A new aspect of the reactivity of sodium dithionite provides a facile route to 2-deoxy-α-glycosides

Article abstract of DOI:10.1016/S0040-4039(02)02280-3

Sodium dithionite, which is known to cause dehalogenation of α-halo carbonyl compounds, also induces dehalogenation of protected 2-iodo-2-deoxyglycosides. Combined with the well-known iodonium-mediated haloalkoxylation, this reaction provides an easy, mild and highly stereoselective route for preparation of 2-deoxy-α-glycosides from glycals.

Full text of DOI:10.1016/S0040-4039(02)02280-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9047–9050
A new aspect of the reactivity of sodium dithionite provides a
facile route to 2-deoxy-a-glycosides
Valeria Costantino,* Ernesto Fattorusso, Concetta Imperatore and Alfonso Mangoni
Dipartimento di Chimica delle Sostanze Naturali, Universita` di Napoli ‘Federico II’, via D. Montesano 49, 80131 Napoli, Italy
Received 30 September 2002; revised 11 October 2002; accepted 14 October 2002
Abstract—Sodium dithionite, which is known to cause dehalogenation of a-halo carbonyl compounds, also induces dehalogena-
tion of protected 2-iodo-2-deoxyglycosides. Combined with the well-known iodonium-mediated haloalkoxylation, this reaction
provides an easy, mild and highly stereoselective route for preparation of 2-deoxy-a-glycosides from glycals. © 2002 Elsevier
Science Ltd. All rights reserved.
Stereoselective synthesis of 2-deoxy-a-glycosides is an
interesting and non-trivial goal. Over the years, several
methods1 have been proposed to accomplish a-glycosi-
dation, but a general procedure to synthesize a-gly-
cosides in good yield has not yet been developed.
involves the use of I+ donors such as N-
iodosuccinimide2
or sym-collidine iodonium
perchlorate3 to induce coupling of glycals with alcohols.
It is well known that the reaction is governed by a
trans-diaxial addition of I+ and the alcohol hydroxyl
group to the double bond of the glycal. Subsequent
removal of the iodine atom produces the a-linked 2-
deoxyglycosides in good yield and stereoselectivity. The
usual ways to remove the iodine atom are reduction
with triphenyltin hydride3 in refluxing benzene or cata-
lytic hydrogenation.
Glycals have been employed as a versatile starting
material in glycosidation reactions, when 2-deoxy-a-
glycosides were required. A well established procedure
In a recent paper,4 we reported that sodium dithionite
(Na2S2O4), an inexpensive and easy-to-use reducing
agent, removes the iodine atom of 2-deoxy-2-iodosug-
ars under very mild conditions, giving the correspond-
ing 2-deoxysugars in good yields. This reagent is
particularly suited to substrates that can suffer at high
temperatures and, in addition, it avoids the use of
ecologically harmful heavy metals.
Dehalogenation using sodium dithionite has been first
described by Chung and Hu in 1982 for a-haloketones.5
The presence of a carbonyl function a to the halogen
atom was claimed to be essential, and indeed dehalo-
genation of 2-deoxy-2-iodosugars can be explained con-
sidering the aldehydic equilibrium form of the sugars.
As a consequence, 2-deoxy-2-iodoglycosides were not
expected to react.
Scheme 1. Dehalogenation of 2-iodo-2-deoxyglycosides with
sodium dithionite.
Surprisingly, we found that sodium dithionite does
cause dehalogenation of many 2-iodo-2-deoxygly-
cosides. A typical experimental procedure is as follows:
methyl 3,4,6-tri-O-acetyl-2-deoxy-2-iodo-a-taloside 1a
* Corresponding author. Tel.: +39-081-678504; fax: +39-081-678552;
e-mail: costanti@unina.it
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02280-3

9048
V. Costantino et al. / Tetrahedron Letters 43 (2002) 9047–9050
In order to explore the potential applications of this
methodology, we performed the dehalogenation reac-
tion using differently protected methyl 2-iodo-2-deoxy-
a-glycosides and different reaction conditions (Table 1).
Even though the results do not allow to establish a
sharp structure–reactivity relationship, some general
trends can be outlined. The presence of electron-with-
drawing (acetyl or benzoyl) protecting groups is essen-
tial for the substrate to be reactive (entries 11–13).
