Development of the photoremovable protecting groups for various hydroxyl-containing and carbonyl compounds
Kostikov, Alexey P.
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Photoremovable protecting groups (PPG), known as “cages” in biochemistry, allows for the spatial and temporal control of a substrate release, as well as “reagentless” deprotection. PPGs found numerous applications in biochemistry, organic synthesis, fabrication of high density probe array (a.k.a biochips), and time-resolved X-ray crystallography. While a large variety of PPGs has been reported in recent years, few of them are suitable for the direct protection of alcohols, glycols, and carbonyl compounds. We have developed a novel family of photoremovable protecting groups based on the photochemical reactivity of 2-hydroxybenzyl alcohol and its derivatives. Cleavage of the benzylic C-O bond and release of the substrate are induced by the excited state transfer of a phenolic proton to an adjacent oxygen atom. Attractive advantages of this family of PPGs include fast and efficient liberation of the substrate; in situ generation of photolabile group from photostable precursors, and bleaching of the UV band corresponding to the caging chromophore. Irradiation of alcohols, phenols, and carboxylic acids “caged” with the 2,5-dihydroxybenzyl group (DHB) or its naphthalene analog 1,4-dihydroxy-2-naphthylmethyl (DHNM) results in deprotection of the substrate in high chemical and quantum yields. These PPGs can be armed in situ by the reduction of photochemically inert p-quinone precursors. Varying the substitution pattern in the aromatic ring allows for tuning of the chemical and photophysical properties of these PPGs. We have also developed photochemically removable equivalent of the conventional benzylidene group, widely used in classical organic synthesis for protection of 1,2- and 1,3-glycols. Cyclic acetals of substituted 2-hydroxybenzaldehydes release glycols upon irradiation at appropriate wavelength in excellent chemical yields and good quantum efficiencies. This group can be applied in synthesis of glycerides, carbohydrate chemistry, drug delivery systems etc. Finally, we have designed a new PPG for carbonyl compounds. Cyclic acetals produced by the reaction of 1-(2,5-dihydroxyphenyl)ethane-1,2-diol with various aldehydes and ketones were shown to efficiently liberate substrates upon photolysis. This group is a photochemical analog of ethyleneglycol, a common protecting group for carbonyl compounds in synthetic organic chemistry.