Stereoselective synthesis of difructose dianhydrides by use of the xylylene group as stereodirecting element in spiroketalisation reactions

Article abstract of DOI:10.1002/ejoc.201000946

The use of the o-xylylene protecting group as an element of remote stereochemical control in bis(spiroketalisation) reactions of D-fructose has been investigated. The presence of the cyclic diether functionality favours the trans-diequatorial disposition

Full text of DOI:10.1002/ejoc.201000946

FULL PAPER
DOI: 10.1002/ejoc.201000946
Stereoselective Synthesis of Difructose Dianhydrides by Use of the Xylylene
Group as Stereodirecting Element in Spiroketalisation Reactions
Alejandro Méndez-Ardoy,[a] Elena Suárez-Pereira,[a] Patricia Balbuena Oliva,[b]
José Luis Jiménez Blanco,*[a] Carmen Ortiz Mellet,[a] and José M. García Fernández[b]
Keywords: Spiroketals / Difructose dianhydrides / Carbohydrates / Anhydrides / Spiro compounds
The use of the o-xylylene protecting group as an element of
remote stereochemical control in bis(spiroketalisation) reac-
features have been exploited to develop stereoselective syn-
theses of dipyranose and difuranose DFAs with the aid of
tions of
D-fructose has been investigated. The presence of
triflic acid activation of 1,2-O-isopropylidene-D-fructose pre-
the cyclic diether functionality favours the trans-diequatorial
disposition of oxygen substituents, a conformational arrange-
cursors. For difuranose DFAs, the combination of this strat-
egy with the concept of rigid spacer-mediated intramolecular
ment that is encountered in the 3-O/4-O segment in β-
D
-fruc-
-fruc-
spiroketalisation, with use of xylylene-tethered D-fructose
topyranoside and β- -fructofuranoside moieties in di-
D
D
precursors, further allows double stereocontrol. The conclu-
sions of this study open new perspectives in the stereoselec-
tive synthesis of complex spiroketal derivatives in general
and in the preparation of pure DFA standards with applica-
tion in food chemistry in particular.
tose dianhydrides (DFAs). Moreover, the presence of the o-
xylylene group in cis-oriented vic-diol segments slows down
the interconversion rate between the two chair conformers
in fructopyranose rings, which has a strong influence on the
stereochemical outcome of the dimerisation reaction. Those
Introduction
Di-d-fructose dianhydrides (DFAs; Figure 1) comprise a
unique class of stereoisomeric mono- or bis(spiroketal) di-
saccharides first identified in mixtures resulting from the
treatment of d-fructose with mineral acids and further iso-
lated from microorganisms and higher plants.[1,2] Their
identification as the major components of the thermolysis
products of sucrose- and d-fructose-containing food materi-
als, such as caramel or chicory,[3–6] together with their
promising prebiotic properties, have strongly stimulated re-
search into their preparation and nutritional properties.[7–11]
Recently, a methodology for the preparation of DFA-en-
riched caramels based on the use of acid ion-exchange res-
ins as caramelisation promoters has been reported.[12] The
resulting products, containing up to 70% of DFA deriva-
tives, exhibited a protective effect against inflammatory
bowel disease (Crohn’s disease) in an animal model.[13]
Those results highlighted the need to obtain pure DFA
standards for their analytical identification and quantifica-
tion in food and biological samples.[14,15]
Figure 1. Spiroketal disaccharide cores (types I–VI) of DFAs.
The underlying spiroketal framework of DFAs is shared
by many biologically relevant natural products such as ste-
roidal saponins, polyether ionophores, macrolide antibiot-
ics, insect pheromones and toxic metabolites from algae and
fungi.[16–19] Many of these compounds exhibit important
biological activities, and consequently there is sustained
interest in the controlled construction of this structural mo-
tif.[20–29] Up to six different tricyclic cores and 14 DFA iso-
mers (types I–VI, Figure 1) differing in the ring sizes, link-
ing positions and stereochemistry of the spiroketal centres
[a] Department of Organic Chemistry, University of Seville,
Prof. García González 1, 41012 Seville, Spain
Fax: +34-954624960
E-mail: jljb@us.es
[b] Instituto de Investigaciones Químicas, CSIC,
Américo Vespucio 49, Isla de la Cartuja, 41092 Seville, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000946.
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have been identified in caramel or in chemically obtained
mixtures.[7] This structural and stereochemical diversity
makes DFAs ideal targets for evaluating new synthetic
methodologies.
Except for structure VI, each DFA possesses a central
1,4-dioxane ring that can adopt a chair (Figure 2, A) or
boat (or skew-boat; Figure 2, B) conformation in order to
optimise all factors governing spiroketal stability: that is,
maximum anomeric effect (i.e., oxygen substituents in axial
relative orientations) and minimum steric interactions (i.e.,
carbon substituents in equatorial disposition). Thermo-
dynamic DFAs have different configurations (α,β) at the
spiroketal centres and can fulfil those requirements in the
chair arrangement. DFA diastereomers with identical con-
figurations at both spirocentres (α,α or β,β) tend to adopt
the less favourable boat arrangement. Some representatives
can be obtained preferentially under kinetic conditions, but
in most cases they are neither thermodynamically nor kinet-
ically favoured: that is, they are contra-thermodynamic[30]
and cannot be accessed in significant yields under reversible
reaction conditions.
Figure 2. Schematic representation of the chair and boat conforma-
tions of dispiro-DFAs for derivatives with different (A), or identical
(B) configurations at the anomeric centres.
Most of the reported approaches for the synthesis of
DFAs are based on the use of protecting group strategies
to block the cyclic form of fructose during the dimerisation/
spiroketalisation of monomeric precursors.[31–34] Non-
participating groups (e.g., benzyl groups; see precursors 6
and 8) then favour the unsymmetrically configured (α,β)
thermodynamic diastereomers (Scheme 1, compounds 1
and 3), whereas in the case of participating groups (e.g.,
benzoyl; see precursors 7 and 9) kinetically favoured sym-
metric DFAs can be accessed through formation of cyclic
oxacarbenium intermediates (Scheme 1, compounds 2 and
4). The incorporation of distance-restriction elements, by
tethering the fructose units under reaction through xylylene
segments (rigid spacer-mediated glycosylation[35,36]/spiro-
cyclisation; e.g. precursor 10), has been exploited to access
contra-thermodynamic DFA derivatives (e.g., 5).[37–41]
The “external” d-fructose rings in DFAs have also been
shown to adopt distinct conformations depending on the
stereochemistry of the corresponding spiroketal centres,
which makes DFAs rather rigid molecules. Thus, α- and β-
d-fructopyranose fragments[1,42–44] are found in the two li-
mit chairs (5C2 and 2C5), whereas α- and β-d-fructofur-
anose moieties[1,45] take on conformational arrangements
Scheme 1. Synthesis of dipyranose (1 and 2) and difuranose (3–5)
DFAs from monomeric or dimeric d-fructose precursors. Reagents
and conditions: (a) Lewis acid, CH2Cl2 or toluene; (b) conventional
catalytic hydrogenolysis (Pd/C) or conventional catalytic transester-
ification (MeOH/NaOMe).
tose subunits. With this idea in mind, we conceived that
cyclic protecting groups favouring precise orientations of
the diol segments might be exploitable as remote stereocon-
trol elements, alone or in combination with tethering strate-
3
close to E and EO, respectively (Figure 3). The close rela-
tionship between configuration aspects and conformation
aspects suggests that it might be possible to influence the
stereochemical courses of DFA-forming reactions by im-
Figure 3. Preferred conformations of fructopyranose (top) and
fructofuranose (bottom) rings in DFA bis(spirodisaccharides). The
relative dispositions of the trans-oriented substituents at C-3 and
posing conformational restrictions on the reacting d-fruc- C-4 are indicated.
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Stereoselective Synthesis of Difructose Dianhydrides
gies. The cyclic di-O-(o-xylylene) protecting group, recently between 3-OH and α,αЈ-dibromo-o-xylene, regioselective
proposed for the selective protection of trans-diequatorial hydrolysis of the non-anomeric isopropylidene group and
hydroxy groups in pyranoses[46–48] and furanoses,[49] seemed intramolecular etherification involving 4-OH, which al-
particularly well suited for such a purpose, because it is lowed a direct confirmation of the structure.[46] Benzylation
stable under the acidic conditions used to promote DFA of the remaining hydroxy group (5-OH) in 12 (Ǟ 13) and
formation.[50] The potential of this approach for the prepa- subsequent TfOH-promoted dimerisation/spirocyclisation
ration of difructofuranose and difructopyranose DFAs has afforded a mixture of the two dipyranose α,β- and β,β-
now been examined. The potential to apply double confor- DFAs 14 and 15 in a 1:3 relative proportion, which repre-
mational control by cyclic protection/tethering of the d- sents a 75-fold increase in selectivity towards the di-β-dia-
fructose precursors and the scope and limitations of the stereomer relative to the result previously observed for the
methods are discussed.
tribenzylated derivative 6 (α,β/β,β = 25:1; Table 1). Simulta-
neous hydrogenolysis of the benzyl and cyclic o-xylylene
groups with Pd/C in the presence of formic acid proceeded
smoothly to give the fully unprotected DFAs 1 and 2 in
quantitative yield (Scheme 2).
Results and Discussion
Synthesis of Di-
D-fructopyranose Dianhydrides
Table 1. Relative proportions (%) of α,β- and β,β-dipyranose DFA
diastereomers obtained by TfOH activation of d-fructopyranose
precursors incorporating cyclic o-xylylene groups (13, 17 and 24–
26) in comparison with classical acyclic protection (6 and 7).[33]
The α- and β-d-fructopyranose subunits in difructopyr-
5
2
anose DFAs adopt the C2 and C5 chair conformations,
respectively, in order to comply with the anomeric effect at
both spiroketal centres (Figure 3, top).[1] This scenario re-
sults in trans-diaxial or trans-diequatorial relative orienta-
tions for the vicinal hydroxy groups 3-OH and 4-OH. The
latter arrangement was expected to be better accommo-
dated in the dioxacyclooctane-type ring after o-xylylene
protection. Actually, cyclic diether protection of these two
hydroxy groups can be effected directly in the triol deriva-
tive 11[51,52] (Scheme 2) by treatment with α,αЈ-dibromo-o-
xylene in the presence of sodium hydride (Ǟ 12; 37% yield,
74% based on reacted 11), which is notable in view of the
general lack of selectivity of benzylation reactions under
these conditions. Compound 12 had previously been ob-
tained by a three-step reaction sequence from 1,2:4,5-di-O-
isopropylidene-d-fructopyranose[50,51] through the reaction
Starting material
α,β diastereomer
β,β diastereomer
6
96
50
25
4
50
75
7
13
17
24
25
26
78[a]
83[b]
80[b]
84[b]
22
17[b]
20[b]
16[b]
[a] Calculated by considering the combined proportions of com-
pounds 18 and 19. [b] Calculated from the relative proportion of
the corresponding unprotected DFAs 1 and 2 after hydrogenolysis
of the oligomeric adducts.
