Controlled Garegg conditions for selective iodination on pyranose templates

Article abstract of DOI:10.1002/ejoc.201001325

Regio- and stereoselective iodinations under controlled Garegg conditions were performed on vicinal diols and contiguous triols located on pyranose templates. β-D-Fructo- orpsicopyranose-based diols were selectively iodinated at C-5 or C-4, respectively,

Full text of DOI:10.1002/ejoc.201001325

FULL PAPER
DOI: 10.1002/ejoc.201001325
Controlled Garegg Conditions for Selective Iodination on Pyranose Templates
Ana-Catarina Simao,[a] Sandrina Silva,[a] Amelia P. Rauter,[b] Patrick Rollin,[a] and
Arnaud Tatibouët*[a]
Keywords: Synthetic methods / Carbohydrates / Halogenation / Iodination
Regio- and stereoselective iodinations under controlled Gar- hydrins. In contrast, the related triols only underwent selec-
egg conditions were performed on vicinal diols and contigu-
ous triols located on pyranose templates. β- -Fructo- or
psicopyranose-based diols were selectively iodinated at C-5
tive iodination at C-5. Application of the process to
D-gluco-
D
and -galactopyranosides resulted in selective iodination at
D
C-3 or C-4, respectively, to afford the
iodohydrins.
D-allo or D-gluco
or C-4, respectively, to afford the L-sorbo or D-tagato iodo-
modified Garegg’s reagent system to perform selective io-
dination of carbohydrate-based vicinal secondary diols[8]
and its extension to triol systems.
Introduction
Direct stereoselective nucleophilic displacement of a hy-
droxy group through Mitsunobu-related processes is an in-
valuable tool in organic synthesis and more specifically in
glycochemistry, Selective iodo-functionalisation on polyhy-
droxylated templates has received a lot of attention over the
years because iodo derivatives can easily be converted into
a number of functions and have shown a broad range of
reactivities based either on radical or on ionic transforma-
tions.[1]
Introduction of iodine by direct replacement of a hy-
droxy group is one of the major approaches, making use
of a large number of reagents, many of them phosphorus-
based.[2] The most popular iodination systems are indisput-
ably those developed over the past decades by Garegg and
Samuelsson.[3] The main drawback of those methods in gly-
cochemistry is the generation of side-products, namely
alkenes, so deoxy-iodo sugars are frequently prepared
through standard nucleophilic displacement of sulfonates,[4]
but also by more unusual methods.[5]
A couple of d-ketopyranose derivatives were used for
preliminary evaluation of the reaction. When the standard
elimination procedure previously described by Lichten-
thaler[7b] was first applied to 1 (Scheme 1), the olefin 3 was
exclusively formed in 63% yield. With a slight change in the
conditions, it could be observed after 1 h (Table 1, Entry 1)
that the olefin 3 was formed in 53% yield together with the
l-sorbo-configured 5-deoxy-5-iodopyranose 2 (40% yield)
resulting from stereoselective introduction of iodine at C-5.
The above result reveals not only the high efficiency of the
reaction (over 93% conversion yield) but also the potential
for selective iodination of a diol system. With that in mind,
we carried out an optimisation study both on the d-fructo
diol 1 and on its d-psico epimer 4.
For the introduction of an iodine atom onto an unpro-
tected carbohydrate skeleton, selective substitution of pri-
mary hydroxy groups over secondary ones is in principle
readily achievable. In contrast, any attempt to achieve reac-
tion of one specific secondary alcohol in the presence of
others often requires the development of a protection/de-
protection sequence, which can be a demanding task.[6] Di-
rect application of Garegg’s reagent system to vicinal diols
is a key elimination method for one-step conversions into
olefins.[7a] Here we disclose our studies on the use of a
[a] Institut de Chimie Organique et Analytique, Université
d’Orléans,
B. P. 6759, 45067 Orléans Cedex 2, France
E-mail: arnaud.tatibouet@univ-orleans.fr
[b] Centro de Química e Bioquímica/Departamento de Química e
Bioquímica, Faculdade de Ciências da Universidade de Lisboa,
Campo Grande, Edifício C8, 5° Piso, 1749-016 Lisboa, Portugal
Scheme 1.[8] Selective iodination of ketopyrano diols.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Selective Iodination on Pyranose Templates
Table 1.[8] Conditions applied to promote selective iodination of
vicinal diols in the d-fructo and the d-psico series.
Entry Starting
ketose
Solvent
I2
Temp. Time Iodide Olefin
(equiv.)[a]
(h)
(%)
(%)
1
2
1
4
toluene
toluene
1.4
1.4
110
°C
110
1
2 (40) 3 (53)
1
5 (8) 6 (67)
°C
r.t.
r.t.
r.t.
[b]
3
4
5
6
7
8
9
10
11
12
1
4
1
4
1
4
1
4
7
7
toluene
toluene
THF
THF
THF
1.4
1.4
1.4
1.4
1.0
1.0
1.0
1.0
1.0
1.4
24
24
15
15
4
–
–
–
–
–
–
–
–
–
–
[b]
2 (7)
[b]
r.t.
–
reflux
reflux
65 °C
65 °C
reflux
reflux
2 (94)
5 (56)
2 (67)
5 (43)
8 (70)
THF
4
1,4-dioxane
1,4-dioxane
THF
72
72
4
THF
20
8 (–) 9 (87)
[a] Together with triphenylphosphane (1.5 equiv.) and imidazole
(3.0 equiv.). [b] No reaction detected by tlc.
To favour selective hydroxy substitution in the vicinal
diol, the numbers of equivalents both of triphenylphos-
phane (1.5 equiv.) and of iodine (1.4 equiv.) were reduced.
