebecca Keller; Kevin D. Moeller, “Building Functionalized Peptidomimetics: Use of Electroauxiliaries for Introducing N-Acyliminium Ions into Peptides,” J. Am. Chem. Soc., 128, 13761 (2006).
• Eden Tesfu; Karl Maurer; Kevin D. Moeller, “Building Addressable Libraries: Spatially Isolated, Chip-Based Reductive Amination Reactions,” J. Am. Chem. Soc., 128, 70 (2006).
• John Mihelcic; Kevin D. Moeller, “Oxidative Cyclizations: The Asymmetric Synthesis of (-)-Alliacol A,” J. Am. Chem. Soc., 126, 9106 (2004).
• Yung-tzung Huang; Kevin D. Moeller, “Anodic cyclization reactions: probing the chemistry of N,O-ketene acetal derived radical cations,” Tetrahedron, 62, 6536 (2006)
• John D. Brandt; Kevin D. Moeller, “Oxidative Cyclization Reactions: Amide Trapping Groups and the Synthesis of Furanones,” Organic Letters, 7, 3553 (2005).