Synthesis of Small Cationic Amphiphiles for Antimicrobial Screening - Transition Metal Catalyzed Pyridine Synthesis and Subsequent Functionalization
Master thesis
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http://hdl.handle.net/11250/2615618Utgivelsesdato
2016Metadata
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- Institutt for kjemi [1404]
Sammendrag
The objective of the present thesis has been the synthesis of small cationic peptidomimetics based on a pharmacophore model devloped by Strøm et al. The peptedomimetics were synthesized by functionalization of substituted pyridines afforded by transition metal catalyzed [2 + 2 + 2] cycloaddition (cyclotrimerization) of a symmetric α,ω-diyne system and seven commercially available aromatic nitriles. In addition, cyclotrimerization with two additional diyne systems was investigated.
The previously undescribed, internal diyne system 6 was obtained by alkylation of 1 with 1-tosylaziridine. Subsequent cyclotrimerizations afforded three pyridine products in good yields (63 81%). Increased reactivity was observed upon cyclotrimerizations with smaller α,ω-diynes, with a Boc-protected diyne affording the highest overall yields. This diyne system afforded the desired pyridines with all nitriles used in the present work in mostly good yields (14 78%).
All cyclotrimerizations were carried out with the commercially available dicarbonylcyclopentadienylcobalt (I) (CpCo(CO)2) catalyst and promoted by visible light. Other catalyst systems based on Rh and Ru were also investigated.
Hydrolytic cleavage of the Boc protecting group with excess HCl (concentrated, aqueous)afforded HCl salts in moderate to excellent yields (28 99%). The HCl salts were further functionalized by guanylation with 1H-pyrazole-1-carboxamidine hydrochloride, affording guanidyl compounds in mostly good yields (14 89%).
The puritiy of the HCl salts and guanidyls was assessed by HPLC, with a purity treshold of 95% for antibacterial screening. A total of five compounds (four HCl salts and one guanylated compound) were found to be sufficiently pure and were submitted for biologial testing.
Preliminary results from the biological testing indicate that three of the compounds exhibit antimicrobial activity against Staphylococcus aureus at concentrations of 50 μg/mL.