By severely limiting the amounts of both reagents relative
to the original procedure (over 4 and 3 equiv., respec-
tively),[3b] we hoped to attain a better selectivity. Both in
the d-fructo and in the d-psico series (Table 1, Entries 1 and
2), however, we observed that olefination was predomina-
ting over iodination even after only 1 h under such condi-
tions. Lowering the temperature (Entries 3 and 4) resulted
in no reaction even after 24 h. However, replacement of tol-
uene by THF (Entries 5 to 8) enhanced both solubilities
and reactivities, and substitutive iodination could be op-
timised both in the d-fructo and in the d-psico series in
THF at reflux over 4 h.
The above protocol, involving a moderate excess of io-
dine (1.4 equiv.), led us to reconsider the mechanism ini-
tially postulated by Garegg (Scheme 2).[3a] The elimination
process appears to take place during the terminal phase
with concomitant regeneration of iodine. In this last step,
iodine could be seen to act as a catalyst, so a reduction in
the amount of iodine to strictly one equivalent should fav-
our selective monosubstitution.
Scheme 2. The elimination mechanism under Garegg’s condi-
tions.[3a]
A comparative experiment was performed with the 3-O-
benzoyl analogue 7 (Scheme 1), in which regio- and stereo-
selective iodo-inversion at C-5, affording the l-sorbo deriv-
ative 8 in 70% yield, was also observed (Entry 11). When
the reaction was forced with iodine (1.4 equiv.) over 20 h
(Entry 12), a clean, high-yielding conversion into the olefin
9 took place, through the transient iodo derivative 8 (easily
detected by tlc monitoring).
With a protocol for selective iodination of cis-vicinal di-
ols to hand, we became interested in exploring the possibil-
ities of selective iodination on triol systems. The trials were
thus extended to 1,2-O-isopropylidene-β-d-fructopyranose
(10, Scheme 3) and 1,2-O-isopropylidene-β-d-psicopyr-
anose (12): application of the previously established condi-
tions also led to regio- and stereoselective iodinations. The
C-5 regioselectivity observed for the d-fructopyrano triol 10
The best result was obtained by treatment of 1 with I2
(1.0 equiv.), triphenylphosphane (1.5 equiv.) and imidazole
(3.0 equiv.) for 4 h in THF at reflux, which provided selec-
tive iodination at C-5 in an excellent 94% yield (Entry 7).
Application of the same conditions to the d-psico epimer 4
(Entry 8) resulted in selective iodination at C-4 and af-
forded a moderate 56% yield of the d-sorbo derivative 5.
Attempts to improve the conversion yields further by re-
placing THF by 1,4-dioxane at the same temperature still
afforded the iodo compounds 2 and 5, albeit with inferior
yields (Entries 9 and 10). In the d-fructo series, iodination
took place regio- and stereoselectively at C-5, whereas in
the d-psico series iodination occurred regio- and stereo-
selectively at C-4. In both cases substitution with inversion
of configuration was ascertained by NMR spectrometric as-
signments.
Scheme 3. Selective iodination of ketopyrano triols.
Eur. J. Org. Chem. 2011, 2286–2292
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A.-C. Simao, S. Silva, A. P. Rauter, P. Rollin, A. Tatibouët
FULL PAPER
was as expected, with inversion of configuration, thus yield-
ing the l-sorbopyrano iodinated diol 11. In contrast, the d-
psicopyrano epimer 12 surprisingly underwent regioselec-
tive substitution not at C-4, but again at C-5, to yield the
l-tagatopyrano iodinated diol 13. The two diols 11 and 13
were quantitatively converted into the di-O-acetates 14 and
15 in order to facilitate the NMR structural analysis and
ascertain the regio- and stereoselectivities of the reactions.
We attempted optimisation of the experimental condi-
tions with the two triols 10 and 12, starting from the pro-
cedure developed for diols (THF, reflux, 1.0 equiv. of io-
dine): in this case (Table 2, Entries 1 and 2), however, the
observed yields did not exceed ca. 20% and even extension
of the reaction time to 3 days (Entries 3 and 4) did not
bring improvement. Replacement of THF with 1,4-dioxane
and running the reaction under reflux for 4 h (Entries 5 and
6) resulted in increases in the yields of 11 and 13 to ca.
38%. No positive change was noted on increasing the reac-
tion time to several days (Entries 7–10). However, on per-
forming the reaction on a one-gram scale at reflux in 1,4-
dioxane for 4 h (Entries 11 and 12), a more efficient conver-
sion was achieved, producing the iodinated diols 11 and 13
in 65% and 63% yields, respectively.
Scheme 4. Proposed mechanism for regioselective iodination in the
d-fructo and the d-psico series.
inversion at C-4 to produce a d-sorbopyrano framework, in
5
which the C2 conformer would also have all substituents
in equatorial positions. This proposed explanation would fit
with the d-fructopyrano triol 10 but not with the d-psico-
pyrano triol 12. The difference in reactivity of the latter
system could be the result of the lower probability of tauto-
mer 18 when R = H, together with contributing anchimeric
assistance of the axial OH-3 group in tautomer 17
(Scheme 4): in such a case, the intermediate 17 would prob-
ably undergo “normal” iodo-inversion at C-5.
We then pushed our investigation further, into contigu-
ous triols based on the aldopyranosides 19, 20 and 21
(Scheme 5). The primary hydroxy groups of the starting β-
pyranosides were first selectively protected in the form of
O-silyl ethers. From the above results, we expected the iodo-
inversion to occur at C-2 in the mannopyranoside 19 and
at C-4 in the galactopyranoside 20: in both cases these reac-
Table 2. Conditions applied to promote selective iodination of vici-
nal triols in the d-fructo and the d-psico series.
