Carbohydrate-derived spiroketals: Stereoselective synthesis of di-D-fructose dianhydrides

Article abstract of DOI:10.1016/j.tet.2004.05.032

A one-pot synthesis of di-D-fructose dianhydrides (DFAs) having the 1,6,9,13-tetraoxadispiro[4.2.4.2]tetradecane and 1,7,10,15-tetraoxadispiro[5.2. 5.2]hexadecane skeleton has been accomplished. The methodology relies on the ability of per-O-protected 1,2-O-isopropylidene β-D-fructofuranose and β-D-fructopyranose derivatives to undergo a tandem acetal cleavage-intermolecular glycosylation-intramolecular spiroketalization process by reaction with suitable acid promoters, such as boron trifluoride etherate or trifluoromethanesulfonic acid, in apolar organic solvents. Spirocyclization proceeds then under irreversible reaction conditions to give binary mixtures of di-D-fructofuranose (α,α and α,β diastereomers) or di-D-fructopyranose 1,2′:2,1′ dianhydrides (β,β and α,β), respectively, the stereochemical outcome being dependent on the non-participating or participating character of the protecting groups. Thus, benzylated and allylated derivatives afford, preferentially, the non-symmetric DFAs (α,β), with diastereomeric excess up to 92%. In contrast, the use of participating benzoyl groups favours the C₂-symmetric diastereomer in both series.

Full text of DOI:10.1016/j.tet.2004.05.032

Tetrahedron 60 (2004) 5899–5906
Carbohydrate-derived spiroketals: stereoselective synthesis
of di-D-fructose dianhydrides
a
Juan M. Benito, Enrique Rubio, Marta Gomez-Garcıa, Carmen Ortiz Mellet
a
b
b
,
*
´
´
and Jose M. Garcıa Fernandez
a
,
*
´
´
a
´
´
Instituto de Investigaciones Quımicas, CSIC, Americo Vespucio 49, Isla de la Cartuja, E-41092 Sevilla, Spain
b
´
´
´
Departamento de Quımica Organica, Facultad de Quımica, Universidad de Sevilla, Aptdo. 553, E-41071 Sevilla, Spain
Received 24 March 2004; revised 12 May 2004; accepted 14 May 2004
Available online 8 June 2004
Abstract—A one-pot synthesis of di-D-fructose dianhydrides (DFAs) having the 1,6,9,13-tetraoxadispiro[4.2.4.2]tetradecane and 1,7,10,15-
tetraoxadispiro[5.2.5.2]hexadecane skeleton has been accomplished. The methodology relies on the ability of per-O-protected 1,2-O-
isopropylidene b-D-fructofuranose and b-D-fructopyranose derivatives to undergo a tandem acetal cleavage-intermolecular glycosylation-
intramolecular spiroketalization process by reaction with suitable acid promoters, such as boron trifluoride etherate or trifluoromethane-
sulfonic acid, in apolar organic solvents. Spirocyclization proceeds then under irr0eversible reaction conditions to give binary mixtures of
di-D-fructofuranose (a,a and a,b diastereomers) or di-D-fructopyranose 1,2 :2,10 dianhydrides (b,b and a,b), respectively, the
stereochemical outcome being dependent on the non-participating or participating character of the protecting groups. Thus, benzylated
and allylated derivatives afford, preferentially, the non-symmetric DFAs (a,b), with diastereomeric excess up to 92%. In contrast, the use of
participating benzoyl groups favours the C2-symmetric diastereomer in both series.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Despite the variety of general methods existing for the
construction of the spiroketal moiety, the control of the
stereochemistry at the anomeric centres relies, almost
exclusively, on the relative thermodynamic stability of the
different isomers in the acid-catalyzed spiroketalization
reaction. When all factors that control spiroketalization, that
is, a maximum anomeric effect and minimum steric
interactions, are reinforcing, a major isomer is produced.
The stereoselectivity is lower when these factors are in
conflict. In tricyclic systems,32–35 however, such general
statements must be applied carefully. A range of structures
can usually accommodate the basic requirements, that is,
oxygen substituents at anomeric centres in axial disposition
and carbon substituents in equatorial disposition, with rather
small differences in energy and low interconversion
barriers.
The spiroketal unit represents a common feature in many
biologically relevant natural products, including steroidal
saponins, polyether ionophores, macrolide antibiotics,
insect pheromones and toxic metabolites from algae and
fungi,1–4 being the target of much synthetic effort.5–13 This
structural element is also present in a unique class of cyclic
disaccharides termed generically diketose dianhydrides, of
which di-D-fructose dianhydrides (DAFs) are paradigmatic
examples.14 Some members of this class of compounds have
been isolated from microorganisms15 and higher plants.16
Their potential use as sweeteners,17,18 bifidogenic agents19
or chiral templates20,21 has triggered intense interest in the
synthesis of these and related spiro-sugars.22– 27 The
identification of DFAs as the major components of the
thermolysis product of sucrose and D-fructose containing
food materials, such as caramel and chicory,28–30 and the
need of pure standards for nutritional studies and analytical
evaluation31 has provided a further impetus.
In the case of DFAs, high yielding preparations have been
previously achieved by protonic activation of D-fructose,
sucrose or inulin with anhydrous hydrogen fluoride (HF) or
its complex with pyridine.36–38 Under such conditions, a
fructosyl oxocarbenium cation is generated, which under-
goes in situ glycosylation into the corresponding keto-
disaccharide. Further spiroketalization is a reversible
process that leads to a complex mixture of bis(spiro)disac-
charides in which the two D-fructose constituents are joined
through a central 1,4-dioxane ring. Up to five different
Keywords: Di-D-fructose dianhydrides; 1,2-Isopropylidene-b-D-
fructofuranose; 1,2-Isopropylidene-b-D-fructopyranose; Spiro-disac-
charides; Spiroketals.
