An efficient and selective method for hydrolysis of acetonides

Article abstract of DOI:10.1055/s-2001-12340

Acetonide was selectively and efficiently cleaved with cerium (III) chloride heptahydrate and oxalic acid in acetonitrile. This method was found to be of good functionalities compatibility with such acid sensitive groups as Tr, PMB, TBDMS, TBDPS, OAc, OBz, OTs, OTf.

Full text of DOI:10.1055/s-2001-12340

LETTER
535
An Efficient and Selective Method for Hydrolysis of Acetonides
Xiangshu Xiao, Donglu Bai*
Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Fax + 86(21)64370269; E-mail: dlbai@mail.shcnc.ac.cn
Received 11 January 2001
ly cleaved obtaining 2 with good yield (86%, entry i). In
Abstract: Acetonide was selectively and efficiently cleaved with
substrates which have more than one acetonide group, re-
gioselectivity could be achieved as well by cleavage of the
cerium (III) chloride heptahydrate and oxalic acid in acetonitrile.
This method was found to be of good functionalities compatibility
least hindered one (entry j). Further experiments were also
conducted in determining whether the present method had
influence on the stereochemistry of the chiral acetonide.
The results (entry a) showed that the stereochemistry of
the product was retained during deprotection. The value
of specific optical rotation of the resulting diol is the same
as that of the deprotected product obtained by using p-
TsOH in MeOH.
with such acid sensitive groups as Tr, PMB, TBDMS,TBDPS, OAc,
OBz, OTs, OTf.
Key words: cerium (III) chloride, oxalic acid, acetonides, diols
The protective groups in organic synthesis, particularly in
multi-step synthesis of structurally complicated natural
products, are very important. Many syntheses failed just
because the protective groups selected were unable to be
cleaved at the appropriate step.1 Acetonide is one of the
most commonly used protective groups to mask the hy-
droxy groups in polyhydroxy natural products, nucleo-
sides and oligosaccharides.2
The amounts of CeCl3 7H2O and oxalic acid used in the
reaction were tested and optimized. Neither cerium (III)
chloride nor oxalic acid alone could effect the hydrolysis
of the acetonide even after 48 h. It was found that the
amount of CeCl3 7H2O was decisive for completion of
hydrolysis of acetonides. When less than one equivalent
of CeCl3 7H2O was used, the hydrolysis proceeded rather
slowly. The optimal molar ratio of substrates,
CeCl3 7H2O and (COOH)2 is 1:2:0.05.8
Over the past years a number of methods have been devel-
oped and reviewed for the hydrolysis of acetonide.3 How-
ever, the development of new selective methods which
have good compatibility with other protecting groups is
still entailing.4 Recently, in the course of our studies di-
rected toward the total synthesis of macrolactin A, we
found that selective removal of acetonide group in 1 giv-
ing deprotected product 2 and leaving the TBDPS group
intact (Scheme 1) was unsatisfactory with CF3COOH5,
CSA6 and p-TsOH.7
In this reaction we suppose that the Brønsted acidity of
oxalic acid, the Lewis acidity and oxyphilicity of cerium
(III) ion generate together a synergic effect on removing
the acetonide.9 Thus, a possible mechanism is envisioned
in Scheme 2, in which cerium (III) ion first coordinates
with the least hindered oxygen and then an -chloro ether
is formed which undergoes acid catalyzed hydrolysis to
furnish the deprotected diol.
Herein we wish to report an efficient and selective method
for the cleavage of the acetonide group using cerium (III)
chloride heptahydrate with a catalytic amount of oxalic
acid in acetonitrile at ambient temperature. This method
does not need expensive reagents and special operations
to exclude the moisture and oxygen from the reaction me-
dium. It has also proved that this method can achieve high
chemo- and regioselectivity with good to excellent yields.
Scheme 2
Scheme 1
In conclusion, we have developed a novel and efficient
method for the selective hydrolysis of acetonide group by
CeCl3 7H2O-(COOH)2 system. This method offers sever-
al advantages like easy handling, good compatibility with
other acid sensitive functional groups, low costs of the re-
agents and high yields of the diols.8
It is evident from the Table that acid labile protective
groups such as Tr, TBDMS, TBDPS, PMB ethers and
OAc, OBz, OTs, OTf esters are all left intact under the re-
action conditions. The acetonide group in 1 was selective-
Synlett 2001 No. 4, 535–537 ISSN 0936-5214 © Thieme Stuttgart · New York