Entry Starting Solvent
ketose
I2
Temp. Time (h) Iodide (%)
(equiv.)[a]
1
2
3
4
5
6
7
8
9
10
12
10
12
10
12
10
12
10
12
10
12
THF
THF
THF
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
4
4
72
72
4
11 (21)
13 (20)
11 (15)
13 (11)
11 (38)
13 (39)
11 (27)
13 (21)
11 (39)
13 (31)
11 (65)[b]
13 (63)[b]
THF
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
4
72
72
120
120
4
10
11
12
4
[a] Together with triphenylphosphane (1.5 equiv.) and imidazole
(3.0 equiv.). [b] Reactions performed on the gram scale.
Although satisfactory results had been obtained in terms
of selective conversion of ketopyrano triols into iodinated
diols, there was still a question about the C-5 regioselectiv-
ity on the d-psicopyranose template, which suggested re-
consideration of the mechanistic pathway (Scheme 4).
An initial postulate with regard to the selectivities in vici-
nal diols could be the driving force of the more thermody-
namically stable isomer to be formed. In the d-fructopyr-
anose case, the intermediate oxyphosphonium species 16
would fix the conformation and favour iodo-inversion at C-
5 to produce an l-sorbopyranose framework, for which the
2C5 conformer would have all substituents in equatorial po-
sitions. In the d-psicopyranose case, the similar intermedi-
ate 17 might enter into an equilibrium between two tauto-
mers 17 and 18, and the latter would preferably undergo Scheme 5. Selective iodination of aldopyrano triols.
2288 Eur. J. Org. Chem. 2011, 2286–2292
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Selective Iodination on Pyranose Templates
tions should afford fully equatorial products, whereas no able 1,2-O-isopropylidene-β-d-fructopyranose (10) into its
prediction of selectivity could reasonably be put forward for 5-azido counterpart 27: this intermediate can be regarded
the glucopyranoside 21.
as a cornerstone in a six-step formal synthesis, involving
Iodination of the d-mannopyranoside 19 was not suc- our selective iodination protocol, of DMDP from d-fruc-
cessful, the reaction leading to an intractable mixture of tose.
compounds. On the other hand, the d-galactopyranoside
20 underwent C-4 regio- and stereoselective substitution to
afford a 42% yield of the 4-deoxy-4-iodo-d-glucopyrano-
side 22, characterised as its 2,3-di-O-acetate 23 to facilitate
Conclusions
We have shown that regio- and stereoselective iodinations
under controlled Garegg conditions can be efficiently per-
formed on vicinal diols and contiguous triols on pyranose
templates. β-d-Fructo- or psicopyranose-derived diols un-
dergo selective iodo inversion at C-5 or C-4, respectively,
to afford l-sorbo or d-tagato iodohydrins. In contrast, only
selective iodination at C-5 occurs in the case of the related
ketopyrano triols. Extension of the procedure to d-gluco-
and d-galactopyranosides results in selective iodination at
C-3 or C-4, respectively, to afford the d-allo or d-gluco
iodohydrins. This method can be profitably applied in a re-
gioselective two-step azidation of pyranose templates.
NMR analysis. Finally, iodination of the d-glucopyranoside
22 occurred regio- and stereoselectively at C-3 to afford the
3-deoxy-3-iodo-d-allopyranoside 24 in 45% yield. This last
case, of hardly predictable selectivity, could be closely corre-
lated with previous results reported for Mitsunobu-type
modifications of pyranosides.[9]
This study of selective iodination of vicinal diols and
contiguous triols on pyranose templates under modified
Garegg conditions has delivered interesting results in terms
of regio- and stereoselectivity. From the above examples, we
might propose some keys to elucidate the mechanism: one
could assume that the first step of the conversion is the
formation of a transient oxyphosphonium species through
the reaction between the iodo-phosphonium reagent and
the more nucleophilic hydroxy group. When a vicinal cis
hydroxy group is present, a pentacoordinating phosphorus
complex can arise, further inducing equilibration between
tautomers (Scheme 4). The nucleophilic iodide ion finally
attacks, in most cases, the better activated carbon site (2, 5,
11, 13, 22) and/or the better accessible position (13, 24) to
produce the more stable iodo derivative in a selective man-
ner.
Over recent years d-fructose has been used as a starting
material to prepare polyhydroxylated pyrrolidines, notably
2,5-dideoxy-2,5-imino-d-mannitol (DMDP).[6b,10] In pre-
vious approaches, multistep sequences were needed to reach
the key intermediate in which an azido group is introduced
at C-5. From the present study it has emerged that selective
iodinations in d-fructopyrano systems should readily allow
efficient introduction of azido moieties at C-5 in the d-
fructo series (Scheme 6).
Experimental Section
General: Anhydrous reactions were performed under argon in pre-
dried flasks, with use of anhydrous solvents (distilled when neces-
sary as described in ref.[20]) All chemicals obtained from commer-
cial suppliers were used without further purification. TLC (pre-
coated aluminium-backed plates, Merck Kieselgel 60F254) were
visualised with UV light (254 nm) and by charring after spraying
with H2SO4 solution in ethanol (10%). Column chromatography
was carried out with silica gel 60N (spherical, neutral, 40–63 μm).
Melting points were determined with a Büchi 510 apparatus and
are uncorrected. Optical rotations were measured at 20 °C with a
Perkin–Elmer 341 polarimeter with a 1 dm path length. IR spectra
(absorption frequencies in cm–1) were measured with a Thermo Sci-
entific Nicolet iS10 FT-IR spectrophotometer. NMR spectra were
recorded with a Bruker DPX 400 Avance 2 (400 MHz for 1H;
100.6 MHz for 13C) spectrometer with TMS as the internal stan-
dard. Chemical shifts are expressed in parts per million (ppm,
δ units) downfield from TMS. Splitting patterns are designated as
br. (broad), s (singlet), d (doublet), t (triplet), q (quartet), m (mul-
tiplet), and coupling constants are expressed in Hertz (Hz). Multi-
plicities were determined by use of the DEPT 135 sequence and
peak assignments were established by NOESY, COSY, HSQC and
HMBC experiments on all reported compounds. Mass spectra
(MS) were recorded with an API300 Applied Biosystems instru-
ment in electrospray (ES) mode and high-resolution mass spectra
(HRMS) were recorded with a MicrOTOF-QII spectrometer in the
electrospray ionisation (ESI) mode.