*
Corresponding authors. Tel.: þ34-954557150; fax: þ34-954624960
(C.O.M.); tel.: þ34-954489559; fax: þ34-954460565 (J.M.G.F.);
e-mail addresses: mellet@us.es; jogarcia@iiq.csic.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.032

5900
J. M. Benito et al. / Tetrahedron 60 (2004) 5899–5906
tricyclic cores (types I–V) and 13 DFA isomers that differ
in the ring size, linking position and stereochemistry of the
ketal stereocenters have been so far identified from reaction
mixtures (Scheme 1).
of the monosaccharides and, eventually, controlling the
stereochemical outcome of the dimerization process.39 This
concept has now been translated into stereoselective
preparations of DFAs having the 1,6,9,13-tetraoxadispiro-
[4.2.4.2]tetradecane and 1,7,10,15-tetraoxadispiro[5.2.5.2]-
hexadecane core structure (types I and III, respectively).
Our strategy relies on the ability of 1,2-O-isopropylidene
D-fructose derivatives to undergo a tandem acetal clea-
vage—intermolecular glycosylation—intramolecular spiro-
ketalization process by reaction with suitable acid
promoters.40,41 The scope and limitations of the methods
as well as the factors influencing the relative proportions of
the products are discussed.
2. Results and discussion
3,4,6-Tri-O-protected 1,2-O-isopropylidene-b-D-fructo-
furanoses 2a-c, readily accessible from the known 1,2-O-
isopropylidene-b-D-fructofuranose42 1, were used as fura-
nose-anchored precursors for the preparation of type I
DFAs. First, a screening of their reactivity in the presence of
a series of acid promoters was carried out (see Table 1 for
selected results). Diethylaluminium chloride was found to
be inefficient to provoke acetal cleavage in either toluene or
dichloromethane, even using a large excess of reagent at
50 8C. Treatment with tin (IV) chloride or zinc chloride
(ZnCl2·Et2O) etherate resulted in removal of the isopropyl-
idene group even at room temperature, but these reagents
were unable to promote the subsequent glycosylation–
spiroketalization reaction. A slight improvement was
observed using ZnCl2·Et2O at 50 8C in toluene, although
the final DFA products (3a–c, 4a–c) were isolated in
disappointingly low yields (4–15%) and poor stereoselec-
tivities (Table 1, entries 1, 4 and 7). Interestingly, boron
trifluoride diethyl etherate (BF3·Et2O) and trifluoromethane-
sulfonic acid (triflic acid, TfOH) succeeded in promoting
the desired tandem transformations in toluene (see Table 1,
entries 2, 5, and 8 for results using BF3·Et2O), which is in
agreement with their broad use for the cleavage of acetal
protecting groups, as glycosylation promoters and as
spiroketalization catalysts.40,41,43,44 The use of dichloro-
methane as solvent was detrimental in the case of BF3·Et2O;
in contrast, it resulted in improved yields in the case of the
protic acid promoter TfOH (Table 1, entries 3, 6 and 9).
Employing these optimal reaction conditions, conversion
Scheme 1. Acid-catalysed dimerization of ketoses.
Difuranose DFA derivatives (types I and V) are formed at
the early stages of the acid-promoted dimerization of
D-fructose. However, they partially isomerize in the reaction
medium to give mixed furanose–pyranose (types II and IV)
and dipyranose species (type III). Although their relative
proportions can be varied to some extent by modulation of
the acid strength, isolation of pure samples from the
isomeric mixtures remains a difficult task. We envisioned
that isomerization reactions would be significantly slowed
in anhydrous apolar solvents. Moreover, the use of protected
D-fructose precursors should allow blocking the cyclic form
Table 1. Acid-promoted dimerization of 1,2-O-isopropyliden-D-fructose derivatives (2a–c and 6a–c) to give DFAs (3a–c, 4a–c and 7a–c, 8a–c, respectively)
Entry
Starting material
Acid promoter (equiv.)
Solvent
Temp. (8C)
Reaction time (h)
Yield (%)
Products (ratio)
1
2
3
4
5
6
7
8
2a
2a
2a
2b
2b
2b
2c
2c
2c
6a
6a
6b
6b
6c
6c
ZnCl2·Et2O (4.0)
BF3·Et2O (1.0)
TfOH (1.5)
ZnCl2·Et2O (4.0)
BF3·Et2O (1.0)
TfOH (1.5)
ZnCl2·Et2O (4.0)
BF3·Et2O (2.0)
TfOH (1.5)
BF3·Et2O (1.5)
TfOH (1.5)
Toluene
Toluene
CH2Cl2
Toluene
Toluene
CH2Cl2
Toluene
Toluene
CH2Cl2
Toluene
CH2Cl2
Toluene
CH2Cl2
Toluene
CH2Cl2
50
220
16
4.5
1
16
3
4
3a:4a (1:1)
3a:4a (2:5)
3a:4a (1:2)
3b:4b (2:3)
3b:4b (1:5)
3b:4b (1:7)
3c:4c (2:3)
3c:4c (24:1)
3c:4c (25:1)
7a:8a (1:25)
7a:8a (1:20)
7b:8b (1:7)
7b:8b (1:6)
7c:8c (1:1)
7c:8c (1:1)
64
75
12
75
92
15
40
91
65
76
68
87
80
87
278!20
50
220
278!20
1
50
4
16
16
2
5
1.5
5
1.5
72
3
9
278!20
10
11
12
13
14
15
220
278!20
220
BF3·Et2O (1.5)
TfOH (1.5)
BF3·Et2O (2.0)
TfOH (2.0)
278!20
20
278!20

J. M. Benito et al. / Tetrahedron 60 (2004) 5899–5906
5901
Scheme 2. Synthesis of type I DFAs. Reagents: (a) BF3·Et2O in toluene or
TfOH in CH2Cl2 (see Table 1); (b) H2/Pd–C, AcOH–MeOH–HCOOH
(90–97%); (c) PdCl2, MeOH (70–80%); (d) NaOMe/MeOH (.95%);
(e) Ac2O-pyridine (.95%).
