An Asymmetric Synthesis Protocol to Prepare Topographically Constrained β-Substituted Aromatic Amino Acids

Abstract

The side chain groups of amino acid residues in polypeptide hormones, neurotransmitters, growth factors, substrates, antigens, and other bioactive peptides have been demonstrated to be extremely important pharmacophores for receptor/acceptor binding and for signal transduction (1). Therefore, complete understanding of the stereochemical requirements of side chain groups important in peptide ligand-receptor/acceptor interactions plays a crucial role in the rational design of bioactive peptides and nonpeptide mimetics. Topographical considerations provide a major approach to explore the structure–activity relationships of the side chains of the amino acid residues in the bioactive peptide analogues (2). This approach can be realized by incorporation of conformationally constrained unusual amino acids into a peptide or nonpeptide template. Thus, design and synthesis of unusual amino acids with specific biased side chain conformations have tremendous impact on the exploration of the mechanism of peptide ligand-receptor recognition and of activating signal transduction. Our laboratory has been engaged in the design and synthesis of conformationally constrained amino acids for almost a decade. One representative family among the special amino acids we have designed is the β-substituted unusual amino acids, in which substitution of the diastereotopic β-hydrogens of natural α-amino acids provides an approach to topographic control of side chain conformation (3). Incorporation of these β-substituted unusual amino acids into bioactive peptide hormones has produced highly selective and potent peptide hormone analogues and provided new insights into the stereochemical requirements in peptide-receptor interactions (4).