The 4-OH/5-OH vic-diol segment adopts analogous cis-
(axial-equatorial) dispositions in either of the two possible
chair conformations of the d-fructopyranose moieties in di-
pyranose DFAs. Nevertheless, installation of a cyclic o-xy-
lylene protection linking those positions was expected to
slow down the conformational interconversion rate. If the
2
precursor has the β-configuration in the C5 conformation,
the di-β-DFA diastereomer should be then kinetically fav-
oured relative to the use of acyclic benzyl protection. To
verify this hypothesis, the known 3-O-benzyl derivative
16[51] (Scheme 3) was transformed into the corresponding
cyclic diether 17. After TfOH activation, the α,β- and β,β-
DFA derivatives 18 and 20 were formed in 3.3:1 relative
proportions (to be compared with 25:1 in the case of 6;
Table 1). A small amount of the α,β-DFA 19, in which the
benzyl group at 2-O had been cleaved, was also isolated. In
all cases, hydrogenolysis afforded the corresponding unpro-
tected DFA 1 or 2 in quantitative yield (Scheme 3).
5
2
The C2 and C5 conformations for the α- and β-fructo-
pyranosyl rings, respectively, in the protected DFA products
14, 15 and 18–20 were confirmed by the corresponding
3JH,H values. The J3,4 and J4,5 coupling constants are diag-
nostic in this respect, ranging from 2.9–3.0 or 9.6–10.0 Hz
for gauche or trans dispositions of the corresponding pro-
tons. The α,β diastereomers 14, 18 and 19 each displayed
two spin systems in their 1H and 13C NMR spectra,
Scheme 2. Reagents and conditions: (a) NaH, DMF, 16 h (37%);
(b) BnBr, NaH, DMF, 30 min (75%); (c) TfOH, CH2Cl2, –78 °C
to room temp., 1 h (14, 20% and 15, 61%); (d) Pd/C, H2 (1 atm),
HCOOH (10%), EtOAc/MeOH (1:1), 16 h (100%).
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rivatives 21–23.[39] In these cases, however, TfOH activation
led to mixtures of oligomers from which no pure com-
pounds could be isolated. Hydrogenation of the mixtures
and gas chromatography (GC) analysis of the spirodisacch-
aride products after trimethylsilylation, by a reported pro-
tocol,[12,14] indicated relative proportions of the α,β and β,β
diastereomers 1 and 2 very close to those obtained from the
monomeric precursor 17 (Table 1). Probably the intramo-
lecular reaction is strongly disfavoured in these systems, due
to the rigidity of the resulting polycyclic structure, pre-
venting a double stereocontrol mechanism (Scheme 4).
Synthesis of Di-D-fructofuranose Dianhydrides
Although in principle more flexible, the furanose rings in
difructofuranose DFAs also adopt distinct conformations
depending on the anomeric α or β configuration, which im-
ply pseudoaxial or pseudoequatorial relative dispositions
for the secondary hydroxy groups 3-OH and 4-OH (Fig-
ure 3, bottom).[1] Imposition of a conformational restriction
in this region by cyclic o-xylylenation in a β-d-fructo-
furanose precursor was thus considered. The known 6-O-
(tert-butyldimethylsilyl)-1,2-O-isopropylidene-β-d-fructofu-
ranose (27,[21] Scheme 5) was transformed into the cyclic
diether 28 and, after removal of the silyl ether group at 6-
O (Ǟ 29), acetylation (Ǟ 30) and benzylation (Ǟ 31) reac-
tions were carried out (Scheme 5).
Scheme 3. Reagents and conditions: (a) NaH, DMF, 16 h (42%);
(b) TfOH, CH2Cl2, –78 °C to room temp., 1 h (18, 50%, 19, 6%
and 20, 15%); (c) Pd/C, H2 (1 atm), HCOOH (10%), EtOAc/
MeOH (1:1), 16 h (100%).
whereas the di-β derivatives 15 and 20 each showed a single
one, consistent with a C2 symmetric structure. The C-2
chemical shifts, which have been shown to be fingerprints
for given DFA structures,[1,53] agreed with the expected ste-
reochemistry. The assignment was further unequivocally
confirmed by comparison of the deprotected products 1
and 2 with authentic samples.
Our next goal was to examine whether or not the selec-
tivity could be further influenced by bridging the fructose
units undergoing reaction, thereby transforming DFA for-
mation into an intramolecular process. Linking of the 3-O
positions by insertion of o-, m- or p-xylylene segments has
previously been found to privilege the thermodynamically
less favoured di-β-DFA by inducing the boat conformation
at the central 1,4-dioxane ring.[37]
The corresponding precursors 24–26 (Scheme 4) were
thus prepared by o-xylylenation of the known tethered de-
Scheme 5. Reagents and conditions: (a) NaH, DMF, 1 h (78%); (b)
Scheme 4. Reagents and conditions: (a) NaH, DMF, 3 h (24, 45%, TBAF, THF, 4 h (93%); (c) Ac2O, pyridine (85%); (d) BnBr, NaH,
25, 30% and 26, 35%); (b) TfOH, CH2Cl2, –78 °C to room temp.,
1 h; (c) Pd/C, H2 (1 atm), HCOOH (10%), EtOAc/MeOH 1:1, 16 h
(100%).
DMF, 3 h (80%); (e) TfOH, CH2Cl2, –78 °C to room temp., 40 min
(32, 12%, 33, 41%, 34, 75% and 35, 70%); (f) Pd/C, H2 (1 atm),
HCOOH (10%), EtOAc/MeOH 1:1, 16 h (100%).
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Stereoselective Synthesis of Difructose Dianhydrides
Dimerisation/spirocyclisation of the 6-O-protected deriv- presence of two fructofuranose rings with α and β configu-
atives 30 and 31 led exclusively to the corresponding α-d- rations. In the β-fructofuranose ring the J3,4 and J4,5 values
fructofuranose β-d-fructofuranose dianhydride derivatives (4.5–6.1 Hz) are consistent with a conformation close to EO,
34 and 35 in excellent yields. No traces of the symmetric meaning that the incorporation of the cyclic protecting
α,α or β,β diastereomers were detected. The latter anomeric group does not cause a significant distortion of the scenario
combination is very unfavourable both under thermo- encountered in other derivatives of DFA 3.[1,27] In the α-
dynamic and under kinetic reaction conditions, and its ab- fructofuranose ring, however, the large J4,5 values (8.9–
sence in the reaction mixtures was expected.[33] Neverthe- 9.0 Hz) imply a trans-diaxial disposition of the correspond-
4
less, the total preference for the unsymmetrical α,β com- ing protons and point to the T5 conformation. This places
pound over the α,α diastereomer is remarkable. Although the 3-O and 4-O substituents in a pseudoequatorial orienta-
the unsymmetrical derivative is thermodynamically fav- tion, in contrast to the pseudoaxial disposition in the ab-
oured, precursors bearing acyclic protecting groups system- sence of cyclic protection.[1,27] This conformational distor-
atically gave mixtures with α,β/α,α relative proportions tion probably implies an energy penalty and might be re-
ranging from 1:1 to 7:1 (for derivatives bearing a nonpar- sponsible for the absence of the α,α diastereomer in the re-
ticipating group at 3-O; e.g., 8) or 1:24 to 1:25 (for deriva- action mixtures. In compound 32 the situation in the α-
tives bearing a participating group at 3-O; e.g., 9).[33] To the fructofuranose ring is analogous. The β-fructopyranose
2
best of our knowledge, the present results represent the first moiety adopts the expected C5 chair conformation, as al-
stereospecific synthesis of the α,β-difructofuranose DFA ready discussed for compounds 18–20.
diastereomer.
The relative proportions of thermodynamic (α,β) versus
Compound 29, in which the 6-OH hydroxy group is free, kinetic or contra-thermodynamic diastereomers (α,α and
can undergo furanose/pyranose interconversion through the β,β) in the difructofuranose DFA series have been shown
open-chain aldehydo form after removal of the anomeric to be influenced by tethering of the primary 6-O positions
isopropylidene group by TfOH activation. In this case the of the reacting d-fructose precursors.[21] To investigate the
spirocyclisation reaction afforded the corresponding α,β-di- effects of simultaneous conformational and distance con-
furanose DFA derivative 33 as the major reaction product, straints on the stereochemical outcome of the reaction, the
accompanied by the α-d-fructofuranose β-d-fructopyranose o-, m- and p-xylylene-bridged precursors 36–38 (Scheme 6)
1,2Ј:2,1Ј-dianhydride derivative 32 (33/32 = 3.4:1). The lat- were synthesised. Use of the two first linkers led preferen-
ter structure is actually the thermodynamically most stable tially to products of intramolecular glycosylation/spiro-
DFA.[1,2,7] The fact that the difuranose compound is prefer- cyclisation. No traces of the α,β-unsymmetric DFA dia-
entially obtained even in this case underlines the impor- stereomers were detected in this fraction, probably because
tance of kinetic considerations when designing stereo- the presence of the bridge induces the boat conformation
selective syntheses of spiroketal derivatives (Table 2). Cata- at the central 1,4-dioxane ring in this series. The α,α-DFA
lytic hydrogenolysis of 33–35 (with prior deacetylation in derivative 40 was the only product in the case of the m-
the case of 34) afforded the fully unprotected DFA 3 xylylene-bridged precursor 37, whereas a 1:1.3 mixture of
(Scheme 5).
the α,α and β,β isomers 39 and 40, respectively, was ob-
tained in the case of the shorter o-xylylene spacer. No intra-
molecular reaction took place with the p-xylylene derivative
38, which led preferentially to the formation of a mixture
of the macrocyclic intermolecular dimers 42, as seen by
mass spectrometry. After hydrogenolysis, a mixture of the
DFAs 4 and 5 (4:1) was obtained. Their identities were un-
equivocally determined by GC after trimethylsilylation and
comparison with authentic standards (Scheme 6 and
Table 2).[14]
The above results indicate that shortening of the
through-space distance between the primary 6-O positions
by the rigid spacer strategy completely reversed the stereo-
chemical outcome of the spirocyclisation reaction from the
unsymmetrical (α,β) to the symmetrical (α,α and β,β) dia-
stereomers. The presence of the cyclic o-xylylene protecting
group results in analogous conformations for the α- and β-
fructofuranose rings that are analogous to those discussed
above for the non-tethered DFAs 33–35, as seen from the
coupling constant values around the five-membered rings.
