High-Yielding Staudinger Ligation of a Phosphinothioester and Azide To Form a Peptide
Bradley L. Nilsson, Laura L. Kiessling and Ronald T. Raines
*Departments of Chemistry and Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706,
Email: rtraines
mit.edu
B. L. Nilsson, L. L. Kiessling, R. T. Raines, Org. Lett., 2001, 3, 9-12.
DOI: 10.1021/ol006739v
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Abstract
The Staudinger ligation can be used to couple a peptide with a C-terminal phosphinothioester to another with an N-terminal α-azido group to form a single peptide that contains no residual atoms.
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proposed mechanism
Details
The document discusses the development of a high-yielding Staudinger ligation method for peptide synthesis. The Staudinger ligation couples a peptide with a C-terminal phosphinothioester to another with an N-terminal azido group, forming a single peptide without residual atoms. This method, using diphenylphosphinomethanethiol thioesters, offers high isolated yields, providing a powerful alternative to native chemical ligation, which relies on cysteine residues. Cysteine is rare in proteins, limiting the utility of native chemical ligation. The Staudinger reaction, involving the reduction of an azide to an amine by a phosphine, overcomes this limitation. The document details the synthesis of a new phosphinothiol, which improves the yields of the Staudinger ligation significantly. The key intermediate, an iminophosphorane, adopts a stable conformation facilitating amide formation. This method does not require cysteine and is traceless, making it versatile for protein synthesis. The document concludes that the Staudinger ligation with the new phosphinothiol could enable efficient protein synthesis for research and drug discovery. The work was supported by NIH and NSF grants, and detailed procedures are available online.
Key Words
ID: J54-Y2001
