A mild and easy one-pot procedure for the synthesis of 2-deoxysugars from glycals

Article abstract of DOI:10.1016/S0040-4039(00)01643-9

Glycals can be converted into the corresponding 2-deoxysugars in good yields by treatment with N-iodosuccinimide in CH₃CN-H₂O 95:5 and removal of the iodide group using Na₂S₂O₄ in DMF/H₂O at room temperature. This method is easy to apply, sufficiently mild to allow the survival of acid-sensitive groups such as silyl and trityl ethers and less harmful to the environment than metal-based reactions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01643-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9177–9180
A mild and easy one-pot procedure for the synthesis of
2-deoxysugars from glycals
Valeria Costantino, Concetta Imperatore, Ernesto Fattorusso* and Alfonso Mangoni
Dipartimento di Chimica delle Sostanze Naturali, Universita` di Napoli ‘Federico II’ via D. Montesano 49,
80131 Napoli, Italy
Received 13 September 2000; accepted 20 September 2000
Abstract
Glycals can be converted into the corresponding 2-deoxysugars in good yields by treatment with
N-iodosuccinimide in CH3CN–H2O 95:5 and removal of the iodide group using Na2S2O4 in DMF/H2O
at room temperature. This method is easy to apply, sufficiently mild to allow the survival of acid-sensitive
groups such as silyl and trityl ethers and less harmful to the environment than metal-based reactions.
© 2000 Elsevier Science Ltd. All rights reserved.
2-Deoxysugars are ideal building blocks in the synthesis of a number of carbohydrate-based
structures, such as glycolipids, glycoproteins and many other bio-active substances. The usual
route to 2-deoxysugars involves direct or indirect hydration of the corresponding glycals. The
synthetic value of this reaction has been greatly increased by the development of the Lewis
acid-catalyzed diene-aldehyde cyclocondensation (LACDAC) reaction,1 which provides an easy
access to glycals of natural and non-natural sugars.
Within a synthetic project still in progress directed to the preparation of 2-deoxy analogs of
agelasphin,2 we needed to prepare the 6-O-TIPS-protected 2-deoxysugar 4 from the correspond-
ing glycal. Several methodologies have been developed to synthesize 2-deoxysugars from glycals,
but none are without drawbacks. The direct acid-catalyzed hydration requires rather drastic
conditions that may affect many protecting groups (including TIPS), as does a procedure
involving the phenylthio derivative3 because of the high temperature (refluxing toluene) required
for the reduction step. On the other hand, the hydration via oxymercuration-demercuration4 is
effective but not ideal from the environmental point of view. Therefore, we developed a simple
two-step, one-pot procedure to carry out this transformation under very mild conditions.
As reported in Scheme 1, in the first step the protected galactal is treated with N-iodosuccin-
imide in the presence of water to obtain the corresponding protected 2-deoxy-2-iodosugar as a
* Corresponding author. Tel: +39-081-678-503; fax: +39-081-678-552; e-mail: fattoru@unina.it
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01643-9

9178
mixture of stereoisomers. The addition to glycals of I+ from N-iodosuccinimide was first
exploited by Thiem5 in the synthesis of 2-deoxy-2-iodoglycosides, but, in that case, the I+
addition was followed by the nucleophilic attack of an alcohol to the resulting cation. To
complete the preparation of the 2-deoxysugar, the iodine atom in the 2-deoxy-2-iodosugar had
to be removed. The usual way to accomplish this task is reduction with (Ph)3SnH in refluxing
benzene.6 Although the reaction works well it requires relatively high temperatures and a reagent
containing a heavy metal that may be harmful to the environment, especially when the reaction
is scaled up. Therefore, we examined the possibility of using sodium dithionite (Na2S2O4) as an
alternative reducing agent.
Scheme 1.
Sodium dithionite is a readily available, inexpensive and an easy-to-use reducing agent. The
utility of sodium dithionite in dehalogenation reactions was not appreciated until 1982, when it
was shown to remove selectively halogen atoms that are a to a ketone function.7 The use of this
reagent for the reductive displacement of iodine from 2-iodo-2-deoxysugars has never been
reported in the literature, but it can be considered a reasonable extension of the above
dehalogenation reaction if the aldehydic form of the iodosugar is considered. We actually found
that sodium dithionite removes the iodine atom of 2-deoxy-2-iodosugars very effectively under
very mild conditions, giving the target 2-deoxysugars in good yields. In addition, the yield was
not lowered if the iodosugar produced in the first step was used without any purification,
allowing us to develop a one-pot procedure.
A typical experimental procedure, as applied to 3,4,6-tri-O-benzyl-
D
-galactal 1, is as follows.
Compound 1 (416 mg, 1 mmol), prepared from 3,4,6-tri-O-acetyl-
D
-galactal according to the
reported procedure,8 was dissolved in 8 ml of CH3CN–H2O 95:5 and cooled at 0°C. Then, the
solution was treated with 1.1 equiv. (247.5 mg) of N-iodosuccinimide, allowed to rise to room
temperature and left to stir for 15 minutes. The solvent was then removed in vacuo. The residue
was dissolved in 10 ml of DMF and 10 ml of a solution of H2O/HCO3− (10 mol equiv.) was then
added, followed by 4 equiv. (768.5 mg) of solid Na2S2O4. The reaction was allowed to proceed
under stirring for 5 hours at room temperature. After that, the reaction mixture was diluted with
400 ml of AcOEt and washed with water (three times, 400 ml each), followed by brine (400 ml).
The organic layer was purified by column chromatography (n-hexane/EtOAc 7:3) to give 389 mg
of 3,4,6-tri-O-benzyl-2-deoxygalactose 2 (90% yield) as a mixture of anomers, identified by
1
comparison of its H and 13C NMR spectra with those reported.4

