Solid-Phase Peptide Synthesis Using a Four-Dimensional (Safety-Catch) Protecting Group Scheme

Abstract

Peptides of importance to both academia and industry are mostly synthesized in the solid-phase mode using a two-dimensional scheme. The so-called Fmoc/tBu strategy, where the groups are removed by piperidine and TFA, respectively, is currently the method of choice for peptide synthesis. However, as the molecular diversity of cyclic and branched peptides becomes a challenging interest, a high level of orthogonal dimensionality is required, such as through triorthogonal protection schemes. Here we present a fourth category of orthogonal protecting groups that are stable under cleavage conditions, including the TFA treatment that removes the tBu-based groups. At the end of the synthetic process and upon some chemical manipulation, the groups in this fourth category were removed with TFA. This new concept of protecting groups could facilitate the synthesis and manipulation of difficult peptides.

A safety-catch protecting group strategy compatible with Boc-chemistry for the synthesis of peptide nucleic acids (PNAs)

“…Previously, our group successfully introduced a new safety-catch protecting group, namely Msz, in SPPS to facilitate the synthesis and manipulation of difficult peptide sequences. 22 Like the HO–Mmsb linker, this protecting group also allows the use of Boc and Fmoc chemistry. In this regard, the protecting group in the form of the Msz carbamate was introduced on nucleobases [A and C (G was left of this initial study)], which are TFA-stable, and in reduced form (Mtz) are TFA-labile.…”

2-Methoxy-4-methylsulfinylbenzyl Alcohol as a Safety-Catch Linker for the Fmoc/tBu Solid-Phase Peptide Synthesis Strategy

“…On the other hand, the large amount of ammonium iodide present in the one-step protocol is difficult to remove. This two-step cleavage developed herein is key for an extension of this “safety-catch” technology to other applications, such as the side-chain protecting amino acids described in the companion paper …”

“…Although not addressed in this study, Mmsb is also compatible with other sets of protecting groups such as allyl p -nitrobenzyl. In this regard, Mmsb together with the Msib (4-(methylsulfinyl)­benzyl) and Msbh (4,4′-bis­(methylsulfinyl)­benzhydryl) described in the accompanying manuscript add a fourth dimension to the SPPS protecting group scheme.…”

“…This two-step cleavage developed herein is key for an extension of this "safety-catch" technology to other applications, such as the side-chain protecting amino acids described in the companion paper. 14 The combination of the two strategies has several advantages. It allows the fine-tuning of some of the side reactions associated with the use of base (piperidine), such as the DKP formation.…”

“…This idea is materialized in the “safety catch” concept, in which a stable group is chemically (or photochemically) converted to its labile form in response to its exposure to a given reagent before the cleavage reaction . As described in the preceding manuscript and references cited therein, , arylalkyl sulfoxides are useful entries for the development of novel “safety-catch” protecting groups. These compounds are stable to both Fmoc and Boc chemistry, but as sulfoxide groups are converted into sulfide-based ones, acidolytic cleavage occurs smoothly and with increased reaction rates as part of the electronic effects conferred by the substituent on the ring (Figure ).…”