4-(tert-Butyldimethylsilyloxy)benzylidene acetal: A novel benzylidene-type protecting group for 1,2-diols

Article abstract of DOI:10.1016/j.tetlet.2004.03.065

A novel 1,2-diol-protecting group, p-silyloxybenzylidene group, has been developed. In addition to the stepwise deprotection conditions including desilylation and the subsequent acidic hydrolysis of the p-hydroxybenzylidene group in AcOH-THF-H₂O, we have established the one-pot deprotection under basic conditions [K₂CO₃ (5equiv), NH ₂OH·HCl (5equiv), and CsF (1equiv) in MeOH-H₂O].

Full text of DOI:10.1016/j.tetlet.2004.03.065

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3817–3821
4-(tert-Butyldimethylsilyloxy)benzylidene acetal: a novel
benzylidene-type protecting group for 1,2-diols
Yosuke Kaburagi, Hiroyuki Osajima, Kousei Shimada, Hidetoshi Tokuyama and
Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 18 February 2004; revised 8 March 2004; accepted 11 March 2004
Abstract—A novel 1,2-diol-protecting group, p-silyloxybenzylidene group, has been developed. In addition to the stepwise
deprotection conditions including desilylation and the subsequent acidic hydrolysis of the p-hydroxybenzylidene group in AcOH–
THF–H2O, we have established the one-pot deprotection under basic conditions [K2CO3 (5 equiv), NH2OHÆHCl (5 equiv), and CsF
(1 equiv) in MeOH–H2O].
Ó 2004 Elsevier Ltd. All rights reserved.
Protection and deprotection of functional groups play
the critical role in successful synthesis of multifunctional
complex molecules. Because of synthetic versatility of
1,2-diols, a variety of protecting groups have been
developed to date.1 Among them, the most frequently
used groups are cyclic acetals and ketals. However, since
their deprotection generally requires strongly acidic
conditions, these protecting groups are generally
incompatible with acid labile functional groups. During
the course of synthetic studies on leustroducsin B (1),2
we have experienced such difficulties. While the
advanced synthetic intermediate 2 was successfully
constructed by protecting the sterically hindered C8–C9
diol with acetonide or p-methoxybenzylidene group,
deprotection of these groups at the later stage of the
synthesis was relatively difficult and required too harsh
acidic conditions to cause significant isomerization of
the conjugated Z,Z-diene moiety. To circumvent this
problem, we devised a novel benzylidene-type protecting
group, p-silyloxybenzylidene group, which could be
deprotected smoothly by a two-step sequence without
affecting other functional groups (Scheme 1). Thus,
treatment of the substrate with (HF)3ÆEt3N to remove
TBS group, followed by subjection to weakly acidic
conditions such as AcOH–THF–H2O to obtain the
corresponding 1,2-diol. We report herein details of the
Scheme 1.
Keywords: Protecting group; Benzylidene acetal; Diol; Deprotection under basic conditions; Hydroxylamine.
* Corresponding author. Tel.: +81-3-5841-4777; fax: +81-3-5802-8694; e-mail: fukuyama@mol.f.u-tokyo.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.065

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Y. Kaburagi et al. / Tetrahedron Letters 45 (2004) 3817–3821
Table 1. Acidic hydrolysis of the benzylidene acetals
Ar
AcOH-THF-H2O
HO
Ph
OH
Ph
(3:1:1)
O
O
rt
Ph
Ph
4a-d
5
Entry
Ar
Ph (4a)
Time (h)
Yield (%)
1
2
3
4
2.5
2.0
2.5
1.0
96
98
96
93
p-MeO–C6H4 (4b)
p-TBSO–C6H4 (4c)
p-HO–C6H4 (4d)
Scheme 2.
scope and the general applicability of the novel p-silyl-
oxybenzylidene protecting group with respect to
appropriate conditions for protection and deprotection
of various 1,2-diols.3
is depicted in Scheme 2. In basic media, a C–O bond
of the acetal 8 would be cleaved by electrons provided
by the phenoxide anion to give 9.4 After addition of
water, the resultant hemiacetal 10 would release the diol
12. At this point, we considered an effectively capturing
the resultant p-hydroxybenzaldehyde (11) would accel-
erate the deprotection process under equilibrium. As
expected, addition of 5 equiv of NH2OHÆHCl shortened
the time to 2.5 h and the desired diol was obtained in
91% yield along with the oxime of 11 (entry 2). Under
these conditions, the silylated substrate 6b could be
converted to the corresponding diol 7 in one-pot (entry
3). Furthermore, addition of 1 equiv of CsF was effective
and reduced the reaction time to 1.3 h (entry 4).
