Synthesis of antibacterial 1,3-diyne-linked peptoids from an Ugi-4CR/Glaser coupling approach

Summary A library of ten 1,3-diyne-linked peptoids has been synthesized through an Ugi four-component reaction (U-4CR) followed by a copper-catalysed alkyne homocoupling (Glaser reaction). The short and chemoselective reaction sequence allows generating diverse (pseudo) dimeric peptoids. A combinatorial version allows the one-pot preparation of, e.g., six-compound-libraries of homo- and heterodimers verified by ESI-MS and HPLC. In a preliminary evaluation, some compounds display moderate activity against the Gram-positive bacterium Bacillus subtilis.


General procedure for the synthesis of compounds 7a-j
To a stirred solution of aldehyde (2.5 mmol) in methanol (2.5 mL) propargylamine (0.14 g, 0.16 mL, 2.5 mmol) was added. After 30 min carboxylic acid (2.5 mmol) and isocyanide (2.5 mmol) were added. The contents were stirred for 24 h. The solvent was concentrated under reduced pressure in a rotavap. The crude material was purified by isocratic column chromatography to afford the pure product. The same solvent system used for R f value measurements was applied for performing flash column chromatography. acetamido)butanamide (7a).

General procedure for the synthesis of compounds 8a-j
In a 10 mL round bottom flask, to stirred solution of a suitable alkyne 7a-j (0.25 mmol) in dry DMSO (0.5 mL), CuCl (1.3 mg, 0.013 mmol/5 mol %) was added.
The contents were stirred at 90 °C under air atmosphere. After 24 h the reaction mixture was diluted with ethyl acetate (10 mL) and filtered through a Celite plug.
The solvent was removed under reduced pressure in a rotavap. The crude material was purified by column chromatography to afford the pure product. The S9 same solvent system for the R f values measurements was employed for column chromatography.

Combinatorial approach to dimers
In a 10 mL round botton flask, to stirred solution of the alkynes 7f, 7j and 7h (0.25 mmol each), CuCl (0.07 mmol / 5 mol%) was added. The contents were stirred at 90 ºC under air atmosphere. After 24 h the reaction mixture was diluted with ethyl acetate (10 mL) and filtered through a Celite plug. The solvent was removed under reduced pressure. The crude material analyzed by HPLC.

Figures of 1 H and 13 C NMR spectra
Please note that spectra of N-alkyl-amides (peptoids) like Ugi products display double signal sets in NMR due to interconvertible isomers with s-cis and s-trans amide bonds. Depending on substitution pattern, solvent and temperature, the