(Triisopropylsilyl)acetaldehyde acetal as a novel protective group for 1,2-diols

Article abstract of DOI:10.1016/j.tetlet.2006.05.121

(Triisopropylsilyl)acetaldehyde dimethyl acetal (TIPS-ADMA) was synthesized from chlorotriisopropylsilane in three steps. Cyclic and acyclic 1,2-diols can be transformed to (triisopropylsilyl)ethylidene acetals (TIPS-AA). Removal of the acetal by LiBF₄ regenerates the starting diol in excellent yield even in the presence of an acetonide of 1,2-diol. The TIPS-AA group can survive under the deprotection conditions of the acetonide in acetic acid at 80 °C. Selective protection of 2,3- and 4,6-diols for O-methyl d-mannoside with TIPS-ADMA and selective deprotection of the acetals have been achieved.

Full text of DOI:10.1016/j.tetlet.2006.05.121

Tetrahedron Letters 47 (2006) 5553–5555
(Triisopropylsilyl)acetaldehyde acetal as a novel protective
group for 1,2-diols
Jun’ichi Uenishi,* Yusuke Tanaka and Nobuyuki Kawai
Kyoto Pharmaceutical University, Misasagi, Kyoto 607-8412, Japan
Received 2 May 2006; accepted 19 May 2006
Available online 15 June 2006
Abstract—(Triisopropylsilyl)acetaldehyde dimethyl acetal (TIPS-ADMA) was synthesized from chlorotriisopropylsilane in three
steps. Cyclic and acyclic 1,2-diols can be transformed to (triisopropylsilyl)ethylidene acetals (TIPS-AA). Removal of the acetal
by LiBF4 regenerates the starting diol in excellent yield even in the presence of an acetonide of 1,2-diol. The TIPS-AA group
can survive under the deprotection conditions of the acetonide in acetic acid at 80 °C. Selective protection of 2,3- and 4,6-diols
for O-methyl D-mannoside with TIPS-ADMA and selective deprotection of the acetals have been achieved.
Ó 2006 Elsevier Ltd. All rights reserved.
Selective protection and deprotection of poly-functional
groups are important issues in synthetic organic chemis-
try. Acetals have been used as a common masking group
of 1,2- and 1,3-diols and widely employed in organic
synthesis.1 Generally, acetals are stable under basic con-
ditions or against with nucleophiles and can be removed
under acidic conditions, although other deprotection
conditions are also available for specific acetals, for
example, hydrogenolysis for arylidene acetals,2 oxida-
tive hydrolysis of p-methoxybenzylidene acetals,3 reduc-
tive cleavage of diphenylidene acetals4 or fluoride-
promoted deprotection for silylene and siloxanylidene
acetals.5 Nonetheless, an alternative method for forma-
tion–removal of acetal is necessary in certain cases.
and cleaved with LiBF4 in acetonitrile specifically (see
Scheme 1).
The synthesis of (triisopropylsilyl)acetaldehyde 5 was
reported previously by Lipshutz et al.7 in four steps from
chlorotriisopropylsilane with vinyl lithium. We have
now improved the synthesis of 5 in two steps. Allylation
of chlorotriisopropylsilane followed by oxidative cleav-
age of the alkenyl bond with ozone to give 5 in 80%
yield.8 An acetal formation of 5 with trimethyl ortho-
formate was carried out in methanol in the presence of
TsOH or CSA to give 2 in 85% yield (see Scheme 2).
Acetalization of 1,2-diols was carried out with 2 in the
presence of TsOH catalyst in benzene.9 The results are
listed in Table 1. The acetal formation of cis-cyclopen-
tane-1,2-diol 1a and 1b proceeded very well at room
temperature to give the corresponding acetal 3a and 3b
in 86% and 85% yields, respectively. The reactions of
cis-cyclohexane-1,2-diol 1c and acyclic 1,2-diols 1d–f re-
quired refluxing conditions to give 3c, 3d–f in excellent
yields.
Recently, Fukuyama reported the p-silyloxyarylidene
acetal of 1,2-diol.6 This protective group is effective for
acid-fragile molecules. In fact, it was removed elegantly
under non-acidic conditions by a combination of fluo-
ride and base. On the other hand, in our on-going pro-
ject, an acetal that can survive under weak to medium
acidic conditions and can be removed under a specific
condition other than acidic conditions is highly
desirable.
Herein, we report a (triisopropylsilyl)acetaldehyde acetal
(TIPS-AA) 3 as a new protective group for 1,2-diols,
which can be formed by the reaction of 1 with (triisopro-
pylsilyl)acetaldehyde dimethyl acetal (TIPS-ADMA) 2,
*
Scheme 1.
Corresponding author. E-mail: juenishi@mb.kyoto-phu.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.121

