Ceric ammonium nitrate/pyridine: A mild reagent for the selective deprotection of cyclic acetals and ketals in the presence of acid labile protecting groups

Article abstract of DOI:10.1055/s-2002-34225

The reagent system ceric ammonium nitrate/pyridine can perform the cleavage of primary and (in some cases) secondary acetonides, benzylidenes and tetrahydropyranyl ethers. The mild acididity of the reaction system (pH 4.4) allows deprotections to be performed in the presence of several acid labile protecting groups.

Full text of DOI:10.1055/s-2002-34225

LETTER
1645
Ceric Ammonium Nitrate/Pyridine: A Mild Reagent for the Selective
Deprotection of Cyclic Acetals and Ketals in the Presence of Acid Labile
Protecting Groups
Selective
D
eprotec
a
tionof
C
yc
s
lic Acetal
p
s
a
ndKetalsare Barone, Emiliano Bedini, Alfonso Iadonisi, Emiliano Manzo, Michelangelo Parrilli*
Dipartimento di Chimica Organica e Biochimica, Università di Napoli Federico II, Complesso Universitario Monte Santangelo Via Cintia,
4 80126 Napoli, Italy
Fax +39(81)674393; E-mail: parrilli@unina.it
Received 31 May 2002
This paper is dedicated to Prof. Lorenzo Mangoni on the occasion of his 70th birthday.
preferential cleavage of secondary cyclic acetonides is de-
Abstract: The reagent system ceric ammonium nitrate/pyridine can
scribed. As a matter of fact, a survey of all reported
perform the cleavage of primary and (in some cases) secondary ac-
etonides, benzylidenes and tetrahydropyranyl ethers. The mild aci-
methods2–18 shows just one example2 for this kind of
deprotection. However, there is no comparison with trityl
ethers and the cleaved acetonide is somehow constrained
being located on a cyclic trans diol. Therefore, to the best
of our knowledge this seems to be the first report on the
removal of a secondary acetonide in the presence of a pri-
mary trityl ether.
didity of the reaction system (pH 4.4) allows deprotections to be
performed in the presence of several acid labile protecting groups.
Key words: ceric ammonium nitrate, lanthanides, hydroxyl-pro-
tecting groups, hydrolysis, carbohydrates
The search for novel conditions for the selective deprotec-
tion of substituted hydroxyl groups is one of the most ac-
tive research topics in synthetic organic chemistry,1
especially in the field of carbohydrate chemistry. In this
context, a widespread interest has been devoted to the se-
lective cleavage of cyclic acetals and ketals, commonly
used for the protection of 1,2- and 1,3-diols, in the pres-
ence of other functional groups.2–18
The higher tetrahydropyranyl cleavage ability of CAN
with respect to the proton is shown on compound 3a
(entries c, c ), which in every case retains both ketal
groups. The 3,4-ketal group, which is cleaved in 2a, re-
mains unchanged in 3a even after adding five aliquots of
CAN (3%) suggesting that the presence of the 1,2-ketal
group is responsible of the increased stability of the
3,4-ketal group. In general, under the conditions of hy-
drolysis of acetals, tetrahydropyranyl ethers also are
Very recently, we reported the cleavage of sugar cyclic
acetals (ketals) under mildly acidic conditions using
CAN/pyridine in acetone/water.19 An optimized proce-
dure was found adopting catalytic amounts of the reagent
system and following a gradual addition protocol. Herein
we wish to report the noteworthy selectivity of this proce-
dure towards a wide range of acid labile hydroxyl protect-
ing groups, as evinced by the the application of the
method on compounds 1a–18a (Figure 1, Table 1) easily
prepared following standard protocols.
4,12,11,14,18
cleaved,
being themselves acetals. However, in
some cases a discordant behaviour is found owing to
peculiar structural features of the substrate.2,3,9,15,16
The primary tosyl- (Ts), methylthiomethyl- (MTM), allyl-
oxycarbonyl- (Alloc), p-methoxybenzyl (PMB) groups
were completely inert (entries d–g, compounds 4a–7a)
under the reaction conditions.
The role of CAN in the cleavage of the primary ketal
group of diacetone glucofuranose derivatives 8a–10a de-
pends on the nature of the substituent at the 3-position.
