Selective iodination of vicinal cis-diols on ketopyranose templates

Article abstract of DOI:10.1016/j.tetlet.2010.06.107

A regio- and stereoselective iodination has been performed on vicinal diols located on ketopyranose templates using the controlled- Garegg conditions. 3-O-Benzyl-1,2-O-isopropylidene-β-d-fructo- or psicopyranoses (1 or 4) were selectively iodinated, respectively, at C-5 or C-4 of the ketoses to afford the l-sorbo or d-sorbo iodohydrins.

Full text of DOI:10.1016/j.tetlet.2010.06.107

Tetrahedron Letters 51 (2010) 4602–4604
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Tetrahedron Letters
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Selective iodination of vicinal cis-diols on ketopyranose templates
b
a
Ana Catarina Simao a,b, Arnaud Tatibouët a, , Amelia P. Rauter , Patrick Rollin
*
a ICOA—UMR 6005, Université d’Orléans, CNRS, BP6759, F-45067 Orléans Cedex 2, France
b Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
A regio- and stereoselective iodination has been performed on vicinal diols located on ketopyranose tem-
Received 11 March 2010
Revised 18 June 2010
Accepted 22 June 2010
Available online 25 June 2010
plates using the controlled- Garegg conditions. 3-O-Benzyl-1,2-O-isopropylidene-b-
anoses (1 or 4) were selectively iodinated, respectively, at C-5 or C-4 of the ketoses to afford the
-sorbo iodohydrins.
D
-fructo- or psicopyr-
L
-sorbo or
D
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Carbohydrates
Iodine
Direct conversion of an alcohol function into an iodo derivative
is a valuable transformation in organic chemistry: more specifi-
cally in glycochemistry, this has received considerable attention
over the years.1 A number of reagents—many of them being phos-
phorus-based—have been explored for the replacement of an hy-
droxyl by an iodine atom.2 The most popular iodination systems
are indisputably those developed by Garegg and Samuelsson.3
However, deoxy-iodo sugars can also be obtained through stan-
dard nucleophilic displacement of sulfonates,4 but also with more
original approaches.5 Selective substitution of primary over sec-
ondary hydroxyls can be achieved on unprotected carbohydrate
but reacting a specific secondary alcohol usually requires masking
of the other hydroxyls.6 On the other hand, Garegg’s reagent sys-
tem has also been used for the one-step conversion of vicinal diols
into olefins.7 Herein, we report a preliminary study, of a program
devoted to iminosugars6 and thionocarbamates on carbohydrate
scaffolds,8 of the Garegg’s conditions applied to the selective con-
version of ketopyranose-derived cis-diols into iodohydrins.
but moreover the possibility to selectively iodinate a diol. With
that in mind, we have carried out an optimization study on the
D-fructo diol 1 and its
D-psico epimer 4 (Scheme 1).
To selectively substitute only one hydroxyl group of the vicinal
diol, we have reduced the number of equivalents for triphenyl-
phosphine (1.5 equiv) and iodine (1.4 equiv). By limiting severely
the amounts of both reagents compared to the original procedure
(respectively, 4 equiv and 3 equiv),3b we thought to attain a better
selectivity. In both D-fructo and D-psico series (Table 1, entries 1
and 2) we observed that even under such conditions after 1 h only,
olefination was the predominant process over iodination. Lowering
the temperature (entries 3 and 4) resulted in no reaction even after
O
O
O
O
I2, Ph3P, imidazole
toluene or THF
O
O
O
O
O
+
OR
I
OR
OBn
OH
HO
HO
3
1
7
D-fructopyranose:
R = Bn
L-sorbopyranose 2 R = Bn
8 R = Bz
When applying to 3-O-benzyl-1,2-O-isopropylidene-b-D-fructo-
R = OBz
pyranose 1 the standard elimination procedure previously de-
scribed by Lichtenthaler et al.,7b the olefin 3 was exclusively
formed in 63% yield (3 equiv Ph3P, 3 equiv imidazole and 2 equiv
of iodine). Through By slightly changing the conditions (3 equiv
Ph3P, 3 equiv imidazole and 1.4 equiv of iodine), we observed after
1 h reaction that olefin 3 was formed in 53% yield together with a
monosubstituted derivative 2 in which an iodine atom had been
stereoselectively introduced at C-5, thus giving a 40% yield of a L-
sorbo- configurated 5-deoxy-5-iodopyranose. This result reveals
a high efficiency of the reaction with over 93% conversion yield
O
O
O
I
HO
O
O
O
O
O
I
BnO
O
I2, Ph3P, imidazole
toluene or THF
HO OBn
5
OH
HO
OBn
D-sorbopyranose
4
D-psicopyranose
O
O
O
+
OBn
6
* Corresponding author. Tel.: +33 238 49 48 54; fax: +33 238 41 72 81.
