Application of the Excited State Meta Effect in Photolabile Protecting Group Design Pengfei Wang,* Huayou Hu, and Yun Wang Department of Chemistry, UniVersity of Alabama at Birmingham, Birmingham, Alabama 35294 wangp@uab.edu Received May 9, 2007 ABSTRACT A novel photolabile protecting group for carbonyl compounds has been developed, based on the excited state meta effect. Controllable removal of a photolabile protecting group (PPG) by photochemical means typically requires no chemical reagents and can provide high spatial and temporal resolution. These features are appealing to the researchers in the fields of organic synthesis, solid-phase synthesis, combinatorial chemistry, photolithography, and biochemical and biophysi- cal research. 1 Despite advances in developing PPGs for various applications, practically useful PPGs for some important functional groups (e.g., carbonyl group) are still rare. 2 Recently, we developed a robust PPG, 2-[hydroxy- (diphenyl)methyl]-4-methoxyphenol, for the protection of carbonyl groups. 3 Herein we report our progress in the development of another novel type of PPG based on the excited state meta effect. 4,5 The meta effect driven PPGs are available for protecting carboxyl groups, amino groups (in the carbamate form), or phosphate esters. 1,4,6 To our delight, we found that the application of the excited-state meta effect could be further expanded. In our design (Scheme 1), carbonyl compound 1 could be protected by 3,5-dimethoxylsalicylic alcohol (2) in a cyclic acetal/ketal form 3. The π-π* excitation of 3 would increase the electron density at C-1 in S 1 owing to the presence of two m-methoxyl groups. This charge accumulation at C-1 should facilitate the benzylic C-O breakage, leading to the release of 1, presumably via the zwitterionic intermediate 4. (1) For reviews and monographs, see: (a) Pillai, V. N. R. Synthesis 1980, 1. (b) Binkley, R. W.; Flechtner, T. W. In Synthetic organic photochemistry; Horspool, W. M., Ed.; Plenum: New York, 1984; p 375. (c) Pillai, V. N. R. Org. Photochem. 1987, 9, 225. (d) Givens, R. S.; Kueper, L. W., III Chem. ReV. 1993, 93, 55. (e) Pirrung, M. C. Chem. ReV. 1997, 97, 473. (f) Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091. (g) Bochet, C. G. J. Chem. Soc., Perkin Trans. 1 2002, 125. (h) Pelliccioli, A. P.; Wirz, J. Photochem. Photobiol. Sci. 2002, 1, 441. (i) Goeldner, M.; Givens, R. S., Eds. Dynamic studies in biology; Wiley-VCH: Weinheim, Germany, 2005. (j) Mayer, G.; Heckel, A. Angew. Chem., Int. Ed. 2006, 45, 4900. (2) (a) Hebert, J.; Gravel, D. Can. J. Chem. 1974, 52, 187. (b) Gravel, D.; Herbert, J.; Thoraval, D. Can. J. Chem. 1983, 61, 400. (c) Gravel, D.; Murray, S.; Ladouceur, G. J. Chem. Soc., Chem. Commun. 1985, 24, 1828. (d) Friedrich, E.; Lutz, W.; Eichenauer, H.; Enders, D. Synthesis 1977, 12, 893. (e) Hoshino, O.; Sawaki, S.; Umezawa, B. Chem. Pharm. Bull. 1979, 27, 538. (f) Aurell, M. J.; Boix, C.; Ceita, M. L.; Llopis, C.; Tortajada, A.; Mestres, R. J. Chem. Res. Synop. 1995, 12, 452. (g) Ceita, L.; Maiti, A. K.; Mestres, R.; Tortajada, A. J. Chem. Res. Synop. 2001, 10, 403. (h) McHale, W. A.; Kutateladze, A. G. J. Org. Chem. 1998, 63, 9924. (i) Lin, W.; Lawrence, D. S. J. Org. Chem. 2002, 67, 2723. (j) Lu, M.; Fedoryak, O. D.; Moister, B. R.; Dore, T. M. Org. Lett. 2003, 5, 2119. (k) Blanc, A.; Bochet, C. G. J. Org. Chem. 2003, 68, 1138. (l) Kantevari, S.; Narasimhaji, C. V.; Mereyala, H. B. Tetrahedron 2005, 61, 5849. (3) Wang, P.; Hu, H.; Wang, Y. Org. Lett. 2007, 9, 1533. (4) Chamberlin, J. W. J. Org. Chem. 1966, 31, 1658. (5) (a) Zimmerman, H. E.; Sandel, V. R. J. Am. Chem. Soc. 1963, 85, 915. (b) Zimmerman, H. E.; Somasekhara, S. J. Am. Chem. Soc. 1963, 85, 922. (c) Zimmerman, H. E. J. Am. Chem. Soc. 1995, 117, 8988. (d) Zimmerman, H. E. J. Phys. Chem. A 1998, 102, 5616. (6) Birr, C.; Lochinger, W.; Stahnke, G.; Lang, P. Liebigs Ann. Chem. 1972, 763, 162. ORGANIC LETTERS 2007 Vol. 9, No. 15 2831-2833 10.1021/ol071085c CCC: $37.00 © 2007 American Chemical Society Published on Web 06/20/2007