At the outset of this research, relative rates of the de-
protection of several benzylidine-type protecting groups
in weakly acidic media (AcOH–THF–H2O, 3:1:1) were
compared using model substrates 4a–d (Table 1). De-
protection of the parent benzylidene (4a), p-methoxy-
benzylidene (4b), and p-silyloxybenzylidene group (4c)
took almost the same reaction time (2–2.5 h) although
we had anticipated a faster removal of p-silyloxybenzyl-
idene group (4c) owing to the electron donating nature
of the silyloxy group (entries 1–3). However, the step-
wise procedure mentioned above have proved quite
effective. Thus, p-hydroxybenzylidene acetal 4d, which
was derived from 4c by treatment with TBAF, was
deprotected more easily than any other acetals tested
(entry 4).
Having established the basic deprotection conditions of
p-silyloxybenzylidene group, we next applied this
method for a variety of substrates. As shown in Table 3,
basic deprotection generally proceeded smoothly while
sterically hindered acetal 19 required prolonged reaction
time (entry 4). In particular, these deprotection condi-
tions are advantageous for substrates bearing acid labile
functionalities. For example, THP group remained
unaffected during the deprotection (entry 1). While
benzoyl ester could not tolerate under these basic con-
ditions, more robust pivaloyl ester survived (entries 2
and 3).
More significantly, we have found that this newly
developed acetal group, p-silyloxybenzylidene group,
could be deprotected under basic conditions. Upon
treatment of 6b with TBAF, a trace amount of diol 7
was obtained along with the desired p-hydroxybenzyl-
idene acetal 6a. With this observation we considered a
possibility of the deprotection under basic conditions.
Thus, treatment of the p-hydroxybenzylidene acetal 6a
with K2CO3 in MeOH–H2O at 70 °C gave diol 7 in 97%
yield (Table 2, entry 1). A plausible reaction mechanism
Protection of 1,2-diols was carried out by two methods
A and B (Table 4). The conventional acid-mediated
acetalization conditions (method A) provided protected
1,2-diols in high yields, whereas sterically hindered 1,2-
diols required somewhat stronger acid and higher tem-
perature (entries 1–3). On the other hand, TMSOTf
mediated acetalization reaction reported by Noyori and
co-workers5 (method B) provided the corresponding
acetals under mild conditions (entries 4 and 5). The re-
quired reagents for the protection (21 and 22) are readily
prepared from 4-hydroxybenzaldehyde (11) (Scheme 3).2
Table 2. Basic hydrolysis of the benzylidene acetals
OR
K2CO3 (5 eq)
additives
OH
O
OH
O
MeOH-H2O (4:1)
70 °C
6a: R = H
7
6b: R = TBS
Entry
R
Additives
No additive
NH2OHÆHCl (5 equiv)
Time (h) Yield (%)
In conclusion, we have developed a novel 1,2-diol pro-
tecting group, p-silyloxybenzylidene group. The depro-
tection could be performed under not only weakly acidic
conditions but also basic conditions in the presence of
hydroxylamine. To the best of our knowledge, this is the
first example of acetal-type protecting group, which is
1
2
3
4
H
H
9.0
2.5
2.5
1.3
97
91
97
93
TBS NH2OHÆHCl (5 equiv)
TBS NH2OHÆHCl (5 equiv)
CsF (1 equiv)

Y. Kaburagi et al. / Tetrahedron Letters 45 (2004) 3817–3821
Table 3. Selective removal of the protecting groupa
3819
Entry
Substrate
Product
Time (h)
2.5
Yield (%)
93
OH
(p-TBSO)C6H4
OTHP
1
14
O
HO
O
OTHP
13
3
O
O
3
OH
OH
(p-TBSO)C6H4
16
2
3
1.5
3.5
29b
92
O
O
15
HO
HO
OBz
O
(p-TBSO)C6H4
O
OBz
18
17
OPiv
OPiv
OH
(p-TBSO)C6H4
20
OTr
O
HO
4
21
91
19
O
OTr
a Conditions: K2CO3 (5 equiv), NH2OHÆHCl (5 equiv), CsF (1 equiv), MeOH–H2O (4:1), 70 °C.
b Hydrolysis of benzoyl group occurred.
