Competing Pathways in the Photo-Favorskii Rearrangement and Release of Esters: Studies on Fluorinated p-Hydroxyphenacyl-Caged GABA and Glutamate Phototriggers

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• 作者：Kenneth Stensrud ; Jihyun Noh ; Karl Kandler ; Jakob Wirz ; Dominik Heger ; Richard S. Givens
• 刊名：Journal of Organic Chemistry
• 出版年：2009
• 出版时间：August 7, 2009
• 年：2009
• 卷：74
• 期：15
• 页码：5219-5227
• 全文大小：990K
• 年卷期：v.74,no.15(August 7, 2009)
• ISSN：1520-6904

文摘

Three new trifluoromethylated p-hydroxyphenacyl (pHP)-caged γ-aminobutyric acid (GABA) and glutamate (Glu) derivatives have been examined for their efficacy as photoremovable protecting groups in aqueous solution. Through the replacement of hydrogen with fluorine, e.g., a m-trifluoromethyl or a m-trifluoromethoxy versus m-methoxy substituents on the pHP chromophore, modest increases in the quantum yields for the release of amino acids GABA and glutamate as well as improved lipophilicity were realized. The pHP triplet undergoes a photo-Favorskii rearrangement with concomitant release of the amino acid substrate. Deprotonation competes with the rearrangement from the triplet excited state and yields the pHP conjugate base that, upon reprotonation, regenerates the starting ketoester, a chemically unproductive or “energy-wasting” process. When picosecond pump−probe spectroscopy is employed, GABA derivatives 2−5 are characterized by short triplet lifetimes, a manifestation of their rapid release of GABA. The bioavailability of released GABA at the GABA_A receptor improved when the release took place from m-OCF₃ (2) but decreased for m-CF₃ (3) when compared with the parent pHP derivative. These studies demonstrate that pK_a and lipophilicity exert significant but sometimes opposing influences on the photochemistry and biological activity of pHP phototriggers.