Particularly, an acetyl protecting group at position 3 of
the sugar is sufficient to promote the reaction (com-
pound 3d, entry 11,9 and 1e, entry 1210), but it is not
strictly required at that very position, as shown by the
deiodination of methyl 4,6-di-O-acetyl-3-O-TIPS-2-
iodo-2-deoxy-a-taloside (compound 1f, entry 13);11 in
contrast, a single acetyl group either at position 4
(compound 1g) or 6 (compound 1h) was not effective at
all (entries 14 and 15).
(430 mg, 1 mmol, prepared from 3,4,6-tri-O-acetyl-
galactal as described6) was dissolved in 10 ml of DMF/
H2O 1:1, and solid NaHCO3 (840 mg, 10 mol equiv.)
and Na2S2O4 (768 mg, 4 mol equiv.) were added. The
reaction was allowed to proceed overnight under stir-
ring at 25°C. After that, the reaction mixture was
diluted with 400 ml of EtOAc and washed with water
(3×400 ml), followed by brine (400 ml). The solvent was
removed under reduced pressure and column chro-
matography of the residue (n-hexane/EtOAc 7:3) then
provided methyl 3,4,6-tri-O-acetyl-2-deoxy-a-galac-
toside 2a (215.8 mg, 71% yield), identified by compari-
son of its 1H and 13C NMR spectra with those
reported.6 As shown in Table 1 (entries 2–4), we
obtained similar results using methyl 3,4,6-tri-O-ben-
zoyl-2-iodo-2-deoxy-a-taloside 1b as substrate, as well
as with iodoglycosides deriving from protected glucals,
such as methyl 3,4,6-tri-O-acetyl-2-iodo-2-deoxy-a-
mannoside 3a and methyl 3,4,6-tri-O-benzoyl-2-iodo-2-
deoxy-a-mannoside 3b.7 In addition, we found that
different solvent systems such as DMF/H2O 2:1 and
DMF/MeOH 1:1 could be used without affecting sig-
nificantly the outcome of the reaction (entries 5–7). We
selected the last solvent system for the subsequent
experiments, because it was water-free and appeared to
be the most suitable for dissolving most organic
compounds.
In spite of some limitations with the acceptable sub-
strates, deiodination with sodium dithionite appears to
be a promising alternative to complete the preparation
of 2-deoxy-a-glycosides via iodoalkoxylation of glycals.
To test this reaction with a more complex substrate
than methyl glycosides, we prepared 5a-cholest-3-b-yl-
3,4,6-tri-O-acetyl-2-iodo-2-deoxy-a-taloside (5)12 allow-
ing 3,4,6-tri-O-acetylgalactal to react overnight with
N-iodosuccinimide and 5-a-cholestan-3-b-ol. Com-
pound 5 (786 mg, 1 mmol) was then dissolved in 16 ml
of DMF/MeOH 1:1 and solid NaHCO3 (840 mg, 10
mol equiv.) and Na2S2O4 (1.54 mg, 8 mol equiv.) were
added giving 5a-cholest-3-b-yl 3,4,6-tri-O-acetyl-2-
deoxy-a-galactoside 6. In this latter case gentle warm-
ing (40°C) of the reaction mixture was necessary to
raise the yield to a satisfactory 74%.13
However, no reaction took place using methyl 3,4,6-tri-
O-benzyl-2-iodo-2-deoxy-a-taloside (1c) and methyl
3,4,6-tri-O-benzyl-2-iodo-2-deoxy-a-mannoside
(3c),
and we recovered only unreacted 1c or 3c even when we
tried alternative solvent systems and/or raising the reac-
tion temperature (entries 8–10).