Table 4. Protection of diolsa
Entry
Method
Diol
Conditions
Product
Yield (%)
OH
OH
(p-TBSO)C6H4
16
1
A
22, PPTS (10 mol %)
DMF, rt, 3.5 h
O
O
15
96b
84c
HO
OBz
O
OBz
(p-TBSO)C6H4
HO
18
OPiv
2
A
22, CSA (5 mol %)
DMF, rt, 4.0 h
17
O
OPiv
OH
(p-TBSO)C6H4
23
HO
OPiv
O
93c
91d
24
3
4
A
B
22, CSA (5 mol %)
DMF, 50 °C, 3.0 h
O
OPiv
18
(1) TMSCl, imidazole, CH2Cl2
0 °C, 5 min
17
24
(2) 21, TMSOTf (1 mol %)
CH2Cl2, )78 °C, 5 min
(1) TMSCl, imidazole
CH2Cl2, 0 °C, 5 min
5
B
23
94e
(2) 21, TMSOTf (20 mol %)
CH2Cl2, )78 °C, 30 min
a Typical experimental procedures for methods A and B are described in the text.
b 1:1 Diastereomeric mixture.
c 3:1 Diastereomeric mixture.
d 10:1 Diastereomeric mixture.
e 2:1 Diastereomeric mixture.
multifunctional compounds bearing acid sensitive
functionalities.
OH
OTBS
OTBS
TBSCl
imidazole
CSA
CH(OMe)3
CH2Cl2
MeOH
Typical experimental procedure for protection (method
A: Table 4, entry 2): To a stirred solution of diol 18
(57.5 mg, 0.26 mmol) and 22 (148.8 mg, 0.53 mmol) in
DMF (2 mL) under Ar atmosphere was added CSA
(3.1 mg, 0.013 mmol) at room temperature. After the
solution was stirred for 4 h, it was poured into satd
NaHCO3 and extracted with ether. The extract was
washed with 5% NaCl, dried over MgSO4, filtered, and
CHO
11
CHO
21
CH(OMe)2
22
Scheme 3.
removed under basic conditions. We believe that this
protecting group would find a niche for the synthesis of

3820
Y. Kaburagi et al. / Tetrahedron Letters 45 (2004) 3817–3821
evaporated under reduced pressure. The residue was
purified by flash column chromatography (2–10%
AcOEt in hexane) on silica gel to give 17 (96.2 mg, 84%)
as a colorless oil.6
References and notes
1. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999; p 201.
2. Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem.
Soc. 2003, 125, 4048–4049.
For protection (method B: Table 4, entry 5): To a stirred
solution of diol 23 (206 mg, 0.944 mmol) and imidazole
(385 mg, 5.66 mmol) in CH2Cl2 (9 mL) was cooled to
0 °C under Ar atmosphere. To this stirred solution was
added TMSCl (359 lL, 2.83 mmol). After 5 min, the
reaction mixture was poured into satd NaHCO3 and
extracted with AcOEt. The extract was washed with
brine twice, dried over MgSO4, filtered, and evaporated
under reduced pressure. The residue was purified by
flash column chromatography (10% AcOEt in hexane)
on neutral silica gel to give bis-TMS ether (337 mg,
98%). A solution of the bis-TMS ether (111 mg,
0.32 mmol) and 21 (151 mg, 0.64 mmol) in CH2Cl2
(3 mL) was cooled to )78 °C under Ar atmosphere. To
this stirred solution was added TMSOTf (12 lL,
0.064 mmol). After stirring for 30 min, pyridine was
added, and allowed to warm to room temperature. The
reaction mixture was poured into satd NaHCO3 and
extracted with AcOEt. The extract was washed with
brine twice, dried over MgSO4, filtered, and evaporated
under reduced pressure. The residue was purified by
flash column chromatography (2–10% AcOEt in hex-
ane) on silica gel to give 24 (129 mg, 96%) as a white
solid.6
3. Conversion of rather simple silyloxybenzylidene acetals to
their corresponding aldehydes has been reported: (a)
Sabitha, G.; Babu, R. S.; Reddy, E. V.; Yadav, J. S. Chem.
Lett. 2000, 1074; (b) Krishnaveni, N. S.; Surendra, K.;
Reddy, M. A.; Nageswar, Y. V. D.; Rao, K. R. J. Org.
Chem. 2003, 68, 2018.
4. Sekine, M.; Hata, T. J. Org. Chem. 1983, 48, 3011.
5. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett.
1980, 21, 1357.
