MW-assisted Er(OTf)3-catalyzed mild cleavage of isopropylidene acetals in Tricky substrates

Article abstract of DOI:10.1016/j.tetlet.2008.01.089

Erbium(III) trifluoromethane sulfonate is proposed as a very gentle Lewis acid catalyst in a MW-assisted chemoselective method for the cleavage of isopropylidene acetals in awkward substrates by using pure water as the solvent.

Full text of DOI:10.1016/j.tetlet.2008.01.089

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1961–1964
MW-assisted Er(OTf)3-catalyzed mild cleavage of isopropylidene
acetals in Tricky substrates
a,
a
b
a
c
*
Antonio Procopio , Marco Gaspari , Monica Nardi , Manuela Oliverio , Roberto Romeo
a
` `
Dipartimento Farmaco-Biologico, Universita degli Studi della Magna Grascia Complesso Ninı Barbieri, 88021, Roccelletta di Borgia (CZ), Italy
b
`
Dipartimento di Chimica, Universita della Calabria, Ponte Bucci, 87030, Arcavacata di Rende (CS), Italy
c
`
Dipartimento Farmaco-Chimico Universita di Messina, Messina, Italy
Received 17 December 2007; revised 17 January 2008; accepted 21 January 2008
Available online 31 January 2008
Abstract
Erbium(III) trifluoromethane sulfonate is proposed as a very gentle Lewis acid catalyst in a MW-assisted chemoselective method for
the cleavage of isopropylidene acetals in awkward substrates by using pure water as the solvent.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Isopropylidene acetal; Erbium(III) triflate; MW-assisted synthesis; Water as solvent
The occurrence of diols in synthetic targets and in natu-
ral molecules (e.g., carbohydrates and nucleosides) has led
to the development of a number of protective groups of
varying stability. Cyclic isopropylidene acetals, also known
as acetonides, have been used more frequently than any
other protecting group for the protection of diols that
being easily prepared and cleaved almost exclusively in
protic and Lewis acids.1 However, there are many occa-
sions in which isopropylidene acetals are remarkably stable
or there are other functional groups present, which cannot
withstand drastic hydrolysis conditions. Typical examples
of such kind of substrates are nucleosides and carbo-
hydrate building blocks, where normal acidic catalysts for
deprotection of acetonide can also hydrolyse acid-sensitive
linkages.1,2 For this purpose, a rapid increment in the use
of mild Lewis acid catalysts has been registered3 and some
triflate derivatives were proposed as reagents in the very
gentle deprotection procedures of acetals.4 However, a
mild method to deprotect stubborn isopropylidene acetals
in tricky substrates was never reported.
As part of our efforts to develop new catalytic methods
for valuable protection/deprotection steps of various
functional groups,5 we have already reported the use of
Ce(III) and Er(III) trifluoromethane sulfonates as mild
and efficient cleaving agents for acetals and ketals.4a,b
Unfortunately, only low yield or no reaction was registered
when both methods were applied to a particularly stable
isopropylidene groups such as 1,2:5,6-diacetone glucofura-
nose 1 or problematic molecules like 20,30-O-isopropylidene
nucleosides (Table 1, entries 1–4). Nevertheless, raising
reaction temperature up to 60 °C permitted the quantita-
tive isopropylidene cleavage in substrate 2 in only 45 min
(Table 1, entry 5), but the application of this modified
protocol still gave only partial results on different challeng-
ing substrates such as 20,30-O-isopropylideneadenosine 3,
2,3-O-isopropylidene-D-ribono-1,4-lactone 4, and 2,3-O-
isopropylidene-D-erythronolactone 5 (Table 1, entries
6–8). In fact, only in the case of 2,3-O-isopropylidene-D-
ribono-1,4-lactone 4, the acetonide cleavage was completed
very quickly in 30 min (Table 1, entry 7). No improvement
in yield was registered when the amount of catalyst was
raised up to 10 mol % (Table 1, entry 9), but some pro-
gresses were obtained when, in an attempt to improve the
solubility of these substrates, the reactions were conducted
*
Corresponding author. Fax: +30 961391270.
E-mail address: procopio@unicz.it (A. Procopio).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.089