A very interesting result of these investigations is the pref-
erential cleavage of secondary isopropylidene groups of
compounds 1a and 2a (entries a and b) in the presence of
primary trityl ethers. These derivatives remained com-
pletely unaltered when treated at the same pH with only
HNO3 without CAN (entries a , b ), indicating that the
proton acidity was not responsible for the cleavage,
probably due to the Lewis acid behaviour of Ce(IV).19 In
the literature several methods are reported for the selec-
With a p-methoxybenzyl group (compound 8a) the use of
CAN is not required as the 5,6-ketal cleavage is also
achieved in a comparably good yield by the proton acidity
(entries h, h ), with the t-butyldimethylsilyl (TBDMS)
group no cleavage occurs (entry i, compound 9a), while
with the acetyl group the catalytic role of CAN works very
well (entries l, l , compound 10a), but a partial migration
of the acetyl group is also involved. Actually, the isolated
5,6-de-isopropylidenated product (88%) is a 1:1.5:3 mix-
ture of 5-O-, 6-O- and 3-O-acetylated derivatives 10c, 10d
and 10b. The migration of the acetyl group has been re-
ported in other deprotections methodologies applied on
analogous substrates.20,21 The influence of CAN appears
to be more essential in the case of the primary ketal cleav-
age on the allo-derivative 11a where the deprotection oc-
tive cleavage of trityl ethers in the presence of cyclic
20–22
ketals,
while others display the opposite selectivity
trend.11,16,17 In other cases the cleavage selectivity is de-
pending on the structure of substrates.5,9,11 In no case the
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1645,1648,ftx,en;G11002ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1646
G. Barone et al.
LETTER
O
OTr
O
OR
HO
OTr
O
O
OTr
O
HO
HO
O
O
O
O
O
O
3a R: THP
4a R: Ts
5a R: MTM
6a R: Alloc
7a R: PMB
3b R: H
HO
O
OCH3
HO
OCH3
OCH3
1a
2a
1b
R2O
R1O
O
O
O
O
HO
O
OR
O
OR
O
HO
O
O
O
O
O
O
O
O
O
8b R: PMB, R1: R2: H
10b R: Ac, R1: R2: H
10c R1: Ac, R:R2: H
10d R: R1: H, R2: Ac
OR
8a R: PMB
9a R: TBDMS
10a R: Ac
OR
11a R: MTM
12a R: TBDMS
11b R: MTM
11c R: H
12b R: TBDMS
OR
OH
HO
Ph
O
O
O
O
HO
O
R1O
R2O
HO
O
O
AcO
AcO
OCH3
HO
OCH3
13a
OCH3
O
13b R1: R2: Ac
13c R1: H, R2: Ac
13d R
HO
14a
15a R: DMT
16a R: TBDMS
15b R: H
HO
1: Ac, R2: H
OCH3
AcO
AcO
O
CH2OR
O
AcO
OAc
O
O
O
(CH2)7CH3
AcO
OAc
OAc
17a
OAc
19a
18a R: THP
18b R: H
Figure 1
curs in 91% yield (entry m) with respect to the only 4% inert. Removal of the THP protecting group by CAN was
found in the reaction without CAN (entry m ). The isolat- also observed on a non-carbohydrate structure (entry t,
ed yield (68%) is smaller than that evaluated by GLC and compound 18a), which was previously used to show the
the 5,6-de-isopropylidenated product contains a minor ability of CAN to perform the deprotection of THP ethers
amount (7%) of the de-methylthiomethylated derivative under neutral condition.11 We have already shown19 that
11c. In contrast, in another approach to cleave ketals the the described buffered condition at pH = 8 are actually
methylthiomethyl group was found unstable.2 Changing acidic. As a matter of fact, when the pH is rigorously held
the substituent at the 3 position results in a different at 8 the de-tetrahydropyranylation does not ocur at all (en-
course of reaction: in particular with the 3-O-TBDMS de- try u), while under the described conditions11 at pH 2 the
rivative 12a cleavage occurs in low yields even adding deprotection occurs (entry v).
five aliquots of CAN (3%) (entry n). Since this happens
also for the corresponding gluco derivative 9a (entry i),
As for the cleavage of t-butyldimethylsilyl ether, the
above results indicate that both primary and secondary
the minor reactivity of these silylated compounds with re-
(TBDMS) ethers are inert under the acetal cleavage con-
spect to other derivatives can not be simply ascribed to
ditions reported in this paper. This is in agreement with
steric factors but, probably, to electronic effects. The ad-
the general trend of other procedures.2,4,6,10,12,14,15,17 The
vantage of using CAN is also shown for the cleavage
opposite trend seems to occur just for CAN in MeOH8
(94% GLC yield) of the benzylidene acetal of 13a (entry
which is able to cleave both primary and secondary
TBDMS ethers while, in one example, a sterically hin-
o) which proceeded in only 5% of yield without CAN (en-
try o ). The isolated de-acetalated product (92%) contains
dered ethylene ketal group is inert. However, when we
also a 18% of a mixture of 3-O- and 2-O-monoacetylated
treated the less hindered dioxolane 19 with CAN in meth-
derivatives 13d and 13c in a 5:1 ratio. The primary isopro-
pylidene group of 14a was unaltered (entry p), while the
very acid labile dimethoxytrityl group was removed from
compound 15a (entry q).
