Enantioselective organocatalytic Michael reactions: Synthesis and application of new gamma-amino acids in the design of gamma-peptide foldamers

Biological polymers (such as proteins and nucleic acids) perform a wide range of complex functions in biological systems. In the past two decades, many researchers have sought biopolymer-like folding behavior in unnatural oligomers ("foldamers"). Identification of new types of foldamers with strong and discrete secondary structural propensities is a subject of ongoing research. These studies enhance our understanding of the relationship between local conformational preferences and molecular shape. In addition, new folding patterns can be valuable for specific biopolymer-like functions such as molecular recognition, catalysis. This thesis will focus on our recent results obtained with new peptidic foldamers. Extrapolation from the alpha-amino acid backbone of proteins to beta-amino acid backbones, for example, has yielded a large family of beta-peptide "foldamers" that display helix, sheet and reverse turn secondary structures comparable to (but different in detail from) the regular secondary structures found in proteins. beta-Peptides were prominent in the development of the foldamer field, and the structural and functional diversity displayed by beta-peptides has encouraged exploration of higher amino acids as foldamer subunits. However, such efforts are hampered by the difficulty of obtaining stereochemicelly pure building blocks. Although significant structural progress has been made with gamma-peptides, the study of gamma-containing foldamers lags well behind the study of beta-containing foldamers. The thesis will cover both the stereoselective synthesis of novel cyclically constrained gamma-amino acid residues and the structural behavior of peptidic foldamers containing new gamma-residues. (1) We have developed two efficient synthetic routes to new conformationally constrained gamma-peptide building blocks. These efforts focused on Michael addition of aldehydes to cyclic nitroalkenes and Michael addition of nitromethane to an alpha,beta-unsaturated aldehyde that provide gamma-amino acids containing a ring in the backbone, via asymmetric catalysis. These two routes are complementary in that they place the ring in different positions. (2) We have studied the conformational behavior of oligomers that contain constrained gamma-residues to identify new and stable foldamer secondary structures. Our systematic study of alpha/gamma-, beta/gamma- and gamma-peptides showed that these new backbones display strong helical propensities.