The cyclic protection also contributes to the observed ster-
eoselection, because in the case of acyclic benzyl protecting
Table 2. Relative proportions (%) of α,β-, α,α- and β,β-difuranose
DFA diastereomers obtained by TfOH activation of d-fructofur-
anose precursors incorporating cyclic o-xylylene groups (29–31 and
36–38) in comparison with classical acyclic protection (8, 9 and 10-
ortho, -meta or -para).[33,39]
Starting material α,β diastereomer α,α diastereomer β,β diastereomer
8
9
75
4
0
34
0
25
96
11
66
80
0
0
0
43
100
80[b]
0
0
89
0
20
0
0
10-ortho
10-meta
10-para
29
30
31
36
37
38
81[a]
100
100
0
0
0
0
57
0
20[b]
[a] The α-d-fructofuranose β-d-fructopyranose 1,2:2,1Ј-dianhy-
dride diastereomer 32 was also formed in 19% proportion. [b] Cal-
culated from the relative proportion of the corresponding unprotec-
ted DFAs 4 and 5 after hydrogenolysis of the macrocyclic adduct
41 by GC.[14]
1
The H and 13C NMR spectra of the protected DFAs groups the α,β-DFA was present in the reaction mixture in
33–35 each displayed two spin systems and agreed with the a significant proportion, even when the m-xylylene tether
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that is exacerbated in bis(spiroketal) compounds such as
difructose dianhydrides. It was therefore conceivable that
protecting group tactics that favour particular conforma-
tional arrangements in the synthetic intermediates might be
implemented to achieve stereoselective syntheses of DFA
diastereomers. The results collected in Tables 1 and 2 clearly
illustrate the potential of cyclic o-xylylene groups in achiev-
ing this goal. Through stabilisation of the trans-diequatorial
dispositions of the 3-O/4-O substituents, the spiroketalis-
ation reactions of d-fructopyranose and d-fructofuranose
precursors can be directed towards the β,β-dipyranose and
α,β-difuranose diastereomers, respectively. In the difu-
ranose series, further tethering of two fructofuranose units
through their primary 6-O positions by xylylene segments
allows the selectivity to be shifted towards the C2-symmet-
ric α,α- or β,β-DFAs. It is worth mentioning that by this
strategy the first stereospecific syntheses of α-d-fructofur-
anose β-d-fructofuranose 1,2Ј-2,1Ј-dianhydride (3) and di-
α-d-fructofuranose 1,2Ј-2,1Ј-dianhydride (4), two of the
most abundant DFAs in commercial caramel,[7] have been
achieved. Moreover, the use of cyclic o-xylylene groups al-
lows selective protection of trans-diol segments and has
added value in terms of atom economy in relation to classi-
cal benzyl protection.
Experimental Section
General: 1,2-O-Isopropylidene-β-d-fructopyranose (11)[51,52] and
6-O-(tert-butyldimethylsilyl)-1,2-O-isopropylidene-β-d-fructo-
furanose (27)[39] were obtained according to literature procedures.
Reagents and solvents were purchased from commercial sources
and were used without further purification, with the exception that
dichloromethane was distilled under an Ar stream from CaH2. Op-
tical rotations were measured at 20 °C in 1 cm or 1 dm tubes with
a Perkin–Elmer 141 MC polarimeter. IR spectra were recorded
with a Bomem Michelson MB-120 FTIR spectrometer. 1H (and
13C NMR) spectra were recorded at 500 (125.7) and 300 (75.5)
MHz with Bruker 500 DRX spectrometers and 300 AMX spec-
trometers, respectively. 2D COSY and HMQC experiments were
used to assist in NMR assignments. For NMR notation purposes,
f and p indicate proton or carbon atoms located at a furanose or
pyranose unit, respectively. Thin-layer chromatography (TLC) was
carried out on aluminium sheets coated with Kieselgel 30 F245
(E. Merck), with visualisation with UV light and by charring with
H2SO4 (10%). Column chromatography was carried out on silica
gel 60 (E. Merck, 230–400 mesh). FAB mass spectra were obtained
with a Kratos MS-80 RFA instrument. The operating conditions
were as follows: the primary beam consisted of Xe atoms with a
maximum energy of 8 keV, the samples were dissolved in thiogly-
cerol, the positive ions were separated and accelerated over a poten-
tial of 7 keV, and NaI was added as cationising agent. Elemental
analyses were performed at the Instituto de Investigaciones Quím-
icas (Sevilla, Spain). For GC analysis, samples were transformed
into their corresponding per-O-trimethylsilyl or per-O-trimethyl-
silyl oxime derivatives according to literature procedures.[12,14] GC
experiments were carried out with an Agilent 6890 Series Plus chro-
matograph with an EPC injector fitted with a cross-linked 5%
phenyldimethylsiloxane column (HP-5; 30 mϫ320 μmϫ0.25 μm).
Operating conditions were: injection port temperature 310 °C,
Scheme 6. Reagents and conditions: (a) NaH, DMF, 1 h (36, 70%,
37, 73% and 38, 42%); (b) TfOH, CH2Cl2, –78 °C to room temp.,
55–70 min (39, 29%, 40, 37%, 41, 52% and 42, 22%); (c) Pd/C, H2
(1 atm), HCOOH (10%), EtOAc/MeOH 1:1, 16 h, 100%.
was installed[39] (the α,α/α,β ratio shifts from 50:50 to
100:0). The presence of the o-xylylene spacer between the
primary positions is able to induce formation of the elusive
contra-thermodynamic β,β diastereomer 40, although its
combination with cyclic diether protection seems to be det-
rimental in this case relative to the use of classical benzyl
protection at 3-O and 4-O. The α,α/β,β ratio thus shifts
from 1:8 for 10-ortho to 1:1.3 for 36 (Table 2). The confor-
mational constraints in the very rigid macrocyclic products
39 and 40 probably play a more important role in determin-
ing the stereochemical course of the reaction than the pre-
ferred conformation of the relatively flexible furanose rings.
In any case, the results clearly demonstrate that cyclic diol
protection and rigid spacer tethering are very potent strate-
gies for control of the stereochemistry of bis(spiroketal) for-
mation reactions.
Conclusions
Spiroketal compounds exhibit an intimate relationship
between configurational pattern and conformational prefer-
ences as a result of combined stereoelectronic effects, a fact splitting ratio 25:1, injection volume 1 μL of derivatised samples,
522 Eur. J. Org. Chem. 2011, 517–528
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Stereoselective Synthesis of Difructose Dianhydrides
column oven temperature programmed from 180 to 310 °C at
5 °Cmin–1, with 25 min hold at 310 °C, carrier gas helium (constant
flow at 1.2 mLmin–1), detector port temperature 310 °C. Total ac-
quisition time was 56 min.
Data for 15: [α]D = –173.5 (c = 0.29, CHCl3). 1H NMR (500 MHz,
2
CDCl3): δ = 7.29–7.05 (m, 18 H, Ph), 5.10, 4.96 (2 d, JH,H
=
2
14.3 Hz, 4 H, CH2), 5.05 (br. s, 4 H, CH2), 4.74, 4.69 (2 d, JH,H
= 12.4 Hz, 4 H, CH2), 4.12 (dd, J3,4 = 10, J4,5 = 3.21 Hz, 2 H, 4-
H), 4.06 (d, J1a,1b = 11.8 Hz, 1 H, 1a-H), 3.92 (d, 1 H, 3-H), 3.83
(m, 2 H, 5-H), 3.74 (s, 4 H, 6a-H, 6b-H), 3.65 (d, 2 H, 1b-H) ppm.
13C NMR (125.7 MHz, CDCl3): δ = 138.7–127.4 (Ph), 96.6 (C-2),
80.5 (C-3), 78.8 (C-4), 75.9 (C-5), 73.9 (CH2), 73.0 (CH2), 72.4
(CH2), 62.7 (C-6), 64.6 (C-1) ppm. FABMS: m/z (%) = 731 (15) [M
+ Na]+. C42H44O10 (708): calcd. C 71.17, H 6.26; found C 71.35,
H 6.61.
1,2-O-Isopropylidene-3,4-O-(o-xylylene)-β-D-fructopyranose (12):
NaH (60% in mineral oil, 55 mg, 2.9 mmol) was added to a solu-
tion of 11 (250 mg, 1.46 mmol) in DMF (18 mL), and the suspen-
sion was stirred at room temperature for 16 h. A solution of 1,2-
bis(bromomethylbenzene) (302 mg, 1.46 mmol) in DMF (3 mL)
was then added dropwise; the reaction mixture was further stirred
for 3 h, quenched by addition of H2O (0.5 mL) and concentrated.
The residue was purified by column chromatography (EtOAc/pe-
troleum ether, 1:2 Ǟ 1:1) to give 12 (132 mg, 37%), with physico-
chemical and spectroscopic properties identical to those previously
reported,[46] together with unreacted 11 (125 mg, 50%).
3-O-Benzyl-1,2-O-isopropylidene-4,5-O-(o-xylylene)-β-D-fructo-
pyranose (17): NaH (60 % in mineral oil, 135 mg, 3.37 mmol,
5 equiv.) was added at 0 °C to a solution of 16[52] (209 mg,
0.67 mmol) in dry DMF (4 mL), and the reaction mixture was
stirred at room temperature for 15 min. 1,2-Bis(bromomethyl)ben-
zene (356 mg, 1.35 mmol, 2 equiv.) was added, and the solution was
further stirred for 1 h. Et2O (10 mL) and water (10 mL) were
added, and the organic layer was decanted, dried and concentrated.
The residue was purified by column chromatography (EtOAc/pe-
troleum ether, 1:8 Ǟ 2:1) to give 17 (117 mg, 42 %). Rf = 0.60
(EtOAc/petroleum ether, 1:4). [α]D = +35.1 (c = 1.0, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 7.35–7.09 (m, 9 H, Ph), 5.95, 4.59
5-O-Benzyl-1,2-O-isopropylidene-3,4-O-(o-xylylene)-β-D-fructo-
pyranose (13): NaH (60 % in mineral oil, 52 mg, 1.3 mmol) was
added to a solution of 12 (168 mg, 0.522 mmol) in dry DMF
(7 mL), and the suspension was stirred at room temperature for
15 min. Benzyl bromide (130 μL, 10.4 mmol) was added, and the
mixture was stirred at room temperature for 30 min. MeOH
(4 mL), Et2O (16 mL) and H2O (8 mL) were added, and the organic
phase was decanted, dried (MgSO4), filtered and concentrated. The
residue was purified by column chromatography (EtOAc/petroleum
ether, 1:8) to give 13 (161 mg, 75%). [α]D = –158.9 (c = 0.8, CHCl3).