E-mail address: arnaud.tatibouet@univ-orleans.fr (A. Tatibouët).
Scheme 1. Selective iodination of ketopyrano diols.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.107

A. C. Simao et al. / Tetrahedron Letters 51 (2010) 4602–4604
4603
Table 1
Conditions applied to promote selective iodination, 1/7, in D-fructo series
Entry
Starting ketose
Solvent
I2 (equiv)
Temperature (C°)
Time (h)
Iodo (%)
Olefin (%)
1
2
3
4
5
6
7
8
9
1
4
1
4
1
4
1
4
1
4
7
Toluene
Toluene
Toluene
Toluene
THF
THF
THF
THF
1.4
1.4
1.4
1.4
1.4
1.4
1.0
1.0
1.0
1.0
1.0
110
110
rt
rt
rt
1
1
2 (40)
5 (8)
3 (54)
6 (67)
—
—
—
—
—
—
—
a
24
24
15
15
4
—
—
a
2 (7)
a
rt
—
Reflux
Reflux
65
65
Reflux
2 (94)
5 (56)
2 (67)
5 (43)
8 (70)
4
1,4-Dioxane
1,4-Dioxane
THF
72
72
4
10
11
—
a
The starting material was not isolated but observed by TLC.
Ph3P, I2,
imidazole
Ph3P
O
O
OH
OH
OH
imidazole
NaH
DMF
OPPh3
O
2
5
OBn
OPPh3
I
I
O
I2
I
NaN3
D-fructo
94%
9
DMSO
NaN3
100°C, 3 days
MeONa
MeOH 60°C
24h
DMSO
100°C, 3 days
O
O
O
O
O
O
O
O
OBn
92%
OBn
69%
O
MeO
OBn
49%
L-sorbo 10
OH
N3
N3
HO
OH
D-fructo 11
Ph3PO
D-fructo 12
Scheme 3.
Scheme 2. The elimination mechanism using Garegg’s conditions.3a
sion at C-5 was also observed, affording the
in 70% yields.
Such efficient functionalizations of ketopyranose templates
paved the way to preliminary reactivity testing of ketose-derived
iodohydrins confronted with nucleophiles (Scheme 3). Under basic
L
-sorbo derivative 8
24 h. However, replacing toluene by THF (entries 5–8) enhanced
both solubility and reactivity. Substitutive iodination was opti-
mized in D-fructo and D-psico series, no reactivity was observed
at room temperature (entries 5 and 6) while in refluxing THF dur-
ing 4 h, good to excellent yields were obtained (entries 7 and 8).
The above- established protocol using an excess of iodine
(1.4 equiv) led us to reconsider the mechanism postulated by Gar-
egg (Scheme 2).3a The elimination process takes place during the
terminal phase together with the regeneration of iodine. In this last
step, we postulated that iodine could be seen acting as a catalyst.
Thus by lowering the amount of I2 to strictly 1 equiv, a selective
mono-substitution should occur avoiding the elimination process.
Reacting 1.0 equiv I2 duringfor 4 h in refluxing THF resulted in
selective iodination at C-5 with an excellent 94% yield (2, entry
conditions, the
lecular cyclization to deliver the
yield. This epoxide could in turn be opened with sodium methox-
ide to give selectively the -sorbo derivative 10 in 49% yield. A com-
parable efficiency was observed through converting by
nucleophilic substitution into the 5-azido- -fructo derivative 11
in 92% yield.11 The same experiment applied to the
-sorbo iodohy-
L-sorbo iodohydrin 2 readily underwent intramo-
D
-fructo 4,5-epoxide 9 in 94%
L
2
D
D
drin 5 effected azido-inversion to produce the 4-azido-
derivative 12 in 69% yield.
D-fructo
7).9 The same conditions were applied to the
(entry 8), effecting selective iodination with a moderate 54% yield
of
-sorbo derivative 5.10 Trying to improve the conversion yields
D-psico derivative 4
In short, we have disclosed a regio- and stereoselective conver-
sion of fructo- and psicopyrano-based vicinal diols into iodohy-
drins, using modified Garegg conditions. This reaction has proven
useful for introducing through the nucleophilic displacement of
new functionalities onto ketopyranose templates. Despite its selec-
tivity, this selective iodination approach greatly depends on the
carbohydrate series; further explorations are ongoing to decipher
the general rules and mechanism underlying the reaction.