Scheme 3. Synthesis of type III DFAs. Reagents: (a) BF3·Et2O in toluene or
TfOH in CH2Cl2 (see Table 1); (b) H2/Pd–C, AcOH–MeOH–HCOOH
(.95%); (c) PdCl2, MeOH (70–75%); (d) NaOMe/MeOH (.95%);
(e) Ac2O-pyridine (.95%).
yields into the corresponding dispiro-disaccharides 3a–c,
4a–c in the range 75–92% were obtained (Scheme 2).
relative proportion (Table 1, entries 14 and 15), the non-
symmetric a,b-diastereomer (8a and 8b) was favoured in
the case of the benzylated or allylated pairs (Table 1, entries
10–13).
It is noteworthy that only two of the three possible type I
DAF structures (the a,a, b,b and a,b diastereomers) were
formed in all cases, namely the hexa-O-protected di-a-D-
fructofuranose 1,20:2,10-dianhydride (3a–c) and a-D-fruc-
tofuranose b-D-fructofuranose 1,20:2,10-dianhydride deriva-
tives (4a–c). Their relative proportions were strongly
dependent on the nature of the hydroxyl protecting groups.
Thus, in the case of ether-type groups (2a and 2b) the
non-symmetric diastereomer (4a and 4b) was favored,
with 43 and 75% diastereomeric excess (de) values over the
C2-symmetric dianhydride (3a and 3b). The stereochemical
outcome of the spiroketalization reaction was reversed for
the benzoyl counterpart (2c), leading to a 92% de in favour
of the a,a (3c) over the a,b isomer (4c).
Pure samples of the hexa-O-protected individual DFA
isomers could be obtained in all cases after column
chromatography. Nevertheless, in the case of the benzoyl-
ated derivatives (3c, 4c and 7c, 8c), replacing the benzoyl
groups into acetyl (to give 3e, 4e and 7e, 8e, respectively)
prior to column chromatography was advantageous for
preparative purposes. The structure of all DFAs prepared in
this study was confirmed by microanalytical, NMR and MS
data. The chemical shifts of the anomeric C-2 (C-20) carbon
atoms are particularly useful for diagnostic purposes,
behaving as a fingerprint for a given DFA core structure.14
The structural assignment was further confirmed by
transformation into the known fully unprotected DFAs
(3d, 4d, 7d and 8d) by removal of the O-protecting groups
through standard methodologies. The relative proportions of
stereoisomers in the mixtures was established by GC
chromatography after derivatization of the unprotected
DFAs as the corresponding hexa-O-trimethylsilyl deriva-
tives, following the procedure previously reported for
determination of DFAs in food products.31
To implement this approach for the stereoselective prepa-
ration of dispiro-difructopyranose dianhydrides (type III
DFAs), 3,4,5-tri-O-benzyl- (6a),45 3,4,5-tri-O-allyl- (6b)
and 3,4,5-tri-O-benzoyl-b-D-fructopyranose (6c),46 avail-
able in three steps from D-fructose via the corresponding
monoacetonide 5,46 were used as pyranose-anchored
D-fructose templates. As a general rule, the acid-promoted
dimerization process proceeded more slowly in these cases,
in agreement with the lower stability of the six-membered
cyclic oxocarbenium cation. Nevertheless, satisfactory
conversion rates were obtained using either BF3·Et2O or
TfOH by increasing the proportion of the catalyst, the
temperature or using longer reaction times, TfOH in
dichloromethane providing the higher yields on the
corresponding DFA products. Binary mixtures of the
corresponding hexa-O-protected di-b-D-fructopyranose
1,20:2,10-dianhydride (7a–c) and a-D-fructopyranose b-D-
fructopyranose 1,20:2,10-dianhydride (8a–c) were obtained
in all cases (Scheme 3). As previously observed in
the furanose series, a strong stereodirecting effect of the
hydroxyl protecting groups in the generation of
the spiroketal stereocentres was observed. Thus, while the
benzoyl derivatives (7c and 8c) were obtained in identical
The possibility to control not only the ring size but also the
stereochemistry at the spiroketal centres in the synthesis of
DFAs is noteworthy. We hypothesized that, in contrast to
the mineral acid-catalyzed reaction, spiroketalization occurs
in apolar organic solvents under virtually irreversible
conditions, thus limiting isomerization processes. To
confirm this point, the hexabenzylated C2-symmetric
dianhydride 7a was subjected to the reaction conditions
previously used to promote dimerization of 6a. No
isomerization into the favored non-symmetric diastereomer
8a was detected after 24 h, supporting the above assump-
tion. The preference for non-symmetric over C2-symmetric
DFA structures in the case of non-participating protecting
groups (i.e., benzyl and allyl) can be rationalized in terms of

5902
J. M. Benito et al. / Tetrahedron 60 (2004) 5899–5906
Figure 2. Probable structure of the acyloxonium cations involved in
the dimerization reaction of benzoylated D-fructofuranose (A) and
D-fructopyranose (B) precursors.
compensated by the gain in stability due to the chair
arrangement of the central 1,4-dioxane ring in asymmetric
dianhydrides, a situation that would not apply for a C2-
symmetric diastereomer. In fact, no dipyranose DFA
derivatives having the a,a configuration have been reported
up to date. Probably, the a-(2!1)-linked disaccharide
derived from intermediate 10 would necessarily undergo
spiroketalization through the b-face to give 8c.