2
2
(2 d, JH,H = 11.5 Hz, 2 H, CH2), 5.42, 4.71 (2 d, JH,H = 16.0 Hz,
2 H, CH2), 5.30, 4.71 (2 d, 2JH,H = 11.6 Hz, 2 H, CHPh), 4.05 (dd,
J3,4 = 9.8, J4,5 = 2.9 Hz, 1 H, 4-H), 4.02 (d, J1a,1b = 8.5 Hz, 1 H,
Rf = 0.33 (EtOAc/petroleum ether, 1:6). 1H NMR (500 MHz,
1a-H), 3.97 (d, 1 H, 3-H), 3.93 (d, 1 H, 1b-H), 3.84 (dd, J6a,6b
=
2
CDCl3): δ = 7.22–7.08 (m, 9 H, Ph), 5.11, 4.75 (2 d, JH,H
=
12.6, J5,6a = 1.4 Hz, 1 H, 6a-H), 3.79 (m, 1 H, 5-H), 3.59 (dd, J5,6b
= 1.7 Hz, 1 H, 6b-H), 1.44, 1.41 (2 s, 6 H, CMe2) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 140.6–125.5 (Ph), 111.9 (CMe2), 105.8
(C-2), 83.3 (C-4), 75.3 (CH2), 74.2 (C-3), 72.0 (C-1), 71.6, 71.3
(CH2Ph), 69.8 (C-5), 63.3 (C-6), 27.0, 26.2 (CMe2) ppm. FABMS:
m/z (%) = 435 (20) [M + Na]+. C24H28O6 (412): calcd. C 69.88, H
6.84; found C 69.72, H 6.46.
2
13.5 Hz, 2 H, CH2), 4.96, 4.67 (2 d, JH,H = 12.3 Hz, 2 H, CH2),
4.18 (d, J1a,1b = 8.5 Hz, 1 H, 1a-H), 4.04 (d, 1 H, 1b-H), 3.96 (m,
2 H, 3-H, 4-H), 3.84 (m, 1 H, 5-H), 3.82 (dd, J6a,6b = 11.7, J5,6a
=
1.1 Hz, 1 H, 6a-H), 3.74 (dd, J5,6b = 2.0 Hz, 1 H, 6b-H), 1.47, 1.41
(2 s, 6 H, CMe2) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 137.2–
127.4 (Ph), 111.8 (CMe2), 105.9 (C-2), 79.6 (C-4), 77.2 (C-3), 76.1
(C-5), 72.5, 72.0 (CH2), 71.8 (C-1), 62.8 (C-6), 27.1, 26.1 (CMe2)
ppm. FABMS: m/z (%) = 435 (30) [M + Na]+. C24H28O6 (412):
calcd. C 69.88, H 6.84; found C 69.77, H 6.78.
3-O-Benzyl-4,5-O-(o-xylylene)-α-
4Ј,5Ј-O-(o-xylylene)-β- -fructopyranose 1,2Ј:2,1Ј-Dianhydride (18),
4,5-O-(o-Xylylene)-α- -fructopyranose 3Ј-O-Benzyl-4Ј,5Ј-O-β-
fructopyranose 1,2Ј:2,1Ј-Dianhydride (19) and 3,3Ј-Di-O-benzyl-
4:5,4Ј,5Ј-di-O-(o-xylylene)-di-β- -fructopyranose 1,2Ј:2,1Ј-Dianhy-
D-fructopyranose 3Ј-O-Benzyl-
D
D
D-
5-O-Benzyl-3,4-O-(o-xylylene)-α-
3Ј,4Ј-O-(o-xylylene)-β- -fructopyranose 1,2Ј:2,1Ј-Dianhydride (14)
and 5,5Ј-Di-O-benzyl-3,4:3Ј,4Ј-di-O-(o-xylylene)-di-β- -fructopyr-
D-fructopyranose 5Ј-O-Benzyl-
D
D
D
dride (20): TfOH (115 μL, 1.32 mmol, 1.5 equiv.) was added at
–78 °C to a solution of 17 (263 mg, 0.878 mmol) in freshly distilled
CH2Cl2 (24 mL). The reaction mixture was allowed to reach room
temperature and was further stirred for 30 min. Et3N (12 drops)
was then added, the solvent was removed under reduced pressure,
and the residue was purified by column chromatography (EtOAc/
petroleum ether, 1:3 Ǟ 1:1) to give 18 (158 mg, 51%), 19 (19 mg,
6%) and 20 (45 mg, 15%).
anose 1,2Ј:2,1Ј-Dianhydride (15): Trifluoromethanesulfonic acid
(TfOH, 50 μL, 0.580 mmol) was added at –78 °C to a solution of
13 (160 mg, 0.387 mmol) in freshly distilled CH2Cl2 (8 mL). The
reaction mixture was allowed to reach room temperature and fur-
ther stirred for 1 h. Et3N (5 drops) was then added, the solvent was
removed under reduced pressure, and the residue was purified by
column chromatography (EtOAc/petroleum ether, 1:3 Ǟ 1:2) to
give 14 (27 mg, 20%) and 15 (84 mg, 61%).
Data for 14: Rf = 0.54 (EtOAc/petroleum ether, 1:1). [α]D = –72.4
(c = 1.3, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.22–7.02 (m, (c = 0.9, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.41–7.09 (m,
Data for 18: Rf = 0.53 (EtOAc/petroleum ether, 1:1). [α]D = +22.4
1
1
2
18 H, Ph), 5.22–4.62 (12 d, 12 H, CH2), 4.43 (d, J1a,1b = 11.1 Hz,
1 H, 1a-H), 4.16 (d, J1a,1b = 12.2 Hz, 1 H, 1Јa-H), 3.98 (dd, J3,4
9.6, J4,5 = 3.0 Hz, 1 H, 4α-H), 3.95 (br. d, J6a,6b = 13.1 Hz, 1 H, 2 H, CH2), 4.98, 4.66 (2 d, JH,H = 11.8 Hz, 2 H, CH2), 4.67, 4.50
18 H, Ph), 5.90, 4.60 (2 d, JH,H = 11.6 Hz, 2 H, CH2), 5.46, 4.55
2
2
=
(2 d, JH,H = 13.5 Hz, 2 H, CH2), 5.44, 5.42 (2 d, JH,H = 14.4 Hz,
2
2
2
6aβ-H), 3.94 (d, J3,4 = 10.3 Hz, 1 H, 3β-H), 3.83 (m, J6a,6b = 12.2,
(2 d, JH,H = 14.2 Hz, 2 H, CH2), 4.62, 4.51 (2 d, JH,H = 11.5 Hz,
J5,6a = 1.8 Hz, 1 H, 6aα-H), 3.81–3.82 (m, 2 H, 5α-H, 5β-H), 3.68 2 H, CHPh), 4.34 (d, J1a,1b = 11.5 Hz, 1 H, 1a-H), 4.13 (dd, J3,4
=
(d, J3,4 = 9.6 Hz, 1 H, 3α-H), 3.64 (dd, 1 H, 6bβ-H), 3.64 (dd, 1
H, 6bα-H), 3.64 (d, 1 H, 1Јb-H), 3.55 (d, 1 H, 1b-H), 3.51 (dd, J4,5
9.8, J4,5 = 3.0 Hz, 1 H, 4α-H), 3.94 (dd, J6a,6b = 11.7, J5,6a = 7.0 Hz,
1 H, 6aβ-H), 3.87 (m, 1 H, 5β-H), 3.82 (d, J1a,1b = 12.0 Hz, 1 H,
= 3.3 Hz, 1 H, 4β-H) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 1aЈ-H), 3.79 (m, 1 H, 5α-H), 3.76 (d, 1 H, 3α-H), 3.70 (d, 1 H, 1bЈ-
138.7–127.35 (Ph), 96.8 (C-2α), 95.9 (C-2β), 81.7 (C-3β), 79.5 (C-
H), 3.68 (s, 2 H, 3β-H, 4β-H), 3.62 (dd, J5,6b = 3.3 Hz, 1 H, 6bβ-
4β), 78.9 (C-3α), 77.6 (C-4α), 76.0 (C-5β), 75.1 (CH2), 74.6 (CH2), H), 3.61 (br. s, 2 H, 6aα-H, 6aβ-H), 3.41 (d, 1 H, 1b-H) ppm. 13C
74.3 (C-5α), 73.0, 72.6, 72.3 (CH2), 64.1 (C-6β), 62.5 (C-1), 61.7 NMR (125.7 MHz, CDCl3): δ = 140.7–125.7 (Ph), 95.9 (C-2α), 95.3
(C-6α), 56.1 (C-1Ј) ppm. FABMS: m/z (%) = 731 (10) [M + Na]+.
C42H44O10 (708): calcd. C 71.17, H 6.26; found C 71.33, H 6.46.
(C-2β), 81.3 (C-4α), 78.8 (C-4β), 75.1 (C-3β), 74.8 (C-3α), 74.7,
74.1 (CH2), 72.3 (C-5β), 71.5, 71.4, 71.3, 71.0 (CH2), 70.1 (C-5α),
Eur. J. Org. Chem. 2011, 517–528
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
523

J. L. Jiménez Blanco et al.
FULL PAPER
62.5 (C-6α), 61.7 (C-1), 60.9 (C-6β), 59.3 (C-1Ј) ppm. FABMS: m/z
IR: ν
= 2986, 2926, 2889, 1455, 1370, 1216, 1186, 1128, 1104,
˜
max
(%) = 731 (98) [M + Na]+. C42H44O10 (708): calcd. C 71.17, H 6.26; 1022, 881, 735 cm–1. FABMS: m/z (%) = 769 (5) [M + Na]+.
found C 70.95, H 6.15.
C42H50O12 (747): calcd. C 67.54, H 6.75; found C 67.56, H 6.70.
Data for 19: Rf = 0.37 (EtOAc/petroleum ether, 1:1). [α]D = –11.2
1,3-Bis[(1,2-O-isopropylidene-4,5-O-(o-xylylene)-β- -fructopyranos-
D
1
(c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.45–7.09 (m, 3-O-yl)methylbenzene (25): Yield: 114 mg (30%). Rf = 0.34 (EtOAc/
2
18 H, Ph), 5.99, 4.54 (2 d, JH,H = 11.3 Hz, 2 H, CH2), 5.95, 4.57
petroleum ether, 1:2). [α]D = –0.9 (c = 1.0, CH2Cl2). 1H NMR
2
2
2
(2 d, JH,H = 11.8 Hz, 2 H, CH2), 5.52, 4.70 (2 d, JH,H = 15.9 Hz,
(400 MHz, CDCl3): δ = 7.45–7.1 (m, 12 H, Ph), 5.96 (d, JH,H
=
2
2
2 H, CH2), 5.41, 4.70 (2 d, JH,H = 16.0 Hz, 2 H, CH2), 5.00, 4.85 11.4 Hz, 2 H, CH2), 5.45 (d, JH,H = 16.0 Hz, 2 H, CH2), 5.09 (d,
(2 d, 2JH,H = 11.9 Hz, 2 H, CH2), 4.14 (dd, J3,4 = 9.7, J4,5 = 2.9 Hz, 2JH,H = 12.6 Hz, 2 H, CH2), 4.77, 4.72 (2 d, 4 H, CH2), 4.62 (d,
1 H, 4β-H), 4.06 (br. t, J3,4 = J4,5 = 8.8 Hz, 1 H, 4α-H), 3.93 (d, 1 2JH,H = 11.5 Hz, 2 H, CH2), 4.09 (dd, 4 H, 4-H, 1a-H), 3.99 (d, 4
H, 3β-H), 3.92 (d, J1a,1b = 12.4 Hz, 1 H, 1a-H), 3.83 (dd, J6a,6b
12.1, J5,6a = 1.0 Hz, 1 H, 6aα-H), 3.80 (dd, J6a,6b = 12.4, J5,6a
=
=
H, 3-H, 1b-H), 3.88 (dd, J6a,6b = 12.5, J5,6a = 1.6 Hz, 2 H, 6a-H),
3.82 (s, 1 H, 5-H), 3.64 (d, J5,6b = 1.4 Hz, 1 H, 6b-H), 1.46, 1.44
2.0 Hz, 1 H, 6aβ-H), 3.77 (m, 2 H, 5α-H, 3α-H), 3.75 (m, 1 H, 5β- (s, 12 H, CMe2) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 140.5–
H), 3.65 (d, 1 H, 1b-H), 3.62 (m, 1 H, OH), 3.60 (dd, J5,6b = 1.5 Hz,
125.5 (Ph), 111.8 (CMe2), 105.7 (C-2), 83.1 (C-4), 75.1 (CH2), 74.3
1 H, 6bα-H), 3.53 (d, J1a,1b = 12.4 Hz, 1 H, 1aЈ-H), 3.52 (dd, J5,6b (C-3), 72.1 (C-1), 71.5, 71.2 (CH2), 69.7 (C-5), 63.1 (C-6), 27.0, 26.0
= 1.7 Hz, 1 H, 6bβ-H), 3.41 (d, 1 H, 1bЈ-H) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 140.7–125.5 (Ph), 97.1 (C-2α), 96.9 (C-
(CMe ) ppm. IR: νmax = 2985, 2930, 2880, 1444, 1370, 1105, 1022,
˜
2
969, 881, 735 cm–1. FABMS: m/z (%) = 769 (3) [M + Na]+.