1962
A. Procopio et al. / Tetrahedron Letters 49 (2008) 1961–1964
Table 1
vide the isopropylidene cleavage under smooth conditions
and in satisfactory yields, at least for the more stubborn
substrates.
In last years, the use of microwave energy to heat reac-
tion mixtures in organic synthesis is receiving increasing
attention, not only since microwave heating is able to
reduce chemical reaction times from hours to minutes,
but also for its ability to reduce side reactions, increase
yields, and improve reproducibility.6
Very recently, we reported a simple and efficient MW-
assisted hydrolysis of acetals and ketals in simple deionized
water and in extraordinarily short time.7 Although, several
different aliphatic as well as aromatic substrates were suc-
cessfully treated, still some isopropylidene derivatives
showed to be resistant in that experimental conditions.
Nevertheless, such good preliminary results push us to test
the applicability of this technique to develop an efficient
and mild method for isopropylidene cleavage in resistant
and/or multifunctional substrates by using the previously
reported Er(III) trifluoromethanesulfonate.
First, we tested the method on diacetone glucofuranose
1 that contains in 1,2-position one of the most obstinate
isopropylidene protecting group which we were not able
to completely remove in our previous reports4a,b and is
usually cleaved under very drastic conditions.8 The double
isopropylidene cleavage was first attempted in water-satu-
rated nitromethane by using Er(OTf)3 1 mol % as well as
catalyst in a teflon reaction vessel of a Synthos 3000 micro-
wave synthesizer and stirred at 110 °C for 30 min under
microwave irradiation (1000 W applying temperature con-
trol regulate irradiation intensity).
In this case a good yield of completely deprotected prod-
uct was collected and almost the same result was registered
performing the removal in water-saturated acetonitrile
(Table 2, entry 1), but quantitative double isopropylidene
cleavage was accomplished in only 15 min when the reac-
tion was carried out in simple pure water (Table 2, entry
1). This astonishing result drove us toward adopting pure
water as the solvent for the other substrates as well. So,
the deprotection of 20,30-O-isopropylideneuridine 2 was
completed in only 5 min (Table 2, entry 2), but for the most
resistant 20,30-O-isopropylideneadenosine 3 only 70% of
cleavage was registered by using 1 mol % of catalyst and
satisfactory yield of deprotected adenosine was obtained
by increasing up to 5 mol % the amount of Er(OTf)3 (Table
2, entry 3). Noteworthy, no isopropylidene cleavage was
registered performing this reaction in the same experimen-
tal conditions, but using conventional heating system
[refluxing water, 5 mol % the amount of Er(OTf)3] it was
registered. Again, extremely fast was the complete removal
of 2,3-O-isopropylidene-D-ribono-1,4-lactone 4 and 5,6-O-
isopropylidene-L-ascorbic acid 6 when only 5 min were suf-
ficient to complete the reaction (Table 1, entries 4 and 6).
The use of the Er(OTf)3 as Lewis acid catalyst in MW-
assisted protocol showed its helpfulness in another case
of obstinate acetonide removal when the complete clea-
vage of 2,3-O-isopropylidene-D-erythronolactone 5 was
Isopropylidene cleavage by means of Ce(III) and Er(III) triflate
Entry Substrate
Catalyst
(mol %)
Solvent
t
Yield
(min) (%)
O
OH
O
O
1
2
Ce(OTf)3 (30) CH3NO2 180
99a
O
1
O
O
O
OH
O
Er(OTf)3 (1)
CH3NO2 180
78b
O
1
O
HO
HO
HO
U
O
3
4
5
6
Ce(OTf)3 (30) CH3NO2 180
28
O
O
2
U
O
O
Er(OTf) (1)
Er(OTf) (1)
Er(OTf) (1)
CH3NO2 180
CH3NO2 45
CH3NO2 180
CH3NO2 30
48
O
O
O
O
2
U
O
>99c
O
2
HO
A
O
15
O
3
HO
O
O
7
8
Er(OTf) (1)
Er(OTf) (1)
>99
18
O
4
O
O
O
CH3NO2 180
CH3NO2 180
CH3CN
CH3CN
H2O
O
5
9
10
11
12
13
a
3
3
5
3
5
Er(OTf)3 (10)
Er(OTf)3 (10)
Er(OTf)3 (10)
Er(OTf)3 (10)
Er(OTf)3 (10)
20
180
180
180
180
48c
42d
57
H2O
53
After 4 days, the 1,2-O-isopropylidene-D-glucopyranoside is still the
only product formed.
b
After 7 days, using 30 mol % of catalyst, only 25% of D-glucose was
collected.
c
Reaction performed at 60 °C.
Higher temperatures did not improve the yield of product.
d
in water-saturated acetonitrile (Table 1, entries 10 and 11),
and ultimately, the best conditions to accomplish the iso-
propylidene cleavage were experienced when the reaction
was performed in simple water at 60 °C (Table 1, entries
12 and 13).
Nevertheless, on the basis of the preliminary opposite
results reported in Table 1, it is evident that the traditional
way to use Lewis acid catalyst will hardly be able to pro-