Table 1. Protected 2-deoxyglycosides produced via Scheme 1
Entry
Starting material
Reaction product
Protecting groups
Temp. (°C)
Solvent
Yield (%)
R3
R4
R6
1
2
3
4
5
6
7
8
1a
3a
1b
3b
1a
1a
3a
1c
1c
1c
3d
1e
1f
2a
4aa
2bb
4bb
2a
2a
4a
–
Ac
Ac
Bz
Ac
Ac
Bz
Bz
Ac
Ac
Ac
Bn
Bn
Bn
Ac
Ac
Bz
Bz
Ac
Ac
Ac
Bn
Bn
Bn
25
25
25
25
25
25
25
25
25
40
25
25
25
25
25
40
DMF/H2O 1:1
DMF/H2O 1:1
DMF/H2O 1:1
DMF/H2O 1:1
DMF/H2O 2:1
DMF/MeOH 1:1
DMF/MeOH 1:1
DMF/H2O 1:1
DMF/H2O 2:1
DMF/MeOH 1:1
DMF/MeOH 1:1
DMF/MeOH 1:1
DMF/MeOH 1:1
DMF/MeOH 1:1
DMF/MeOH 1:1
DMF/MeOH 1:1
71
76
82
83
71
81
79
–
–
–
81
85
74
–
Bz
Ac
Ac
Ac
Bn
Bn
Bn
Ac
Ac
TIPS
Ac
Bn
Ac
9
–
–
10
11
12
13
14
15
16
4dc
2ed
2fe
–
Si(t-Bu)2
Ac
Ac
Ac
Bn
Ac
TIPS
Ac
TIPS
Ac
1g
1h
5
–
6
–
74
Ac
a Identified by comparison of spectral data with those reported (Ref. 7).
b Identified by comparison of spectral data with those reported (Ref. 8).
c Characterization: Ref. 9.
d Characterization: Ref. 10.
e Characterization: Ref. 11.

V. Costantino et al. / Tetrahedron Letters 43 (2002) 9047–9050
9049
H-2ax), 1.03 (9H, s, t-butylsilyl group), 0.97 (9H, s,
t-butylsilyl group); 13C NMR (CDCl3): l 170.1 (acetyl
CO), 98.9 (CH, C-1), 75.9 (CH, C-4), 66.7 (CH, C-5),
66.3 (CH2, C-6), 54.3 (CH3, methoxy group), 33.8 (CH2,
C-2), 27.4 (CH3, t-butylsilyl group), 26.7 (CH3, t-butylsi-
lyl group), 20.7 (CH3, Ac); HRESI MS (MeOH/CHCl3
1:1, positive ions): m/z 377.5669 ([C18H36O7Si+H]+, calcd
377.5683).
10. Methyl 3,4-di-O-acetyl-6-O-TIPS-2-deoxy-a-galactoside
1
2e: [h]2D5=+3.9 (c 0.3, CHCl3); H NMR (CDCl3): l 5.39
(1H, br s, H-4), 5.29 (1H, dt, J=11.8, 4.4 Hz, H-3), 4.87
(1H, br d, J=3.3 Hz, H-1), 3.96 (1H, t, J=7.3 Hz, H-5),
3.76–3.64 (2H, m, H-6a, H-6b), 3.34 (3H, s, methoxy
group), 2.10 (3H, s, Ac), 2.03 (1H, dd, J=13.2, 4.4 Hz,
H-2eq), 1.96 (3H, s, Ac), 1.85 (1H, dd, J=11.8, 4.8 Hz,
H-2ax), 1.07–0.99 (21H, m, TIPS methyl and methine
groups); 13C NMR (CDCl3): l 170.4, 170.1 (acetyl CO),
95.6 (CH, C-1), 66.8 (CH, C-5), 64.3 (CH, C-4), 63.9
(CH, C-3), 59.4 (CH2, C-6), 52.1 (CH3, methoxy group),
27.8 (CH2, C-2), 18.1 (CH3, Ac), 18.0 (CH3, Ac), 15.0
(CH3, TIPS methyl groups), 9.3 (CH, TIPS methine
group); HRESI MS (MeOH/CHCl3 1:1, positive ions):
m/z 419.2454 ([C20H38O7Si+H]+, calcd 419.2465).
In conclusion, the dehalogenation of 2-iodo-2-deoxy-
glycosides unveils a new aspect of the reactivity of
sodium dithionite. Even though we do not feel to
suggest any mechanistic hypothesis at this stage, it is
clear that this dehalogenation reaction does not follow
any of the mechanisms previously proposed. Combined
with the I+ promoted iodoalkoxylation of glycals, this
reaction provides a route to 2-deoxy-a-glycosides char-
acterized by high stereoselectivity and mild reaction
conditions, particularly useful in molecules with func-
tional groups that could be affected by the conditions
previously used for the removal of the iodine atom.