2β), 82.6 (C-4β), 81.7 (C-3α*), 77.6 (C-3β), 74.9 (CH2), 72.7 (C- C42H50O12 (747): calcd. C 67.54, H 6.75; found C 67.54, H 6.44.
4α), 71.5, 71.3, 71.2, 71.1 (CH2), 69.9 (C-5α*), 69.3 (C-5β), 64.3
1,4-Bis[(1,2-O-isopropylidene-4,5-O-(o-xylylene)-β-D-fructo-
(C-1), 64.2 (C-1Ј), 63.7 (C-6α), 63.3 (C-6β) ppm. FABMS: m/z (%)
= 641 (90) [M + Na]+. C35H38O10 (614): calcd. C 67.95, H 6.19;
found C 67.92, H 6.00.
pyranos-3-O-yl)methylbenzene (26): Yield: 133 mg (35%). Rf = 0.5
(EtOAc/petroleum ether, 1:2). [α]D = +0.9 (c = 1.0, CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 7.42–7.1 (m, 12 H, Ph), 5.99 (d,
2
Data for 20: Rf = 0.66 (EtOAc/petroleum ether, 1:1). [α]D = –11.0
2JH,H = 11.4 Hz, 2 H, CH2), 5.48 (d, JH,H = 16.0 Hz, 2 H, CH2),
1
2
(c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.31–7.11 (m, 5.08 (d, JH,H = 12.6 Hz, 2 H, CH2), 4.77, 4.74 (2 d, 4 H, CH2),
2
2
18 H, Ph), 5.85, 5.45 (2 d, JH,H = 12.0 Hz, 4 H, CH2), 4.97, 4.73
4.64 (d, JH,H = 11.5 Hz, 2 H, CH2), 4.07 (dd, 4 H, 4-H, 1a-H),
2
2
(2 d, JH,H = 12.0 Hz, 4 H, CH2), 4.67, 4.56 (2 d, JH,H = 11.5 Hz,
4 H, CH2), 4.22 (dd, J3,4 = 10, J4,5 = 3.0 Hz, 2 H, 4-H), 3.94 (d, 2
3.98 (d, 4 H, 3-H, 1b-H), 3.88 (dd, J6a,6b = 12.5, J5,6a = 1.6 Hz, 2
H, 6a-H), 3.84 (s, 1 H, 5-H), 3.63 (d, J5,6b = 1.4 Hz, 1 H, 6b-H),
H, 3-H), 3.84 (d, J1a,1b = 12.0 Hz, 2 H, 1a-H), 3.79 (m, 2 H, 5-H), 1.46, 1.44 (s, 12 H, CMe2) ppm. 13C NMR (125.7 MHz, CDCl3):
3.76 (dd, J6a,6b = 12.5, J5,6a = 1.5 Hz, 2 H, 6a-H), 3.57 (dd, J5,6b
=
δ = 140.7–125.5 (Ph), 112.0 (CMe2), 106 (C-2), 83.3 (C-4), 75.1
2.0 Hz, 2 H, 6b-H), 3.54 (d, 2 H, 1b-H) ppm. 13 C NMR
(125.7 MHz, CDCl3): δ = 140.4–126.1 (Ph), 97.5 (C-2), 80.5 (C-4),
77.5 (C-3), 73.4, 71.4, 71.2 (CH2), 70.6 (C-5), 63.9 (C-1), 63.4 (C-
6) ppm. FABMS: m/z (%) = 731 (98) [M + Na]+. C42H44O10 (708):
calcd. C 71.17, H 6.26; found C 70.97, H 6.23.
(CH2), 74.3 (C-3), 72.2 (C-1), 71.6, 71.3 (CH2), 69.8 (C-5), 63.4 (C-
6), 27.1, 26.3 (CMe ) ppm. IR: νmax = 2986, 2930, 2891, 2360, 1455,
˜
2
1370, 1254, 1216, 1184, 1128, 1105, 1021, 981, 882, 772, 735 cm–1.
FABMS: m/z (%) = 769 (6) [M + Na]+. C42H50O12 (747): calcd. C
67.54, H 6.75; found C 67.61, H 6.64.
General Procedure for the Preparation of the Cyclic (4-O,5-O)-o- 6-O-(tert-Butyldimethylsilyl)-1,2-O-isopropylidene-3,4-O-(o-xyl-
Xylylene-Protected (3-OǞ3Ј-O)-Xylylene-Tethered Fructopyranose
Derivatives 24–26: NaH (60% in mineral oil, 204 mg, 5.085 mmol,
10 equiv.) was added to a solution of the corresponding 1,2-, 1,3-
or 1,4-bis[(1,2-O-isopropylidene-β-d-fructopyranos-3-O-yl)-
methyl]benzene 21–23[21] (275 mg, 0.51 mmol) in dry DMF
(3.1 mL), and the suspension was stirred under Ar at room tem-
perature for 1 h. A solution of 1,2-bis(bromomethylbenzene)
ylene)-β-D-fructofuranose (28): A suspension of NaH (60% in min-
eral oil, 80 mg, 2 mmol) was added to a solution of 27[39] (135 mg,
0.4 mmol) in dry DMF (2.5 mL), and the suspension was stirred at
room temperature for 20 min. 1,2-Bis(bromomethylbenzene)
(264 mg, 1 mmol) was then added, and the reaction mixture was
further stirred for 1 h, quenched by addition of H2O (0.5 mL) and
concentrated. The residue was purified by column chromatography
(603 mg, 2.54 mmol, 5 equiv.) in dry DMF (3.1 mL) was then (EtOAc/petroleum ether, 1:10, containing 0.5% Et3N) to give 28
added, the reaction mixture was further stirred under Ar for 3 h
and quenched by addition of water (0.63 mL), and the solvents
were evaporated. The resulting residue was extracted with Et2O
(136 mg, 78%). Rf = 0.31 (EtOAc/petroleum ether, 1:6). [α]D = –5.0
1
(c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.24–7.32 (m,
2
4 H, Ph), 5.07 (d, JH,H = 12.6 Hz, 1 H, CHPh), 4.80 (m, 3 H,
(2ϫ20 mL), washed with water (20 mL), dried (MgSO4), concen- CH2), 4.18 (dd, J3,4 = 6.3, J4,5 = 4.6 Hz, 1 H, 4-H), 3.96 (d, J1a,1b
trated and purified by column chromatography (EtOAc/petroleum
ether, 1:2, containing 0.5% Et3N).
= 8.9 Hz, 1 H, 1a-H), 3.89 (ddd, J5,6b = 6.9 Hz, 1 H, 5-H), 3.86 (d,
1 H, 1b-H), 3.84 (d, 1 H, 3-H), 3.72 (dd, J6a,6b = 10.3 Hz, 1 H, 6a-
H), 3.67 (dd, 1 H, 6b-H), 1.45, 1.40 (2 s, each 3 H, CMe2), 0.88 (s,
9 H, SiCMe3), 0.02 (s, 6 H, SiMe2) ppm. 13C NMR (125.7 MHz,
CDCl3): δ = 137.1–129.4 (Ph), 111.7 (CMe2), 110.5 (C-2), 83.1 (C-
4), 82.9 (C-5), 81.2 (C-3), 71.0 (C-1), 69.6, 69.4 (CH2), 64.9 (C-6),
27.1, 26.0 (CMe2), 25.9 (SiCMe3), 18.3 (SiCMe3) ppm. FABMS:
m/z (%) = 459 (100) [M + Na]+. C23H36O6Si (436): calcd. C 63.30,
H 8.30; found C 63.36, H 8.30.
1,2-Bis[(1,2-O-isopropylidene-4,5-O-(o-xylylene)-β-D-fructo-
pyranos-3-O-yl)methyl]benzene (24): Yield: 144 mg (38%). Rf = 0.70
(EtOAc/petroleum ether, 1:1). [α]d = +4.7 (c = 1.0, CH2Cl2). 1H
NMR (500 MHz, CDCl3): δ = 7.48–7.01 (m, 12 H, Ph), 5.92 (d,
2
2JH,H = 11.5 Hz, 2 H, CH2), 5.41 (d, JH,H = 16.0 Hz, 2 H, CH2),
2
5.21 (d, JH,H = 12.0 Hz, 2 H, CH2), 4.80, 4.70, 4.50 (3 d, 6 H,
CH2), 4.01 (dd, J3,4 = 9.5, J4,5 = 2.5 Hz, 2 H, 4-H), 3.94 (d, 2 H,
3-H), 3.86 (d, 2JH,H = 9.0 Hz, 2 H, 1a-H), 3.83 (d, 2 H, 1b-H), 3.81
1,2-O-Isopropylidene-3,4-O-(o-xylylene)-β-D-fructofuranose (29):
(dd, J6a,6b = 12.5, J5,6a = 1.0 Hz, 2 H, 6a-H), 3.76 (br. s, 1 H, 5- TBAF (1 m in THF, 1.21 mL) was added under Ar at 0 °C to a
H), 3.53 (dd, J5,6b = 1.5 Hz, 1 H, 6b-H), 1.41 (s, 12 H, CMe2) stirred solution of 28 (478 mg, 1.09 mmol) in THF (25 mL). The
ppm. 13C NMR (125.7 MHz, CDCl3): δ = 140.6–125.2 (Ph), 111.7 reaction mixture was stirred for 4 h until disappearance of the start-
(CMe2), 105.7 (C-2), 83.6 (C-4), 74.0 (C-3), 72.3 (CH2), 72.1 (C-1),
71.7, 71.1 (CH2), 69.4 (C-5), 63.2 (C-6), 26.7, 26.3 (CMe2) ppm.
