Silyl substituted amino acid derivatives: Developing rapid routes to lactam-based peptide mimetic scaffolds

Peptide libraries that include conformationally constrained peptidomimetics can potentially provide an attractive means for gathering information about the three-dimensional requirements of ligand-receptor binding. But how does one build a peptide library that contains conformationally constrained analogs?; As part of an effort to answer this question, silylated amino acids have been incorporated into peptides and then converted into N-acyliminium ions with the use of an anodic oxidation reaction. The result is that either constrained peptidomimetics or external nucleophiles can be systematically introduced into the peptide, a development that should greatly expand our ability to rapidly construct modified peptides from readily available amino acid starting materials.; Furthermore, the removal of silyl electroauxiliaries from peptide substrates with chemical oxidants has also been examined as a method for inserting N-acyliminium ions into the peptides. To this end, it was found that both 4-methoxyphenyldimethylsilyl and 2,4-dimethoxyphenyldimethylsilyl electroauxiliaries were readily cleaved with the use of ceric ammonium nitrate. Of the two groups, the 2,4-dimethoxypheyldimethylsilyl electroauxiliary was the most labile under the oxidative conditions. The oxidation reactions were shown to be compatible with the use of a solid phase substrate. In addition, we have shown that the placement of multiple electroauxiliaries having different oxidation properties into a peptide allows for the selective insertion of an N-acyliminium ion into the peptide at only one of the sites. The result is a modified peptide that still has an electroauxiliary present for introducing new groups, and hence more diversity, into the peptide.; In addition to these efforts, work has begun in connection with the generation of peptide libraries using a parallel electrosynthesis setup. Ongoing work in this area is centering on optimizing the reaction conditions for this system, as well as the development of new electroauxiliaries that will optimize reactions using chemical oxidants.