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[86]

468 | 6.1 Linkers for Solid-phase Synthesis 6.1.5.2

Special Linkers Photocleavable Linkers

Light-induced cleavage offers new possibilities for orthogonal use of linkers and acid- or base-labile protecting groups. The first photolabile linker, 88, which was based on the o-nitrobenzyl protecting group, was developed by Rich and Gurwara [87] for synthesis of protected peptides (Scheme 6.1.18). This linker was developed further, because in the synthesis of the original linker a nitration of Merrifield resin was involved, leading to nitration of excess phenyl rings. Preformed handles have, therefore, usually been used. On UV-photolysis the photo-by-product, a ni-trosobenzaldehyde, is also always photoactive and leads to reduction in cleavage yield from the support. To circumvent this problem an additional methyl group was introduced to the linkers; this led to the photoreactive nitrosoacetophenone system [88]. Introduction of methoxy groups para to the nitro groups (vanillin-type linker) [89] also improves cleavage properties and the compounds are typically released within 3 h in >90% yield and >95% purity under neutral conditions [90, 91]. These linkers are therefore biocompatible and suitable for Fmoc solid-phase peptide synthesis (Fmoc-SPPS) [92].

88 89

Scheme 6.1.18. The prototype photolabile linker.

88 89

Scheme 6.1.18. The prototype photolabile linker.

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