Synthesis of Small Cationic Amphiphiles for Antimicrobial Screening - Transition Metal Catalyzed Benzene Synthesis and Subsequent Functionalization

Abstract

The goal of this project has been to synthesize small cationic amphiphiles with bulky aromatic substituents on a benzene scaffold, for antimicrobial screening. The aromatic and cationic substituents were chosen based on earlier work by our collaborators at the University of Tromsø The Arctic University of Norway (UiT), as they have shown to have potent antimicrobial activity.

The preparation of multi-substituted benzenes was done via a transition-metal-catalyzed [2+2+2]-cyclotrimerization of diynes with terminal aromatic alkynes. Several synthetic routes were investigated with different metal catalysts and diynes. It was found that 1,6-diynes with substituents on the tethered chain undergo the most successful cyclotrimerization with Cp*RuCl(cod), presumably due to the Thorpe-Ingold effect. The aromatic substituents on the benzene scaffold were easily varied by changing alkynes.

Further modifications of the prepared benzene compounds were investigated, and cationic hydrochloric compounds were successfully prepared by cleaving the Boc-protection group with excess HCl (2 M in diethyl ether). These compounds 14 were obtained with high purity (>98% on HPLC), and were submitted for antimicrobial screening. Further modifications of 14 gave the guanidine containing compounds 16, but unfortunately with insufficient purity for antimicrobial screening.

A synthetic route for the preparation of small cationic amphiphiles were established.