A phenacyl ester derivative bearing a benzoquinolone as a model for photocleavable linkers: synthesis and photolysis studies

Abstract

The use of light of appropriate wavelength for the efficient breaking of bonds is very appealing for solid phase peptide synthesis (SPPS) where the substrate is bound to a polymeric matrix, usually through a linker that can be cleaved by light in the very last step of the sequence, in order to liberate the desired product [1]. Additionally, photocleavable protecting groups can be used in the intermediate coupling cycles as temporary protection for the amino acids terminal function, since during the synthesis it is necessary that side chain protecting groups remain in place while those at the main chain terminal should be cleaved before starting a new cycle [2]. The use of photolabile linkers became widespread in the generation of combinatorial libraries of organic molecules because it allows a release of the library compounds under very mild conditions, as the light-induced detachment is orthogonal to acid and basic reaction conditions and therefore affords additional flexibility in the synthesis on solid support. The prerequisite for a photochemically removable linker are the same as those described for photochemically removable protecting groups [3]. Considering our previous experience in this field [4], we now report the synthesis of a phenacyl ester derivative linked to a benzoquinolone, in order to obtain a system that could be applied as a photocleavable linker for solid phase synthesis, allowing photolysis at longer wavelengths with short irradiation times. Through a modified Knorr synthesis [5] between 7-(N-methylamino)naphthalen-2-ol and ethyl 3-oxobutanoate, in acidic media, 9-hydroxy-1,4-dimethylbenzo[f]quinolin-3(4H)-one 1 was obtained. After introduction of a spacer, the phenacyl ester derivative 4 was synthesised by coupling of 2-bromo-1-phenylpropan-1-one, acting as a model for the solid support (such as the brominated Wang resin), to the carboxylic acid terminal of the benzoquinolone in N,N-dimethylformamide, at room temperature, in the presence of potassium fluoride [6]. Compound 4 was tested as a photocleavable linker by irradiation in a photochemical reactor at different wavelengths (300, 350 and 419 nm), in methanol/HEPES buffer solution (80:20).