Catalytic Deprotection of Protected Alcohols in Water Using Low-Loading and Alkylated Polystyrene-Supported Sulfonic Acid

Article abstract of DOI:10.1021/jo035178t

Catalytic deprotection of various protected alcohols was efficiently conducted using a hydrophobic low-loading and alkylated polystyrene-supported sulfonic acid (LL-ALPS-SO₃H) in water as the sole solvent. Transprotection of an alcohol from a silyl ether to the corresponding benzylic ether or ester also proceeded smoothly in water.

Full text of DOI:10.1021/jo035178t

TABLE 1. Dep r otection of TBS Eth er w ith Va r iou s
Br On sted Acid Ca ta lysts
Ca ta lytic Dep r otection of P r otected
Alcoh ols in Wa ter Usin g Low -Loa d in g a n d
Alk yla ted P olystyr en e-Su p p or ted Su lfon ic
Acid
entry
catalyst
TsOH
H2SO4
HCl
DOWEX 50W-X2
PS-SO3H
ALPS-SO3H
ALPS-SO3H
PEG-PS-SO3H
loading (mmol/g)
yielda (%)
Shinya Iimura, Kei Manabe, and Shuj Kobayashi*
1
2
3
4
5
6
7
8
0
Graduate School of Pharmaceutical Sciences, The University
of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, J apan
2b
7c (92)d
4.41
0.42
0.41
0.17
0.19
0
51
87
90
4
skobayas@mol.f.u-tokyo.ac.jp
Received August 11, 2003
a
Isolated yields. b In 2 N H2SO4 (600 mol %). c In 2 N HCl (1200
Abstr a ct: Catalytic deprotection of various protected al-
cohols was efficiently conducted using a hydrophobic low-
loading and alkylated polystyrene-supported sulfonic acid
(LL-ALPS-SO3H) in water as the sole solvent. Transprotec-
tion of an alcohol from a silyl ether to the corresponding
benzylic ether or ester also proceeded smoothly in water.
d
mol %). In 6 N HCl (3600 mol %).
The protection-deprotection sequence is one of the
most frequently encountered functional-group transfor-
mations in organic synthesis.1,2 In particular, the se-
quence for hydroxyl groups is extremely important
because of enormous demands in natural product syn-
thesis, etc. Although numerous methods for the depro-
tection of those protected alcohols have been reported,
the use of more than equimolar amounts of catalysts or
reagents is needed in many cases. In addition, organic
solvents are generally used to dissolve the substrates
when they are water-insoluble. From the atom-economi-
cal3 and environmental points of view, however, reusable
catalyst-mediated deprotection in water without the use
of harmful organic solvents is strongly desirable.4,5
In the course of our investigations on organic reactions
in water, we have recently found that a hydrophobic
polystyrene-supported sulfonic acid (PS-SO3H) is an
effective and reusable catalyst for formation of esters,
hydrolysis of thioesters, and Mannich-type reactions in
water.6 In addition, as a result of continuous studies on
the loading levels and the structures of the catalyst, we
have developed a low-loading (e.g., 0.17 mmol/g) and
alkylated polystyrene-supported sulfonic acid (LL-ALPS-
SO3H), which is one of the best catalysts for several acid-
catalyzed organic reactions in water.7 Thus, we envisaged
that LL-ALPS-SO3H would also be highly effective for
deprotection of protected alcohols in water without using
organic cosolvents. In this paper, we report an effective
and environmentally friendly methodology for the depro-
tection using LL-ALPS-SO3H.
The tert-butyldimethylsilyl (TBS) ether is a frequently
used protective group for alcohol functions.1,8 Therefore,
we first examined deprotection of TBS ethers in water.
Several Brønsted acids were tested in a model reaction
of dodecyl TBS ether in water at 40 °C for 12 h (Table
1). The deprotection did not proceed at all with 5 mol %
of TsOH, and surprisingly, the reaction hardly proceeded
even when carried out in 2 N H2SO4 or HCl despite the
presence of excess amounts of the acids (entries 1-3).
This is probably because of the insolubility of the
substrate in water. On the other hand, hydrophobic
polystyrene-supported sulfonic acids were effective for the
deprotection (entries 5-7). Interestingly, remarkable
effects of the loading levels (entries 4 and 5)9 and the
structures (entries 5 and 6) of the polymer catalysts were
revealed. Although the use of amphiphilic polymer-
supported catalysts is a traditional approach to realize
organic reactions in water,5 this type of catalyst was less
active under these conditions (entry 8). It should be noted
that only 5 mol % of LL-ALPS-SO3H gave almost the
same result as 6 N HCl (3600 mol %) (entries 3 and 7).
Next, we investigated substrate generality in the LL-
ALPS-SO3H-catalyzed deprotection of TBS ethers (Table
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; J ohn Wiley & Sons: New York, 1999.
(2) For a recent review of protecting groups, see: J arowicki, K.;
Kocienski, P. J . Chem. Soc., Perkin Trans. 1 2001, 2109.
(3) (a) Trost, B. M. Science 1991, 254, 1471. (b) Sheldon, R. A. Pure
Appl. Chem. 2000, 72, 1233.
(4) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie
Academic and Professional: London, 1998. (b) Li, C.-J .; Chan, T.-H.
Organic Reactions in Aqueous Media; J ohn Wiley & Sons: New York,
1997.
(5) For recent examples of polymer-supported catalysts which work
in water, see: (a) Nagayama, S.; Kobayashi, S. Angew. Chem., Int.
Ed. 2000, 39, 567. (b) Bergbreiter, D. E.; Liu, Y.-S. Tetrahedron Lett.
1997, 38, 7843. (c) Bergbreiter, D. E.; Case, B. L.; Liu, Y.-S.; Caraway,
J . W. Macromolecules 1998, 31, 6053. (d) Chen, C.-W.; Chen, M.-Q.;
Serizawa, T.; Akashi, M. Chem. Commun. 1998, 831. (e) Danjo, H.;
Tanaka, D.; Hayashi, T.; Uozumi, Y. Tetrahedron 1999, 55, 14341. (f)
Uozumi, Y.; Shibatomi, K. J . Am. Chem. Soc. 2001, 123, 2919. (g)
Tanaka, N.; Masaki, Y. Synlett 1999, 1960. (h) Masaki, Y.; Yamada,
T.; Tanaka, N. Synlett 2001, 1311. (i) Sakamoto, T.; Pac, C. J .
Tetrahedron Lett. 2000, 41, 10009. (j) Yamada, Y. M. A.; Ichinohe, M.;
Takahashi, H.; Ikegami, S. Org. Lett. 2001, 3, 1837.
(7) Iimura, S.; Manabe, K.; Kobayashi, S. Org. Biomol. Chem. 2003,
1, 2416.
(6) (a) Manabe, K.; Kobayashi, S. Adv. Synth. Catal. 2002, 344, 270.
(b) Iimura, S.; Manabe, K.; Kobayashi, S. Org. Lett. 2003, 5, 101. (c)
Iimura, S.; Nobutou, D.; Manabe, K.; Kobayashi, S. Chem. Commun.
2003, 1644.
(8) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.
(9) DOWEX 50W-X2 is a commercially available polystyrene-sup-
ported sulfonic acid, which is regarded as very high-loading PS-SO3H.
10.1021/jo035178t CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/09/2003
J . Org. Chem. 2003, 68, 8723-8725
8723

