Development of photocleavable linker groups for application to photocleavage of liposomes and of caging alcohols and carboxylic acids

by Kulikov, Anton Vadimirovich.

Vladimir V. Popik, Advisor The experimental work described in this dissertation is addresses two problems: the design of a novel photocleavable analog of natural lipids and the development of a new photolabile protecting group for alcohols and carboxylic acids. Several designs of a photocleavable lipid have been explored. The most promising design contained a 3’,5’-dialkoxybenzoin chromophore (photolabile linker), substituted with a pentacosan-13-oxy group (hydrophobic tails), and aspartic acid (polar “head”). Photochemical studies of this de novo designed photolabile lipid showed that upon irradiation with 350 nm light it, in fact, undergoes cleavage, forming benzofuran derivatives and releasing aspartic acid. In our search for a new photolabile protecting (caging) group for alcohols, we have explored the photochemical properties of two chromophores. 3-Hydroxy-2-naphthalenemethanol ethers and esters and 4,4’-dimethoxytrityl ethers were synthesized and their ability to release the protected substrate upon irradiation was examined. 3-Hydroxy-2-naphthalenemethanol derivatives were found to be the more suitable for this purpose. Alkoxy and carboxy derivatives of 3-hydroxy-2-naphthalenemethanol release model substrates, i. e., benzoic acid and benzyl alcohol quantitatively with good quantum yields. The photodeprotection reaction is assumed to proceed via concerted excited state proton transfer, thus avoiding C-O bond heterolysis and the formation of ion pairs. The commonly known problem of lowering the photoefficiency of deprotection reaction due to ion pair recombination is therefore circumvented. Surprisingly, in some cases the chemical yield of substrate release was far from quantitative. This is probably caused by a side reaction of the substrate with a quinone methide intermediate. iii 5-O’-(4,4’-Dimethoxytrityl) derivatives of a number of DNA nucleosides were shown to regenerate the free nucleoside upon irradiation with 254 nm light with good to excellent chemical yields. Since the 4,4’-dimethoxytrityl group is widely employed in oligonucleotide synthesis, this photoreaction provides a useful orthogonal alternative for deprotection of the 5’ position despite the poor quantum yields. iv