The design and synthesis of novel amino acids and their usein synthesis of beta-turn mimetics and their incorporation into biological active peptides

Abstract

Peptide ligands represent the most important hormones and neurotransmitters in physiological processes. Although native biologically active peptides have a great potential for medical applications, they often need to be modified to overcome certain inherent problems. A new research area called peptidomimetics has been developed in the last twenty years. The first generation of β-turn mimetics was focused on mimicking the β-turn backbone. In the last decade, many types of bicyclic β-turn dipeptides (BTD) have been design and synthesized. However, these methods do not have straightforward ways to introduce side chain groups on both rings. The introduction of functionalities on BTD, as the second generation of β-turn mimetics, is the major goal of my dissertation. By retrosynthetic analysis, convergent synthetic methodologies were initiated for [5,5]- and [6,5]-BTDs. Two kinds of nonproteinous amino acids are required in the strategies. One is the β-substituted cysteine derivatives and the other is β-substituted ω-unsaturated amino acids. The racemic β-vinylphenylalanine was synthesized by using Kazmaier-Claisen rearrangement, and the ω-unsaturated amino acids and β-substituted δ,ε-unsaturated amino acids were synthesized by using Ni(II)-complexes as chiral auxiliaries. Using these starting materials, [5,5]-BTD analogues were synthesized by a five-step strategy. The synthesis of [6,5]-BTDs has to proceed without formation of the 5-membered hemiaminal, which blocks further reaction. A Nᵅ-TFA protection group was used in this strategy and finally an efficient methodology was developed to generate the side chain groups into [6,5]-BTD analogues in nine steps. During the development of these methods, we solved the challenge to synthesize all 16 or 32 of the possible diastereomeric dipeptide mimetics. A novel idea to solve these problems was to synthesize the targeted peptide mimetics by solid phase methods in a combinatorial fashion, as the third generation of β-turn mimetics. We have succeeded in the synthesis of [3,3,0]-BTD²,³-Leu-enkephalins by unconventional solid phase synthesis, and four analogues have been synthesized and purified. This method is ready to expand to other sizes of BTD and to other target peptides with different functionalities.