Peptide secondary structure provides an exceptional scaffold on which to design highly reactive and selective enzyme-like catalysts. This work describes the rational design and synthesis of a suite of helical peptide catalysts that are capable of achieving proximity-induced rate enhancement in Diels-Alder cycloadditions and indole alkylations. Microwave assisted synthesis of resin-supported polypeptides enables incorporation of non-natural amino acid residues that induce helicity (Aib) or provide functional handles on which organic catalytic residues can be attached. These small peptide catalysts exhibit binding-driven selectivity rather than relying on the inherent reactivity of substrates, which allows access to products that are not obtainable with traditional catalysts in solution. Catalyst efficiency reached up to 28,000 turn overs, which mimics natural enzymatic systems. Studies were also conducted into the stabilization of peptide secondary structure via covalent linking of nucleophilic amino acid side chains with squaric acid residues. Under mild conditions, stapling of nitrogen, sulfur and oxygen residues can readily be achieved in either organic or aqueous media. Squaric acid staples display pH selectivity for specific side chains and selective removal of diester staples (diserine staple) is demonstrated with methylamine. This new method for peptide stapling is shown to dramatically increase the proteolytic stability of eIF4E cancer inhibitor proteins, which typically are prone to quick degradation. Tyrosidine and RGD peptide analogues were synthesized and cyclized on resin in order to provide a new pathway to macrocyclization of antibacterial and integrin binding cyclic peptides.

Enzymes are some of nature's most powerful tools in chemical processes. However, their molecular complexity makes them difficult to synthesize and complicates their application in traditional organic synthesis. Peptides, a building block of enzymes, can be rapidly synthesized and have been used as a possible alternative in achieving enzyme-like catalysis. However, most peptide-based catalysts are limited in reaction-scope and are unable to incorporate traditional organic catalysts. We have designed a helical peptide scaffold capable of being functionalized with a wide variety of organocatalysts as well as transition-metal based catalysts. In order to understand how the peptide structure effects reactivity and selectivity we designed and studied a helical peptide functionalized with enamine and thiourea catalysts for the conjugate addition reaction of a variety of nitroolefins to cyclohexanone. By rationally engineering the peptide backbone, we were able to achieve up to 95%ee. Our studies emphasized the crucial role the peptide secondary structure plays in this reaction and its potential to serve as a general catalytic platform for future reaction development. Progress particularly toward the development of peptide scaffolds capable of binding transition-metals and performing organometallic catalysis is also described. Peptides are promising motifs in therapeutics. They are more specific and are able to bind to a larger range of targets than small-molecule based drugs while also having lower immunogenicity than larger biologic-based drugs. However, their poor in vivo stability is problematic for their more widespread use. Peptide stapling has been shown to increase peptide stability by covalently linking two ends of the peptide. Squaric esters are commonly used in conjugation chemistry and have shown to selectively react with primary amine nucleophiles, such as those on lysine sidechains. However, their potential to act as peptide stapling reagents has remained unexplored. We have developed a method whereby helical peptides can be stapled with squaric methyl ester on-resin. Peptides can be stapled at the i+1, i+4, and i+7 positions in good yields. The staple is also stable under the highly acidic conditions used to cleave the peptides from resin. Circular dichroism studies show that the staple is able to increase peptide helicity when compared with an unstapled control.