2-Nitrobenzyl alcohol linkers

Photolabile linkers for amides are most often based on 2-nitrobenzyl derivatives (Table 3.10 for the preparation of these and similar linkers, see also [147,153,235]). The mechanism of photolysis is the same as for the related 2-nitrobenzyl alcohol linkers (Section 3.1.3). 

Benzyl carbamate protection (Cbz or Z group see Table 10.15) was initially chosen by Merrifield for solid-phase peptide synthesis [255], The strongly acidic conditions required for its solvolysis (30% HBr in AcOH, 25 °C, 5 h) demanded the use of an acid-resistant nitrobenzyl alcohol linker. Z-protection of the a-amino group in solid-phase peptide synthesis was, however, quickly abandoned and replaced by the more acid-labile Boc protection. Benzyl carbamates can be cleaved by strongly ionizing... 

This linker proved to be stable under a variety of reaction conditions (e.g. 50% TFA or 5% BF3OEt2 in DCM, 20 °C, 2 h 5% DBU in toluene, 80 °C, 2 h). An additional advantage of this linker, as compared with 2-nitrobenzyl alcohol derivatives, is that no UV-absorbing products are formed during photolysis. This enables fast and complete photolytic detachment of the resin-bound product. Relatively short wavelengths (< 340 nm) are, however, required to effect cleavage. 

Photolabile carbonate supports 2j have been constructed by attachment of a preformed handle consisting of the reaction scaffold and an ortho-nitrobenzyl alcohol photolabile linker to PEG-PS [121]. Peptide sequences were constructed from the scaffold, and final products were liberated in a form suitable for direct biological screening by irradiation at 365 nm in an aqueous medium. 

---