6. Spectroscopic data for p-silyloxybenzylidene acetals. For 13
(a colorless oil, an inseparable 1:1 diastereomeric mixture):
IR (neat, cmꢀ1) 2936, 2859, 1611, 1513, 1254, 1078, 1031,
914, 839; 1H NMR (400 MHz, CDCl3) d 7.38–7.34 (m, 2H),
7.15 (d, J ¼ 8:4 Hz, 2H), 6.86–6.82 (m, 4H), 5.87 (s, 0.5H),
5.76 (s, 0.5H), 4.60 (t, J ¼ 3:6 Hz, 1H), 4.35–4.24 (m, 1.5H),
4.16–4.08 (m, 0.5H), 4.06–3.88 (m, 3H), 3.82–3.72 (m,
1.5H), 3.68–3.56 (m, 1.5H), 3.50–3.44 (m, 1H), 2.86 (t,
J ¼ 7:0 Hz, 2H), 2.04–1.47 (m, 10H), 0.99 (s, 9H), 0.20 (s,
6H); 13C NMR (100 MHz, CDCl3) d 157.3, 156.4, 131.2,
130.9, 130.3, 129.9, 128.0, 127.7, 119.9, 114.3, 104.0, 103.0,
98.7, 77.2, 76.1, 70.9, 69.9, 68.5, 67.4, 62.3, 35.4, 30.6, 30.2,
30.0, 25.6, 25.4, 19.5, 18.2, )4.5; HRMS (FABþ) calcd for
C31H46O6Si 542.3064 (M)þ, found 542.3087. For 15 (a
colorless oil, an inseparable 1:1 diastereomeric mixture): IR
(neat, cmꢀ1) 2955, 2930, 2857, 1720, 1611, 1514, 1273, 1109,
1071, 914, 840; 1H NMR (400 MHz, CDCl3) d 8.05 (d,
J ¼ 7:2 Hz, 2H), 7.56 (t, J ¼ 7:4 Hz, 1H), 7.45 (t,
J ¼ 7:6 Hz, 2H), 7.35 (t, J ¼ 7:8 Hz, 2H), 6.84 (d,
J ¼ 8:4 Hz, 1H), 6.83 (d, J ¼ 8:4 Hz, 1H), 5.87 (s, 0.5H),
5.76 (s, 0.5H), 4.40–4.38 (m, 2H), 4.31–4.25 (m, 1.5H), 4.11
(t, J ¼ 7:2 Hz, 0.5H), 3.74 (t, J ¼ 7:2 Hz, 0.5H), 3.64 (s,
0.5H), 2.06–1.70 (m, 4H), 0.98 (s, 9H), 0.19 (s, 6H); 13C
NMR (100 MHz, CDCl3) d 166.5, 156.6, 132.9, 130.8,
130.2, 129.5, 128.3, 128.0, 127.7, 120.0, 104.1, 103.1, 76.5,
75.9, 70.7, 69.9, 64.6, 30.2, 30.0, 25.6, 25.3, 25.2, 18.2, )4.5;
HRMS (FABþ) calcd for C25H34O5Si 442.2176 (M)þ, found
442.2166. For 17 (a colorless oil, an inseparable 3:1
diastereomeric mixture): IR (neat, cmꢀ1) 2959, 2932, 2859,
1731, 1611, 1514, 1264, 1163, 1092, 915, 840; 1H NMR
(400 MHz, CDCl3) d 7.33 (d, J ¼ 8:6 Hz, 1.5H), 7.31 (d,
J ¼ 8:8 Hz, 0.5H), 6.83 (d, J ¼ 8:8 Hz, 0.5H), 6.82 (d,
J ¼ 8:6 Hz, 1.5H), 5.99 (s, 0.25H), 5.73 (s, 0.75H), 4.35–
4.03 (m, 4H), 1.90–1.78 (m, 2H), 1.71–1.44 (m, 2H), 1.19 (s,
For deprotection under basic conditions (Table 3, entry
1): To a stirred solution of 13 (77.5 mg, 0.14 mmol) in
MeOH–H2O (4:1, 1 mL) at room temperature was
added CsF (21.7 mg, 0.14 mmol), K2CO3 (98.7 mg,
0.71 mmol), and NH2OHÆHCl (49.6 mg, 0.71 mmol) in
this sequence. The reaction mixture was heated at 70 °C
and stirred for 2.5 h. The reaction mixture was cooled to
room temperature, and extracted with AcOEt three
times. The extracts were dried over MgSO4, filtered, and
evaporated under reduced pressure. The residue was
purified by preparative TLC (60% AcOEt in hexane) to
give diol 14 (43.3 mg, 93%) as a white solid.
For preparation of 21: A 100-mL round-bottom flask
was charged with 4-hydroxybenzaldehyde (1.04 g,
8.5 mmol) and dry CH2Cl2 (40 mL) at room temperature
under Ar atmosphere. To the solution was added TBSCl
(1.54 g, 10 mmol) and imidazole (1.45 g, 21 mmol). After
the solution was stirred for 15 min, the reaction mixture
was diluted with CH2Cl2 and washed with brine twice.