ing material (TLC) and was then diluted with Et2O (15 mL),
washed with water (2ϫ8 mL), dried (MgSO4), filtered and concen-
524
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 517–528

Stereoselective Synthesis of Difructose Dianhydrides
trated. Purification of the residue by column chromatography
(EtOAc/petroleum ether, 1:1) gave 29 (326 mg, 93%). Rf = 0.58
(EtOAc/petroleum ether, 2:1). [α]D = +11.6 (c = 1.0, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 7.38–7.24 (m, 4 H, Ph), 5.10, 4.76
(2 d, JH,H = 13.0 Hz, 2 H, CH2), 4.81, 4.78 (2 d, JH,H = 8.7 Hz,
2 H, CH2), 4.50 (dd, J3,4 = 6.6, J4,5 = 5.5 Hz, 1 H, 4-H), 4.01 (ddd,
J5,6b = 3.4, J5,6a = 2.6 Hz, 1 H, 5-H), 3.98 (d, J1a,1b = 9.2 Hz, 1 H,
Dianhydride (33): TfOH (37 μL, 0.43 mmol) was added at –78 °C
to a solution of 29 (92 mg, 0.29 mmol) in freshly distilled CH2Cl2
(8 mL). The reaction mixture was allowed to reach room tempera-
ture and was stirred for 10 min. Et3N (2 mL) was then added, the
solvent was removed under reduced pressure, and the residue was
purified by column chromatography (EtOAc/petroleum ether, 1:1
Ǟ 6:1) to give 32 (9 mg, 12%) and 33 (31 mg, 41%).
2
2
1a-H), 3.91 (d, 1 H, 1b-H), 3.84 (d, 1 H, 3-H), 3.74 (dt, J6a,6b
=
Data for 32: Rf = 0.26 (EtOAc/petroleum ether, 3:1). [α]D = –24.0
12.1, JOH,6a = 2.3 Hz, 1 H, 6a-H), 3.63 (ddd, JOH,6b = 9.7 Hz, 1 H,
6b-H), 2.72 (br. s, 1 H, OH), 1.50, 1.41 (2 s, each 3 H, CMe2)
ppm. 13C NMR (125.7 MHz, CDCl3): δ = 137.2–129.5 (Ph), 112.1
(CMe2), 110.2 (C-2), 83.8 (C-5), 81.0 (C-3), 80.7 (C-4), 70.9 (C-1),
69.9, 69.0 (CH2), 63.0 (C-6), 27.1, 25.5 (CMe2) ppm. FABMS: m/z
(%) = 345 (98) [M + Na]+. C17H22O6 (322): calcd. C 63.34, H 6.88;
found C 63.00, H 6.92.
1
(c = 0.6, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.29–6.99 (m,
2
8 H, Ph), 5.35, 4.63 (2 d, JH,H = 12.5 Hz, 2 H, CH2), 5.28, 4.68
2
2
(2 d, JH,H = 15.3 Hz, 2 H, CH2), 4.94, 4.65 (2 d, JH,H = 12.3 Hz,
2 H, CH2), 4.77 (s, 2 H, CH2), 4.27 (d, J1a,1b = 11.2 Hz, 1 H, 1Јa-
H), 4.12 (dd, J4,5 = 8.5, J3,4 = 4.7 Hz, 1 H, 4f-H), 4.01 (m, 1 H,
5p-H), 3.97 (dd, J3,4 = 9.1, J4,5 = 3.5 Hz, 1 H, 4p-H), 3.96 (d, J1a,1b
= 12.2 Hz, 1 H, 1a-H), 3.95 (m, 1 H, 5f-H), 3.93 (d, J6a,6b
=
6-O-Acetyl-1,2-O-isopropylidene-3,4-O-(o-xylylene)-β-
D
-fructo-
12.5 Hz, 1 H, 6af-H), 3.92 (d, 1 H, 3f-H), 3.81 (dd, J6a,6b = 12.6,
J5,6a = 1.5 Hz, 1 H, 6ap-H), 3.73 (d, 1 H, 6bp-H), 3.72 (d, 1 H,
6bf-H), 3.68 (br. s, 1 H, OH), 3.63 (d, 1 H, 1b-H), 3.50 (d, 1 H,
3p-H), 3.39 (d, 1 H, 1Јb-H), 2.44 (s, 1 H, OH) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 136.5–127.7 (Ph), 102.1 (C-2f), 96.1 (C-
furanose (30): Acetic anhydride (0.4 mL) was added at 0 °C to a
solution of 29 (120 mg, 0.37 mmol) in pyridine (0.4 mL). The solu-
tion was stirred at room temperature overnight. The solvent was
removed under reduced pressure, and the residue was dissolved in
CH2Cl2 (15 mL) and washed with H2SO4 (2 n, 3 ϫ 5 mL) and 2p), 87.4 (C-3f), 81.4 (C-4f), 79.1 (C-6f), 77.1 (C-3p), 75.1 (C-5f),
NaHCO3 (3 ϫ 5 mL), dried, filtered and concentrated. The re-
74.4, 71.5, 70.8 (CH2), 68.8 (C-5p), 67.6 (CH2), 62.6 (C-6p), 62.3
(C-1), 61.7 (C-1Ј), 60.8 (C-4p) ppm. FABMS: m/z (%) = 551 (100)
sulting residue was purified by column chromatography (EtOAc/
petroleum ether, 1:5 Ǟ 1:3). Yield: 115 mg (85 %). Rf = 0.31 [M + Na]+. C28H32O10 (528): calcd. C 63.63, H 6.10; found C 63.25,
(EtOAc/petroleum ether, 1:2). [α]D = +7.9 (c = 1.0, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 7.38–7.30 (m, 4 H, Ph), 5.08, 4.80
H 5.76.
Data for 33: Rf = 0.17 (EtOAc/petroleum ether, 7:1). [α]D = +28.7
2
(2 d, JH,H = 12.5 Hz, 2 H, CH2), 4.79 (s, 2 H, CH2), 4.23 (dd,
1
(c = 1.0, MeOH). H NMR (500 MHz, CDCl3): δ = 7.28–7.24 (m,
J6a,6b = 11.0, J5,6a = 4.5 Hz, 1 H, 6a-H), 4.18 (dd, J3,4 = 6.8, J4,5
= 5.0 Hz, 1 H, 4-H), 4.17 (dd, J5,6b = 7.5 Hz, 1 H, 6b-H), 4.04 (dt,
1 H, 5-H), 3.96 (d, J1a,1b = 8.8 Hz, 1 H, 1a-H), 3.86 (d, 1 H, 1b-
H), 3.84 (d, 1 H, 3-H), 2.04 (s, 3 H, OAc), 1.44, 1.39 (2 s, 6 H,
CMe2) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 170.8 (CO),
136.9–129.6 (Ph), 112.0 (CMe2), 110.6 (C-2), 82.7 (C-4), 80.5 (C-
3), 80.0 (C-5), 70.8 (C-1), 69.6, 69.4 (CH2Ph), 65.7 (C-6), 27.0, 25.9
(CMe2), 20.9 (MeCO) ppm. FABMS: m/z (%) = 387 (20)
[M + Na]+. C19H24O7 (364): calcd. C 62.63, H 6.64; found C 62.51,
H 6.57.
2
8 H, Ph), 5.07, 4.79 (2 d, JH,H = 12.8 Hz, 2 H, CH2), 4.92, 4.63
2
(2 d, JH,H = 12.3 Hz, 2 H, CH2), 4.77 (s, 2 H, CH2), 4.75 (s, 2 H,
CH2), 4.38 (dd, J3,4 = 6.1, J4,5 = 5.6 Hz, 1 H, 4β-H), 4.12 (d, J1a,1b
= 12.3 Hz, 1 H, 1aα-H), 4.08 (m, 1 H, 5β-H), 4.07 (d, J1a,1b
=
11.8 Hz, 1 H, 1aβ-H), 4.05 (dd, J4,5 = 9.3, J3,4 = 4.5 Hz, 1 H, 4α-
H), 3.94 (dd, J6a,6b = 12.4, J5,6a = 2.6 Hz, 1 H, 6aα-H), 3.90 (m, 1
H, 5α-H), 3.86 (d, 1 H, 3α-H), 3.76 (dd, J6a,6b = 11.9, J5,6a = 4.1 Hz,
1 H, 6aβ-H), 3.70 (dd, J5,6b = 6.1 Hz, 1 H, 6bβ-H), 3.67 (dd, J5,6b
= 2.6 Hz, 1 H, 6bα-H), 3.64 (d, 1 H, 1bα-H), 3.59 (d, 1 H, 3β-H),
3.28 (d, 1 H, 1bβ-H) ppm. 13C NMR (125.7 MHz, CDCl3): δ =
136.9–129.6 (Ph), 102.1 (70.7, C-2α, 101.3 (C-2β), 87.3 (C-3α), 84.2
(C-5β), 82.8 (C-3β), 81.6 (C-4β), 81.5 (C-4α), 79.0 (C-5α), 69.7,
69.2, 67.6 (CH2), 64.0 (C-6β), 63.3 (C-1β), 63.0 (C-1α), 61.0 (C-6α)
ppm. FABMS: m/z (%) = 551 (80) [M + Na]+. C28H32O10 (528):
calcd. C 63.63, H 6.10; found C 63.34, H 5.88.
6-O-Benzyl-1,2-O-isopropylidene-3,4-O-(o-xylylene)-β-D-fructo-
furanose (31): A suspension of NaH (60% in mineral oil, 17 mg,
0.43 mmol) and benzyl bromide (21 μL, 0.17 mmol) were added to
a solution of 29 (55 mg, 0.17 mmol) in dry DMF (2 mL). The reac-
tion mixture was stirred at room temperature for 3 h, saturated
aqueous NH4Cl (2 mL) was then added, and the solvents were
evaporated. The resulting residue was extracted with Et2O (5 mL),
washed with water (3 mL), dried (MgSO4), concentrated and puri-
fied by column chromatography (EtOAc/petroleum ether, 1:4) to
yield 30 (57 mg, 80%). Rf = 0.59 (EtOAc/petroleum ether, 1:2).
