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Molecules 2013, 18(5), 5155-5162; doi:10.3390/molecules18055155

Understanding Acid Lability of Cysteine Protecting Groups

, 1,2,3,†
, 1,2,3
, 3
, 1,2 and 1,2,3,4,*
Received: 16 February 2013 / Revised: 26 April 2013 / Accepted: 2 May 2013 / Published: 6 May 2013
(This article belongs to the Special Issue Disulfide and Diselenide Chemistry)
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Abstract: Cys-disulfide bonds contribute to the stabilization of peptide and protein structures. The synthesis of these molecules requires a proper protection of Cys residues, which is crucial to prevent side-reactions and also to achieve the correct Cys connectivity. Here we undertook a mechanistic study of a set of well-known acid-labile Cys protecting groups, as well other new promising groups, in order to better understand the nature of their acid-lability. The stability of the carbocation generated during the acid treatment was found to have a direct impact on the removal of the protective groups from the corresponding protected Cys-containing peptides. Hence a combination of steric and conjugative effects determines the stability of the carbocations generated. Here we propose diphenylmethyl (Dpm) as a promising protecting group on the basis of its intermediate relative carbocation stability. All the optimized geometries and energies presented in this study were determined using a B3LYP/6-31G(d,p) calculation. The results discussed herein may be of broader applicability for the development of new protecting groups.
Keywords: acid lability; benzyl; carbocation stability; Cys protecting groups; diphenylmethyl (Dpm); peptide synthesis acid lability; benzyl; carbocation stability; Cys protecting groups; diphenylmethyl (Dpm); peptide synthesis
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Ramos-Tomillero, I.; Mendive-Tapia, L.; Góngora-Benítez, M.; Nicolás, E.; Tulla-Puche, J.; Albericio, F. Understanding Acid Lability of Cysteine Protecting Groups. Molecules 2013, 18, 5155-5162.

AMA Style

Ramos-Tomillero I, Mendive-Tapia L, Góngora-Benítez M, Nicolás E, Tulla-Puche J, Albericio F. Understanding Acid Lability of Cysteine Protecting Groups. Molecules. 2013; 18(5):5155-5162.

Chicago/Turabian Style

Ramos-Tomillero, Iván; Mendive-Tapia, Lorena; Góngora-Benítez, Miriam; Nicolás, Ernesto; Tulla-Puche, Judit; Albericio, Fernando. 2013. "Understanding Acid Lability of Cysteine Protecting Groups." Molecules 18, no. 5: 5155-5162.

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