The organic layer was dried over MgSO4, filtered, and
evaporated under reduced pressure. The residue was
purified by flash column chromatography (10% AcOEt
in hexane) on a silica gel to give 217 (1.84 g, 92%) as a
colorless oil.
9H), 1.05 (t, J ¼ 7:2 Hz, 3H), 0.98 (s, 9H), 0.17 (s, 6H); 13
C
NMR (100 MHz, CDCl3) d 178.2, 156.4, 156.0, 132.3,
130.3, 128.0, 127.3, 119.8, 103.1, 101.4, 80.4, 79.7, 77.2,
75.1, 61.5, 38.6, 29.4, 27.7, 27.1, 25.5, 22.8, 21.8, 18.1, 10.7,
10.5, )4.6; HRMS (FABþ) calcd for C24H40O5Si 436.2645
(M)þ, found 436.2647. For 19 (a colorless foam, an
inseparable 3:1 diastereomeric mixture): IR (neat, cmꢀ1
)
2930, 2858, 1514, 1262, 1077, 914, 839; 1H NMR (400 MHz,
CDCl3) d 7.51–7.42 (m, 6H), 7.36–7.11 (m, 11H), 6.84 (d,
J ¼ 8:6 Hz, 0.5H), 6.80 (d, J ¼ 8:6 Hz, 1.5H), 5.87 (s,
0.25H), 5.82 (s, 0.75H), 4.07–4.03 (m, 1H), 3.60–3.56 (m,
1H), 3.12–3.07 (m, 0.75H), 3.05–3.01 (m, 0.25H), 1.52 (s,
0.75H), 1.41 (s, 2.25H), 1.11 (s, 2.25H), 1.10 (s, 0.75H), 0.97
(s, 9H), 0.16 (s, 6H); 13C NMR (100 MHz, CDCl3) d 156.4,
143.9, 131.9, 130.5, 128.6, 128.0, 127.8, 127.7, 127.0, 119.8,
101.7, 101.5, 87.0, 83.3, 81.7, 81.1, 79.9, 62.8, 62.5, 26.6,
26.3, 25.6, 22.9, 19.6, 18.1, )4.5; HRMS (FABþ) calcd for
C37H44O4Si 580.3009 (M)þ, found 580.2997. For 24 (a
white solid, an inseparable 2:1 diastereomeric mixture): IR
(neat, cmꢀ1) 2959, 2932, 2860, 1735, 1612, 1515, 1264, 1163,
Acknowledgements
This work was financially supported in part by PRE-
STO, JST. Y.K. is a recipient of the JSPS pre-doctoral
research fellowships for young scientists.

Y. Kaburagi et al. / Tetrahedron Letters 45 (2004) 3817–3821
3821
915, 840; 1H NMR (400 MHz, CDCl3) d 7.37–7.31 (m, 2H),
6.83 (d, J ¼ 8:4 Hz, 2H), 5.98 (s, 0.33H), 5.83 (s, 0.67H),
4.33–4.11 (m, 2H), 4.02–3.98 (m, 1H), 1.47 (s, 1H), 1.44 (s,
7. Spectroscopic data for 21: IR (neat, cmꢀ1) 2956, 2931,
2887, 2859, 1700, 1599, 1577, 1508, 1472, 1275, 1211,
1156, 909, 842, 800, 784; 1H NMR (400 MHz, CDCl3)
d 9.88 (s, 1H), 7.78 (d, J ¼ 8:4, Hz, 2H), 6.94 (d, J ¼ 8:4 Hz,
2H), 0.99 (s, 9H), 0.24 (s, 6H); 13C NMR (100 MHz,
CDCl3) d 191.5, 161.2, 131.7, 130.3, 120.3, 25.4, 18.0,
)4.6; HRMS (FABþ) calcd for C13H20O2Si 236.1233
(M)þ, found 236.1239. Spectroscopic data for 22: see
Ref. 2.
2H), 1.31 (s, 3H), 1.22 (s, 9H), 0.97 (s, 9H), 0.18 (s, 6H); 13
C
NMR (100 MHz, CDCl3) d 178.2, 156.7, 156.4, 131.6,
130.1, 128.1, 127.7, 120.0, 102.0, 101.9, 82.0, 80.8, 79.7,
62.9, 62.6, 38.7, 27.2, 26.2, 26.0, 25.6, 23.0, 20.1, 18.2, )4.5;
HRMS (FABþ) calcd for C23H39O5Si 423.2567 (M+1)þ,
found 423.2571.