9179
In order to evaluate the scope of this new procedure, several protected glycals were used as
starting materials. The corresponding 2-deoxysugars (Chart 1) were purified by chromato-
graphy; compound 3 was identified by comparison with literature data,9 while the structures of
compounds 4,10 5,11 and 612 were elucidated by mass spectral and NMR (including two-dimen-
sional COSY and HMQC experiments) data. As shown in Table 1, optimal reaction conditions
may slightly change depending on starting material, but the yields are good with all the
substrates.
Table 1
Protected 2-deoxysugars produced via Scheme 1
Target compound
Starting material
Reaction time (hours)
Yield (%)
2
3
4
5
6
3,4,6-Tri-O-benzyl-
3,4,6-Tri-O-benzyl-
6-O-TIPS-3,4-di-O-benzyl-
6-O-TIPS-3,4-di-O-benzyl-
D
D
-galactal
-glucal
5
5
7
7
5
90
94
89
80
83
D
-galactal
-glucal
D
6-O-Trityl-3,4-di-O-benzyl-D-galactal
The ready availability and the low price of the reagents, the ease of the procedure, and the
high yield of the products make this the method of choice for the preparation of 2-deoxysugars
from glycals, if mild and neutral reaction conditions are required.
Acknowledgements
This work is the result of research supported by MURST (‘Progetto Giovani Ricercatori’
1999). Mass and NMR spectra were recorded at the ‘Centro Interdipartimentale di Analisi
Strumentale’, Universita` di Napoli ‘Federico II’. The assistance of the staff is gratefully
acknowledged.
References
1. Danishefsky, S.; Bilodeau, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380–1419.
2. Costantino, V.; Fattorusso, E.; Mangoni, A. manuscript in preparation.
3. Wild, R.; Schmidt, R. Liebigs Ann. 1995, 755–764.
4. Bettelli, E.; Cherubini, P.; D‘Andrea, P.; Passacantilli, P.; Piancatelli, G. Tetrahedron 1998, 54, 6011–6018.
5. Thiem, J.; Karl, H.; Schwentner, J. Synthesis 1978, 696–697.
6. Suzuki, K.; Sulikowski, G. A.; Friesen, R. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 8895–8902.
7. Chung, S.; Hu, Q. Synth. Commun. 1982, 12, 261–266.
8. Bovin, N. V.; Zurabyan, S. E.; Khorlin, A. Y. Carbohydr. Res. 1981, 98, 25–35.
9. Barnes, R. J.; Probert, M. A.; Wightman, R. H. J. Chem. Soc., Perkin Trans 1 1996, 5, 431–438.
10. 6-O-TIPS-3,4-di-O-benzyl-
-2-deoxygalactose 4: [h]D25 +32 (CHCl3, c=0.2); 1H NMR (CDCl3, a anomer): l
D
7.42–7.22 (10H, m, aromatic protons), 5.45 (1H, br. s, H-1), 4.96 (1H, d, J=11.4 Hz, benzylic proton), 4.70 (1H,
d, J=11.4 Hz, benzylic proton), 4.62 (2H, s, benzylic protons), 4.01 (1H, br. s, H-4), 3.99 (2H, H-3 and H-5,
overlapped), 3.84 (1H, dd, J=9.7 and 8.0 Hz, H-6a), 3.72 (1H, dd, J=9.7 and 5.9 Hz, H-6b), 2.22 (1H, br. t,
J=12.1, H-2ax), 2.02 (1H, br. dd, J=12.7, 4.2 Hz, H-2eq), 1.10 (3H, m, TIPS methine protons), 1.05 (18H, d,
J=6.5 Hz, TIPS methyl protons); 13C NMR (CDCl3, a anomer): l 127.7 (aromatic carbons), 92.7 (C-1), 74.5
(C6 H2Ph), 74.3 (C-3), 71.7 (C-5), 70.3 (C6 H2Ph), 62.4 (C-6), 31.2 (C-2), 18.1 (TIPS methine groups), 18.0 (TIPS

