Nitroveratryl linker

It was Zehavi [16] who first used the nitroveratryl linker (4) in 1973 to synthesize an oligosaccharide using a photolabile solid phase strategy. Starting with isovanillin, 4 was prepared by nitration, alkylation with the Merrifield polystyrene resin and reduction of the aldehyde. Photolysis using UV irradiation (>320 nm) in dioxane produced product in 13% yield after 32 h of irradiation (Scheme 17.4). 

Scheme 17.4 An early example of the synthesis of an oligosaccharide using nitroveratryl linker (4).

The bathochromic and hyperchromic shifts of n—mi or ti—mi absorbances (Figure 17.5) of the aryl rings caused by the introduction of two alkoxy groups correlated well with the increased photolability of nitroveratryl linkers during 365 nm irradiation. 

A similar comparison was made by Geysen [26], in which the photocleavage yields of 18, 19, and his new linker 20 were monitored at various times (Table 17.4). Surprisingly, his new linker 20 showed similar or slightly better results than the nitrobenzyl linker 18 and the a-methyl nitroveratryl linker 19 when irradiated at 350nm. 

Other variations of the nitrobenzyl linker are the nitroveratryl (4) and hydroxynitrobenzyl (5) linkers, which are characterized by one or two alkoxy substituents on the nitrobenzene ring. The increased electron density at the benzylic position in these linkers improves photochemical cleavage efficiency through stabilization of radical intermediates in photolysis and also retards diketopiperazine formation during the coupling of the third amino acid in peptide synthesis. 

To address the problems of slow cleavage kinetics and methionine oxidation associated with the use of photolabile support Ij (Table 1), a linker based o -methyl-6-nitroveratryl alcohol [227,228] was designed. The additional ring alkoxy groups and the a-methyl group of support 5q facilitate cleavage and lead to fewer side products that result from the photoproduct, a resin-bound nitroso ketone, compared with Ij and other conventional photolabile linkers. Support 5q has been used for the synthesis of sultams [229], which were cleaved from the resin by irradiation in 2-propanol at 365 nm. 

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