milder protocols have appeared, utilizing TMG,7a N-oxide,7b
and DMSO-H2O.7c Because many biologically significant
natural products such as vancomycin,8 novobiocin,9 and phenolic
glycoconjugates10 possess both phenol and alcohol functions,
selective removal of phenolic TBS protection in the presence
of aliphatic TBS ether (“aryl selectivity”) is of great value to
total synthesis and medicinal chemistry.3,11 To this end, the
difference in the electronic nature of alkyl and aryl groups was
to be exploited, for phenols are better leaving groups than
alcohols, and thus aryl silyl ethers are more liable to base
hydrolysis.4a Although this approach worked nicely in many
cases, it involved prolonged exposure to excess basic reagents,
which is apparently less desirable in multistep synthesis. Second,
a closer examination revealed that catalytic procedure for the
removal of phenolic silyl protection is uncommon, except one
system using silica-gel-supported phosphomolybdic acid12 and
another using PdCl2(MeCN)2.13 Unfortunately, both preferen-
tially attack aliphatic TBS ethers, and the latter also removes
acetonide at room temperature.14 A substoichiomeric amount
(0.2-0.4 equiv) of Verkade’s azaphosphatrane also removes
TBS protection from phenols; however, the “superbase” pro-
moter is reactive toward many functional groups including
alkenes.15 Third, it should be noted that good chemoselectivity
between two different aryl silyl ethers is not easy to achieve,
whereas such protections for alcohols are readily differentiated.3
For example, there are only two reports of preferential cleavage
of phenolic TBS protection over TBDPS,4c,16 although the steric
bulk and acid/base stability of the two silyls are considerably
varied. Herein we describe a highly efficient protocol using
LiOAc as the catalyst to address all the aforementioned issues.
Since alkali hydroxides and carbonates are known to cleave
aryl TBS ethers in a number of solvents,6 we turned our attention
to weaker bases in order to achieve deprotection under milder
conditions with better chemoselectivity. The TBS ether of 4-tert-
butylphenol was chosen as a benchmark substrate, for it reflected
the true relative activity of the catalysts, while substrates bearing
strong electron-withdrawing groups (EWGs) were too labile and
thus exhibited a “leveling effect” for catalyst activity. We
screened several acetates as the catalyst, and to our delight,
LiOAc stood out as the most effective (Table 1).17 Interestingly,
the catalytic activity decreased rapidly when the cation went
LiOAc-Catalyzed Chemoselective Deprotection of
Aryl Silyl Ethers under Mild Conditions
Bing Wang,*,† Hui-Xia Sun,† and Zhi-Hua Sun*,‡
Department of Chemistry, Fudan UniVersity, 220 Handan
Road, Shanghai 200433, China, and Shanghai Saijia
Chemicals Co., Ltd., Suite 402, No. 54, Lane 33, Shilong
Road, Shanghai 200232, China
wangbing@fudan.edu.cn; sungaris@gmail.com
ReceiVed NoVember 7, 2008
An efficient and chemoselective deprotection protocol for
aryl silyl ethers using LiOAc as a bifunctional Lewis
acid-Lewis base catalyst was described. Acetates, epoxides,
and aliphatic silyl ethers were preserved, whereas aryl TBS
and TBDPS ethers can be differentiated.
Trialkylsilyls are popular protective groups for both alcoholic
and phenolic hydroxyls.1 Take tert-butyl-dimethylsilyl (TBS)
as an example; since its introduction by Corey,2 it has been
one of the most widely used protective groups in modern organic
synthesis. The cleavage of alkyl TBS ethers has been extensively
investigated, leading to a wide array of deprotection methods.1
In contrast, there are relatively fewer options available for the
removal of phenolic TBS protections.1,3 The latter usually
required more than stoichiomeric amounts of fluoride sources
(TBAF,2,4a KF/18-C-6,4b KF/Al2O34c,d), acids (HF,5a,b CSA5c)
or strong bases (alkoxides,6a-c carbonates6d-f). Recently, some
† Department of Chemistry, Fudan University.
‡ Shanghai Saijia Chemicals Co., Ltd.
(1) Wuts, P. G. M.; Greene, T. W. Greene’s ProtectiVe Groups in Organic
Synthesis, 4th ed.; John Wiley & Sons: Hoboken, NJ, 2007.
(8) Evans, D. A.; Dinsmore, C. J.; Ratz, A. M.; Evrard, D. A.; Barrow, J. C.