D
by replacing THF by 1,4-dioxane at the same temperature afforded
iodo compounds 2 and 5, albeit with inferior yields (entries 9 and
10). In
D-fructo series, iodination of 1 took place regio- and stere-
oselectively at position 5. In contrast in
D-psico series, iodination
of 4 regio- and stereoselectively occurred at position 4. In both
cases the iodine atom was introduced with inversion of configura-
tion, according to NMR spectrometric assignments.9,10
Acknowledgments
A postulated explanation for the selectivities observed could be
the driving force of the most thermodynamically stable isomer to
We are grateful to the ANR and the CNRS for the financial sup-
port and to the FCT for a fellowship (A.C.S.). We would also like to
thank the Universidade de Lisboa, the Université d’Orléans, and the
PESSOA program for multiform support.
be formed. On the
sults in a
-sorbopyrano frame, for which the 2C5 conformer exhib-
its all the substituents in equatorial position. On the -psicopyrano
D-fructopyrano frame, iodo-inversion at C-5 re-
L
D
frame, inversion at C-4 results in a D-sorbopyrano frame, for which
the 5C2 conformer also points all the substituents in equatorial
position.
References and notes
1. (a) Barnett, J. E. Adv. Carbohydr. Chem. Biochem. 1967, 22, 177; (b) Szarek, W. A.
Adv. Carbohydr. Chem. Biochem. 1973, 28, 225; (c) Vaino, A. R.; Szarek, W. A. Adv.
Carbohydr. Chem. Biochem. 2000, 56, 9.
A comparative experiment was performed on substrate 7, a 3-
O-benzoyl analogue of 1: a regio- and stereoselective iodo-inver-

4604
A. C. Simao et al. / Tetrahedron Letters 51 (2010) 4602–4604
10. Procedure for the synthesis of iodohydrin 5: Applying to diol 4 (1 g, 3.22 mmol)
2. Castro, B. R. Org. React. 1983, 29, 1.
3. (a) Garegg, P. J. Pure Appl. Chem. 1984, 56, 845; (b) Garegg, P. J.; Samuelsson, B.
Chem. Commun. 1979, 978; (c) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin
Trans. 1 1980, 2866.
4. Skaanderup, P. R.; Poulsen, C. S.; Hyldtoft, L.; Jorgensen, M. R.; Madsen, R.
Synthesis 2002, 1721.
the protocol described in Ref. 8 led to the D-sorbo iodohydrin 5 (0.76 g, 56%
yield) as a beige solid; Rf = 0.22 PE/EA (4:1); mp = 98–101 °C; ½a D20
þ 21 (c 0.54,
ꢀ
CHCl3); IR (neat):
m
(cmꢁ1): 3449 (OH); 2987, 2921 (CH); 1497, 1453, 1407
(Ph). 1H NMR (250 MHz, CDCl3): d 1.42 and 1.53 (2s, 6H, CH3), 2.86 (d, 1H,
J5-OH = 7.0 Hz, OH); 3.45 (dd, 1H, J6b-6a = 12.3 Hz, J6b-5 = 7.0 Hz, H-6b), 3.76 (d,
1H, J3-4 = 7.8 Hz, H-3), 3.91–4.00 (m, 1H, H-5), 4.04 (d, 1H, J1b-1a = 9.1 Hz, H-1b),
4.09–4.13 (m, 1H, H-4), 4.14 (d, 1H, H-1a), 4.24 (dd, 1H, J6a-5 = 3.8 Hz, H-6a),
4.77 and 4.82 (2d, AB system, 2H, Jgem = 10.8 Hz, PhCH2O), 7.28–7.37 (m, 5H,
Ph). 13C NMR (62.89 MHz, CDCl3): d 26.2, 27.1 (Me2C), 36.7 (C-4), 64.6 (C-6),
69.2 (C-1), 74.7 (PhCH2O), 79.7 (C-3), 105.6 (C-2), 112.4 (Me2C), 128.3, 128.4,
128.5 (CH-Ar), 137.0 (CIV-Ar). HRMS: C16H21IO5 calcd for [M+Na]+ 443.0331;
found: 443.0334.
5. Ellwood, A. R.; Porter, M. J. J. Org. Chem. 2009, 74, 7982.
6. (a) Tatibouët, A.; Lefoix, M.; Nadolny, J.; Martin, O. R.; Rollin, P.; Yang, J.;
Holman, G. D. Carbohydr. Res. 2001, 333, 327; (b) Izquierdo, I.; Plaza, M. T.;
Yanez, V. Tetrahedron 2007, 63, 1440.
7. (a) Garegg, P. J.; Samuelsson, B. Synthesis 1979, 469; (b) Lichtenthaler, F. W.;
Doleschal, W.; Hahn, S. Liebigs Ann. Chem. 1985, 2454.
8. Simão, A. C.; Rousseau, J.; Silva, S.; Rauter, A. P.; Tatibouët, A.; Rollin, P.
Carbohydr. Chem. 2009, 35, 127–172.