anol under the described conditions,8 almost quantitative
formation of the corresponding ketone occurred. Other
cleavages of primary TBDMS ethers, induced by metal
cations, are reported 3,16 but they are performed in wet sol-
The methyl glycoside linkage (entries a, b, o–r), the pri- vents and no acidity measurement was performed. Differ-
mary TBDMS ether of derivative 16a (entry r) and the ent reactivity according to the nature of TBDMS ether can
glycosidic bond of peracetylated sucrose 17a (entry s) are be expected.23 In the case of FeCl3/SiO2,5 the removal of
Synlett 2002, No. 10, 1645–1648 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Selective Deprotection of Cyclic Acetals and Ketals
1647
Table 1. Reactivity of 1a–18a with CAN/Pyridine or HNO3 in Acetone/Water at pH 4.4 and at 68 °C
Entry
Substrate
Reagent
Time (h)
4
Productsa
GLC yield
Isolated yieldb
67 (95)
a
a
1a
1a
1
CAN (3%)
1b
94
HNO3
no reaction
b
b
2a
2a
3
CAN (3%)
6
6
1b
60
HNO3
no reaction
c
c
d
e
f
3a
3a
4a
5a
6a
7a
5
CAN (3%)
10
10
4
4
4
3b
3b
88
41
HNO3
1
1
1
1
CAN (3%)
no reaction
no reaction
no reaction
no reaction
CAN (3%)
CAN (3%)
CAN (3%)
g
4
h
h'
i
8a
8a
9a
8
CAN (3%)
12
7
4
8b
8b
66
62
82
HNO3
1
5
CAN (3%)
CAN (3%)
no reaction
81
l
10a
10
10b
10c
10d
48
16
24
l
10a
11a
HNO3
7
4
no reaction
91
m
2
CAN (3%)
11b
11c
11b
12b
61
7
m
n
11a
12a
HNO3
4
10
4
14
5
CAN (3%)
o
13a
5
CAN (3%)
10
13b
13c
13d
13b
94
74
3
15
o
p
13a
14a
HNO3
10
4
5
1
CAN (3%)
no reaction
q
r
15a
16a
1
1
CAN (3%)
CAN (3%)
4
15b
94
no reaction
s
17a
1
1
CAN (3%)
CAN (3%)
4
4
no reaction
t
u
v
18a
18a
18a
18b
18b
89
CAN pH = 8
no reaction
95
CAN pH = 2c
a All products were identified by 1H and 13C NMR spectroscopy.
b In parenthesis is indicated the yield evaluated on the reacted substrate.
c Under reaction conditions of ref.11
the TBDMS group is rather sluggish for secondary alco- cleaved only under conditions of ref.17. No explanation is
hols and does not proceed with primary derivatives, while given for these different reactivities of CeCl3 7H2O. As
the removal of both primary and secondary TBDMS for CAN, in addition to the two conditions reported 8,11 it
groups is described for substrates lacking acetal (ketal) has been used on SiO2 for the selective removal of trityl
groups.24
and silyl groups27 and for the opening of cyclic ketals
erroneously19 believed to occur under alkaline and/or neu-
tral conditions.28–30
A particular discussion is required for the methods based
on the use of CeCl3 7H2O which, together with CAN, is
by far the most used salt for hydroxyl deprotection. In conclusion, the peculiar reactivity of Ce(IV), when
CeCl3 7H2O has been always used in MeCN under two used in the reagent system CAN/pyridine at pH = 4.4, has
different conditions according to the presence21,24–26 or been highlighted. Under these conditions, the Lewis acid-
not16,17 of NaI which results to a different selectivity for ity of cerium was found to play a prominent role in the se-
some functional groups. Some procedures16,17 show a sim- lective deprotection of several acetonides in the presence
ilar behaviour as for primary and secondary cyclic ketals. of other commonly used hydroxyl protecting groups. In
However, a different selectivity was observed for trityl- particular, a comparative analysis of several reported
and p-methoxybenzyl ethers, which are only cleaved un- methods emphasizes the wider compatibility of this ap-
der conditions of ref.21, and TBDMS ethers, which are not proach with the stability of several acid labile protecting
Synlett 2002, No. 10, 1645–1648 ISSN 0936-5214 © Thieme Stuttgart · New York

1648
G. Barone et al.
LETTER
(29) Ates, A.; Gautier, A.; Bern, L.; Plancher, J.-M.; Quesnel, Y.;
Markó, I. Tetrahedron Lett. 1999, 40, 1799.
