Facile Synthesis of a Next Generation Safety‐Catch Acid‐Labile Linker, SCAL‐2, Suitable for Solid‐Phase Synthesis, On‐Support Display and for Post‐Synthesis Tagging

Abstract

The SCAL linker, a safety catch linker, is amongst the most versatile linkers for solid phase synthesis. It was originally described in 1991 by Pátek and Lebl. Yet, its application has been hindered by the low yields of published synthetic routes. Over time, the exceptional versatility of this linker has been demonstrated in several applications of advanced solid phase synthesis of peptides and peptidomimetics. Recently, an updated synthesis of the original linker has also been presented at the 22nd American Peptide Symposium, comprising 10 steps. Herein, the design and synthesis of a next generation SCAL linker, SCAL‐2, is reported. SCAL‐2 features a simplified molecular architecture, which allows for a more efficient synthesis in 8 steps with superior yields. Both linkers, SCAL and SCAL‐2 are compared in terms of their cleavage properties adding valuable information on how to best utilize the versatility of these linkers for solid phase synthesis.

Safety-Catch Linkers for Solid-Phase Peptide Synthesis

“…In contrast, under reductive acidolysis with SiCl 4 -thioanisole-anisole-TFA for 3 h, 94% of Leu was successfully cleaved from the resin [58]. Likewise, Undén and Erlandsson [57] Portal et al [69] developed a new safety-catch acid-labile linker (SCAL-2) (Figure 2) with a simplified molecular architecture, easier chemical accessibility, and improved stability compared to the original Patek and Lebl SCAL-1. Kiso and colleagues employed similar strategies in SPPS while designing DSA [61] (4-(4-methoxyphenyl-aminomethyl)-3-methoxyphenylsulfinyl-6-hexanoic acid) and DSB [58] (4-(2,5-dimethyl-4-methylsulfinylphenyl)-4-hydroxybutanoic acid) (Scheme 9).…”

“…Scheme 8. Patek safety-catch acid-labile (SCAL) linker.Portal et al[69] developed a new safety-catch acid-labile linker (SCAL-2) (Figure2) with a simplified molecular architecture, easier chemical accessibility, and improved stability compared to the original Patek and Lebl SCAL-1.…”

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

“…Patek 21 and Lebl 21 described a SCAL linker based on the bis(methylsulfinyl)benzydrylamine moiety for the preparation of C-terminal amide peptides. 21,22 This linker was further improved by Auer 23 and co-workers. 23 Finally, Alewood 24 and co-workers 24 converted 4,4′-bis-(methylsulfinyl)benzydryl (Msbh) into a Cys thiol protecting group for regioselective disulfide formation using four different types of Cys protecting groups.…”

“…21,22 This linker was further improved by Auer 23 and co-workers. 23 Finally, Alewood 24 and co-workers 24 converted 4,4′-bis-(methylsulfinyl)benzydryl (Msbh) into a Cys thiol protecting group for regioselective disulfide formation using four different types of Cys protecting groups. The elimination of the protecting group was also carried out using reductive acidolysis.…”