Figure 1. Conformations for non-symmetric and C2-symemtric DFAs of
types I (A) and III (B).
In conclusion, we have demonstrated that 1,2-O-isopropyl-
idene-D-fructose derivatives are suitable precursors for the
synthesis of difuranose and dipyranose DFAs. Boron
trifluoride diethyl etherate complex and triflic acid are
capable to promote acetal deprotection and dimerization to
the corresponding spiro-cyclic disaccharides in organic
solvents, under irreversible conditions. Both the ring size
and the stereochemistry at the spiroketal centres can be
controlled by judicious choice of the protecting groups in
the monosaccharide template, non-participating groups
favouring non-symmetric structures and participating
groups the C2-symmetric diastereomers.
the relative stability of the incipient 1,4-dioxane ring
leading to a given isomer. In the case of the a,b
diastereomers, the central ring can accommodate the
oxygen substituents in axial disposition and the carbon
substituents in equatorial disposition in the chair confor-
mation. Such situation does not prevail for the symmetric
isomers, which must adopt a boat conformation at the
central ring to accommodate the anomeric effect at both
anomeric centres, a less favourable arrangement (Fig. 1(A)
and (B)).14
The dimerization reaction of substrates bearing partici-
pating ester groups (2c and 6c) probably proceeds through
acyloxonium entities. The lower reactivity of these species
as compared with the fructosyl cation is in agreement with
the observed lower reactivity of benzoylated D-fructose
derivatives towards dimerization (Table 1). In the furanose
series, the formation of a cis-fused 2,3-acyloxonium cation
intermediate (9) prevents O-10 attack through the b-face in
both the glycosylation and spirocyclization steps (Fig.
2(A)). Consequently, the thermodynamically less favoured
di-a isomer 3c is formed almost exclusively. In the pyranose
series, however, glycosylation of the corresponding 2,3-
acyloxonium cation (10) may compete with the attack by the
benzoate group at C-5 to give a 2,5-acyloxonium inter-
mediate (11), which blocks the nucleophilic attack by O-10
through the a-face (Fig. 2(B)). At its turn, this cation will
undergo selectively glycosylation-spiroketalization
through the more accessible b-face to give 7c (Fig. 2). It
must be noticed that the a- and b-D-fructopyranose rings in
a-fructopyranose b-fructopyranose 1,20:2,10-dianhydride
derivatives adopts the 4C1 and 1C4 chair conformation,
respectively, in order to fit the anomeric effect (Fig. 1(B)).
The unfavourable steric interactions in the a-ring are
3. Experimental
3.1. General methods
All solvents and reagents were purchased from commercial
sources and used without further purification, except for
toluene and dichloromethane, which were distilled under Ar
stream over Na and CaH2, respectively. 1,2-O-Isopropyl-
idene-b-D-fructofuranose42 (1), 1,2-O-isopropylidene-b-D-
fructopyranose46 (5) and 3,4,5-tri-O-benzoyl-1,2-O-iso-
propylidene-b-D-fructopyranose46 (6c) were prepared
according to described procedures. 3,4,5-Tri-O-benzyl-
1,2-O-isopropylidene-b-D-fructopyranose (6a) has been
previously obtained from 5 in 17% yield by treatment
with benzyl bromide in tetrahydrofurane.45 An improved
preparation (70% yield), including full characterization
data, is given hereinafter. Optical rotations were measured
at room temperature in 1-cm or 1-dm tubes on a Perkin–
Elmer 141 MC polarimeter. 1H (and 13C NMR) spectra were
recorded at 300 (75.5) and 500 (125.7) MHz with Bruker
300 AMX and 500 DRX instruments, respectively. 2D

J. M. Benito et al. / Tetrahedron 60 (2004) 5899–5906
5903
COSY, HMQC and HSQC experiments were used to assist
on NMR assignments. Thin-layer chromatography (TLC)
was carried out on aluminium sheets coated with Kieselgel
60 F254 (E. Merck), with visualisation by UV light and by
charring with 10% H2SO4. 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 the following:
the primary beam consisted of Xe atoms with a maximum
energy of 8 keV; the samples were dissolved in thioglycerol,
and the positive ions were separated and accelerated over a
potential of 7 keV; NaI was added as cationizing agent.
Elemental analyses were performed at the Instituto de
NMR (500 MHz, CDCl3) d 1.38, 1.43 (2s, each 3H, CMe2),
3.52 (dd, 1H, J6a,6b¼10.0 Hz, J5,6a¼6.2 Hz, H-6a), 3.56 (dd,
1H, J5,6b¼6.4 Hz, H-6b), 3.87 (d, 1H, J3,4¼6.5 Hz, H-3),
3.94, (dd, 1H, J4,5¼5.1 Hz, H-4), 3.98 (ddd, 1H, H-5), 3.99
(d, 1H, J1a,1b¼9.5 Hz, H-1a), 4.05 (d, 1H, H-1b), 3.97–4.17
(m, 6H, CH2O), 5.13–5.30 (m, 6H, CH2vCH), 5.83–5.95
(m, 3H, CH2vCH); 13C NMR (125.7 MHz, CDCl3) d 26.5,
26.6 (CMe2), 71.2, 71.3 (3CH2), 72.2 (C-6), 72.4 (C-1), 80.1
(C-5), 83.2 (C-3), 84.5 (C-4), 109.0 (C-2), 111.5 (CMe2),
117.0, 117.4 (3CHvCH2), 134.2, 134.5 (3CHvCH2);
FABMS: m/z 341 (30%, [MþH]þ). Anal. Calcd for
C18H28O6: C, 63.51; H, 8.29; found: C, 63.46; H, 8.58.