3-O-Benzyl-1,2-O-isopropylidene-β-
D-fructopyranose (1): Prepara-
tion from d-fructose as described in ref.[11] [70551-32-5].
Scheme 6. Two-step formation of d-fructo azides from d-fructo-
pyrano diols or triol.
3-O-Benzoyl-1,2-O-isopropylidene-β- -fructopyranose (7): Prepara-
D
tion in quantitative yield as described in ref.[12] [99648-49-4].
3-O-Benzyl-1,2-di-O-isopropylidene-β-D-psicopyranose (4): Prepara-
Conversions through double inversions at C-5 in the d-
fructo precursors 1 and 7 readily afforded the 3-O-benzyl-
d-fructo azide 25 and the 3-O-benzoyl-d-fructo azide 26 in
moderate to excellent overall yields. Even more attractive
tion in five steps from d-fructose as described in ref.[13] [872345-40-
9].
General Procedure for Regioselective Iodination of Diols: Tri-
was the 40% yield two-step conversion of the readily avail- phenylphosphane (315 mg, 1.5 equiv.), imidazole (164 mg,
Eur. J. Org. Chem. 2011, 2286–2292
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A.-C. Simao, S. Silva, A. P. Rauter, P. Rollin, A. Tatibouët
FULL PAPER
3.0 equiv.) and iodine (203 mg, 1.0 equiv.) were added to a solution
of the diol (0.8 mmol) in THF (5 mL) and the mixture was stirred
under reflux for 4 h. After concentration in vacuo and co-evapora-
tions with toluene, the residue was purified by flash column
chromatography (eluent PE/EtOAc 19:1 then 9:1).
= 9.1 Hz, 1 H, 1b-H), 3.96 (d, 1 H, 1a-H), 4.89 and 5.12 (2ϫd,
Jvic = 5.8 and 5.3 Hz, 2 H, OH-4, OH-5), 5.01 (d, Jvic = 8.0 Hz, 1
H, OH-3) ppm. 13C NMR: δ = 26.3, 26.9 (CH3), 64.8 (C-6), 66.4
(C-4), 68.5 (C-5), 72.0 (C-1), 72.9 (C-3), 105.8 (C-2), 110.6
(Me C) ppm. IR (film): ν = 3390, 3290 (OH) cm–1. MS (ES+): m/z
˜
2
= 243.0 [M + Na]+.
3-O-Benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-α-L-sorbopyranose
(2): Obtained from 1 (1.27 g, 94%) as a white solid, m.p. 123–
Methyl 6-O-tert-Butyldimethylsilyl-α-
D-mannopyranoside (19):
125 °C, [α]D = +51 (c = 0.14, CHCl3), see ref.[8]
Preparation as described in ref.[18] [74247-81-7].
3-O-Benzyl-4,5-dideoxy-1,2-O-isopropylidene-α-
L
-glycero-hex-4-en-
Methyl 6-O-tert-Butyldimethylsilyl-α- -galactopyranoside (20):
D
2-ulopyranose (3): Detection in trace amounts, see ref.[14] [132369-
Preparation in 90% yield as described in ref.[17b,19] [181480-80-8].
48-3].
Methyl 6-O-tert-Butyldimethylsilyl-β-D-glucopyranoside (21): Prep-
3-O-Benzoyl-5-deoxy-5-iodo-1,2-O-isopropylidene-α-
L
-sorbo-
aration in 92% yield as described in ref.[17] [74264-88-3].
pyranose (8): Obtained from 7 (0.97 g, 70%) as a white solid, m.p.
148–151 °C (PE/AcOEt), [α]D = –136 (c = 0.75, CHCl3). 1H NMR
(CDCl3): δ = 1.43, 1.51 (2ϫs, 6 H, CH3), 2.69 (d, Jvic = 4.4 Hz, 1
H, OH-4), 3.92 and 3.97 (2ϫd, Jgem = 9.2 Hz, 2 H, AB system,
1b-H, 1a-H), 3.93 (dd, Jvic = 5.0 Hz, 1 H, 6b-H), 4.03 (m, 1 H, 5-
H), 4.14 (d, Jgem = 11.2 Hz, 1 H, 6a-H), 4.18 (dt, Jvic = 10.0 Hz, 1
H, 4-H), 5.16 (d, J3,4 = 9.6 Hz, 1 H, 3-H), 7.43 (t, Jvic = 7.5 Hz, 2
H, meta-H-Ar), 7.58 (t, Jvic = 7.6 Hz, 1 H, para-H-Ar), 8.07 (d, Jvic
= 7.5 Hz, 2 H, ortho-H-Ar) ppm. 13C NMR: δ = 26.3, 26.8 (CH3),
29.3 (C-5), 65.5 (C-6), 71.9 (C-1), 72.3 (C-3), 74.5 (C-4), 104.8 (C-
2), 112.7 (Me2C), 128.7 (CH-Ar meta), 129.2 (CIV–Ar), 130.1 (CH-
General Procedure for Regioselective Iodination of Triols: Tri-
phenylphosphane (315 mg, 1.5 equiv.), imidazole (164 mg,
3.0 equiv.) and iodine (203 mg, 1.0 equiv.) were added to a solution
of the triol (0.8 mmol) in 1,4-dioxane (5 mL) and the mixture was
stirred under reflux for 4 h. After concentration in vacuo and co-
evaporations with toluene, the residue was purified by flash column
chromatography (eluent PE/EtOAc 19:1 then 9:1).