J. Am. Chem. Soc. 1997, 119, 3417.
(2) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
(3) For excellent reviews, see: (a) Nelson, T. D.; Crouch, R. D. Synthesis
1996, 1031. (b) Crouch, R. D. Tetrahedron 2004, 60, 5833.
(4) (a) Collington, E. W.; Finch, H.; Smith, I. J. Tetrahedron Lett. 1985, 26,
681. (b) Just, G.; Zamboni, R. Can. J. Chem. 1978, 56, 2725. (c) Blass, B. E.;
Harris, C. L.; Portlock, D. E. Tetrahedron Lett. 2001, 42, 1611. Under ultrasound
irridation: (d) Schmittling, E. A.; Sawyer, J. S. Tetrahedron Lett. 1991, 32, 7207.
(5) (a) Kendall, P. M.; Johnson, J. V.; Cook, C. E. J. Org. Chem. 1979, 44,
1421. (b) Sinhababu, A. K.; Kawase, M.; Borchardt, R. T. Synthesis 1988, 710.
(c) Angle, S. R.; Wada, T. Tetrahedron Lett. 1997, 38, 7955.
(6) LiOH: (a) Ankala, S. V.; Fenteany, G. Tetrahedron Lett. 2002, 43, 4729.
NaOH: (b) Crouch, R. D.; Stieff, M.; Frie, J. L.; Cadwallader, A. B.; Bevis,
D. C. Tetrahedron Lett. 1999, 40, 3133. KOH: (c) Jiang, Z.-Y.; Wang, Y.-G.
Chem. Lett. 2003, 32, 568. K2CO3: (d) Wilson, N. S.; Keay, B. A. Tetrahedron
Lett. 1997, 38, 187. Cs2CO3: (e) Jiang, Z.-Y.; Wang, Y.-G. Tetrahedron Lett.
2003, 44, 3859. K2CO3/Kriptofix 222: (f) Prakash, C.; Saleh, S.; Blair, I. A.
Tetrahedron Lett. 1994, 35, 7565.
(9) (a) Blagosklonny, M. V. Leukemia 2002, 16, 455. For novel novobiocin
analogs and SAR studies, see: (b) Burlison, J. A.; Neckers, L.; Smith, A. B.;
Maxwell, A.; Blagg, B. S. J. J. Am. Chem. Soc. 2006, 128, 15529. (c) Yu, X. M.;
Shen, G.; Neckers, L.; Blake, H.; Holzbeierlein, J.; Cronk, B.; Blagg, B. S. J.
J. Am. Chem. Soc. 2005, 127, 12778.
(10) Glycoscience: Chemistry and Chemical Biology III; Fraser-Reid, B. O.,
Tatsuta, K., Thiem, J., Eds.; Springer: Berlin, 2001.
(11) Deprotection protocols with the opposite “alkyl selectivity” are more
abundant, for representative recent examples; see: (a) Khan, A. T.; Ghosh, S.;
Choudhury, L. H. Eur. J. Org. Chem. 2004, 2198. (b) Shah, S. T. A.; Giury,
P. J. Org. Biomol. Chem. 2008, 6, 2168. (c) Oriyama, T.; Kobayashi, Y.; Noda,
K. Synlett 1998, 1047. (d) Lipshutz, B. H.; Keith, J. Tetrahedron Lett. 1998, 39,
2495.
(12) Kumar, G. D. K.; Baskaran, S. J. Org. Chem. 2005, 70, 4520.
(13) Wilson, N. S.; Keay, B. A. Tetrahedron Lett. 1996, 37, 153.
(14) Lipshutz, B. H.; Pollart, D.; Monforte, J.; Kotsuki, H. Tetrahedron Lett.
1985, 26, 705.
(7) (a) Oyama, K.-i.; Kondo, T. Org. Lett. 2003, 5, 209. (b) Zubaidha, P. K.;
Bhosale, S. V.; Hashmi, A. M. Tetrahedron Lett. 2002, 43, 7277. (c) Maiti, G.;
Roy, S. C. Tetrahedron Lett. 1997, 38, 495.
(15) Yu, Z.; Verkade, J. G. J. Org. Chem. 2000, 65, 2065.
(16) Ito, H.; Knebelkamp, A.; Lundmark, S. B.; Nguyen, C. V.; Hinsberg,
W. D. J. Polym. Sci. A: Polym. Chem. 2000, 38, 2415.
10.1021/jo802472s CCC: $40.75
Published on Web 01/15/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1781–1784 1781