´
Investigaciones Quımicas (Sevilla, Spain).
3.1.3. 3,4,6-Tri-O-benzoyl-1,2-O-isopropylidene-b-D-
fructofuranose (2c). A solution of 1 (1 g, 4.5 mmol) and
benzoyl chloride (2.65 mL, 23.3 mmol) in pyridine (8 mL)
was stirred for 16 h at room temperature. Iced water
(40 mL) was added to the reaction mixture and the
suspension was extracted with CH2Cl2 (2£20 mL), the
organic layer was dried (MgSO4) and concentrated.
The resulting residue was purified by column chroma-
tography (1:5 EtOAc–petroleum ether) to yield 2c (1.77 g,
73%). Rf¼0.43 (1:4 EtOAc–petroleum ether); [a]D¼252.0
Debenzylation of hexa-O-benzylated DAFs (3a, 4a, 7a and
8a) or their mixtures was effected by catalytic hydrogen-
ation with 10% Pd/C at 1 atm in 1:1 EtOAc–MeOH
containing 10% formic acid. Deallylation reactions (3b, 4b,
7b and 8b) were accomplished by treatment with PdCl2 in
MeOH.47 Conventional debenzoylation (3c, 4c, 7c and 8c)
was carried out with methanolic NaOMe (1 M). Acetylation
of fully unprotected DAF mixtures was performed with 1:1
Ac2O–pyridine. In all cases, the physicochemical data for
the individual fully unprotected DFAs (3d, 4d, 7d and 8d)
or the corresponding per-O-acetates (3e, 4e, 7e and 8e) were
identical to those previously reported.
1
(c 1.0, CH2Cl2); H NMR (500 MHz, CDCl3) d 1.26, 1.44
(2s, each 3H, CMe2), 4.21 (d, 1H, J1a,1b¼9.4 Hz, H-1a),
4.36 (d, 1H, H-1b), 4.51 (ddd, 1H, J4,5¼5.1 Hz, J5,6a
¼
4.6 Hz, J5,6b¼6.4 Hz, H-5), 4.67 (dd, 1H, J6a,6b¼11.6 Hz,
H-6a), 4.82 (dd, 1H, H-6b), 5.87 (d, 1H, J3,4¼5.1 Hz, H-3),
5.95 (t, 1H, H-4), 7.39–8.12 (m, 15H, Ph); 13C NMR
(125.7 MHz, CDCl3) d 26.0 (CMe2), 65.1 (C-6), 71.3 (C-1),
75.9 (C-3), 77.0 (C-4), 79.2 (C-5), 108.9 (C-2), 112.0
(CMe2), 128.2–134.5 (Ph), 165.6, 165.7, 166.1 (3CO);
FABMS: m/z 555 (100%, [MþNa]þ). Anal. Calcd for
C30H28O9: C, 67.66; H, 5.30; found: C, 67.68; H, 5.29.
3.1.1. 3,4,6-Tri-O-benzyl-1,2-O-isopropylidene-b-D-fruc-
tofuranose (2a). To a solution of 1 (1 g, 4.5 mmol) in DMF
(15 mL), NaH (0.44 g, 18.2 mmol, 1.4 equiv.) and benzyl
bromide (2.43 mL, 20 mmol, 1.5 equiv.) were added and the
reaction mixture was stirred for 4 h at room temperature.
Then, MeOH (5 mL) was added, the solvents were
evaporated under reduced pressure and the residue was
extracted with Et2O (20 mL), washed with water (20 mL),
dried (MgSO4), concentrated and purified by column
chromatography (1:8 EtOAc–petroleum ether) to furnish
2a (1.78 g, 81%). Rf¼0.33 (1:8 EtOAc–petroleum ether);
[a]D¼227.3 (c 1.1, CH2Cl2); 1H NMR (500 MHz, CDCl3)
3.1.4. 2,3,4-Tri-O-benzyl-1,2-O-isopropylidene-b-D-fruc-
topyranose (6a). Compound 6a was prepared from 5 (0.6 g,
2.72 mmol) as above described for 2a, followed by column
chromatography purification (1:9!1:7 EtOAc–petroleum
ether). Yield: 0.90 g (70%); [a]D¼298.5 (c 1.0, CH2Cl2);
Lit. [a]D¼281.2 (c 0.92, CHCl3); Rf¼0.30 (1:5 EtOAc–
petroleum ether); 1H NMR (500 MHz, CDCl3) d 1.56, 1.66
(2s, each 3H, CMe2), 3.84 (m, 1H, H-5), 3.88 (m, 2H, H-6),
4.04 (dd, 1H, J3,4¼2.5 Hz, J4,5¼9.9 Hz, H-4), 4.08 (d, 1H,
H-3), 4.09 (d, 1H, J1a,1b¼8.7 Hz, H-1a), 4.11 (d, 1H, H-1b),
4.58–5.16 (m, 6H, CH2Ph), 7.31–7.49 (m, 15H, Ph); 13C
NMR (125.7 MHz, CDCl3) d 26.3, 27.2 (CMe2), 62.4 (C-6),
67.5 (C-3), 70.0 (C-4), 70.2 (C-5), 71.8 (C-1), 71.6, 72.0,
75.4 (CH2Ph), 104.2 (C-2), 111.8 (CMe2), 127.4–138.5
(Ph); FABMS: m/z 513 (100%, [MþNa]þ). Anal. Calcd for
C30H34O6: C, 73.45; H, 6.99; found: C, 73.49; H, 6.87.
