Hydroxamic acids (HAs) are utilized in many pharmaceutical and medical applications such as in the treatment of many cancers. They are also precursors in a broad range of organic transformations such as protecting groups in transketalization reactions, used in the synthesis of a variety of block– and star–copolymer architectures, and used as bidentate ligands with different transition metals. Nevertheless, the synthesis of HAs is known to be problematic because of the use of harsh synthetic conditions and the difficulties of purifying them. Difficulties in synthesizing and purifying these types of compounds are routinely circumvented by adding protecting groups (PGs) to the reactive functional groups. However, as scientists start utilizing lengthy synthetic routes and the number of functional groups that need PGs increase within a molecule, it becomes challenging to remove a PG individually and selectively when needed. Conditions such as acidic, basic, reductive, and oxidative conditions are generally used during the removal of conventional PGs, which can potentially degrade the protected molecule. Here, we developed a more attractive synthetic approach to overcome the challenges associated with the synthesis and purification of HAs that requires less harsh conditions and reduces the side by-products by developing a new class of o-nitrobenzyl (o-NB) photolabile protective groups (PPGs), based on 2(phenylethynyl)thiophene PPGs. It has been shown that a major limitation of most o-NB PPG derivatives is that their chromophores absorb light mostly in the UV region of the spectrum where extended exposure of cells or tissues to UV light can lead to cell damage or death. Here, we utilized 2(2-(4-nitrophenyl)ethynyl)thiophene as the core of our PPG to release HAs in high yield via a photocleavable protecting group with a diagnostic fluorescent by-product. Therefore, designing our PPG to absorb light in the visible region of the optical spectrum will be advantageous because it will allow for irradiation with visible light and prevent exposure of cells or tissues to UV light for efficiency in biological applications.

Development of thiophene-based o-nitrobenzyl photolabile protecting groups for the synthesis of hydroxamic acids

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