Synthetic Strategies Toward Complex Molecule Synthesis: from Glycan Mimetics to Complex Terpenoids

Abstract

Glycans are ubiquitously expressed on the surface of cells and are responsible for mediating a host of critical cellular interactions. Specifically, bacteria have evolved to produce a diverse array of carbohydrate structures including lipopolysaccharides, capsular polysaccharides, and cellulosic polysaccharides which are key components for bacterial survival and virulence. A major thrust in glycobiology is to understand how specific glycan structures contribute to mechanisms of pathogenesis. Phosphoethanolamine cellulose (pEtN cellulose) is a newly identified cellulose derivative produced and excreted into the extracellular matrix by gram negative bacteria such as uropathogenic E. coli (UPEC)- the major causative agent of urinary tract infections. The discovery of this zwitterionic, modified cellulose has prompted studies into the functional significance of this glycan and its role in pathogenesis. However, the insolubility of pEtN cellulose and its poorly defined phosphoethanolamine modification pattern have hindered the elucidation of specific structure-activity relationships for this glycan. To address these limitations, we designed a set of well-defined synthetic glycopolymers as chemical tools to evaluate pEtN cellulose based on the hypothesis that these glycopolymers would mimic the native polysaccharide. The glycopolymers were prepared through ring-opening metathesis polymerization of a monomer containing the minimal repeat unit of pEtN cellulose detailed in Chapter 2. The glycopolymers were evaluated for their biofilm modulating properties and demonstrated biofilm repression in E. coli laboratory strain 11755T and UPEC strain 700415 in a size dependent manner. Scanning electron microscopy analyses further revealed that glycopolymer treatment resulted in changes in E. coli cell morphology and surface appendages. Our results indicate that the pEtN cellulose mimics exhibit varying biofilm modulating properties similar to native cellulosic polysaccharides. Chapter 3 details our synthetic efforts towards the total synthesis of Yaretol, a norditerpene isolated from the Chilean shrub Azorella madreporica, which features an unprecedented tetracyclic carbon skeleton. The chapter outlines several generations of synthetic strategies to arrive at a key intermediate for the crux of the synthesis- an intramolecular Diels-Alder cycloaddition (IMDA) between an unsaturated carbonyl and a furan diene to forge the tetracyclic scaffold. Lastly, initial exploration of the IMDA are described which lay the groundwork to access Yaretol.