d 1.49, 1.53 (2s, each 3H, CMe2), 3.46 (dd, 1H, J5,6a
¼
6.2 Hz, J6a,6b¼9.8 Hz, H-6a), 3.70 (dd, 1H, J5,6b¼6.2 Hz,
H-6b), 3.99 (d, 1H, J1a,1b¼9.4 Hz, H-1a), 4.06 (d, 1H, J3,4
¼
5.0 Hz, H-3), 4.09 (d, 1H, H-1b), 4.17 (td, 1H, J4,5¼5.0 Hz,
H-5), 4.19 (t, 1H, H-4), 4.60–4.77 (m, 6H, CH2Ph), 7.33–
7.39 (m, 15H, Ph); 13C NMR (125.7 MHz, CDCl3) d 26.4,
26.5 (CMe2), 71.3 (C-1), 72.2 (C-6), 73.5 (3CH2Ph), 80.1
(C-5), 83.2 (C-3), 84.5 (C-4), 109.2 (C-2), 111.5 (CMe2),
127.5–138.1 (Ph); FABMS: m/z 513 (100%, [MþNa]þ).
Anal. Calcd for C30H34O6: C, 73.45; H, 6.99; found: C,
73.52; H, 6.90.
3.1.2. 3,4,6-Tri-O-allyl-1,2-O-isopropylidene-b-D-fructo-
furanose (2b). To a solution of 1 (1.06 g, 4.8 mmol) in
DMF (15 mL), NaH (0.87 g, 36 mmol) and allyl bromide
(1.34 mL, 15.8 mmol) were added and the reaction mixture
was stirred for 15 min at room temperature. Then water
(5 mL) was added and the reaction mixture was extracted
with Et2O (5£40 mL). The organic layer was washed with
H2O (5£25 mL), dried (MgSO4), and concentrated, and the
residue purified by column chromatography (1:7 EtOAc–
petroleum ether) to afford 2b (1.31 g, 80%). Rf¼0.50 (1:5
3.1.5. 2,3,4-Tri-O-allyl-1,2-O-isopropylidene-b-D-fructo-
pyranose (6b). Compound 6b was prepared from 5 (1.19 g,
5.4 mmol) as above described for 2b, followed by column
chromatography purification (1:7 EtOAc–petroleum ether).
Yield: 1.37 g (75%); (1:7 EtOAc–petroleum ether). Rf¼
0.53 (1:5 EtOAc–petroleum ether); [a]D¼2113.3 (c 1.0,
CHCl3); 1H NMR (500 MHz, CDCl3) d 1.38, 1.43 (2s, each
3H, CMe2), 3.66 (d, 1H, J3,4¼2.9 Hz, H-3), 3.71 (dd, 1H,
J4,5¼9.7 Hz, H-4), 3.75 (m, 1H, H-5), 3.79 (m, 2H, H-6),
3.96 (d, 1H, J1a,1b¼8.4 Hz, H-1a), 4.03 (d, 1H, H-1b),
4.04–4.17 (m, 6H, CH2O), 5.08–5.30 (m, 6H, CH2vCH),
1
EtOAc–petroleum ether); [a]D¼232.1 (c 1.4, CHCl3); H

5904
J. M. Benito et al. / Tetrahedron 60 (2004) 5899–5906
5.83–5.95 (m, 3H, CH2vCH); 13C NMR (125.7 MHz,
CDCl3) d 26.1, 27.2 (CMe2), 70.9, 71.1, 74.4 (3CH2O),
111.8 (CMe2), 116.4, 116.6, 117.4 (3CHvCH2), 134.9,
135.2 (3CHvCH2); FABMS: m/z 341 (100%, [MþH]þ).
Anal. Calcd for C18H28O6: C, 63.51; H, 8.29; found: C,
63.63; H, 8.00.
FABMS: m/z 887 (100%, [MþNa]þ). Anal. Calcd for
C54H56O10: C, 74.98; H, 6.52; found: C, 74.77; H, 6.29.
3.2.2. 3,4,6,30,40,60-Hexa-O-allyl-di-a-D-fructofuranose
1,20:2,10-dianhydride (3b). Rf¼0.60 (1:3 EtOAc–petro-
leum ether); [a]D¼þ92.1 (c 0.55, CHCl3); 1H NMR
(500 MHz, CDCl3) d 3.52 (dd, 2H, J5,6a¼5.4 Hz, J6a,6b
¼
3.2. General procedure for the preparation of difructose
dianhydrides (3a–c, 4a–c, 7a–c, 8a–c)
11.0 Hz, H-6a), 3.56 (dd, 2H, J5,6b¼4.9 Hz, H-6b), 3.70 (dd,
2H, J3,4¼3.9 Hz, J4,5¼6.7 Hz, H-4), 3.71 (d, 2H, J1a,1b
¼
12.8 Hz, H-1a), 3.86 (d, 2H, H-3), 3.97 (d, 2H, H-1b), 4.01
(m, 2H, H-5), 4.00–4.18 (m, 12H, CH2O), 5.14–5.29 (m,
12H, CH2vCH), 5.83–5.93 (m, 6H, CH2vCH); 13C NMR
(125.7 MHz, CDCl3) d 59.7 (C-1), 69.8 (C-6), 71.2, 71.4,
72.4 (6CH2O), 79.3 (C-5), 83.2 (C-4), 87.9 (C-3), 105.4
(C-2), 117.0, 117.3, 117.6 (6CHvCH2), 134.2, 134.5, 134.7
(6CHvCH2). Anal. Calcd for C30H44O10: C, 63.81; H, 7.85;
found: C, 63.46; H, 8.05.