5-Deoxy-5-iodo-1,2-O-isopropylidene-β-L-sorbopyranose (11): Prep-
aration from 10 (0.97g, 65%) as a yellowish solid, m.p. 82–85 °C
1
(PE/AcOEt), [α]D = –11 (c = 0.51, MeOH). H NMR (CDCl3): δ
= 1.46 and 1.51 (2ϫs, 6 H, CH3), 2.10 (d, Jvic = 9.6 Hz, 1 H, OH-
3), 2.80 (d, Jvic = 1.6 Hz, 1 H, OH-4), 3.44 (t, Jvic = 9.2 Hz, 1 H,
3-H), 3.81 (dt, Jvic = 8.8 Hz, 1 H, 4-H), 3.87 (dd, 1 H, 6b-H), 3.93–
3.97 (m, 1 H, 5-H), 3.97 (d, 1 H, 1b-H), 4.04 (d, Jgem = 10.8 Hz, 1
H, 6a-H), 4.18 (d, Jgem = 8.8 Hz, 1 H, 1a-H) ppm. 13C NMR: δ =
26.4, 26.7 (CH3), 28.2 (C-5), 66.0 (C-6), 72.1 (C-1), 72.9 (C-3), 77.0
Ar ortho), 133.8 (CH-Ar para), 166.4 (C=O) ppm. IR (film): ν =
3540 (OH), 1708 (C=O). ESI-HRMS: calcd. for C16H19INaO6:
457.0124; found 457.0133.
˜
3-O-Benzoyl-4,5-dideoxy-1,2-O-isopropylidene-α-
en-2-ulopyranose (9): See ref.[7b] [99648-50-7].
L-glycero-hex-4-
3-O-Benzyl-4-deoxy-4-iodo-1,2-O-isopropylidene-β-
(5): This compound was obtained from 4 (0.76 g, 56%) in 56%
D
-sorbopyranose
(C-4), 105.7 (C-2), 112.6 (Me C) ppm. IR (film): ν = 3555
˜
2
(OH) cm–1. MS (ES+): m/z = 413.0 [M + AcOH + Na]+.
yield as a pale yellow solid, m.p. 98–101 °C (PE/AcOEt), [α]D
+21 (c = 0.54, CHCl3), see ref.[8]
=
3,4-Di-O-acetyl-5-deoxy-5-iodo-1,2-O-isopropylidene-β-L-sorbo-
pyranose (14): Preparation from 11 in quantitative yield by stan-
3-O-Benzyl-4,5-dideoxy-1,2-O-isopropylidene-β-
D
-glycero-hex-4-en-
dard acetylation; yellowish solid, m.p. 95–98 °C (PE/AcOEt), [α]D
1
2-ulopyranose (6): Preparation in trace amounts [99685-19-5]. = +6 (c = 0.18, CHCl3). H NMR (CDCl3): δ = 1.43, 1.49 (2ϫs,
1
Orange oil, [α]D = –240 (c = 5.53, CHCl3). H NMR (CDCl3): δ = 6 H, CH3), 2.06, 2.08 (2ϫs, 6 H, CH3CO), 3.84 (d, Jgem = 9.3 Hz,
1.37, 1.52 (2ϫs, 6 H, CH3), 3.78 (dd, Jvic = 4.3, J3,5 = 1.8 Hz, 1 1 H, 1b-H), 3.89–4.04 (m, 3 H, 1a-H, 5-H, 6b-H), 4.12 (d, Jgem
=
H, 3-H), 4.13 (s, 2 H, 1-H), 4.26 (br. d, Jgem = 17.1 Hz, 1 H, 6b-
H), 4.39 (ddd, J5,6a = J4,6a = 2.0 Hz, 1 H, 6a-H), 4.56 and 4.66
(2ϫd, Jgem = 11.8 Hz, 2 H, AB system, PhCH2), 5.98 (br. d, J4,5
= 10.3 Hz, 1 H, 5-H), 6.09 (br. d, 1 H, 4-H), 7.24–7.38 (m, 5 H,
Ar-H) ppm. 13C NMR: δ = 26.3, 27.1 (CH3), 61.7 (C-6), 70.3
10.3 Hz, 1 H, 6a-H), 4.97 (d, Jvic = 9.7 Hz, 1 H, 3-H), 5.48 (t, Jvic
= 9.7 Hz, 1 H, 4-H) ppm. 13C NMR: δ = 20.8, 21.0 (2ϫCH3CO),
22.3 (C-5), 26.1, 26.2 (CH3), 65.8 (C-6), 70.7 (C-3), 71.9 (C-1), 74.0
(C-4), 104.4 (C-2), 112.9 (Me2C), 169.5, 170.3 (C=O) ppm. IR
(film): ν = 1740 (C=O). ESI-HRMS: calcd. for C13H19INaO7:
˜
(PhCH2), 71.9 (C-1), 72.9 (C-3), 103.9 (C-2), 111.9 (Me2C), 122.2 437.0073; found 437.0063.
(C-5), 127.8, 127.9, 128.9 (CH-Ar), 131.0 (C-4), 138.3 (CIV
–
5-Deoxy-5-iodo-1,2-O-isopropylidene-α-L-tagatopyranose (13):
Ar) ppm. MS (ES+): m/z = 299.0 [M + Na]+.
