Trimethoxysilane-Mediated Peptide Bond Formation from Unprotected Amino Acids and Amino Acid t -Butyl Esters

Although the conventional approach to peptide synthesis has been employed for decades, it requires multiple protection–deprotection steps, stoichiometric amounts of coupling reagents and additives, and large volumes of solvent. Consequently, it is accompanied by limitations, such as low atom economy and waste generation. One favorable alternative to combating this problem is the direct formation of peptide bonds using unprotected amino acids. However, this strategy poses issues, such as the low solubility of the unprotected amino acids in organic solvents, unwanted side reactions, and racemization. To overcome these drawbacks, a method has been developed for direct peptide bond formation using trimethoxysilane, an inexpensive and commercially available reagent. Trimethoxysilane helps solubilize the unprotected amino acids in organic solvents, transiently protects the amine group, and simultaneously activates carboxylic acids for coupling. This method represents a one-pot strategy for the synthesis of N -terminal free dipeptides from unprotected amino acids and amino acid tert -butyl esters at 70 °C for 20 h in moderate to good yields (up to 95% yields). Notably, the reactions exhibit high stereoselectivities of >20:1 dr with broad substrate scope compatibility, and the developed approach was applied in the synthesis of tripeptides including bioactive motifs.