Proceedings of the 24 th American Peptide Symposium Ved Srivastava, Andrei Yudin, and Michal Lebl (Editors) American Peptide Society, 2015 http://dx.doi.org/10.17952/24APS.2015.274 Trends to Acid-Labile Cys Protecting Groups: Thp as an Efficient and Non-Aromatic Cys Protecting Group for Fmoc Chemistry Iván Ramos-Tomillero 1-3 , Hortensia Rodríguez 4 , and Fernando Albericio 1-5 1 Institute for Research in Biomedicine; 2 Department of Organic Chemistry, University of Barcelona; 3 CIBER-BBN, 08028, Barcelona, Spain; 4 School of Chemistry, Yachay Tech, Urcuqui, Ecuador; 5 School of Chemistry University of KwaZulu Natal Durban, 4000, South Africa Introduction Since the discovery of solid-phase peptide synthesis (SPPS) by Merrifield [1], the peptide field has suffered a dramatic change in a wide set of points such as the development of new solid supports, the discovery of highly efficient coupling reagents and additives, as well as the fashionable design of linkers and protecting groups. Consequently, the solid phase peptides synthesis is considered the most efficient way to synthesize a broad number of complex molecules. Into the complete process of the SPPS, a large number of problematic side reactions occur, in consequence during the past decades tremendous efforts have been done in order to avoid this drawbacks that jeopardize the efficiency of this methodology. Amino acid racemization is still an issue in SPPS because of the similarity between the desired product and the concomitant racemic product. In this sense, several factors such as the coupling reagents, the handles or the protecting groups, or even the basic conditions used during the peptide synthesis, could affect directly the integrity of the α-proton, which are able to modulate the amino acid racemization. Cysteine In nature, cysteine (Cys) is crucial due to its capacity to confer stability to peptides and proteins, but also constrain the specific conformation of these biomolecules through disulfide bonds [2,3]. In addition, its use has modernized the chemical synthesis of large polypeptides and proteins by Native Chemical Ligation [4]. Accordingly, Cys is considered one of the most problematic amino acid in SPPS, due to the high instability of its α-proton caused by the proximity of the thiol group, which promotes the racemization of its chiral center. Furthermore, β-elimination, oxidation and alkylation are other examples of potentials Cys side reactions. All these Cys collateral reactions are responsible of the complex peptide crude products obtained during the synthesis of Cys-rich peptides [5]. Nowadays, extensive possibilities to avoid these Cys promoted side reactions have been studied. In that sense, the development of new coupling reagents and additives for SPPS, assisted the by-products minimization [6]. Additionally, special efforts were focused into Cys side chain protection and as a result, a myriad of Cys protecting groups stable to a set of chemical conditions have been developed for their use in SPPS [7]. Protection schemes The stability and lability of protecting groups play an important role into the strategy selection criteria for SPPS. While Boc chemistry requires base-labile protecting groups, the Fmoc/tBu strategy involves the use of acid cleavable groups. The conferred stability is related by the kind of binding between the β-thiol group of Cys and the protecting group. As reported in the literature, thioether linkage is the most commonly used thiol protection form, due to the stability under several conditions. Thus, in recent years the development of the most successful protecting groups for Cys are based on this special linkage. In this regard, herein we will focus our attention in acid-labile Cys protecting groups in general, and in the recently developed non-aromatic acid-labile Cys protecting group, in particular. Acid-labile Cys protecting groups The conscious design of protecting groups had triggered a myriad of groups, which are stable in a broad range of acidic conditions (Figure 1). Therefore, the selective protecting group elimination is possible, depending on the acidic conditions used. As a result of years of studies in the field, there are several Cys protecting groups available; some of them are labile in low acid concentration such as