5554
J. Uenishi et al. / Tetrahedron Letters 47 (2006) 5553–5555
Table 2. Deprotection of TIPS-AA by LiBF4
O , CH Cl
2
3
2
ClMg
Entry
Acetal 3
Conditionsa
Time (h)
Yieldb
(%)
i
-78 °C
Pr Si
3
(isoPr) SiCl
3
THF, rt
then
OMe
reduction
O
4
BzO
1
3a
15
89
CH(OMe)
3
i
Pr Si
CHO
O
O
3
(isoPr) SiCH CH(OMe)
2 2 2
Cat. TsOH
MeOH, rt
i
5
Si Pr
2 (TIPS-ADMA)
3
O
O
O
Scheme 2.
2
3
3b
3c
19
8
85
92
i
Si Pr
3
Initially, we considered that fluoride anion might pro-
mote desilylation of 3 and that successive cleavage of
the O–C bond of acetal could give vinyl ether, which
would be hydrolyzed easily by a very weak acid to regen-
erate the original diol 1. However, a number of fluoride
ion sources such as TBAF, KF, and CsF under various
reaction conditions, including reactions at high temper-
ature and under microwave assistance were all fruitless.
These results indicate that a selective deprotection of
silyl ether is possible in the presence of TIPS-AA. The
deprotection proceeded by treatment with mineral and
organosulfonic acids such as HCl or TsOH. In fact,
compound 3a is hydrolyzed quickly below pH 2 but
slowly at pH 3. Interestingly, it is stable above pH 4,
and survives in acetic acid even at 80 °C for several
i
Si Pr
O
3
MeOOC
COOMe
O
O
i
4
3d
3
84
Si Pr
3
5
6
3e
3f
5
90
85
O
O
i
10
Si Pr
hours. Subsequently we have examined LiBF4 and
3
found to be effective for removal of TIPS-AA.11
Although the reaction required heating in acetonitrile
O
Ph
11
O
i
Si Pr
3
a In CH3CN at 70 °C.
Table 1. The reaction of 1,2-diols with TIPS-ADMA
b Isolated yields.
Entry Diol 1
Conditionsa Product 3 Yieldb
(temp)
(%)
at 70 °C, a clean deprotection took place for 2-tri-
isopropylsilylmethy-1,3-dioxolanes 3a–f.12 The results
are listed in Table 2.
OMe
O
3ac
86
BzO
1
1a rt
HO
OH
OH
The failure in deprotection with simple fluoride anion
clearly indicates that fluoride anion itself cannot initiate
cleavage of the C–Si bond. In order to cleave this bond,
an activation of the C–O bond is required. Lithium cat-
ion of LiBF4 may play an important role in the activa-
tion of the acetal bond to assist nucleophilic cleavage
of the C–Si bond with fluoride anion. After this process,
vinyl ether and lithium alkoxytrifluoroborate could
be produced, and this intermediate may be hydrolyzed
during an aqueous work-up to give acetaldehyde and 1
(see Scheme 3).
2
3
4
5
6
1b rt
60 °Ce
3bc
3cc
3dc
3ec
3fc
69d
85
OH
OH
1c Reflux
1d Reflux
1e Refluxf
1f Reflux
84
OH
MeOOC
COOMe
OH
89
HO
81d
98
HO
Ph
OH
LiBF
O
4
OH
OH
LiBF
4
H2O
a In benzene for 1 h.
b Isolated yields.
1
O
Li
B
O
O
CH3CHO
F
F
(isoPr)3SiF
c Diastereomeric ratios; 3a (1:3), 3b (1:5), 3c (2:5), 3e (1:1), 3f (3:5).
d Some recovery of the starting diol.
Si
F
F
LiBF
3
e 3 h.
f 2 h.
Scheme 3.

