Microwave Assisted Aza-Michael Additions Towards β-Amino Acids

Abstract

β-amino acids are non-natural amino acids, where the amino group is attached to the β-carbon instead of the α-carbon. Peptides containing β-amino acids present with particular secondary structures and remarkable chemical and biological properties. β-peptides are used as peptidomimetics, based on the resistance to hydrolysis in vivo, with various important applications in the field of Medicine. Several synthetic methods have appeared in recent years, with the Aza- Michael conjugate addition reactions, being a very effective approach towards β-amino acids. Microwave irradiation mediated reactions have also attracted much interest since they significantly improve the reaction yields while reducing the reaction time and avoiding by-products formation. The aim of this project has been the development of a reliable and general synthetic methodology towards β2 and β3 amino acids with the use of conjugate additions of N-nucleophiles to substituted acrylate derivatives. The application of effective catalysts has been also examined here. The results show that the acrylate precursors of β2 and β3 amino acids with side chains corresponding to Phe, Asp, Ile, Leu, Val, and Tyr have been synthesized successfully by using a one-pot Horner-Wadsworth-Emmons reaction, and they have been used for the addition of N-nucleophiles, with a study on conditions and yields optimization. With the main challenge for β-amino acid synthesis being that there is still no general method to synthesize different types of β-amino acids corresponding to all-natural α-amino acids, the proposed synthetic methodology may offer this possibility. N/A