Despite the remarkable developments of Ugi reactions and its variants, the use of ammonia in the Ugi reaction has long been recognized as impractical and unsuccessful. Indeed, the ammonia-Ugi reaction often requires harsh reaction conditions, such as heating and microwave irradiation, and competes with the Passerini reaction, and thereby resulting in low yields. Here, this study describes a robust and practical ammonia-Ugi reaction protocol. Using originally prepared ammonium carboxylates in trifluoroethanol, the ammonia-Ugi reaction proceeded at room temperature in high yields and showed a broad substrate scope, and thus synthesizing a variety of α,α-disubstituted amino acid derivatives, including unnatural dipeptides. The reaction required no condensing agents and proceeded without racemization of the chiral stereocenter of α-amino acids. Furthermore, using this protocol, we quickly synthesized a novel dipeptide, D-Leu-Aic-NH-CH2Ph(p-F), which exhibited a potent inhibitory activity against α-chymotrypsin with a Ki value of 0.091 μM.

This article is Open Access

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