(a) By treatment with BF3·Et2O. To a stirred 0.15 M solution
of the corresponding 1,2-O-isopropylidene-D-fructose
derivative 2a–c or 6a–c in dry toluene under Ar, the acid
promoter BF3·Et2O was added. Reaction conditions
(equivalents of acid, reaction temperature and reaction
time) are collected in Table 1. The reaction mixture was
quenched by addition of MeOH, washed with 5% aq.
NaHCO3, the organic layer was dried (MgSO4), the solvents
were evaporated under reduced pressure, and the products
were separated by column chromatography with the eluent
indicated in each case.
3.2.3. 3,4,6,30,40,60-Hexa-O-benzoyl-di-a-D-fructofura-
nose 1,20:2,10-dianhydride (3c). Rf¼0.21 (1:20 EtOAc–
toluene); [a]D¼21.0 (c 1.0, CH2Cl2); 1H NMR (500 MHz,
CDCl3) d 4.17 (d, 2H, J1a,1b¼12.2 Hz, H-1a), 4.21 (d, 2H,
(b) By treatment with TfOH. To a stirred 50 mM solution of
the corresponding 1,2-O-isopropylidene-D-fructose deriva-
tive 2a–c or 6a–c in freshly distilled CH2Cl2 under Ar at
278 8C, TfOH was added. The reaction mixture was
allowed to warm up to room temperature and stirred for
the indicated time (Table 1). Et3N (0.5 mL) was added, the
reaction mixture was stirred for 10 min, the solvents were
evaporated under reduced pressure and the products were
separated by column chromatography with the eluent
indicated in each case.
H-1b), 4.58 (ddd, 2H, J4,5¼5.4 Hz, J5,6a¼4.9 Hz, J5,6b¼
3.1 Hz, H-5), 4.66 (dd, 2H, J6a,6b¼11.9 Hz, H-6a), 4.79 (dd,
2H, H-6b), 5.55 (dd, 2H, J3,4¼1.8 Hz, H-4), 5.77 (d, 2H,
H-3), 7.39–8.07 (m, 30H, Ph); 13C NMR (125.7 MHz,
CDCl3) d 60.8 (C-1), 63.0 (C-6), 80.0 (C-3), 80.4 (C-5),
78.4 (C-4), 103.8 (C-2), 128.2–133.5 (Ph), 164.7, 165.6,
166.0 (CO); FABMS: m/z 971 (100%, [MþNa]þ). Anal.
Calcd for C54H44O16: C, 68.35; H, 4.67; found: C, 68.20;
H, 4.51.
3.2.4. 3,4,6-Tri-O-benzyl-a-D-fructofuranose 3,4,6-tri-O-
benzyl-b-D-fructofuranose 1,20:2,10-dianhydride (4a).
Rf¼0.32 (1:4 EtOAc–petroleum ether); [a]D¼25.2 (c 3.4,
CH2Cl2); 1H NMR (500 MHz, CDCl3) d 3.46 (d, 1H,
Conversion yields are collected in Table 1. For benzylated
(3a, 4a and 7a, 8a) and allylated derivatives (3b, 4b and 7b,
8b), efficient separations of the individual diastereomers
were achieved after column chromatography. In the case of
perbenzoylated derivatives (3c, 4c and 7c, 8c), however,
only small amounts of the pure DFAs could be obtained
after a second column chromatography. Transformation
into the corresponding per-O-acetates (3e, 4e and 7e, 8e)
allowed the efficient separation of individual isomers
(column chromatography, eluent 1:3 EtOAc–petroleum
ether). The relative proportions of C2-symmetric versus
non-symmetric diastereomers in the reaction mixtures were
determined by GC after transformation into the correspond-
ing mixtures of fully unprotected DFAs (3d, 4d or 7d, 8d)
and further derivatization as the corresponding hexa-O-
trimethylsilyl derivatives, following the protocol previously
reported.31 The identity of the peaks was confirmed by
comparison with authentic standards.
J1 a,1 b¼10.5 Hz, H-10a), 3.60 (dd, 1H, J5 ,6 a¼5.8 Hz,
0
0
0
0
J6 a,6 b¼9.6 Hz, H-60a), 3.67 (dd, 1H, J5 ,6 b¼6.8 Hz,
0
0
0
0
H-60b), 3.68 (dd, 1H, J5,6a¼5.1 Hz, J6a,6b¼10.8 Hz, H-6a),
3.75 (dd, 1H, J5,6b¼4.6 Hz, H-6b), 3.84 (1H, d, J1a,1b
¼
13.1 Hz, H-1a), 3.95 (1H, dd, J3,4¼2.0 Hz, J4,5¼5.4 Hz,
H-4), 4.04 (d, 1H, H-3), 4.14 (m, 1H, H-50), 4.15 (d, 1H,
H-100b), 4.18 (d, 1H, H-1b),0 4.20 (m, 1H, H-3 ), 4.21 (m, 1H,
H-4 ), 4.27 (bdd, 1H, H-5 ), 4.39–4.74 (m, 12H, CH2Ph),
7.21–7.31 (m, 30H, Ph); 13C NMR (125.5 MHz, CDCl3) d
62.5 (C-1), 63.3 (C-10), 70.1 (C-6), 71.6 (C-60), 71.9, 72.0,
72.2, 72.4, 73.2, 73.4 (CH2Ph), 80.2 (C-5), 81.8 (C-40), 83.6
(C-4), 84.7 (C-50), 88.2 (C-3, C-30), 99.6 (C-20), 102.5 (C-2),
127.4–138.1 (Ph); FABMS: m/z 887 (100%, [MþNa]þ).
Anal. Calcd for C54H56O10: C, 74.98; H, 6.52. Found: C,
75.05; H, 6.50.