Preparation from 12 (0.94g, 63%) as a yellowish solid, m.p. 155–
158 °C (PE/AcOEt), [α]D = –13 (c = 0.45, MeOH). 1H NMR
(CDCl3): δ = 1.40, 1.50 (2ϫs, 6 H, CH3), 2.44 (d, Jvic = 3.6 Hz, 1
H, OH-3), 2.54 (d, Jvic = 4.4 Hz, 1 H, OH-4), 3.83 (t, Jvic = 3.0 Hz,
1 H, 3-H), 3.94 (dd, Jvic = 5.2, Jgem = 11.2 Hz, 1 H, 6b-H), 4.01–
1,2-O-Isopropylidene-β-D-fructopyranose (10): Preparation in two
steps from d-fructose as described in refs.[14,15] [66900–93–4].
Colourless solid, m.p. 98–103 °C (AcOEt), [α]D = –145 (c = 0.43,
1
MeOH). H NMR ([D6]DMSO): δ = 1.31, 1.37 (2ϫs, 6 H, CH3),
3.46–3.50 (m, 3 H, 3-H, 4-H, 6b-H), 3.68 (br. s, 1 H, 5-H), 3.71 (d, 4.05 (m, 1 H, 4-H), 4.04 (d, Jgem = 9.4 Hz, 1 H, 1b-H), 4.09 (d, 1
Jgem = 10.8 Hz, 1 H, 6a-H), 3.73 (d, Jgem = 8.4 Hz, 1 H, 1b-H),
4.01 (d, 1 H, 1a-H), 4.56 (d, Jvic = 3.6 Hz, 1 H, OH-5), 4.64 and
H, 6a-H), 4.12 (d, 1 H, 1a-H), 4.22 (m, 1 H, 5-H) ppm. 13C NMR:
δ = 26.5, 26.8 (CH3), 29.7 (C-5), 65.9 (C-6), 68.3 (C-1), 73.4, 73.6
4.76 (2ϫd, Jvic = 5.2 and 6.8 Hz, 2 H, OH-3, OH-4) ppm. 13C (C-3, C-4), 96.0 (C-2), 112.6 (Me C) ppm. IR (film): ν = 3555
˜
2
NMR: δ = 26.2, 27.0 (CH3), 64.5 (C-6), 67.4 (C-4), 68.9 (C-5), 70.3
(C-1), 71.1 (C-3), 106.4 (C-2), 110.6 (Me2C) ppm.
(OH) cm–1. MS (ES+): m/z = 413.0 [M + AcOH + Na]+.
3,4-Di-O-acetyl-5-deoxy-5-iodo-1,2-O-isopropylidene-α-
L
-tagato-
1,2-O-Isopropylidene-β-D-psicopyranose (12): Preparation from pyranose (15): Preparation from 13 in quantitative yield by stan-
1,2;4,5-di-O-isopropylidene-β-d-psicopyranose in quantitative yield
dard acetylation; yellowish solid, m.p. 106–109 °C (PE/AcOEt),
as described in ref.[16] [20789–58–6]. Colourless solid, m.p. 159–
[α]D = –26 (c = 0.17, CHCl3). 1H NMR (CDCl3): δ = 1.41, 1.49
1
162 °C (AcOEt). [α]D = –124 (c = 0.53, MeOH). H NMR ([D6]- (2ϫs, 6 H, CH3), 2.04, 2.12 (2ϫs, 6 H, CH3CO), 3.78 (d, Jgem
=
DMSO): δ = 1.29, 1.38 (2ϫs, 6 H, CH3), 3.46 (dd, J3,4 = 2.4 Hz,
1 H, 3-H), 3.60–3.72 (m, 4 H, 4-H, 5-H, 6a-H, 6b-H), 3.88 (d, Jgem
9.2 Hz, 1 H, 1b-H), 3.93 (d, 1 H, 1a-H), 4.08 (dd, Jgem = 10.4, Jvic
= 3.6 Hz, 1 H, 6b-H), 4.14–4.23 (m, 2 H, 5-H, 6a-H), 5.17 (d, J3,4
2290
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2286–2292

Selective Iodination on Pyranose Templates
= 3.2 Hz, 1 H, 3-H), 5.35 (dd, J4,5 = 10.8 Hz, 1 H, 4-H) ppm. 13C
NMR: δ = 20.8 (2ϫCH3CO), 21.2 (C-5), 26.4, 26.9 (CH3), 66.6
afforded the azide 26 (595 mg, 74% yield) as a colourless oil, [α]D
= –63 (c = 0.86, CHCl3). H NMR (CDCl3): δ = 1.42, 1.49 (2ϫs,
1
(C-6), 72.2 (C-3), 72.7 (C-4), 73.4 (C-1), 103.9 (C-2), 113.6 (Me2C), 6 H, CH3), 3.72–3.80 (m 1 H, 6-H), 3.93–4.08 (m, 4 H, 1a-H, 4-H,
169.5, 169.9 (C=O) ppm. IR (film): ν = 1750 (C=O). ESI-HRMS: 5-H, 6b-H), 4.20 (d, Jgem = 8.8 Hz, 1 H, 1b-H), 5.43 (d, J3,4
=
˜
calcd. for C13H19INaO7: 437.0073; found 437.0090.
10.0 Hz, 1 H, 3-H), 7.43 (t, Jvic = 7.5 Hz, 2 H, meta-H-Ar), 7.58
(t, Jvic = 7.6 Hz, 1 H, para-H-Ar), 8.07 (d, Jvic = 7.5 Hz, 2 H, ortho-
H-Ar) ppm. 13C NMR: δ = 26.4, 26.6 (CH3); 60.7 (C-4), 62.3 (C-
6), 67.5 (C-5), 72.1 (C-1), 74.1 (C-3), 106.2 (C-2), 112.6 (Me2C),
128.6, 128.7, 130.1 (CH-Ar); 133.8 (CIV–Ar), 166.7 (C=O) ppm. IR
Methyl 2,3-Di-O-acetyl-6-O-tert-butyldimethylsilyl-4-deoxy-4-iodo-
α-D-glucopyranoside (23): The crude iodination mixture obtained
from the d-galactopyranoside 20 was concentrated in vacuo and
the residue was subjected to a standard acetylation procedure. Puri-
fication by flash column chromatography (eluent PE/EtOAc 19:1)
afforded 23 (0.22 g, 40% overall yield from 20) as a yellowish solid,
m.p. 93–96 °C (PE/AcOEt), [α]D = +58 (c = 0.23, CHCl3). 1H
NMR (CDCl3): δ = 0.09, 0.10 (2ϫs, 6 H, Me2Si), 0.92 (s, 9 H,
tBuSi), 2.06, 2.10 (2ϫs, 3 H, CH3CO), 3.39 (s, 3 H, OMe), 3.95–
(film): ν = 3459 (OH), 2104 (N ), 1717 (C=O). ESI-HRMS: calcd.
