Model studies for new o-nitrobenzyl photolabile linkers: Substituent effects on the rates of photochemical cleavage
Model studies for new o-nitrobenzyl photolabile linkers: Substituent effects on the rates of photochemical cleavage
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DOI：
10.1021/jo961602x
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发表时间：
1997-04-18
影响因子：
3.6
通讯作者：
Holmes, CP
中科院分区：
文献类型：
--
作者：
Holmes, CP
从文献中制备了一个模型苯甲酰甲基和a-硝基苄基光不稳定连接体沿着与四个新的邻硝基苄基连接体，并在溶液中研究了它们的光解裂解动力学。通过用苄胺酰胺化羧酸锚定系链来制备接头，并且选择可裂解的苄基取代基为乙酸或乙酰胺。在365 nm下在四种溶剂（甲醇、对二氧六环和水性缓冲液+/-二硫苏糖醇）中照射接头并通过HPLC分析，得到适合于比较目的的裂解动力学速率。发现苯甲酰甲基接头在水性条件下缓慢裂解，在有机溶剂中未观察到可检测的裂解。已知的邻硝基苄基接头4在水性和有机溶剂中显示出适度的裂解速率。在苯环中引入两个烷氧基以产生基于藜芦基的接头13 a显著增加了裂解速率，并且引入另外的苄基甲基（13 b）将裂解速率增加了另外的5倍。将锚定羧酸系链的长度从乙酸增加到丁酸（19）适度地改善了有机介质中的裂解动力学，并且略微降低了水中的速率。酰胺模型接头21的裂解速度比相应的酯键19快3至7倍。制备酰胺生成接头26，并简要检查其生成光不稳定固体载体的性能。通过凝胶相C-13 NMR证明了连接体的稳定性和随后从富含同位素的4-噻唑烷酮的载体光解后的裂解。
Both a model phenacyl and a-nitrobenzyl photolabile linker from the literature along with four new o-nitrobenzyl linkers were prepared and the kinetics of their photolytic cleavage examined in solution. The linkers were prepared by amidation of the carboxylic acid anchoring tether with benzylamine, and the cleavable benzylic substituent was chosen to be either acetic acid or acetamide. Irradiation of the linkers in four solvents (methanol,p-dioxane, and aqueous buffer +/- dithiothreitol) at 365 nm and analysis via HPLC afforded kinetic rates of cleavage suitable for comparative purposes, The phenacyl linker was found to cleave slowly under aqueous conditions with no detectable cleavage being observed in the organic solvents. Known o-nitrobenzyl linker 4 showed modest rates of cleavage in aqueous and organic solvents. Incorporation of two alkoxy groups in the benzene ring to generate the veratryl-based linker 13a increased the rate of cleavage dramatically, and introduction of an additional benzylic methyl group (13b) increased the rate of cleavage by an additional 5 fold. Increasing the length of the anchoring carboxylic acid tether from acetic to butyric acid (19) improved the cleavage kinetics modestly in organic media and slightly diminished the rates in water. The amide model linker 21 cleaved from 3 to 7 times faster than the corresponding ester linkage 19. An amide-generating linker 26 was prepared, and its performance to generate photolabile solid supports was briefly examined. The stability of the linker and subsequent cleavage upon photolysis from the support of an isotopically enriched 4-thiazolidinone was demonstrated by gel phase C-13 NMR.