Date of Award
Program or Major
Doctor of Philosophy
Charles K Zercher
A streamlined synthetic pathway to target the core of plakortether B through a zinc-mediated homologation-aldol reaction has been developed. This chemistry was performed on a chiral beta-keto amide, which was synthesized in a few steps. In a one-pot reaction the beta-keto amide could be converted into a furanyl-ketal with high stereocontrol at two chiral centers. The homologation-aldol reaction was followed by a cyclization-allylation to obtain the plakortether backbone.
During the synthesis of plakortether B, a serendipitous byproduct was identified as a [3.1.0] bicyclic lactone. The lactone was seen as a precursor to a peptidomimetic that would contain an embedded hydroxycyclopropyl moiety. The formation of the bicyclic lactones was proposed to involve a cascade of homologation-cyclopropanation-rearrangement-lactonization reactions. Amino acid-derived beta-keto imides were synthesized in order to enhance the stereocontrol of the tandem lactonization reaction. The use of amino acid derived beta-keto imides was beneficial in two ways; first it incorporates an amino acid directly into the peptide isotere and influences the diastereocontrol.
The homologation-cyclization-rearrangement-lactonization reaction of beta-keto imides has proven to be successful for the formation of [3.1.0] bicyclic lactones as precursors to peptide isosteres.
Taschner, Ian Scott, "I Progress towards the synthesis of plakortether B through a zinc-mediated homologation II Synthesis of novel hydroxy-cyclopropyl peptides isosteres" (2011). Doctoral Dissertations. 576.