A. Procopio et al. / Tetrahedron Letters 49 (2008) 1961–1964
1963
Table 2
MW-assisted isopropylidene cleavage by means of Er(III) triflate in water
Table 2 (continued)
Entry Substrate
Catalyst
(mol %)
t
Yielda,b
Entry
Substrate
Catalyst
(mol %)
t
Yielda,b
(%)
(min) (%)
(min)
O
O
14
1
5
10
20
>99
88
O
OH
O
O
OBz
1
1
1
1
30
30
15
78c
80d
>99
14
O
1
O
OH
O
OH
O
O
STol
HO
15
O
HO
O
U
HO
HO
O
2
3
1
5
>99
15
O
O
2
a
All products were purified by chromatographic column and identified
by comparison of their 1H and 13C NMR spectral data with those of
authentic compounds and the literature reported data.
HO
A
O
b
1
5
30
30
70
88
For hydrosoluble products the yield was determined by HPLC using
O
O
the standard addition method.
c
3
The reaction was performed in water saturated nitromethane.
The reaction was performed in water-saturated acetonitrile.
d
HO
O
O
4
5
6
7
8
9
1
5
1
5
5
5
5
>99
>99
>99
93
O
O
O
4
performed in only 30 min (Table 2, entry 5), much milder
than the harsh conditions previously reported for similar
substrates.9 More difficult was the cleavage of acetonide
group from the three nucleosides 20,30-O-isopropyl-
idenecytidine 7, 20,30-O- isopropylideneguanosine 8, and
20,30-O-isopropylideneinosine 9, where higher amounts
of catalyst were needed to collect satisfactory yields of
deprotected nucleosides (Table 2, entries 7–9). Deoxynucleo-
sides are interesting medicinal agents, since such material
cannot be phosphorylated and incorporated into nucleic
acids offering thus the possibility to reduce toxicity and
increase specificity.10 50-Deoxy-20,30-O-isopropylidene-
5-fluorouridine 10, 50-deoxy-20,30-O-isopropylidene-5-fluor-
ocytidine 11, and 1-(50-deoxy-20,30-O-isopropylidene-b-
D-lyxofuranosyl)-5-fluorouridine 12 are considered strate-
gic intermediates in some important synthetic pathways
to furnish nucleoside analogues.
O
O
30
5
O
O
5
O
O
O
HO
OH
6
HO
C
O
30
30
30
O
O
7
O
8
HO
G
O
85
O
HO
The present MW-assisted Er(OTf)3-catalyzed mild
method provided acetonide cleavage in these substrates in
very efficient way, as shown in Table 2, entries 10–12.
The usefulness of the present method was further explored
and some other multifunctional substrates were submitted
to the action of Er(OTf)3 in water under MW-assistance.
Recently, the selective cleavage of 1,2-O,-isopropylidene-
6-O-benzylhexane-1,2,6-triol 13 and 1,2-O-isopropylidene-
6-O-benzoylhexane-1,2,6-triol 14 was reported to have
been accomplished in 3 h and 86% and 78% of yields,
respectively, using several equivalents of ZnBr2 in dichloro-
methane.11 Remarkably, in our system, the same molecules
reported the complete acetonide removal in only 10 min
(Tabel 2 entries 13 and 14). Since the wide application of
isopropylidene protecting group in the synthesis of awk-
ward carbohydrates, we tested the present protocol in the
deprotection of the acetonide system in the 30,40-O,O-iso-
I
O
86
O
O
9
5F
U
O
10
1
5
>99
O
O
10
5F
C
O
11
12
5
1
30
15
84
94
O
O
11
5F
U
O
O
O
12
propylidene-4-methyl
(1?4)-1-thio-b-D-glucopyranoside 15 which was recently
reported to happen at rt, but in 17 h by means of
phenyl
(b-D-galactopyranosyl)-
O
13
1
10
>99
O
OBn
13

1964
A. Procopio et al. / Tetrahedron Letters 49 (2008) 1961–1964
20 mol % vanadyl triflate as the catalyst.12 Still surpris-
ingly, the cleavage of the acetal accomplished in only
20 min registered a comparable yield to that reported in
the above quoted reference (Table 2, entry 15).
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The MW-assisted Er(OTf)3 catalyzed isopropylidene
cleavage protocol can be considered a tangible improve-
ment with respect to the other existing mild methods that
showed to be incapable of removing the acetonide protect-
ing group from tricky substrates and/or very resistant posi-
tion. Er(OTf)3 is easy to handle and is one of the cheapest
commercially available lanthanoid triflate derivatives. It is
used in true catalytic amounts, all reactions run smoothly
in very short time, and almost under neutral conditions;
moreover, the process can really be considered ‘green’ since
it is performed in pure water.13
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13. Typical procedure: 1H spectra were recorded with a Bruker WM 300
instrument, at 300 MHz. Samples were dissolved in CDCl3, CD3OD,
(CD3)CO, or DMSO-d6. ‘Chemical shifts’ are given in parts per
million (ppm) from tetramethylsilane as the internal, coupling
constants (J) are given in Hertz. All the chemicals were purchased
from commercial sources besides the protected acetals 10–15, synthe-
sized according to trivial literature methods.9–11 Compound
2
(100 mg, 0.352 mmol) was suspended in water (6.0 ml) containing
1 mol % of Er(OTf)3 in the teflon reaction vessel of a Synthos 3000
microwave synthesizer and the teflon tube tapped and stirred at
120 °C for 5 min under MW irradiation (1000 W). After 5 min, the
deprotection was completed and the yield was determined by HPLC
using the standard addition method. The evaporation of water
solution furnished the crude product, which could be purified by
flash-chromatography.