Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides

The synthesis of a novel category of pseudo-peptides via intramolecular Ugi reaction of levulinic acid (4-oxopentanoic acid), aromatic and aliphatic amines, and amino acid-based isocyanides is reported. Levulinic acid was applied as a bifunctional substrate containing both carbonyl and acid moieties suitable for the Ugi reaction. This article provides a facile and convenient one-pot procedure for the synthesis of peptide-like heterocyclic molecules containing 2-pyrrolidone (γ-lactam), amide and ester functional groups with good to excellent yields.


General experimental procedure and characterization data for all compounds
General. All reagents and solvents were analytically pure and were used as received. Column chromatographic purification was carried out using SiO 2 (0.040-0.060 mm, type KG 60). TLC was performed on Macherey-Nagel SiO 2 F254 plates on aluminum sheets. Melting points were determined with a Branstead Electrothermal 9200 apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer FT RX1spectrophotometer over the range 400-4000 cm −1 . 1 H and 13 C NMR spectra of isolated products were recorded on a Bruker AMX R500 (measuring frequency: 1 H NMR = 500.1 MHz, 13 C NMR = 125.8 MHz) or a Bruker Avance III 500 (measuring frequency: 1 H NMR = 499.9 MHz, 13 C NMR = 125.7 MHz) in CDCl 3 solution. HRMS (high-resolution mass spectra) were measured on a THERMO SCIENTIFIC Advantage and a THERMO SCIENTIFIC Exactive instrument. Elemental analyses were conducted with a Perkin-Elemer 2004 (II) CHN analyzer.
General procedure for the synthesis of amino acid-based isocyanides 3a-c (a) General procedure for the preparation of DL-amino acid methyl ester hydrochlorides: DLamino acid (50 mmol) was dissolved in MeOH (550 mL) and the solution was cooled in an ice/salt bath. Then, thionyl chloride (50 mmol) was added dropwise for 1 hour. The reaction temperature was maintained between −5-0 °C during the addition. Then, the reaction mixture was stirred for 24 h at room temperature. Finally, the reaction mixture was concentrated on a rotary evaporator to give the crude product. The crude product was washed with DCM (two times) to give the corresponding pure racemic amino acid ester hydrochloride.
(b) General procedure for the formylation of DL-amino acid methyl ester hydrochlorides: DLaminoacid methyl ester hydrochloride (20 mmol) was dissolved in ethyl formate (100 mL)/EtOH (30 mL) mixture. Then, sodium bicarbonate (20 mmol) was added to the flask. The reaction mixture was stirred at 50 °C for 2 days. After the completion of the reaction, the mixture was filtered for removing the excess amount of sodium bicarbonate. Then, the filtrate was concentrated on a rotary evaporator to give the product.
(c) General procedure for the transformation of DL-formamide to DL-isocyanide: DLformylated amino acid methyl ester (20 mmol) was dissolved in DCM (200 mL) and TEA (100 mmol) was added to the solution at room temperature. Then the reaction mixture was cooled in an ice/salt bath to maintain the temperature between −10 and −5 °C. Then, phosphorus oxychloride (20 mmol) was added dropwise to the reaction mixture and was stirred for 2 h. The reaction mixture was quenched by aqueous NaHCO 3 and the organic phase was separated, dried over Na 2 SO 4 , and evaporated under reduced pressure to give a precipitate. The precipitate was purified by column chromatography using DCM as solvent.

General procedure for the synthesis of Ugi adducts:
A solution of levulinic acid (1, 1 mmol) and an amine 2 (1 mmol) in MeOH (5 mL) was stirred for 0.5 h at room temperature. Then, DL-amino acid-based isocyanide 3 (1 mmol) was added to the reaction mixture at the same temperature. The reaction progress was monitored by TLC. After 24 h, the solvent was removed under reduced pressure and the precipitate purified by column chromatography using petroleum ether and ethyl acetate mixture as eluent (SiO 2 , PE/EtOAc; 2:1 v/v). All products were obtained as 1:1 mixture of diastereomers after column chromatography as determined by 1 H NMR spectroscopy. All compounds were characterized using IR, 1 H NMR, 13 C NMR and HRMS or CHN analyses.