Cross Metathesis and Ring-Closing Metathesis Reactions of Modified Amino Acids and Peptides.
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
This thesis investigates the application of cross metathesis and ring-closing metathesis to amino acid and peptide-based substrates that are suitably modified to contain an olefin tether. Chapter One introduces olefin metathesis, describes the mechanism of cross metathesis (CM) and ring-closing metathesis (RCM), and outlines the catalysts that can be used for these transformations. The application of CM and RCM to amino acid and peptide-based systems is reviewed. Chapter Two describes the CM coupling between modified lysine- (2.34 - 2.37, 2.43), serine- (2.45, 2.46), and cysteine-based (2.48, 2.49a, 2.51) amino acids and dipeptides (2.54, 2.57) to a terminal alkene (2.61, 2.65), carbohydrate (1.51b), or fatty acid (2.76) target compound using catalyst 1.17. The amino acid and dipeptide-based CM substrates were prepared by side-chain acylation of the parent amino acid with carboxylic acids containing variable but controllable olefin tether lengths. A CM model study in which these amino acid-based substrates were coupled to terminal alkene 2.61 and 2.65 gave CM products 2.66 - 2.74. CM was then carried out between amino acid-based substrates and a carbohydrate (1.51b) or fatty acid derivative (2.76), that afforded a novel series of glycoamino acids (2.80 - 2.85) and lipoamino acids (2.94 - 2.101). Chapter Three describes the synthesis of amino acid dimers by CM. Two serine-based (3.22 - 3.23) and two cysteine-based (3.24 - 3.25) symmetrical dimers along with two unsymmetrical serine-cysteine dimers (3.26 - 3.27) were prepared from the same side-chain acylated amino acid substrates described in chapter 2. These compounds are examples of novel cross-linked amino acid-based dimers, and further illustrate the versatility of the CM methodology developed in this thesis. Chapter Four describes the synthesis of cyclic amino acids and dipeptides via RCM of acyclic precursors that are suitably modified with acyl olefin tethers of variable length. Cyclic compounds based on lysine (4.6, 4.13), serine (4.31, 4.33), and cysteine (4.40, 4.42) single amino acid residues, and compounds based on lysine (4.16, 4.21, 4.27), serine (4.37), and cysteine (4.45, 4.46) dipeptides were prepared. All these compounds were constructed using the same, versatile general method, which involves acylation of the natural amino acid substrate with a carboxylic acid of controllable olefin tether length followed by RCM with catalyst 1.17 to give cyclic products containing variable ring sizes.