The Synthesis of Conformationally Restricted Amino Acides and Peptide Mimics Using Ring-Closed Metathesis.
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
Peptidomimetics have found wide application as biostable, bioavailable, and often potent mimics of natural peptides. Examples of peptidomimetics have been isolated as natural products, synthesized as libraries from novel subunits, and designed on the basis of X-ray crystallographic studies and through an intricate knowledge of the biological mode of action of natural peptides. They offer challenging synthetic targets and are increasingly important medicinal agents and biological probes. Chapter One introduces the fields of peptidomimetics and peptidomimetic design, with relevant examples taken from biochemistry, synthesis, and medicinal chemistry used to illustrate important concepts. The sources of peptidomimetics, along with common tools used for the conformational restriction of peptides, is then reviewed. Ring-closing metathesis (RCM), an important new method for the formation of carbocyclic rings is then reviewed, and discussed in terms of its application towards the synthesis of conformationally restricted peptidomimetics. This section emphasises the importance of RCM as a new and versatile tool for use in peptidomimetic synthesis. Chapter Two describes the enantioselective synthesis of the conformationally constrained, substituted tetrahydropyridine, and piperidine peptide mimics, 2.9 and 2.12 respectively, via RCM. The solid-state conformations of 2.9 and 2.12 are examined and their application as potential cis-amide bond mimics discussed. Further derivatisation of 2.9 gave dihydroxy analogues 3.13, and dibromo analogues 2.14. A novel bicyclic lactone 2.16 was also formed upon crystallisation of the major isomer of 2.14. The enantiomeric purity of a key intermediate 2.7 was analysed, and determined to be >95%, confirming the stereoselectivity of a key alkylation step.