Suppression of alpha-carbon racemization in peptide synthesis based on a thiol-labile amino protecting group

Yifei Zhou, Hongjun Li, Yi Huang, Jiahui Li, Guiyu Deng, Gong Chen, Zhen Xi and Chuanzheng Zhou ()
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Yifei Zhou: Nankai University
Hongjun Li: Nankai University
Yi Huang: Nankai University
Jiahui Li: Nankai University
Guiyu Deng: Nankai University
Gong Chen: Nankai University
Zhen Xi: Nankai University
Chuanzheng Zhou: Nankai University

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract In conventional solid-phase peptide synthesis (SPPS), α-amino groups are protected with alkoxycarbonyl groups (e.g., 9-fluorenylmethoxycarbonyl [Fmoc]). However, during SPPS, inherent side reactions of the protected amino acids (e.g., α-C racemization and aspartimide formation) generate by-products that are hard to remove. Herein, we report a thiol-labile amino protecting group for SPPS, the 2,4-dinitro-6-phenyl-benzene sulfenyl (DNPBS) group, which is attached to the α-amino group via a S–N bond and can be quantitatively removed in minutes under nearly neutral conditions (1 M p-toluenethiol/pyridine). The use of DNPBS greatly suppresses the main side reactions observed during conventional SPPS. Although DNPBS SPPS is not as efficient as Fmoc SPPS, especially for synthesis of long peptides, DNPBS and Fmoc are orthogonal protecting groups; and thus DNPBS SPPS and Fmoc SPPS can be combined to synthesize peptides that are otherwise difficult to obtain.

Date: 2023
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DOI: 10.1038/s41467-023-41115-x

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