9180
methyl groups); HRFABMS (thioglycerol/m-nitrobenzyl alcohol matrix, positive ions): m/z 501.3003
(C29H45SiO5, calcd 501.3036).
11. 6-O-TIPS-3,4-di-O-benzyl-
-2-deoxyglucose 5: [h]2D5 +28 (CHCl3, c=0.3); 1H NMR (CDCl3, a anomer): l
D
7.40–7.28 (10H, m, aromatic protons), 5.38 (1H, br. s, H-1), 4.95 (1H, d, J=11.4 Hz, benzylic proton), 4.72 (1H,
d, J=11.4 Hz, benzylic proton), 4.68 (2H, s, benzylic protons), 4.05 (1H, ddd, 11.9, 8.9, and 4.9 Hz, H-3), 3.98
(1H, dd, J=11.2 and 4.4 Hz, H-6a), 3.89 (1H, br. d, J=11.2 Hz, H-6b), 3.87 (1H, m, H-5), 3.61 (1H, t, J=8.9
Hz, H-4), 2.29 (1H, br. dd, J=13.1 and 4.9 Hz, H-2eq), 1.67 (1H, br. t, J=12.1 Hz, H-2ax), 1.10 (3H, m, TIPS
methine protons), 1.07 (18H, d, J=6.5 Hz, TIPS methyl protons); 13C NMR (CDCl3, a anomer): l 126–128
(aromatic carbons), 92.0 (C-1), 78.5 (C-4), 76.9 (C-3), 75.3 (C6 H2Ph), 72.9 (C-5), 72.2 (C6 H2Ph), 62.9 (C-6), 35.6
(C-2), 18.1 (TIPS methine groups), 18.0 (TIPS methyl groups); HRFABMS (thioglycerol/m-nitrobenzyl alcohol
matrix, positive ions): m/z 501.3015 (C29H45SiO5, calcd 501.3036).
12. 6-O-Trityl-3,4-di-O-benzyl-
-2-deoxygalactose 6: [h]D25 +33 (CHCl3, c=0.3); 1H NMR (CDCl3, a anomer): l
D
7.43–7.15 (25H, m, aromatic protons), 5.40 (1H, br. d, J=3.1 Hz, H-1), 4.82 (1H, d, J=11.6 Hz, benzylic
proton), 4.63 (1H, d, J=11.4 Hz, benzylic proton), 4.60 (1H, d, J=11.4 Hz, benzylic proton), 4.49 (1H, d,
J=11.4 Hz, benzylic proton), 4.09 (1H, m, H-5), 3.98 (1H, br. s, H-4), 3.97 (1H, overlapped, H-3), 3.37 (1H, dd,
J=9.4 and 5.8 Hz, H-6a), 3.22 (1H, dd, J=9.4 and 7.3 Hz, H-6b), 2.16 (1H, ddd, J=12.3, 12.3, and 3.3 Hz,
H-2ax), 2.02 (1H, br. dd, J=12.3 and 4.4 Hz, H-2eq); 13C NMR (CDCl3, a anomer): l 128.4–128.0 (aromatic
carbons), 92.4 (C-1), 74.3 (-C6 H2Ph), 73.9 (C-3), 73.2 (C-4), 70.3 (C-5), 63.0 (C-6), 30.9 (C-2); ESI MS (MeOH
solution, positive ions): m/z 609 ([M+Na]+); ESI MS/MS (positive ions, precursor ion at m/z 609): m/z 374
[M+Na–trityl]+, 234 [trityl]+.
.
.