11. Methyl 4,6-di-O-acetyl-3-O-TIPS-2-deoxy-a-galactoside
1
2f: [h]2D5=+46 (c 0.7, CHCl3); H NMR (CDCl3): l 5.23
(1H, br s, H-4), 4.82 (1H, br d, J=3.3 Hz, H-1), 4.23
(1H, dt, J=11.4, 4.4 Hz, H-3), 4.04 (1H, t, J=7.7 Hz,
H-5), 4.15–4.09 (2H, m, H-6a, H-6b), 3.29 (3H, s,
methoxy group), 2.08 (3H, s, Ac), 2.03 (3H, s, Ac), 1.96
(1H, dd, J=11.4, 3.3 Hz, H-2ax), 1.84 (1H, dd, J=13.2,
4.4 Hz, H-2eq), 1.05 (3H, m, TIPS methine groups), 1.01
(18H, m, TIPS methyl groups); 13C NMR (CDCl3): l
170.3, 170.1 (acetyl CO), 95.7 (CH, C-1), 68.4 (CH, C-4),
65.6 (CH, C-5), 62.8 (CH, C-3), 61.0 (CH2, C-6), 51.1
(CH3, methoxy group), 34.1 (CH2, C-2), 18.6 (CH3, Ac),
18.2 (CH3, Ac), 18.0 (CH3, TIPS methyl groups), 15.4
(CH, TIPS methine group); HRESI MS (MeOH/CHCl3
1:1, positive ions): m/z 419.2474 ([C20H38O7Si+H]+, calcd
419.2465).
Acknowledgements
This work is the result of research supported by
MURST PRIN, Rome, Italy and CNR. Mass and
NMR spectra were recorded at the ‘Centro Interdiparti-
mentale di Analisi Strumentale’, Universita` di Napoli
‘Federico II’. The assistance of the staff is gratefully
acknowledged.
References
12. 5a-Cholest-3-b-yl
3,4,6-tri-O-acetyl-2-iodo-2-deoxy-a-
1. Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed.
2001, 40, 1576–1624.
2. Thiem, J.; Karl, H.; Schwentner, J. Synthesis 1978, 696–
697.
taloside 5: [h]D25=+44.5 (c 2.3, CHCl3); 1H NMR
(CDCl3): l 5.43 (1H, br s, H-1%), 5.35 (1H, m, H-4%), 4.92
(1H, t, J=4.4 Hz, H-3%), 4.38 (1H, t, J=6.6 Hz, H-5%),
4.21 (1H, br d, J=4.8 Hz, H-2%), 4.15 (2H, br d, J=6.6
Hz, H-6%a, H-6%b), 3.54 (1H, m, H-3), 2.16 (3H, s, Ac),
2.05 (3H, s, Ac), 2.03 (3H, s, Ac), 0.88 (3H, d, J=6.6 Hz,
H-21), 0.85 (6H, d, J=6.7 Hz, H-26, H-27), 0.79 (3H, s,
H-18), 0.63 (3H, s, H-19); 13C NMR (CDCl3): l 169.0
(CO), 170.0 (CO), 170.3 (CO), 101.1 (CH, C-1%), 78.2
(CH, C-3), 66.8 (CH, C-5%), 65.6 (CH, C-4%), 65.4 (CH,
C-3%), 62.3 (CH2, C-6%), 56.5 (CH, C-14), 56.3 (CH, C-17),
54.4 (CH, C-9), 45.1 (CH, C-5), 42.6 (C, C-13), 40.0
(CH2, C-16), 39.5 (CH2, C-24), 36.9 (CH2, C-1), 36.2
(CH2, C-22), 35.8 (CH2, C-4), 35.7 (CH, C-8), 35.6 (CH,
C-20), 35.5 (C, C-10), 32.1 (CH2, C-7), 28.8 (CH2, C-6),
28.2 (CH2, C-12), 28.0 (CH, C-25), 27.8 (CH2, C-2), 24.2
(CH2, C-15), 23.8 (CH2, C-23), 22.8 (CH3, C-27), 22.6
(CH, C-2%), 22.5 (CH3, C-26), 21.2 (CH2, C-11), 20.9–20.6
(CH3, Ac), 18.7 (CH3, C-21), 12.2 (CH3, C-18), 12.1
(CH3, C-19); ESI MS (1 mM LiCl in MeOH/CHCl3 4:1,
positive ions): m/z 793 ([M+Li]+).