[α]D = +4.6 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
7.39–7.24 (m, 9 H, Ph), 5.08, 4.81 (2 d, 2JH,H = 12.6 Hz, 2 H, CH2),
6-O-Acetyl-3,4-O-(o-xylylene)-α-
D-fructofuranose 6Ј-O-Acetyl-
3Ј,4Ј-O-(o-xylylene)-β- -fructofuranose 1,2Ј:2,1Ј-Dianhydride (34):
D
TfOH (39 μL, 0.45 mmol) was added at –78 °C to a solution of 30
(110 mg, 0.30 mmol) in freshly distilled CH2Cl2 (8 mL). The reac-
tion mixture was allowed to reach room temperature and stirred
for 40 min. Et3N (2 mL) was then added, the solvent was removed
under reduced pressure, and the residue was purified by column
chromatography (EtOAc/petroleum ether, 1:3 Ǟ 1:1) to give 34
(70 mg, 75%). Rf = 0.32 (EtOAc/petroleum ether, 1:1). [α]D = +69.1
2
4.82, 4.78 (2 d, JH,H = 12.9 Hz, 2 H, CH2), 4.56 (s, 2 H, CH2),
4.18 (dd, J3,4 = 6.5, J4,5 = 4.8 Hz, 1 H, 4-H), 4.09 (ddd, J5,6a = 7.5,
J5,6b = 5.4 Hz, 1 H, 5-H), 3.99 (d, J1a,1b = 8.9 Hz, 1 H, 1a-H), 3.88
(d, 1 H, 1b-H), 3.87 (d, 1 H, 3-H), 3.65 (dd, J6a,6b = 9.9 Hz, 1 H,
6a-H), 3.56 (dd, 1 H, 6b-H), 1.45, 1.40 (2 s, each 3 H, CMe2) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 138.2–127.6 (Ph), 111.8
(CMe2), 110.6 (C-2), 83.2 (C-4), 81.4 (C-5), 80.9 (C-3), 72.2 (C-6),
71.0 (C-1), 69.6, 69.4 (CH2), 27.1, 26.0 (CMe2) ppm. FABMS: m/z
(%) = 435 (35) [M + Na]+. C24H28O6 (413): calcd. C 69.88, H 6.84;
found C 69.85, H 6.70.
1
(c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.34–7.25 (m,
2
8 H, Ph), 5.04, 4.78 (2 d, JH,H = 12.8 Hz, 2 H, CH2), 4.86, 4.64
2
2
(2 d, JH,H = 12.5 Hz, 2 H, CH2), 4.78, 4.70 (2 d, JH,H = 12.5 Hz,
2 H, CH2), 4.76 (s, 2 H, CH2Ph), 4.34 (dd, J6a,6b = 12.0, J5,6a
2.7 Hz, 1 H, 6aα-H), 4.23 (t, J3,4 = J4,5 = 6.0 Hz, 1 H, 4β-H), 4.22
(dd, J6a,6b = 11.3, J5,6a = 5.1 Hz, 1 H, 6aβ-H), 4.17 (dd, J5,6b
=
=
6.8 Hz, 1 H, 6bβ-H), 4.15 (m, 1 H, 5β-H), 4.12 (dd, J5,6b = 5.6 Hz,
1 H, 6bβ-H), 4.07 (dd, J1a,1b = 12.4 Hz, 1 H, 1aα-H), 4.06 (d, J1a,1b
= 11.6 Hz, 1 H, 1aβ-H), 4.00 (ddd, J4,5 = 8.9 Hz, 1 H, 5α-H), 3.88
(d, J3,4 = 4.6 Hz, 1 H, 3α-H), 3.79 (dd, 1 H, 4α-H), 3.59 (d, 1 H,
3β-H), 3.57 (d, 1 H, 1bα-H), 3.25 (d, 1 H, 1bβ-H), 2.09, 2.04 (2 s,
3,4-O-(o-Xylylene)-α-
fructopyranose 1,2Ј:2,1Ј-Dianhydride (32) and 3,4-O-(o-Xylylene)-α-
-fructofuranose 3Ј,4Ј-O-(o-Xylylene)-β- -fructofuranose 1,2Ј:2,1Ј-
D-fructofuranose 3Ј,4Ј-O-(o-Xylylene)-β-D-
D
D
Eur. J. Org. Chem. 2011, 517–528
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
525

J. L. Jiménez Blanco et al.
6 H, MeCO) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 170.9 (CO), 1,3-Bis[(1,2-O-isopropylidene-3,4-O-(m-xylylene)-β-
-fructofuranos-
FULL PAPER
D
136.7–129.6 (Ph), 102.0 (C-2α), 101.7 (C-2β), 87.3 (C-3α), 83.1 (C-
4β), 82.8 (C-4α), 82.5 (C-3β), 80.7 (C-5β), 76.2 (C-5α), 70.4, 69.6,
69.4, 68.0, (CH2), 65.6 (C-6β), 63.5 (C-6α), 63.2 (C-1β), 62.7 (C-
1α), 20.9 (MeCO) ppm. FABMS: m/z (%) = 635 (98) [M + Na]+.
C32H36O12 (612): calcd. C 62.74, H 5.92; found C 62.71, H 5.81.
6-O-yl)methyl]benzene (37): Yield: 207 mg, 73%. Rf = 0.68 (EtOAc/
petroleum ether, 1:1). [α]D = +8.4 (c = 1.0, CH2Cl2). 1H NMR
2
(300 MHz, CDCl3): δ = 7.38–7.16 (m, 12 H, Ph), 5.11 (d, JH,H
=
13.0 Hz, 2 H, CH2), 4.83 (m, 3 H, CH2), 4.58 (2 d, 2JH,H = 12.5 Hz,
2 H, CH2), 4.21 (dd, J3,4 = 6.5, J4,5 = 5.0 Hz, 1 H, 4-H), 4.11 (ddd,
J5,6a = 7.5, J5,6b = 5.5 Hz, 1 H, 5-H), 4.02 (d, JH,H = 9.0 Hz, 1 H,
2
6-O-Benzyl-3,4-O-(o-xylylene)-α-
D-fructofuranose 6Ј-O-Benzyl-
1a-H), 3.91 (d, 1 H, 1b-H), 3.88 (d, 1 H, 3-H), 3.67 (dd, J6a,6b
=
3Ј,4Ј-O-(o-xylylene)-β- -fructofuranose 1,2Ј:2,1Ј-Dianhydride (35):
D
10.0 Hz, 1 H, 6a-H), 3.60 (dd, 1 H, 6b-H), 1.48, 1.43 (2 s, 12 H,
CMe2) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 138.0–126.9 (Ph),
111.7 (CMe2), 110.5 (C-2), 83.2 (C-4), 81.1 (C-5), 80.8 (C-3), 73.2
(CH2), 72.1 (C-6), 70.9 (C-1), 69.6, 69.4 (CH2), 27.0, 26.0 (CMe2)
TfOH (28 μL, 0.33 mmol, 1–5 equiv.) was added at –78 °C to a
solution of 31 (90 mg, 0.22 mmol) in freshly distilled CH2Cl2
(6 mL). The reaction mixture was allowed to reach room tempera-
ture and was stirred for 10 min. Et3N (1.6 mL) was then added, the
solvent was removed under reduced pressure, and the residue was
purified by column chromatography (EtOAc/petroleum ether, 1:4
Ǟ 1:3) to give 35 (54 mg, 70%). Rf = 0.48 (EtOAc/petroleum ether,
ppm. IR: ν
= 3065, 2989, 2928, 2878, 1456, 1370, 1217, 1187,
˜
max
1125, 1073, 893, 792, 741 cm–1. FABMS: m/z (%) = 769 (6) [M +
Na]+. C42H50O12 (746): calcd. C 67.54, H 6.75; found C 67.51, H
6.68.
1
1:2). [α]D = +47.2 (c = 1.0, CHCl3). H NMR (500 MHz, CDCl3):
δ = 7.27–7.23 (m, 18 H, Ph), 5.02, 4.76 (2 d, 2JH,H = 12.5 Hz, 2 H,
1,4-Bis[(1,2-O-isopropylidene-3,4-O-(p-xylylene)-β-D-fructo-
2
furanos-6-O-yl)methyl]benzene (38): Yield: 106 mg, 42%. Rf = 0.62
(EtOAc/petroleum ether, 1:1). [α]D = +9.9 (c = 1.0, CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 7.43–7.29 (m, 12 H, Ph), 5.11 (d,
2JH,H = 13.0 Hz, 2 H, CH2), 4.83 (m, 3 H, CHPh, CH2), 4.58 (2 d,
2JH,H = 12.0 Hz, 2 H, CH2), 4.22 (dd, J3,4 = 6.5, J4,5 = 5.0 Hz, 1
H, 4-H), 4.11 (ddd, J5,6a = 7.2, J5,6b = 5.5 Hz, 1 H, 5-H), 4.02 (d,
2JH,H = 9.0 Hz, 1 H, 1a-H), 3.92 (d, 1 H, 1b-H), 3.89 (d, 1 H, 3-
H), 3.67 (dd, J6a,6b = 16.0 Hz, 1 H, 6a-H), 3.58 (dd, 1 H, 6b-H),
1.49, 1.44 (2 s, 12 H, CMe2) ppm. 13C NMR (100.6 MHz, CDCl3):
δ = 137.5–127.6 (Ph), 111.7 (CMe2), 110.5 (C-2), 83.1 (C-4), 81.1
(C-5), 80.8 (C-3), 73.1 (CH2), 72.2 (C-6), 70.9 (C-1), 69.3, 69.2
CH2), 4.86, 4.63 (2 d, JH,H = 12.7 Hz, 2 H, CH2), 4.79, 4.75 (2 d,
2
2JH,H = 13.0 Hz, 2 H, CH2), 4.78, 4.70 (2 d, JH,H = 13.0 Hz, 2 H,
2
CHPh), 4.62, 4.59 (2 d, JH,H = 12.0 Hz, 2 H, CH2), 4.58, 4.55 (2
2
d, JH,H = 12.5 Hz, 2 H, CH2), 4.22 (dd, J3,4 = 5.9, J4,5 = 4.7 Hz,
1 H, 4β-H), 4.14 (td, J5,6a = J5,6b = 6.5 Hz, 1 H, 5β-H), 4.06 (d,
J1a,1b = 11.7 Hz, 2 H, 1aα-H, 1aβ-H), 4.02 (ddd, J4,5 = 9.0, J5,6b
=
6.0, J5,6a = 2.5 Hz, 1 H, 5α-H), 3.89 (d, J3,4 = 4.5 Hz, 1 H, 3α-H),
3.83 (dd, 1 H, 4α-H), 3.72 (dd, J6a,6b = 11.4 Hz, 1 H, 6aα-H), 3.64
(dd, J6a,6b = 9.5 Hz, 1 H, 6aβ-H), 3.61 (dd, 1 H, 6bα-H), 3.58 (d,
1 H, 3β-H), 3.54 (dd, 1 H, 6bβ-H), 3.53 (d, 1 H, 1bα-H), 3.24 (d,
1 H, 1bβ-H) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 136.9–127.5
(Ph), 102.0 (C-2α), 101.6 (C-2β), 87.4 (C-3α), 83.9 (C-4β), 82.9 (C-
3β), 82.8 (C-4α), 81.6 (C-5β), 78.5 (C-5α), 73.4, 73.1, 70.4, 69.5,
69.3, 68.1 (CH2), 71.9 (C-6β), 69.7 (C-6α), 63.3 (C-1β), 62.8 (C-1α)
ppm. FABMS: m/z (%) = 731 (98) [M + Na]+. C42H44O10 (708):
calcd. C 71.17, H 6.26; found C 70.99, H 6.16.
