Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 58, Issue 17, Pages 5729-5733Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201900988
Keywords
desulfurization; disulfide bonds; palladium; protein synthesis; S-acetamidomethyl-cysteine
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Funding
- Technion-Guangdong Fellowship
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One of the applied synthetic strategies for correct disulfide bond formation relies on the use of orthogonal Cys protecting groups. This approach requires purification before and after the deprotection steps, which prolongs the entire synthetic process and lowers the yield of the reaction. Amajor challenge in using this approach is to be able to apply one-pot synthesis under mild conditions and aqueous media. In this study, we report the development of an approach for rapid disulfide bond formation by employing palladium chemistry and S-acetamidomethyl-cysteine [Cys(Acm)]. Oxidation of Cys(Acm) to the corresponding disulfide bond is achieved within minutes in a one-pot operation by applying palladium and diethyldithiocarbamate. The utility of this reaction was demonstrated by the synthesis of the peptide oxytocin and the first total chemical synthesis of the protein thioredoxin-1. Our investigation revealed a critical role of the Acm protecting group in the disulfide bond formation, apparently due to the generation of a disulfiram in the reaction pathway, which significantly assists the oxidation step.
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