536
X. Xiao, D. Bai
Table Selective Hydrolysis of Acetonide by CeCl3 7H2O-(COOH)2 in Acetonitrile
LETTER
a All products show satisfactory 1H NMR data.8
b Isolated yields after purification.
Acknowledgement
(5) Leblanc, Y.; Fitzsimmons, B.J.; Adams, J.; Perez, F.; Rokach,
J. J. Org. Chem. 1986, 51, 789.
(6) Bäurle, S.; Hoppen, S.; Koert, U. Angew. Chem., Int. Ed.
1999, 38, 1263.
(7) Ichihara, A.; Ubukata, M.; Sakamura, S. Tetrahedron. Lett.
1977, 3473.
We thank National Natural Sciences Foundation of China and State
Key Laboratory of Bioorganic and Natural Products Chemistry for
financial supports.
(8) Typical experimental procedure: To a stirred solution of
acetonide protected diol (1mmol) and CeCl3 7H2O (745mg,
2mmol) in acetonitrile (5ml) was added (COOH)2 (6.3mg,
0.05mmol) at ambient temperature. Stirring was continued for
the time period as indicated (Table). Upon completion of the
reaction, the mixture was cooled to 0 °C, solid sodium
bicarbonate was added to neutralize the pH of the reaction
mixture, which was then concentrated in vacuo. The residue
was treated with ethyl acetate and filtered. The filtrate was
then concentrated, and the resulting product was subjected to
flash chromatography (silica gel, ethyl acetate) to afford the
corresponding diol. 1H NMR (400MHz, CDCl3) entry a:
6.90 (dd, 1H, J = 15.7Hz, 2.4Hz), 6.15 (d, 1H, J = 15.7Hz),
4.40-4.45 (m, 1H), 4.20 (q, 2H, J = 7.0Hz), 3.92 (brs, 2H),
3.75-3.81 (m, 2H), 1.31 (t, 3H, J = 7.0Hz); entry b: 7.22
(dd, 2H, J = 6.6Hz, 2.2Hz), 6.86 (dd, 2H, J = 6.6Hz, 2.2Hz,),
4.43 (s, 2H), 3.82-3.87 (m, 1H), 3.78 (s, 3H), 3.56-4.22 (m,
References and Notes:
(1) For example: Schkeryantz, J.M.; Danishefsky, S.J. J. Am.
Chem. Soc. 1995, 117, 4722. Masters, J.J.; Link, J.T.; Snyder,
L.B.; Young, W.B., Danishefsky, S.J. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1723. Boyce, R.J.; Pattenden, G. Tetrahedron.
Lett. 1996, 37, 3501.
(2) Clode, D.M. Chem. Rev. 1979, 79, 491. Nicolaou, K.C.;
Daines, R.A.; Uenishi, J; Li, W.S.; Papahatjis, D.P.;
Chakraborty, T.K. J. Am. Chem. Soc. 1988, 110, 4672. Kim,
Y; Singer, R.A; Carreira, E.M. Angew. Chem., Int. Ed. 1998,
37, 1261.
(3) Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic
Synthesis; 3rd ed.; John Wiley and Sons: New York, 1999.
(4) Markó, I.E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.;
Quesnel, Y.; Vanherck, J.-C. Angew. Chem., Int. Ed. 1999, 38,
3207.
Synlett 2001, No. 4, 535–537 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
An Efficient and Selective Method for Hydrolysis of Acetonides
537
2H) 3.22-3.28 (m, 2H), 1.64-1.80 (m, 2H); entry c: 7.42 (dd,
6H, J = 7.6Hz, 1.1Hz), 7.31 (td, 6H, J = 7.6Hz, 1.1Hz), 7.22
4.39-4.43 (m, 1H), 3.87-3.90 (m, 1H), 3.68-3.72 (m, 1H),
3.50-3.56 (m, 1H), 2.97 (brs, 2H), 1.80-1.93 (m, 2H); entry h:
5.67-5.72 (m, 2H), 4.10 (d, 2H, J = 5.1Hz), 3.76-3.79 (m,
1H), 3.42-3.47 (m, 2H), 2.37-2.41 (m, 1H), 2.25-2.30 (m, 1H),
1.85 (brs, 2H), 0.91 (s, 9H), 0.02 (s, 6H); entry i: 7.62-7.67
(m, 4H), 7.26-7.39 (m, 6H), 4.19-4.26 (m, 1H), 4.12-4.17 (m,
1H), 4.00 (brs, 3H), 3.85-3.92 (m, 2H), 3.45-3.64 (m, 2H),
1.70-1.78 (m, 2H), 1.55-1.65 (m, 2H), 1.05 (s, 9H); entry j:
4.18-4.22 (m, 1H), 4.00-4.10 (m, 1H), 3.71-3.78 (m, 2H),
1.43 (s, 3H).
(td, 3H, J = 7.6Hz, 1.1Hz), 3.86-3.92 (m, 1H), 3.42-3.47 (m,
1H), 3.59-3.62 (m, 1H), 3.45-3.50 (m, 1H), 3.37-3.40 (m, 1H),
2.29 (brs, 2H), 1.79-1.87 (m, 2H); entry d: 4.25-4.32 (m,
1H), 4.16-4.18 (m, 1H), 3.75-3.80 (m, 1H), 3.61-3.67 (m, 1H),
3.42-3.49 (m, 1H), 3.01 (brs, 2H), 2.05 (s, 3H), 1.69-1.79 (m,
2H); entry e: 7.78 (d, 2H, J = 7.7Hz), 7.30 (d, 2H,
J = 7.7Hz), 4.20-4.28 (m, 1H), 4.10-4.18 (m, 1H), 3.82-3.90
(m, 1H), 3.60-3.66 (m, 1H), 3.40-3.46 (m, 1H), 2.42 (s, 3H),
2.18 (brs, 2H), 1.66-1.82 (m, 2H); entry f: 4.48-4.55 (m,
1H), 4.33-4.38 (m, 1H), 3.78-3.83 (m, 1H), 3.62-3.67 (m, 1H),
3.42-3.46 (m, 1H), 2.70 (brs, 2H), 1.76-1.89 (m, 2H); entry g:
8.04 (dd, 2H, J = 7.0Hz, 1.1Hz), 7.78 (td, 1H, J = 7.0Hz,
1.1Hz), 7.43 (td, 2H, J = 7.0Hz, 1.1Hz), 4.59-4.62 (m, 1H),
(9) Yadav, J.S.; Reddy, B.V.S. Synlett 2000, 1275.
Article Identifier:
1437-2096,E;2001,0,04,0535,0537,ftx,en;Y21900ST.pdf
Synlett 2001, No. 4, 535–537 ISSN 0936-5214 © Thieme Stuttgart · New York