9-Anthraldehyde acetals as protecting groups

Article abstract of DOI:10.1016/S0040-4039(03)00276-4

Anthraldehyde acetals can be introduced regioselectively to carbohydrates in high yields. Advantages over conventional acetal protecting groups are increased crystallinity and strong absorbance and fluorescence which facilitate purification and reaction monitoring. The anthraldehyde acetals can be deprotected selectively in the presence of benzylidene acetals and can be cleaved regioselectively to yield 6-O-(9-anthracenyl)methyl ethers.

Full text of DOI:10.1016/S0040-4039(03)00276-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2279–2281
9-Anthraldehyde acetals as protecting groups
Ulf Ellervik*
Organic and Bioorganic Chemistry, Center for Chemistry and Chemical Engineering, Lund University, PO Box 124,
SE-221 00 Lund, Sweden
Received 19 December 2002; revised 22 January 2003; accepted 29 January 2003
Abstract—Anthraldehyde acetals can be introduced regioselectively to carbohydrates in high yields. Advantages over conventional
acetal protecting groups are increased crystallinity and strong absorbance and fluorescence which facilitate purification and
reaction monitoring. The anthraldehyde acetals can be deprotected selectively in the presence of benzylidene acetals and can be
cleaved regioselectively to yield 6-O-(9-anthracenyl)methyl ethers. © 2003 Elsevier Science Ltd. All rights reserved.
Chemical manipulation of polyfunctional organic com-
pounds usually requires extensive use of protecting
groups. These protecting groups should preferably be
readily available, easily introduced and removed, well
characterized, stable to a wide range of reactions, work-
up and purification conditions and leave no by-prod-
ucts.1 In addition, protecting groups can give the
molecules specific properties such as crystallinity or
enhanced traceability.
dimethyl acetal 27,8 for selective protection of diols.
Anthraldehyde dimethyl acetal 2 was synthesized by
treatment of anthraldehyde with trimethyl orthofor-
mate under acidic conditions. The resulting anthralde-
hyde dimethyl acetal 2 was washed with methanol and
isolated as pale yellow crystals in 82% yield (Scheme 1).
The crystals grew darker7 over time which did not seem
to influence the yield of the protection step.
2-(Trimethylsilyl)ethyl b-
-glucopyranoside 39 was pro-
D
In order to facilitate reaction monitoring during the
synthesis of carbohydrate derivatives on solid supports,
we were looking for a protecting group which was
required to be stable under basic conditions and be
highly fluorescent, and thus, our attention was directed
towards anthraldehyde acetals.
tected with 2 by transacetalisation in MeCN catalyzed
by pTSA to give 4 in 96% yield as a crystalline material
(Scheme 2).
In order to study the stability of the new acetal protect-
ing group, compound 4 together with the analogous
benzylidene protected compound9 as reference were
subjected to acetic acid (80% in water). At 90°C, both
the anthraldehyde acetal and the benzylidene acetal
were completely deprotected in less than 5 min. How-
ever, at room temperature compound 4 was more than
95% deprotected in less than an hour, while the
analogous benzylidene compound was deprotected to
less than 5% in the same time, indicating that an
anthraldehyde acetal can be selectively deprotected in
the presence of benzylidene acetals. This is in full
A number of aromatic acetals (e.g. benzylidene,2 4-
methoxybenzylidene,3 2-nitrobenzylidene,4 and benzo-
phenone5) have been used as protecting groups in syn-
thetic organic chemistry. These are easily introduced
under slightly acidic conditions and can be cleaved
using either acidic conditions to yield the diol or reduc-
tive or oxidative conditions to yield monoprotected
compounds. However, the corresponding anthralde-
hyde acetals have so far not been used as protecting
groups for diols.
Benzaldehyde dimethyl acetal has been shown to be a
powerful reagent for introducing benzylidene acetals6
and it was decided to use the analogous anthraldehyde
Scheme 1. Reagents and conditions: (a) (MeO)3CH, MeOH,
* Tel.: +46-46-222 8220; fax: +46-46-222 8209; e-mail: ulf.ellervik@
bioorganic.lth.se
Amberlite IR-120 H+, 60°C, 15 h, 82%.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00276-4

