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

The SCAL linker, a safety catch linker, is amongst the most versatile linkers for solid phase synthesis. It was originally described in 1991 by Patek 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.