(30) Markó, I.; Ates, A.; Gautier, A.; Bern, L.; Plancher, J.-M.;
Quesnel, Y.; Vanherck, J.-C. Angew. Chem. Int. Ed. 1999,
38, 3207.
groups (trityl, TBDMS, methylthiomethyl, p-methoxy-
benzyl). To the best of our knowledge, this procedure31
appears to be the first one which is also able to cleave sec-
ondary isopropylidenes in the presence of primary trityl
groups.
(31) General Procedure for Removal of Acetal (Ketal)
Protecting Groups with CAN/Pyridine.
An aqueous solution of CAN at pH = 4.4 is prepared
dissolving 105 mg of CAN (purchased from Fluka) (0.19
mmol) in 19 mL of water and adding 60 L of pyridine. An
aliquot of this solution (1 mL, 0.01 mmol) is added to a
solution of substrate (0.33 mmol) in acetone (1 mL). The
mixture is kept at 68 °C and every 2 h another aliquot of
CAN solution is added until completion of the reaction (see
Table 1 for the amounts of catalyst added). The reaction is
quenched with pyridine and the mixture is then concentrated
under vacuum and product is extracted in chloroform or
ethyl acetate and then purified by silica gel chromatography
(eluent chloroform:methanol mixtures). The upscaling of the
process (to a 3 mmolar scale) was performed in the
deprotection of entry o with a comparable yield of 13b. In
this case an equal volume of acetone was added after every
addition of the aqueous solution of CAN/pyridine to prevent
the precipitation of the starting compound and the mixture
was extracted with ethyl acetate after neutralization without
concentrating the reaction solvent under vacuum. GLC
analysis was performed after peracetylation of the crude
reaction mixture.
References
(1) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999, 23.
(2) Guindon, Y.; Yoakim, C.; Morton, H. E. J. Org. Chem.
1984, 49, 3912.
(3) Lipshutz, B. H.; Pollart, D.; Monforte, J.; Kotsuki, H.
Tetrahedron Lett. 1985, 26, 705.
(4) Otera, J.; Nozaki, H. Tetrahedron Lett. 1986, 27, 5743.
(5) Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J. Org.
Chem. 1986, 51, 404.
(6) Ukaji, Y.; Koumoto, N.; Fujisawa, T. Chem Lett. 1989,
1623.
(7) Park, K. H.; Yoon, J. Y.; Lee, S. G. Tetrahedron Lett. 1994,
35, 9737.
(8) DattaGupta, A.; Singh, R.; Singh, V. K. Synlett 1996, 69.
(9) Rao, B. V.; Sarma, B. V. N. B. S.; Ravindranadh, S. V.;
Gurjar, M. K. Carbohydr. Lett. 1997, 377.
(10) Haraldsson, G. G.; Stefansson, T.; Snorrason, H. Acta Chem.
Scand. 1998, 52, 824.
(11) Markó, I. E.; Ates, A.; Augustyns, B.; Gautier, A.; Quesnel,
Y.; Turet, L.; Wiaux, M. Tetrahedron Lett. 1999, 40, 5613.
(12) Majumdar, S.; Bhattacharjya, A. J. Org. Chem. 1999, 64,
5682.
(13) Bose, D. S.; Jayalakshmi, B.; Narsaiah, A. V. Synthesis
2000, 67.
(14) Vijayasaradhi, S.; Singh, J.; Aidhen, I. S. Synlett 2000, 110.
(15) Sabitha, G.; Babu, R. S.; Reddy, E. V.; Yadav, J. S. Chem.
Lett. 2000, 1074.
Spectroscopic data of isolated saccharidic products.
1b: 1H NMR (200 MHz): = 7.20–7.50 (aromatic protons),
4.82 (1 H, d, J1,2 = 3.6 Hz, H-1), 4.05 (1 H, m, H-4), 3.74–
3.90 (3 H, m, H-2, H-3, H-5), 3.43 (3 H, s, -OCH3), 3.36–
3.48 (2 H, m, 6-CH2). 13C NMR: = 143.7, 128.6, 127.8 and
127.0 (aromatic carbons), 99.4 (C-1), 86.8 (non aromatic
trityl carbon), 71.0, 69.7, 69.5, 69.1, 63.2 (C-2, C-3, C-4,
C-5, and C-6), 55.2 (-OCH3).