˜
3
for C16H19N3NaO6: 372.1172; found 372.1177.
5-Azido-5-deoxy-1,2-O-isopropylidene-β-D-fructopyranose (27): Ob-
tained from 10 in 62% yield as a colourless solid, m.p. 113–114 °C,
see ref.[6a] [94801-01-1].
4.09 (m, 4 H, 4-H, 5-H, 6a-H, 6b-H), 4.78 (dd, J2,1 = 3.6, J2,3
=
10.0 Hz, 1 H, 2-H), 4.95 (d, 1 H, 1-H), 5.61 (t, J3,4 = 10.0 Hz, 1 H,
3-H) ppm. 13C NMR: δ = –5.0, –5.2 (Me2Si), 18.5 (CIV–tBuSi),
20.9, 21.1 (CH3CO), 25.6 (C-4), 26.1 (Me3CSi), 55.5 (OMe), 64.3
(C-6), 71.9 (C-2), 72.6 (C-3), 72.9 (C-5), 97.3 (C-1), 169.6, 170.3
Acknowledgments
We are grateful to the Agence Nationale pour la Recherche (ANR)
for financial support and to the Fundação para a Ciência ea Tecno-
logia (FCT) for a fellowship (A. C. S.). We would also like to thank
the Universidade de Lisboa, the Université d’Orléans and the Part-
enariat Hubert Curien (PHC) franco-portugais (PESSOA program)
for multiform support.
(C=O) ppm. IR (film): ν = 1755 (C=O) cm–1. MS (ES+): m/z =
˜
503.0 [M + H]+. ESI-HRMS: calcd. for C17H32IO7Si: 503.0956;
found 503.0952.
Methyl 6-O-tert-Butyldimethylsilyl-3-deoxy-3-iodo-β-D-allopyran-
oside (24): Obtained from 21 (0.31g, 45%) as a yellowish solid, m.p.
152–155 °C (PE/AcOEt), [α]D = +9 (c = 0.87, MeOH). 1H NMR
(CDCl3): δ = 0.09 (s, 6 H, Me2Si), 0.89 (s, 9 H, tBuSi), 2.85 (d,
JOH,2 = 2.8 Hz, 1 H, OH-2), 3.36 (ddd, J5,4 = 4.8, J5,6a = 6.3, J5,6b
= 8.8 Hz, 1 H, 5-H), 3.54 (s, 3 H, OMe), 3.59 (dd, J2,3 = 2.6, J2,1
= 7.4 Hz, 1 H, 2-H), 3.65 (d, JOH,4 = 1.6 Hz, 1 H, OH-4), 3.79–
3.85 (m, 1 H, 4-H), 3.82 (d, Jgem = 10.2 Hz, 1 H, 6b-H), 3.90 (d, 1
H, 6a-H), 3.93 (m, 1 H, 3-H), 4.18 (d, 1 H, 1-H) ppm. 13C NMR:
δ = –5.3 (Me2Si), 18.3 (CIV–tBuSi), 25.9 (Me3CSi), 38.9 (C-3), 57.2
(OMe), 64.8 (C-6), 74.8 (C-2, C-4), 76.6 (C-5), 103.8 (C-1) ppm. IR
[1] a) J. E. G. Barnett, Adv. Carbohydr. Chem. Biochem. 1967, 22,
177–227; b) W. A. Szarek, Adv. Carbohydr. Chem. Biochem.
1973, 28, 225–306; c) A. R. Vaino, W. A. Szarek, Adv. Car-
bohydr. Chem. Biochem. 2000, 56, 9–63.
[2] B. R. Castro, Org. React. 1983, 29, 1–62.
[3] a) P. J. Garegg, Pure Appl. Chem. 1984, 56, 845–858; b) P. J.
Garegg, B. Samuelsson, J. Chem. Soc., Chem. Commun. 1979,
978–980; c) P. J. Garegg, B. Samuelsson, J. Chem. Soc. Perkin
Trans. 1 1980, 2866–2869.
(film): ν = 3250 (OH) cm–1. MS (ES+): m/z = 419.0 [M + H]+. ESI-
˜
HRMS: calcd. for C13H27INaO5Si: 441.0565; found 441.0561.
[4] P. R. Skaanderup, C. S. Poulsen, L. Hyldtoft, M. R. Jorgensen,
R. Madsen, Synthesis 2002, 1721–1727.
[5] A. R. Ellwood, M. J. Porter, J. Org. Chem. 2009, 74, 7982–7985.
[6] a) A. Tatibouët, M. Lefoix, J. Nadolny, O. R. Martin, P. Rollin,
J. Yang, G. D. Holman, Carbohydr. Res. 2001, 333, 327–334; b)
I. Izquierdo, M. T. Plaza, V. Yanez, Tetrahedron 2007, 63,
1440–1447.
[7] a) P. J. Garegg, B. Samuelsson, Synthesis 1979, 813–814; b)
F. W. Lichtenthaler, W. Doleschal, S. Hahn, Liebigs Ann. Chem.
1985, 2454–2464.