11. Representative azido formation: To a solution of the L-sorbo iodohydrin 2 (1 g,
9. Procedure for the synthesis of iodohydrin 2: A solution of diol 1 (1 g, 3.22 mmol)
in THF (8 mL) containing imidazole (0.657 g, 9.65 mmol) and triphenyl-
phosphine (1.18 g, 4.5 mmol) was cooled to 0 °C and then iodine (0.82 g,
3.22 mmol) was added. The mixture was stirred under reflux for 4 h, then
evaporated and co-evaporated with toluene. The residue was purified by silica
gel column chromatography (petroleum ether/ethyl acetate 19/1 then 9/1) to
2.38 mmol) in DMSO (8 mL) sodium azide (0.46 g, 3 equiv) was added and the
reaction mixture was heated at 100 °C for 3 days. After cooling, the mixture
was treated with water and then extracted with EtOAc (3ꢂ). The combined
organic phase was washed with water (4ꢂ), then brine, dried over MgSO4, and
evaporated. The resulting residue was purified on
a silica gel column
(petroleum ether/ethyl acetate 9/1) to afford azide 11 as colorless solid
afford the
L
-sorbo iodohydrin 2 (1.27 g, 94% yield) as a white solid; Rf = 0.26 PE/
(0.73 g, 91% yield); Rf = 0.24 PE/EA (9:1); mp = 107–109 °C; ½a D20
ꢁ 117 (c 0.25,
ꢀ
EA (9:1); mp = 123–125 °C; ½a D20
ꢀ
þ 51 (c 0.14, CHCl3); IR (neat):
m
(cmꢁ1): 3429
CHCl3); IR (neat): m
(cmꢁ1): 3541 (OH); 2993, 2909 (CH); 2119 (N3); 1457, 1371
(OH); 2921, 2851 (CH); 1455, 1373 (Ph). 1H NMR (250 MHz, CDCl3): d 1.42 and
1.49 (2s, 6H, CH3), 2.60 (br s, 1H, OH), 3.44 (d, 1H, J3-4 = 8.8 Hz, H-3), 3.84 (dd,
1H, J6b-6a = 14.7 Hz, J6b-5 = 4.4 Hz, H-6b), 3.85 (d, 1H, J1b-1a = 8.5 Hz, H-1b), 3.96
(dd, 1H, J6a-5 = 4.4 Hz, H-6a), 3.98 (d, 1H, H-1a), 4.03 (t, 1H, H-4), 4.07 (s, 1H, H-
5), 4.72 and 4.91 (2d, AB system, 2H, Jgem = 11.6 Hz, PhCH2O), 7.28–7.37 (m, 5H,
Ph). 13C NMR (62.89 MHz, CDCl3): d 26.2, 27.2 (Me2C), 30.5 (C-5), 65.5 (C-6),
71.9 (C-1), 75.6 (PhCH2O), 79.6 (C-3), 105.8 (C-2), 112.6 (Me2C), 128.1, 128.2,
128.7 (CH-Ar), 137.8 (CIV-Ar). HRMS: C16H21IO5 calcd for [M+Na]+ 443.0331;
found: 443.0332.
(Ph). 1H NMR (400 MHz, CDCl3): d 1.42 and 1.48 (2s, 6H, CH3), 2.31 (d, 1H, JOH-
4 = 5.2 Hz, OH), 3.67 (d, 1H, J3-4 = 9.6 Hz, H-3), 3.74 (dd, 1H J6b-6a = 12.4 Hz, J6b-
5 = 1.6 Hz, H-6b), 3.93–3.95 (m, 1H, H-5), 3.96 (d, 1H, J1b-1a = 8.6 Hz, H-1b), 3.99
(dd, 1H, J6a-5 = 1.6 Hz, H-6a), 4.03 (d, 1H, H-1a), 4.19 (ddd, 1H, J4-3 = 4.4 Hz, J4-
OH = 5.2 Hz, J4-5 = 9.6 Hz, H-4),4.75 and 4.84 (2d, AB system, 2H, Jgem = 11.6 Hz,
PhCH2O), 7.32–7.38 (m, 5H, Ph). 13C NMR (100 MHz, CDCl3): d 26.2, 27.0
(Me2C), 61.9 (C-6), 62.4 (C-5), 71.7 (C-4), 72.0 (C-1), 73.0 (C-3), 75.8 (PhCH2O),
105.7 (C-2), 112.3 (Me2C), 128.1, 128.3, 128.8 (CH-Ar), 137.8 (CIV-Ar). HRMS:
C
16H21N3O5 calcd for [M+Na]+ 358.1379; found: 358.1377.