Circular Aqueous Fmoc/t‐Bu Solid‐Phase Peptide Synthesis

Circular economy and aqueous synthesis are attractive concepts for sustainable chemistry. Here it is reported that the two can be combined in the universal method for peptide chemistry, fluorenylmethoxycarbonyl(Fmoc)/t‐Bu solid‐phase peptide synthesis (SPPS). It was demonstrated that Fmoc/t‐Bu SPPS could be performed under aqueous conditions using standard Fmoc amino acids (AAs) employing TentaGel S as resin and 4 : 1 mixture of water with inexpensive green solvent PolarClean. This resin/solvent combination played a crucial dual role by virtue of improving resin swelling and solubility of starting materials. In a model coupling, TCFH and 2,4,6‐collidine afforded a full conversion at only 1.3 equiv. AA, and these conditions were used in SPPS of Leu enkephaline amide affording the model peptide in 85 % yield and 86 % purity. A method to recycle the waste by filtration through a mixed ion exchange resin was developed, allowing reusing the waste without affecting quality of the peptide. The method herein obviates the use of unconventional or processed AAs in aqueous SPPS while using lower amounts of starting materials. By recycling/reusing SPPS waste the hazardous dipolar aprotic solvents used in SPPS were not only replaced with an aqueous medium, solvent use was also significantly reduced. This opens up a new direction in aqueous peptide chemistry in which efficient use of inexpensive starting materials and waste minimization is coupled with the universal Fmoc/t‐Bu SPPS. Peptide synthesis: A proof‐of‐principle of a new concept in circular aqueous peptide synthesis is reported. Viability of fluorenylmethoxycarbonyl (Fmoc)/t‐Bu solid‐phase peptide synthesis (SPPS) in H2O/PolarClean (4 : 1) is demonstrated in a synthesis of Leu enkephalin amide on TentaGel S resin using 1.3 equiv. Fmoc amino acids without any processing with TCFH (N,N,N′,N′‐Tetramethylchloroformamidinium hexafluorophosphate)/collidine (1 : 3) for couplings. SPPS waste is recycled by filtering through a mixed ion exchange resin and reused in the synthesis without affecting the quality of the peptide.