[8] A. C. Simao, A. Tatibouët, A. P. Rauter, P. Rollin, Tetrahedron
Lett. 2010, 51, 4602–4604.
[9] a) K. Weinges, S. Haremsa, W. Maurer, Carbohydr. Res. 1987,
164, 453–458; b) I. Dancy, L. Laupichler, P. Rollin, J. Thiem,
Liebigs Ann. Chem. 1993, 343–350.
[10] a) I. Izquierdo, M. T. Plaza, M. Rodriguez, J. A. Tamayo, A.
Martos, Tetrahedron 2006, 62, 2693–2697; b) M. I. Garcia-Mo-
reno, M. Aguilar, C. Ortiz Mellet, J. M. Garcia Fernandez,
Org. Lett. 2006, 8, 297–299 and references cited therein .
[11] J. Kang, G. J. Lim, S. K. Yoon, M. Y. Kim, J. Org. Chem. 1995,
60, 564–577.
[12] A. Tatibouët, J. Yang, C. Morin, G. D. Holman, Bioorg. Med.
Chem. 2000, 8, 1825–1833.
[13] I. Izquierdo, M. T. Plaza, M. Rodriguez, F. Franco, A. Martos,
Tetrahedron 2005, 61, 11697–11704 and references cited
therein.
5-Azido-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-D-fructo-
pyranose (25): Sodium azide (464 mg, 3.0 equiv.) was added to a
solution of the iodo derivative 1 (1.0 g, 2.38 mmol) in DMSO
(8 mL) and the mixture was then stirred at 90 °C for 3 days. After
the mixture had cooled, ethyl acetate (200 mL) was added and the
solution was washed with water (3 ϫ 40 mL) and then brine
(40 mL). After drying over MgSO4 and concentration in vacuo, the
crude residue was purified by column chromatography (eluent PE/
EtOAc 9:1) to afford the azide 25 (734 mg, 92% yield) as a colour-
less solid, m.p. 107–109 °C (PE/AcOEt), [α]D = –117 (c = 0.25,
CHCl3). 1H NMR (CDCl3): δ = , 1.42, 1.48 (2ϫs, 6 H, CH3), 2.31
(d, JOH,4 = 5.2 Hz, 1 H, OH), 3.67 (d, J3,4 = 9.6 Hz, 1 H, 3-H),
3.74 (dd, Jgem = 12.4, J6b,5 = 1.6 Hz, 1 H, 6b-H), 3.94 (m, 1 H, 5-
H), 3.96 (d, Jgem = 8.6 Hz, 1 H, 1b-H), 3.99 (dd, J6a,5 = 1.6 Hz, 1
H, 6a-H), 4.03 (d, 1 H, 1a-H), 4.19 (ddd, J4,3 = 4.4, J4,OH = 5.2,
J4,5 = 9.6 Hz, 1 H, 4-H), 4.75 and 4.84 (2ϫd, Jgem = 11.6 Hz, 2
H, AB system, PhCH2), 7.32–7.38 (m, 5 H, Ph) ppm. 13C NMR: δ
= 26.2, 27.0 (CH3), 61.9 (C-6), 62.4 (C-5), 71.7 (C-4), 72.0 (C-1),
73.0 (C-3), 75.8 (PhCH2), 105.7 (C-2), 112.3 (Me2C), 128.1, 128.3,
128.8 (CH-Ar), 137.8 (CIV–Ar) ppm. IR (film): ν = 3541 (OH),
˜
2119 (N3) cm–1. MS (ES+): m/z = 374.5 [M + K]+. ESI-HRMS:
calcd. for C16H21N3NaO5: 358.1379; found 358.1377.
[14] I. Izquierdo Cubero, M. T. Plaza Lopez-Espinosa, An. Quim.
1990, 86, 554–560.
[15] E. Kaji, E. Kurimoto, R. Saiga, A. Matsuura, K. Harada, T.
Nishino, Heterocycles 2005, 66, 453–468.
[16] a) N. Nakajima, M. Matsumoto, M. Kirihara, M. Hashimoto,
T. Katoh, S. Terashima, Tetrahedron 1996, 52, 1177–1194; b)
5-Azido-3-O-benzoyl-5-deoxy-1,2-O-isopropylidene-β-D-fructo-
pyranose (26): Sodium azide (450 mg, 3.0 equiv.) was added to a
solution of the iodo derivative 7 (1.0 g, 2.3 mmol) in DMSO (8 mL)
and the mixture was then stirred at 90 °C for 3 days. After similar
workup as for 25, column chromatography (eluent PE/EtOAc 9:1)
Eur. J. Org. Chem. 2011, 2286–2292
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2291

A.-C. Simao, S. Silva, A. P. Rauter, P. Rollin, A. Tatibouët
FULL PAPER
P. C. M. Hervé du Penhoat, A. S. Perlin, Carbohydr. Res. 1979,
71, 149–167.
[19]
D. J. Chambers, G. R. Evans, A. Fairbanks, Tetrahedron 2005,
61, 7184–7192.
[17] a) H. H. Brandstetter, E. Zbiral, Helv. Chim. Acta 1980, 63,
327–343; b) M.-K. Chung, G. Orlova, J. D. Goddard, M.
Schlaf, R. Harris, T. J. Beveridge, G. White, F. R. Hallett, J.
Am. Chem. Soc. 2002, 124, 10508–10518.
[18] V. Belakhov, E. Dovgolevsky, E. Rabkin, S. Shulami, Y. Sho-
ham, T. Baasov, Carbohydr. Res. 2004, 339, 385–392.
[20] D. D. Perrin, W. L. F. Armarego, D. R. Perrin, Purification of
Laboratory Chemicals, Pergamon, Oxford, 1986.
Received: September 22, 2010
Published Online: March 4, 2011
2292
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2286–2292