J. Uenishi et al. / Tetrahedron Letters 47 (2006) 5553–5555
5555
The resulting TIPS-AA 3 is stable in hot acetic acid and
can be removed by LiBF4 selectively.13 TIPS-AA is a un-
ique protecting group and will be useful in organic syn-
thesis.12 The specific use for the synthesis of complex
natural products are in progress.
2 (2 eq.)
cat. TsOH
O
OMe
OH
O
OMe
O
HO
HO
benzene, rt, 15 h
O
OH
i
Si Pr
OH
OH
3
6
7
2 (6 eq.)
cat. TsOH
benzene
Acknowledgements
reflux, 1.5 h
This work was supported by Grant-in-Aid for Scientific
Research on Priority Areas 17035084 and in part by the
21st COE Program from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
O
OMe
O
O
O
OMe
O
HO
HO
LiBF (2 eq.)
4
O
CH CN
O
3
i
Si Pr
O
rt, 14 h
3
i
i
Si Pr
Si Pr
3
3
9
8
References and notes
´
1. (a) Kocienski, P. J. Protecting Groups, 3rd ed.; Georg
Thieme: Stuttgart, 2004; (b) Greene, T. W.; Wuts, P. G.
M. Protective Groups in Organic Synthesis, 3rd ed.; Wiley:
New York, 1999; p 201; (c) Reese, C. B. In Protective
Group in Organic Chemistry; McOmie, J. F. W., Ed.;
Plenum: London, 1973; p 95; (d) Ley, S. V.; Baeschlin, D.
K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.; Priepke, H. W.
M.; Reynold, D. J. Chem. Rev. 2001, 101, 53.
O
O
OMe
HO
AcOH
9
+
9
6
+
+
HO
O
80 °C
6 hr
10
2. Calinaud, P.; Gelas, J. In Preparative Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker: New York,
1997; p 3.
3. Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron
Lett. 1982, 23, 889.
LiBF (2 eq.)
4
6
10
CH CN
3
70 °C, 3 hr
4. Mori, Y.; Asai, M.; Kawade, J.; Furukawa, H. Tetra-
hedron 1995, 51, 5315.
Scheme 4.
5. (a) Trost, B. M.; Caldwell, C. G. Tetrahedron Lett. 1981, 22,
4999; (b) Markiewicz, W. T. J. Chem. Res. Synop. 1979, 24.
6. Kaburagi, Y.; Osajima, H.; Shimada, K.; Tokuyama, H.;
Fukuyama, T. Tetrahedron Lett. 2004, 45, 3817.
7. Lipshutz, B. H.; Lindsley, C.; Susfalk, R.; Gross, T.
Tetrahedron Lett. 1994, 35, 8999.
Since the rates of cyclic acetal formation of 1,2-diol and
1,3-diol, and the rates of deprotection of five-membered
and six-membered cyclic acetals were different, selective
protection and deprotection for polyols could be possi-
ble1b and be useful for carbohydrate synthesis. Selective
protections of 2,3- and 4,6-diols of O-methyl D-manno-
side have been accomplished, as shown in Scheme 4.
When 6 was treated with 2 in the presence of TsOH in
benzene at room temperature, mono acetal 7 was
obtained in 68% yield. While, the reaction with an excess
of 2 at refluxing temperature in benzene gave diacetal 8
in 85% yield. Six-membered acetal was removed selec-
tively with LiBF4 in acetonitrile at room temperature
to give mono acetal 9 in 74% yield.
8. Alternatively, OsO4 catalyzed dihydroxylation and NaIO4
promoted cleavage of the diol gave 5.
9. General procedure: A mixture of diol 1 (1 mmol), 2
(252 mg, 2 mmol), and anhydrous p-TsOH (17 mg) was
stirred in benzene (2 mL) at the temperature indicated in
Table 1. After the reaction was completed, the mixture
was quenched with saturated NaHCO3 solution and
extracted with EtOAc. Compound 3 was obtained after
a purification by column chromatography on silica gel.
10. Hydrolysis of 2-substituted 1,3-dioxolane was known at a
slow rate in wet acetonitrile with LiBF4. Lipshutz, B. H.;
Harvey, P. F. Syn. Commun. 1982, 12, 267.
Studies of chemo-selective deprotection in TIPS-AA 9
and acetonide 10 were examined. When a mixture of
compounds 9 and 10 was exposed to acetic acid at
80 °C for 6 h, acetonide 10 was hydrolyzed to give 6
but 9 was recovered quantitatively. On the other hand,
the same mixture was heated with LiBF4 in acetonitrile
at 70 °C for 3 h, only the TIPS-AA of 9 was hydrolyzed
to give 6 selectively.
11. A mixture of 3 (1 mmol) and LiBF4 (184 mg, 2 mmol) in
acetonitrile (8 mL) was heated at 70 °C. After cooling,
the mixture was diluted with EtOAc (50 mL) and
washed with water and brine. The organic extract was
dried over MgSO4 and condensed. The residue was
purified by flush column chromatography on silica gel to
give diol 1.
12. Similar deprotection of 4-trimethysilylmethyl-1,3-dioxol-
anes lead to ketone or aldehyde was reported. See, Lillie,
B. M.; Avery, M. A. Tetrahedron Lett. 1994, 35, 969.
13. More details of protection and deprotection for TIPS-AA
of 1,2- and 1,3-diols including scope and limitation will be
described in a full article.
In summary, we have prepared TIPS-ADMA 2 in three
steps from chlorotriisopropylsilane. TIPS-ADMA
serves as an excellent acetalization reagent for 1,2-diols.