Rapid and Mild Synthesis of Amino Acid N‐Carboxy Anhydrides: Basic‐to‐Acidic Flash Switching in a Microflow Reactor

Abstract

Polymerization of N-carboxy anhydrides (NCAs) is the primary process used to prepare polypeptides. The synthesis of various pure NCAs is key to the efficient synthesis of polypeptides. The only practical method that can be used to synthesize NCAs requires harsh acidic conditions that make acid-labile substrates unusable and results in an undesired ring opening of NCAs. Basic-to-acidic flash switching and subsequent flash dilution technology in a microflow reactor was used to demonstrate the synthesis of NCAs. It is both rapid (0.1 s) and mild (20 °C) and includes substrates containing acid-labile functional groups. The basic-to-acidic flash switching enabled both an acceleration of the desired NCA formation and avoided the undesired ring opening of NCAs. The flash dilution precluded the undesired decomposition of acid-labile functional groups. The developed process allowed the synthesis of various NCAs which cannot be readily synthesized using conventional batch methods.

Peptide Synthesis Utilizing Micro‐flow Technology

“…[38] NCAs are the primal starting materials for polypeptide synthesis. We recently repoted the efficient preparation of variousN CAs using micro-flow technology.…”

“…We recently repoted the efficient preparation of variousN CAs using micro-flow technology. [38] NCAs are the primal starting materials for polypeptide synthesis. Micro-flow synthesis of polypeptides with an arrow molecular weight distribution was reported.…”

Peptide‐Chain Elongation Using Unprotected Amino Acids in a Micro‐Flow Reactor

“…In addition, a limited number of micro‐flow syntheses of peptides using unprotected amino acids or peptides have been reported, although those approaches require premodification of substrates or the use of a Cys residue . We recently reported a highly efficient amino acid N ‐carboxyanhydride synthesis based on the rapid mixing (<0.1 s) of an MeCN/water biphasic system using micro‐flow technology . Here, we report mixed carbonic anhydride‐based amidation with unprotected amino acids using micro‐flow technology (Scheme (IV)).…”

“…[26] We recently reported ah ighly efficient amino acid N-carboxyanhydride synthesis based on the rapid mixing [27] (< 0.1 s) of an MeCN/water biphasic system using micro-flow technology. [28] Here, we reportm ixed carbonic anhydride-based amidation with unprotecteda minoa cids using micro-flow technology (Scheme1 (IV)). Micro-flow technology enabledt he rapid mixingo fa no rganic layer containing ap rotected amino acido rd ipeptide and an aqueous layer containing an unprotecteda mino acid or dipeptide to accelerate the desired amidation, and this approach successfully suppressed the undesired racemization/epimerization ( 0.4 %).…”

Single‐Step, Rapid, and Mild Synthesis of β‐Amino Acid N‐Carboxy Anhydrides Using Micro‐Flow Technology

“…We have reported efficient micro‐flow peptide synthesis . In addition, we recently reported a rapid, mild, and high‐yielding synthesis of α‐NCAs using flash pH switching and flash dilution in a micro‐flow reactor (Scheme –iii) . The developed approach enabled a single‐step synthesis of acid‐labile α‐NCAs.…”