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U. Eller6ik / Tetrahedron Letters 44 (2003) 2279–2281
Compound 4 was then acetylated using Ac2O/pyridine
to give 5 in 98% yield. In order to confirm the base
stability of the anthraldehyde acetal, 5 was deacetylated
(NaOMe–MeOH) to restore 4 in 95% yield.
In order to test if the anthraldehyde acetal could be
selectively cleaved under reductive conditions, 5 was
subjected to NaBH3CN/THF/HCl/Et2O10 which gave
the 6-O-(9-anthracenyl)methyl ether 6 in 91% yield.†
The same reaction sequence (a–e) was repeated using
phenyl 1-thio-b-
-galactopyranoside 711 which gave
D
similar yields (Scheme 3). The galactose acetal 8 seemed
to be slightly more stable towards acidic hydrolysis
compared to the corresponding glucose derivative 4.
Deprotection using acetic acid (80% in water at room
temperature) required 2 h to give more than 95%
deprotection. The corresponding benzylidene acetal12
showed less than 5% deprotection during the same
reaction time, again indicating selective deprotection.
Reductive opening of the galactose acetal 9 gave com-
pound 10 in a modest 57% yield, despite several
attempts to optimize the yield. There is at present no
explanation for this observation.‡
Scheme 2. Reagents and conditions: (a) 2, MeCN, pTSA, 3 h,
96%. (b) AcOH (80%, aq.), 90°C, 2 h, 97%. (c) Pyridine,
Ac2O, 24 h, 98%. (d) NaOMe–MeOH (0.05 M), 2 h, 95%. (e)
NaBH3CN, THF, HCl/Et2O, 2 h, 91%.
All synthesized compounds 3–10 were easily crystallized
and were highly fluorescent. They could be followed
Figure 1. Absorbance spectrum of compound 5 (0.10 mM in
MeCN, solid line) and fluorescence spectrum of compound 5
(0.010 mM in MeCN, uEx=364 nm, dotted line).
Scheme 3. Reagents and conditions: (a) 2, MeCN, pTSA, 15
h, 94%. (b) AcOH (80%, aq.), 90°C, 1 h, 94%. (c) Pyridine,
Ac2O, 24 h, 97%. (d) NaOMe–MeOH (0.05 M), 1 h, 100%. (e)
NaBH3CN, THF, HCl/Et2O, 2 h, 57%.
† The structure of compound 6 was confirmed using two-dimensional
NMR techniques.
agreement with earlier observations where electron
releasing groups gave faster acetal hydrolysis.3 Depro-
tection of compound 4 using standard conditions
(90°C) gave compound 3 in 97% yield.
‡ The structure of compound 10 was confirmed using two-dimen-
sional NMR techniques. Regioselective reductive opening of the
corresponding benzylidene compound gave a moderate 70% yield.

U. Eller6ik / Tetrahedron Letters 44 (2003) 2279–2281
2281
during chromatography by simply using a hand-held
UV-lamp to illuminate the column. The absorbance
(mmax=6440 M−1 (364 nm)) and fluorescence spectra
were recorded from a solution of compound 5 in
MeCN (Fig. 1).13,14
To summarize, anthraldehyde acetals can be introduced
selectively to carbohydrates in high yields, induce crys-
tallinity and show strong absorbance and fluorescence.
The anthraldehyde acetals can be deprotected selec-
tively in the presence of benzylidene acetals and can be
cleaved regioselectively to yield 6-O-(9-anthracenyl)-
methyl ethers.
Anthraldehyde dimethyl acetal 2. Anthraldehyde (3.09 g,
15 mmol) and trimethyl orthoformate (1.86 mL) were
dissolved in MeOH (15 mL) and Amberlite IR-120 H+
(75 mg) was added and the mixture was stirred at 60°C
for 15 h. The mixture was cooled to rt and CH2Cl2 (10
mL) was added. The solution was filtered and concen-
trated. MeOH (25 mL) was added and the mixture was
cooled to −20°C and the product was filtered and
washed with MeOH (−20°C) to give 2 (3.09 g, 82%).
13C NMR (CDCl3): l 131.91, 130.36, 129.62, 129.43,
126.40, 125.32, 125.29, 104.60, 56.32.
Acknowledgements
This work was supported by the Swedish Research
Council and the Knut and Alice Wallenberg
Foundation.
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