TABLE 2. LL-ALP S-SO3H-Ca ta lyzed Dep r otection of
Va r iou s P r otective Alcoh ols
SCHEME 1. LL-ALP S-SO3H-Ca ta lyzed Selective
Dep r otection
a
b
Isolated yields. 1 mol % of the catalyst was used.
ether was attained using LL-ALPS-SO3H in water.
Moreover, it was revealed that the selective deprotection
of a MOM ether also performed in excellent yield in the
presence of a Bn ether moiety. It is particularly note-
worthy that the selective deprotection of a substrate with
multiple protecting groups such as benzoyl (Bz) and
p-methoxybenzyl (PMB) was achieved using this catalytic
system. These results not only demonstrate an effective
selective deprotection methodology but also provide use-
ful information on the use of this novel catalytic system.
Interestingly, transprotection of an alcohol from the
corresponding silyl ether to benzylic ether11 was realized
in water by carrying out the deprotection of the TBS
ether in the presence of benzhydrol (eq 2).12 Furthermore,
the TBS ether was successfully used directly for the
esterification with the carboxylic acid in water (eq 3).12
Since isolation of the intermediate is not needed, these
catalytic transformations are considered as useful and
economical processes.
2). The reactions proceeded not only for primary but also
for aromatic and secondary TBS ethers in high yields
under mild conditions in water (entries 1-3). Although
a sterically crowded simple tertiary ether was hardly
deprotected (entry 4), the double deprotection of com-
pound 1 having a TBS-protected tertiary alcohol moiety
proceeded smoothly under mild conditions (entry 5).
These results encouraged us to test the deprotection of
other protected alcohols in water. As a result, the
reactions proceeded smoothly in high to excellent yields
with 5 mol % of LL-ALPS-SO3H not only for other silyl
ethers such as triisopropylsilyl (TIPS) and tert-butyl-
diphenylsilyl (TBDPS) but also for trityl (Tr) and meth-
oxymethyl (MOM) ethers (entries 6-9). Furthermore,
only 1 mol % of the catalyst is enough to catalyze the
reaction in the case of an acetyl (Ac)-protected alcohol
(entry 10). Therefore, it was revealed that LL-ALPS-
SO3H was effective for the catalytic deprotection of
various protected alcohols in water as the sole solvent.
As expected, the catalyst was easily recovered and reused
without any loss of catalytic activity (eq 1).
We then turned our attention to selective deprotection
to demonstrate the utility of this methodology (Scheme
1).10 Although various useful selective deprotection meth-
ods have been reported, the present catalytic system also
enables the selective deprotection of TBS ethers in the
presence of other protective groups such as benzyl (Bn)
and TBDPS. In addition, the selective deprotection of an
aliphatic TBS ether in the presence of an aromatic TBS
Finally, it was found that an easy workup process
without the use of organic solvents was possible when
(11) Suzuki, T.; Kobayashi, K.; Noda, K.; Oriyama, T. Synth.
Commun. 2001, 31, 2761.
(12) Recently, we have developed dehydration reactions such as
esterification and etherification in water: (a) Manabe, K.; Sun, X.-M.;
Kobayashi, S. J . Am. Chem. Soc. 2001, 123, 10101. (b) Manabe, K.;
Iimura S.; Sun, X.-M.; Kobayashi, S. J . Am. Chem. Soc. 2002, 124,
11971. See also ref 6a. For transprotection in water, see ref 6b.
(10) For an excellent review of the selective deprotection of silyl
ethers, see: Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031.
8724 J . Org. Chem., Vol. 68, No. 22, 2003

