Ionic or radical α-amino Schiff base methods are well known for the synthesis of α,α-disubstituted α-amino acids. However, the incorporation of sterically demanding groups is challenging with ionic methods, and radical methods require prefunctionalization of the substrates. Now we have developed a dehydrogenative coupling process of α-amino acid Schiff bases with hydrocarbon feedstocks for the synthesis of α,α-disubstituted α-amino acid derivatives. These α-amino acid derivatives were transformed into C- and N-protected amino acids, which could be easily incorporated into peptide synthesis. A range of α-amino acid derivatives could be readily accessed, which includes, notably, those that bear contiguous quaternary centres. Circular dichroism measurements show that the helical peptide structure is stabilized by the highly sterically congested unnatural α-amino acid. Mechanistic studies revealed that deprotonation of the α-amino acid Schiff base is a turnover-limiting step and the use of an enhanced Brønsted basic copper(I) tert-butoxide complex produced a superior catalytic performance. Photoinduction of the catalytic reaction, using blue light-emitting diode radiation, allowed the reaction to proceed without external heating.
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This work was financially supported by JSPS KAKENHI grant no. JP15H05846 in Middle Molecular Strategy and no. JP18H04263 in Precisely Designed Catalysts with Customized Scaffolding, a Grant-in-Aid for Scientific Research (B) (no. 17H03972 and no. 21H02607), a Grant-in-Aid for Challenging Research (Exploratory) (no. 19K22501), Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) (no. JP20am0101091) and no. JP21ak0101167 from AMED. T. Tsuji, and T. Tanaka thank the JSPS for predoctoral fellowships. R.Y. thanks the Qdai-jump Research Program, the Takeda Science Foundation, the Uehara Memorial Foundation, the Noguchi Institute and the Astellas Foundation for Research on Metabolic Disorders for financial support. We are grateful to T. Koike at the Tokyo Institute of Technology for fruitful discussions about photoredox chemistry, to A. Ojida, E. Kawanishi and S. Uchinomiya at Kyushu University for fruitful discussions about solid-phase peptide synthesis and to Y. Matsuoka at Kyushu University for electrochemical analysis.
A provisional patent application for part of this work has been filed (Kyushu University, PCT/JP2019/041918).
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Tsuji, T., Hashiguchi, K., Yoshida, M. et al. α-Amino acid and peptide synthesis using catalytic cross-dehydrogenative coupling. Nat. Synth 1, 304–312 (2022). https://doi.org/10.1038/s44160-022-00037-0