8b: 1H NMR (200 MHz): = 7.30–6.90 (aromatic protons),
5.90 (1 H, d, J1,2 = 3.8 Hz, H-1), 4.58 (1 H, d, H-2), 4.54 (2
H, AB, Jgem = 11.6 Hz, -O-CH2Ar), 3.92–4.14 (3 H, m, H-3,
H-4 and H-5), 3.78 (OCH3), 1.46 and 1.30 (6 H, 2 s,
acetonide CH3). 13C NMR: = 129.6, 129.2, 114.1 (aromatic
carbons), 111.7 (acetonide quaternary carbon), 105.1 (C-1),
82.1, 81.5, 79.8, 71,7, 69.2 and 64.3 (C-2, C-3, C-4 and C-5,
C-6 and –OCH2Ar), 55.2 (-OCH3), 26.7 and 26.2 (acetonide
CH3).
(16) Sabitha, G.; Babu, R. S.; Rajkumar, M.; Srividya, R.; Yadav,
J. S. Org. Lett. 2001, 1119.
(17) Xiao, X.; Bai, D. Synlett 2001, 535.
(18) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. S. Chem. Lett. 2001,
430.
(19) Manzo, E.; Barone, G.; Bedini, E.; Iadonisi, A.; Mangoni,
L.; Parrilli, M. Tetrahedron 2002, 58, 129.
(20) Yadav, J. S.; Reddy, B. V. S. Carbohydr. Res. 2000, 329,
885.
11b: 1H NMR (200 MHz): = 7.30–6.90 (aromatic protons),
5.75 (1 H, d, J1,2 = 3.8 Hz, H-1), 4.74 (2 H, AB, Jgem = 13.1
Hz, -OCH2SCH3), 4.70 (1 H, dd, J2,3 = 8.7 Hz, H-2), 4.18 (1
H, dd, J3,4 = 3.4 Hz, H-3), 3.95–4.10 (2 H, m, H-4 and H-5),
3.69 (2 H, m, 6-CH2), 2.18 (3 H, s, -OCH2SCH3), 1.55 and
1.32 (6 H, 2 s, acetonide CH3). 13C NMR: = 113.1
(acetonide quaternary carbon), 104.0 (C-1), 78.5, 77.6, 75.0,
74,7, 71.2 and 63.0 (C-2, C-3, C-4 and C-5, C-6 and
-OCH2SCH3), 26.7 and 26.4 (acetonide CH3), 14.5
(-OCH2SCH3).
(21) Yadav, J. S.; Reddy, B. V. S. Synlett 2000, 1275.
(22) Lu, R. J.; Liu, D.; Giese, R. W. Tetrahedron Lett. 2000, 41,
2817.
(23) Yang, Y.; Yang, W.; Teo, C.; Lin, C. Synlett 2000, 1634.
(24) Bartoli, G.; Bosco, M.; Marcantoni, E.; Sambri, L.;
Torregiani, E. Synlett 1998, 209.
(25) Cappa, A.; Marcantoni, E.; Torregiani, E.; Bartoli, G.;
Bellucci, M. C.; Bosco, M.; Sambri, L. J. Org. Chem. 1999,
64, 5696.
(26) Marcantoni, E.; Nobili, F.; Bartoli, G.; Bosco, M.; Sambri,
L. J. Org. Chem. 1997, 62, 4183.
13b: 1H NMR (200 Mhz, CDCl3): = 5.30 (1 H, t, J2,3
3,4 = 9.8 Hz, H-3), 4.91 (1 H, d, J1,2 = 3.8 Hz, H-1), 4.83
=
J
(27) Hwu, J. R.; Jain, M. L.; Tsai, F.; Tsay, S.; Balakumar, A.;
Hakimelahi, H. J. Org. Chem. 2000, 65, 5077.
(28) Nair, V.; Nair, L. G.; Balagopal, L.; Rajan, R. Indian J.
Chem., Sect. B 1999, 38, 1234.
(1 H, dd, H-2), 3.65–3.90 (3 H, m, H-4, H-5, H-6), 3.40 (3 H,
s, 1-OCH3), 2.08 and 2.10 (6 H, 2 s, 2 -COCH3).
13C NMR (50 Mhz, CDCl3): = 171.2 and 170.4 (COCH3),
96.6 (C-1), 72.6, 71.1, 70.8 and 68.6 (C-2, C-3, C-4 and
C-5), 61.2 (C-6), 55.0 (1-OCH3), 20.7 and 20.6 (COCH3).
Synlett 2002, No. 10, 1645–1648 ISSN 0936-5214 © Thieme Stuttgart · New York