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

Understanding Acid Lability of Cysteine Protecting Groups

1,2,3,†
,
1,2,3,†
,
1,2,3
,
3
,
1,2 and 1,2,3,4,*
1 Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028-Barcelona, Spain 2 CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Baldiri Reixac 10, Barcelona 08028, Spain 3 Department of Organic Chemistry, University of Barcelona, Martí i Franqués 1-11, Barcelona 08028, Spain 4 School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
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 (CC BY 3.0).

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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.

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