(CH ), 27.0, 26.0 (CMe ) ppm. IR: ν = 2983, 2929, 2878, 1455,
˜
max
2
2
1370, 1309, 1262, 1216, 1187, 1126, 1074, 1020, 984, 950, 892, 824,
792, 741 cm–1. FABMS: m/z (%) = 769 (2) [M + Na]+. C42H50O12
(746): calcd. C 67.54, H 6.75; found C 67.21, H 6.54.
3,4:3Ј,4Ј:6,6Ј-Tri-O-(o-xylylene)di-α-
anhydride (39) and 3,4:3Ј,4Ј:6,6Ј-Tri-O-(o-xylylene)di-β-
D
-fructofuranose 1,2Ј:2,1Ј-Di-
-fructo-
D
General Procedure for the Preparation of the Cyclic (4-O,5-O)-o-
Xylylene-Protected (6-OǞ6Ј-O)-Xylylene-Tethered Fructofuranose
Derivatives 36–38: NaH (60% in mineral oil, 78 mg, 1.9 mmol,
2.5 equiv.) was added to a solution of 29 (250 mg, 0.76 mmol) in
dry DMF (7 mL), and the suspension was stirred under Ar at room
temperature for 5 min; 1,2-, 1,3- or 1,4-bis(bromomethyl)benzene
(100 mg, 0.38 mmol, 0.5 equiv.) was then added, the reaction mix-
ture was further stirred under argon for 1 h and quenched by ad-
dition of saturated aqueous NH4Cl (9 mL), and the solvents were
evaporated. The resulting residue was partitioned between Et2O
(30 mL) and water (30 mL), extracted with Et2O (2 ϫ 20 mL),
washed with water (30 mL), dried (MgSO4), concentrated and puri-
fied by column chromatography (EtOAc/petroleum ether, 1:1).
furanose 1,2Ј:2,1Ј-Dianhydride (40): TfOH (21 μL, 0.24 mmol,
1.5 equiv.) was added at –78 °C under Ar to a solution of 36
(120 mg, 0.16 mmol) in freshly distilled CH2Cl2 (21 mL). The mix-
ture was stirred for an additional 10 min, allowed to reach room
temperature and then stirred for 1 h. Et3N (5 drops) was then
added, the solvent was eliminated under reduced pressure, and the
residue was purified by column chromatography (EtOAc/petroleum
ether, 1:4 Ǟ 1:2) to give 39 (5 mg, 5%) and 40 (23 mg, 23%).
Data for 39: Rf = 0.73 (EtOAc/petroleum ether, 1:1). [α]D = +117
(c = 0.9, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.37–7.21 (m,
2
2
12 H, Ph), 4.89 (d, JH,H = 13.0 Hz, 2 H, CH2), 4.87 (d, JH,H
=
2
12.5 Hz, 2 H, CH2), 4.81 (d, JH,H = 12.5 Hz, 2 H, CH2), 4.74 (d,
2 H, CH2), 4.71 (d, 2 H, CH2), 4.68 (d, 2 H, CH2), 4.10 (d, JH,H
2
1,2-Bis[(1,2-O-isopropylidene-3,4-O-(o-xylylene)-β-D-fructo-
= 12.0 Hz, 2 H, 1a-H), 3.99 (ddd, J4,5 = 9.0, J5,6b = 7.5, J5,6a
=
furanos-6-O-yl)methyl]benzene (36): Yield: 195 mg, 69%. Rf = 0.48
(EtOAc/petroleum ether, 1:1). [α]D = +15 (c = 0.9, CH2Cl2). 1H
NMR (500 MHz, CDCl3): δ = 7.36–7.14 (m, 12 H, Ph), 5.06 (d,
2JH,H = 13.0 Hz, 1 H, CH2), 4.78 (m, 3 H, CH2), 4.62, 4.57 (2 d,
2JH,H = 12.5 Hz, 2 H, CH2), 4.16 (dd, J3,4 = 6.5, J4,5 = 5.0 Hz, 1
H, 4-H), 4.06 (ddd, J5,6a = 7.5, J5,6b = 5.5 Hz, 1 H, 5-H), 3.97 (d,
2JH,H = 9.0 Hz, 1 H, 1a-H), 3.86 (d, 1 H, 1b-H), 3.85 (d, 1 H, 3-
H), 3.62 (dd, J6a,6b = 10.0 Hz, 1 H, 6a-H), 3.55 (dd, 1 H, 6b-H),
1.44, 1.39 (2 s, 12 H, CMe2) ppm. 13C NMR (125.7 MHz, CDCl3):
2.0 Hz, 2 H, 5-H), 3.81 (dd, J6a,6b = 12.0 Hz, 2 H, 6a-H), 3.58 (d,
J4,5 = 5.0 Hz, 2 H, 3-H), 3.59 (d, 2 H, 1b-H), 3.58 (dd, 2 H, 4-H),
3.43 (dd, J = Hz, 2 H, 6b-H) ppm. 13C NMR (125.7 MHz, CDCl3):
δ = 136.7–127.1 (Ph), 103.0 (C-2), 87.2 (C-3), 83.3 (C-4), 78.3 (C-
5), 71.2, 70.4 (CH2), 70.3 (C-6), 68.4 (CH2), 63.6 (C-1) ppm. IR:
ν
max = 2915, 1454, 1359, 1264, 1105, 1013, 951, 739 cm–1. FABMS:
˜
m/z (%) = 653 (35) [M + Na]+. C36H38O10 (630): calcd. C 68.56, H
6.07; found C 68.39, H 5.96.
δ = 137.9–127.5 (Ph), 111.7 (CMe2), 110.5 (C-2), 83.2 (C-4), 81.1 Data for 40: Rf = 0.53 (EtOAc/petroleum ether, 1:1). [α]D = +49 (c
(C-5), 80.8 (C-3), 72.4 (C-6), 70.9 (C-1), 70.7, 69.5, 69.3 (CH2), = 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.38–7.20 (m,
2
2
26.9, 25.9 (CMe ) ppm. IR: ν
= 2985, 2932, 2879, 1457, 1370,
12 H, Ph), 5.03 (d, JH,H = 13.0 Hz, 2 H, CH2), 4.98 (d, JH,H =
˜
2
max
1216, 1187, 1126, 1074, 893, 741 cm–1. FABMS: m/z (%) = 769 (2) 11.5 Hz, 2 H, CH2), 4.77 (m, 4 H, CH2), 4.73 (d, 2 H, CH2), 4.51
[M + Na]+. C42H50O12 (746): calcd. C 67.54, H 6.75; found C 67.28,
H 6.57.
(d, 2 H, CH2), 4.06 (m, 4 H, 4-H, 5-H), 3.94 (d, JH,H = 12.0 Hz,
2 H, 1a-H), 3.84 (dd, J6a,6b = 11.5, J5,6a = 2.0 Hz, 2 H, 6a-H), 3.73
2
526
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 517–528

Stereoselective Synthesis of Difructose Dianhydrides
(dd, J5,6b = 9.5 Hz, 2 H, 6b-H), 3.68 (d, 2 H, 1b-H), 3.58 (d, J3,4
= 5.9 Hz, 2 H, 3-H) ppm. 13C NMR (125.7 MHz, CDCl3): δ =
137.3–127.3 (Ph), 105.0 (C-2), 83.0 (C-4), 82.8 (C-3), 82.1 (C-5),
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2880, 1454, 1365, 1216, 1180, 1127, 1016, 950, 741 cm–1. FABMS:
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68.56, H 6.07; found C 68.37, H 5.81.
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6,6Ј-O-(m-Xylylene)-3,4:3Ј,4Ј-di-O-(o-xylylene)di-α-D-fructo-
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(97 mg, 0.129 mmol) in freshly distilled CH2Cl2 (17 mL). The mix-
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added, the solvent was removed under reduced pressure, and the
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2
[10]
[11]
[12]
[13]
(500 MHz, CDCl3): δ = 7.45–7.23 (m, 12 H, Ph), 4.97 (d, JH,H
=
2
13.0 Hz, 2 H, CH2), 4.87 (d, JH,H = 12.5 Hz, 2 H, CH2), 4.78 (d,
2JH,H = 12.5 Hz, 2 H, CH2), 4.76 (d, 2 H, CH2), 4.66 (d, 2 H, CH2),
4.61 (d, 2 H, CH2), 4.14 (d, 2JH,H = 12.0 Hz, 2 H, 1a-H), 4.04 (ddd,
J4,5 = 9.0, J5,6b = 7.5, J5,6a = 2.0 Hz, 2 H, 5-H), 3.98 (d, J4,5
=
5.0 Hz, 2 H, 3-H), 3.83 (dd, J6a,6b = 10.0, J5,6a = 2.0 Hz, 2 H, 6a-
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=
7.5 Hz, 2 H, 6b-H) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 139–
126 (Ph), 103.5 (C-2), 86.7 (C-3), 82.4 (C-4), 77.4 (C-5), 72.0, 70.3
(CH ), 69.7 (C-6), 68.3 (CH ), 61.7 (C-1) ppm. IR: ν = 2921,
˜
max
[14]
[15]
2
2
1714, 1628, 1454, 1363, 1261, 1187, 1107, 1011, 949, 790, 740 cm–1.
ESIMS: m/z (%) = 653 [M + Na]. C36H38O10 (630): calcd. C 68.56,
H 6.07; found C 68.39, H 6.00.
[16]
[17]
[18]
Macrocyclic DFA Derivatives 42: TfOH (28 μL, 0.33 mmol,
1.5 equiv.) was added at –78 °C under Ar to a solution of 38
(167 mg, 0.223 mmol) in freshly distilled CH2Cl2 (29 mL). The mix-
ture was stirred for 10 min and was then allowed to reach room
temperature and further stirred for 45 min. Et3N (8 drops) was then
added, the solvent was removed under reduced pressure, and the
residue was purified by column chromatography (EtOAc/petroleum
ether, 1:1 Ǟ 4:1, Ǟ EtOAc) to give 42 (63 mg, 22%) as an insepa-
rable mixture of diastereomers. Rf = 0.28 (EtOAc/petroleum ether,
2:1). FABMS: m/z (%) = 1284 [M + Na].
[19]
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[21]
[22]
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Acknowledgments
This work was financially supported by the Spanish Ministerio de
Ciencia e Innovación (contract numbers CTQ2006-15515-C02-01/
BQU, CTQ2007-61180/PPQ) and the Junta de Andalucía. A. M.-
A. is an FPU fellow. E. S.-P. is a “Project of Excellence” fellow
(Junta de Andalucía, Ref: P06AGR-02150).
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Received: July 5, 2010
Published Online: December 3, 2010
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Eur. J. Org. Chem. 2011, 517–528