the products were soluble in water. The pure product was
obtained quantitatively after the reaction mixture was
filtered, washed with water, and concentrated in the case
of deprotection of the TBS ether shown in eq 4. This
simple procedure is a remarkable advantage of the
present catalytic reaction system.
tion of various types of protected alcohols and will expand
the utility of LL-ALPS-SO3H as a powerful green cata-
lyst.
Exp er im en ta l Section
Typ ica l P r oced u r e for LL-ALP S-SO3H-Ca ta lyzed Dep r o-
tection of P r otected Alcoh ols in Wa ter . A mixture of dodecyl
TBS ether (60.5 mg, 0.20 mmol) and the polymer-supported
catalyst (LL-ALPS-SO3H (0.172 mmol/g), 58.3 mg, 0.010 mmol)
in degassed water (1.2 mL) was stirred for 12 h at 40 °C. The
reaction mixture was quenched with saturated aq NaHCO3. The
polymer was filtered and washed with water and ethyl acetate.
The organic layer was dried over Na2SO4 and evaporated. The
mixture was purified by preparative TLC on silica gel to give
dodecanol (33.4 mg, 90%).
Ack n ow led gm en t. This work was partially sup-
ported by CREST and SORST, J apan Science and
Technology Corporation (J ST), and a Grant-in-Aid for
Scientific Research from J apan Society of the Promotion
of Science.
In summary, catalytic deprotection of various protected
alcohols is efficiently catalyzed by LL-ALPS-SO3H in
water as the sole solvent. Remarkable effects of the
loading levels and the structures on the polymer-sup-
ported sulfonic acid were observed in the deprotection of
TBS ethers. Selective deprotection and useful one-pot
transformations were also realized in water using this
catalytic system. This work will provide an effective and
environmentally friendly methodology for the deprotec-
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal information, experimental details, and spectral data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O035178T
J . Org. Chem, Vol. 68, No. 22, 2003 8725