3. Danishefsky, S. J.; Friesen, R. W. J. Am. Chem. Soc.
1989, 111, 6656–6660.
4. Costantino, V.; Fattorusso, E.; Imperatore, C.; Mangoni,
A. Tetrahedron Lett. 2000, 41, 9177–9180.
5. Chung, S.; Hu, Q. Synth. Commun. 1982, 12, 261–266.
6. Chen, S. H.; Hoyath, R. F.; Joglar, J.; Fisher, M. J.;
Danishefsky, S. J. J. Org. Chem. 1991, 56, 5834–5845.
7. Nowacki, A.; Smiataczowa, K.; Kasprzykowska, R.;
Dmochowska, B.; Wisniewski, A. Carbohydr. Res. 2002,
337, 265–272.
8. Hadfield, A.; Sartorelli, A. C. Carbohydr. Res. 1982, 101,
197–208.
9. Methyl 3-O-acetyl-4,6-di-O-t-butylsilanediyl-2-deoxy-a-
glucoside 4d: [h]2D5=+30 (c 1.6, CHCl3); 1H NMR
(CDCl3): l 5.19 (1H, m, H-3), 4.73 (1H, br d, J=3.3 Hz,
H-1), 4.08 (1H, dd, J=10.3, 4.0 Hz, H-6a), 3.87 (1H, t,
J=10.3 Hz, H-5), 3.78–3.74 (2H, m, H-6b), 3.33 (3H, s,
methoxy group), 2.18 (1H, dd, J=12.5, 5.1 Hz, H-2eq),
2.05 (3H, s, Ac), 1.70 (1H, ddd, J=12.5, 12.5, 3.3 Hz,
13. 5a-Cholest-3-b-yl 3,4,6-tri-O-acetyl-2-deoxy-a-galactoside
6: [h]2D5=+61.7 (c 0.9, CHCl3); 1H NMR (CDCl3): l

9050
V. Costantino et al. / Tetrahedron Letters 43 (2002) 9047–9050
45.1 (CH, C-5), 42.6 (C, C-13), 40.0 (CH2, C-16), 39.5
5.34–5.29 (2H, m, H-3%, H-4%), 5.16 (1H, d, J=2.6 Hz,
H-1%), 4.24 (1H, t, J=6.6 Hz, H-5%), 4.11–4.03 (2H, m,
H-6%a, H-6%b), 3.51 (1H, m, H-3), 2.12 (3H, s, Ac), 2.04 (3H,
s, Ac), 1.97 (3H, s, Ac), 0.89 (3H, d, J=6.6 Hz, H-21), 0.85
(6H, d, J=6.6 Hz, H-26, H-27), 0.79 (3H, s, H-18), 0.64
(3H, s, H-19); 13C NMR (CDCl3): l 170.4 (CO), 170.1
(CO), 170.0 (CO), 95.7 (CH, C-1%), 76.9 (CH, C-3), 66.9
(CH, C-4%), 66.7 (CH, C-5%), 66.4 (CH, C-3%), 62.7 (CH2,
C-6%), 56.5 (CH, C-14), 56.3 (CH, C-17), 54.4 (CH, C-9),
(CH2, C-24), 36.9 (CH2, C-1), 36.2 (CH2, C-22), 35.9 (CH2,
C-4), 35.8 (CH, C-8), 35.6 (C, C-10), 35.5 (CH, C-20), 32.1
(CH2, C-7), 30.8 (CH2, C-2%), 28.9 (CH2, C-6), 28.2 (CH2,
C-12), 28.0 (CH, C-25), 27.7 (CH2, C-2), 24.2 (CH2, C-15),
23.8 (CH2, C-23), 22.8 (CH3, C-27), 22.5 (CH3, C-26), 21.2
(CH2, C-11), 20.9–20.7 (CH3, Ac), 18.7 (CH3, C-21), 12.3
(CH3, C-18), 12.1 (CH3, C-19), ESI MS (1 mM LiCl in
MeOH/CHCl3 4:1, positive ions): m/z 667 ([M+Li]+).