Synthesis of Small Cationic Amphiphiles for Antimicrobial Screening - Transition Metal Catalysed, Microwave-Mediated Indane Synthesis, and Subsequent Functionalisation
MetadataShow full item record
- Institutt for kjemi 
Infectious diseases are a leading cause of death worldwide and account for more than 13 million deaths annually. A growing ratio of these casualties can be attributed to antimicrobial resistance (AMR). In order to combat this threat, the development of novel antimicrobials is imperative. The objective of this Master s thesis has been to investigate a new synthetic route affording small cationic amphiphiles based on a pharmacophore model developed by Strøm et al. The amphiphiles were synthesised by functionalisation of substituted fused benzene compounds (indane) prepared from transition metal catalysed [2+2+2] cycloaddition of a symmetric 1,6diyne compound and three commercially available aromatic alkynes. In addition, microwavemediated cycloadditions with four other alkynes and one nitrile were investigated.The internal diyne 2 was obtained by alkylation of diethyl malonate with propargyl bromide. Subsequent [2+2+2] cycloadditions afforded seven indane products in decent yields (35 90%). Massive decrease in reaction rates were observed upon microwave-mediated cycloadditions, but running reactions in a microwave limits the reaction volume. The [2+2+2] cycloadditions were carried out with the commercially available Cp*RuCl(cod) and Ni(CO)2(PPh3)2 catalysts. viii The ruthenium-catalyst was used when executing such reactions at r.t, while the latter nickelcatalyst was utilised in the microwave-mediated reactions. After [2+2+2] cycloaddition, the diesters 4a-c were subjected to acidic hydrolysis, decarboxylation and esterification, giving the monoesters 6a-c in 95 100% yields, see Scheme 0.1. The monoesters were reacted with ethylenediamine and afforded the amidoamines 8a-c which could further be functionalised in two ways. Reactions of 8a-c in excess HCl (aq., conc.) afforded the three HCl salts (9a-c) in good to excellent yields (72 99%). The amidoamines 8a-c were also guanylated using the electrophilic guanylation agent 1H-pyrazole-1carboxamidine hydrochloride, affording the guanidyl compounds 11a-c in decent yields (39 65%). The purity of the HCl salts and the guanidyl compounds were assessed by HPLC, with a purity threshold of 95% for antibacterial screening. A total of four compounds, three HCl salts (9a-c) and one guanylated compound (11a) were found to be sufficiently pure and were submitted to biological testing.