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TCI Practical Example: Condensation Using DCC and HOBt

We are proud to present the amidation using DCC as a condensing agent, and HOBt as an activator.

Used Chemicals

• N-(tert-Butoxycarbonyl)-L-leucine Monohydrate [B1187]
• L-Phenylalanine Methyl Ester Hydrochloride [P1278]
• N,N'-Dicyclohexylcarbodiimide (= DCC) [D0436]
• N,N-Diisopropylethylamine [D1599]
• 1-Hydroxybenzotriazole Monohydrate (= HOBt·H₂O) [H0468]
• Acetonitrile

Procedure

To a solution of N-(tert-butoxycarbonyl)-L-leucine monohydrate (2.49 g, 10.0 mmol), L-phenylalanine methyl ester hydrochloride (2.16 g, 10.0 mmol), N,N-diisopropylethylamine (2.59 g, 20.0 mmol) and HOBt·H₂O (1.53 g, 10.0 mmol) in acetonitrile (46 mL) was added DCC (granulated, 2.06 g, 10.0 mmol) in acetonitrile (7 mL) at 0 °C and the mixture was stirred at 0 °C for 1 hour. The suspension was warmed at room temperature for 3 hours. The suspension was filtrated and the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (75 mL) and washed with 0.33 mol/L citric acid solution (50 mL), saturated aqueous sodium bicarbonate solution (50 mL, twice) and water (50 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate : hexane = 1 : 3 on silica gel), giving Boc-Leu-Phe-OMe as a white solid (3.42 g, 87%).

Experimenter’s Comments

The reaction mixture was monitored by TLC (ethyl acetate : hexane = 2 : 1, Rf = 0.38).
To avoid a rash by DCC, appropriate protective equipment is used and the work was done in a fume hood.

Analytical Data

Boc-Leu-Phe-OMe

¹H NMR (400 MHz, CDCl₃); δ 7.28–7.19 (m, 3H), 7.08 (brd, 2H, J = 7.2 Hz), 6.51 (d, 1H,J = 8.0 Hz), 4.85–4.80 (m, 2H), 4.12–4.07 (m, 1H), 3.68 (s, 3H), 3.15–3.03 (m, 2H), 1.66–1.57 (m, 2H), 1.41　(brs, 10H), 0.89 (t, 6H, J = 6.0 Hz).

¹³C NMR (101 MHz, CDCl₃); δ 172.1, 171.6, 155.4, 135.7, 129.2, 128.5, 127.1, 80.0, 53.1, 52.2, 41.2, 37.9, 28.2, 24.6, 22.8, 21.9.

Lead Reference

• 17α-Ethynylestradiol Peptide Labeling by ‘Click’ Chemistry
  • O. I. Bol'shakov, I. O. Lebedyeva, A. R. Katritzky, Synthesis 2012, 44, 2926.

Other References

• Synthesis of Natural and Unnatural Cyclooligomeric Depsipeptides Enabled by Flow Chemistry
  • D. Lücke, T. Dalton, S. V. Ley, Z. E. Wilson, Chem. Eur. J. 2016, 22, 4206.