Synthesis of Totarol Analogs for Inhibition of FtsZ

Abstract

The recent emergence in antibiotic‐resistant strains of pathogenic bacteria has driven research on the discovery of new molecular scaffolds with efficient synthesis. Natural product synthesis provides a method for scaffold discovery. More than two‐thirds of clinically used antibiotics are natural products or their semisynthetic derivatives. Totarol, a diterpene natural product, is an antibacterial substance effective against gram‐positive bacteria (1.5 μM in B. subtilis). Although totarol may have multiple targets, experiments confirm totarol's ability to inhibit FtsZ protein, a prokaryotic analog of tubulin essential for bacterial cytokinesis. Since the total synthesis of totarol is known, we propose the synthesis of totarol analogs to gain insight into structure‐activity relationships between totarol and FtsZ. We utilized a copper‐catalyzed coupling of a benzylic grigard to an epoxyacetate. However, synthesis of the benzyl grignard proved to be difficult. Consequently, a second route was proposed that uses concepts from the umplong reaction. The analysis of chemical structures focuses on the use of Gas Chromatography – Mass Spectrometry and 1H NMR.