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TCI Practical Example: Condensation Reaction Using HBTU

We are proud to present the amidation of the protected proline and the protected leucine using HBTU as a condensing agent.

Used Chemicals

• L-Leucine tert-Butyl Ester Hydrochloride [L0197]
• Fmoc-L-Proline [F0298]
• HBTU [B1657]
• 2,4,6-Collidine [T0716]
• Dichloromethane
• DMF

Procedure

L-Leucine tert-butyl ester hydrochloride (1.00 g, 4.47 mmol), Fmoc-L-proline (1.51 g, 4.47 mmol) and HBTU (2.54 g, 6.70 mmol) were dissolved in dichloromethane (7.45 mL) and DMF (7.45 mL). 2,4,6-Collidine (1.08 g, 8.94 mmol) was added to the mixture and stirred at room temperature for 4 hours. After the completion of the reaction, 1 mol/L HCl(aq) (50 mL) was added. The mixture was extracted with dichloromethane (50 mL) and the organic layer was washed with water (50 mL, twice), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (on silica gel, ethyl acetate:hexane = 1:1) to give compound 1 as a white solid (2.11 g, 93% yield).

Experimenter's Comments

The reaction mixture was monitored by TLC (ethyl acetate:hexane = 1:1, Rf = 0.64) and UPLC.

Analytical Data

Compound 1

¹H NMR (400 MHz, CDCl₃); δ 7.80 (d, J = 7.2 Hz, 2H), 7.66–7.57 (m, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 4.42–4.15 (m, 5H), 3.62–3.42 (m, 2H), 2.38–2.16 (m, 1H), 2.12–1.84 (m, 3H), 1.78–1.49 (m, 3H), 1.43 (d, J = 9.2 Hz, 9H), 0.92 (dd, J = 18.0, 6.4 Hz, 3H), 0.72 (dd, J = 25.2, 6.4 Hz, 3H).

Lead Reference

• Progress toward the Total Synthesis of Lucentamycin A: Total Synthesis and Biological Evaluation of 8-epi-Lucentamycin A
  • R. N. Daniels, B. J. Melancon, E. A. Wang, B. C. Crews, L. J. Marnett, G. A. Sulikowski, C. W. Lindsley, J. Org. Chem. 2009, 74, 8852.