3.2.1. 3,4,6,30,40,60-Hexa-O-benzyl-di-a-D-fructofuranose
1,20:2,10-dianhydride (3a). Rf¼0.33 (1:4 EtOAc–petro-
leum ether); [a]D¼þ71.0 (c 1.0, CH2Cl2); 1H NMR
(500 MHz, CDCl3) d 3.58 (dd, 2H, J6a,6b¼10.9 Hz,
J5,6a¼4.9 Hz, H-6a), 3.61 (dd, 2H, J5,6b¼4.9 Hz, H-6b),
3.2.5. 3,4,6-Tri-O-allyl-a-D-fructofuranose 3,4,6-tri-O-
allyl-b-D-fructofuranose 1,20:2,10-dianhydride (4b). Rf¼
0.40 (1:3 EtOAc–petroleum ether); [a]D¼þ4.3 (c 1.3,
CHCl3); 1H NMR (500 MHz, CDCl3) d 3.46 (d, 1H, J1 a,1 b
¼
0
0
11.5 Hz, H-10a), 3.51 (dd, 1H, J5 ,6 a¼6.4 Hz, J6 a,6 b¼9.8
0
0
0
0
0
0
3.84 (d, 2H, J1a,1b¼12.7 Hz, H-1a), 3.87 (dd, 2H, J3,4
¼
Hz, H-60a), 3.58 (dd, 1H, J5 ,6 b¼5.8 Hz, H-60b), 3.59 (dd,
3.8 Hz, J4,5¼6.8 Hz, H-4), 4.06 (d, 2H, H-3), 4.12 (d, 2H,
H-1b), 4.20 (dt, 2H, H-5), 4.43–4.73 (m, 12H, CH2Ph),
7.26–7.33 (m, 30H, Ph); 13C NMR (125.7 MHz, CDCl3) d
59.9 (C-1), 68.0 (C-6), 72.2, 72.7, 73.5 (CH2Ph), 79.3 (C-5),
83.2 (C-4), 88.0 (C-3), 105.4 (C-2), 127.5–138.1 (Ph);
1H, J5,6a¼3.1 Hz, J6a,6b¼11.5 Hz, H-6a), 3.61 (dd, 1H,
0
0
0
J5,6b¼3.8 Hz, H-6b), 3.65 (d, 1H, J3 ,4 ¼6.2 Hz, H-3 ), 3.69,
(d, 1H, J1a,1b¼12.0 Hz, H-1a), 3.75 (dd, 1H, J3,4¼2.6 Hz,
J4,5¼5.8 Hz, H-4), 3.84 (d, 1H, H-3), 4.01 (m, 1H, H-40),
4.03 (m, 1H, H-5), 4.06 (m, 1H, H-50), 4.06 (d, 1H, H-1b),

J. M. Benito et al. / Tetrahedron 60 (2004) 5899–5906
5905
3.95–4.12 (m, 12H, CH2O), 4.14 (d, 1H, H-10b), 5.10–5.30
(m, 12H, CH2vCH), 5.78–5.92 (m, 6H, CH2vCH); 13C
NMR (125.7 MHz, CDCl3) d 62.7 (C-1), 63.5 (C-10), 70.3
(C-6), 71.9 (C-60), 70.9, 71.1, 71.2, 71.9, 72.3, 72.4 (CH2O),
80.1 (C-5), 81.4 (C-50), 83.8 (C-4), 84.6 (C-30), 84.7 (C-40),
88.3 (C-3), 99.6 (C-20), 102.4 (C-2), 116.8, 117.1, 117.2,
117.3, 117.4, 117.9 (CHvCH2), 134.0, 134.3, 134.4, 134.5,
134.6, 134.8 (CHvCH2). Anal. Calcd for C30H44O10: C,
63.81; H, 7.85; found: C, 63.74; H, 7.79.
4.05 (dd, 2H, J5,6a¼1.3 Hz, J6a,6b¼13.2 Hz, H-6a), 4.15 (d,
2H, H-1b), 4.23 (dd, 2H, J5,6b¼1.0 Hz, H-6b), 5.70 (m, 2H,
H-5), 5.83 (dd, 2H, J3,4¼10.7 Hz, J4,5¼3.5 Hz, H-4), 5.97
(d, 2H, H-3), 7.09–8.10 (m, 30H, Ph); 13C NMR
(125.7 MHz, CDCl3) d 62.8 (C-6), 63.3 (C-1), 68.7 (C-4),
70.3 (C-5), 71.6 (C-3), 97.3 (C-2), 128.1–133.6 (Ph),
164.4–171.7 (CO); FABMS: m/z 971 (100%, [MþNa]þ).
Anal. Calcd for C54H44O16: C, 68.35; H, 4.67; found: C,
68.22; H, 4.54.
3.2.6. 3,4,6-Tri-O-benzoyl-a-D-fructofuranose 3,4,6-tri-
O-benzoyl-b-D-fructofuranose 1,20:2,10-dianhydride
(4c). Rf¼0.58 (1:2 EtOAc–petroleum ether); [a]D¼246.0
(c 1.0, CH2Cl2); 1H NMR (300 MHz, CDCl3) d 3.90 (d, 1H,
3.2.10. 3,4,5-Tri-O-benzyl-a-D-fructopyranose 3,4,5-tri-
O-benzyl-b-D-fructopyranose 1,20:2,10-dianhydride (8a).
Rf¼0.44 (1:2 EtOAc–petroleum ether) [a]D¼236.9 (c 1.0,
CH2Cl2); 1H NMR (500 MHz, CDCl3) d 3.33 (d, 1H,
J1 a,1 b¼11.8 Hz, H-10a), 3.98 (d, 1H, J1a,1b¼11.9 Hz, H-1a),
J1 a,1 b¼11.6 Hz, H-10a), 3.54 (d, 1H, J5,6a¼0 Hz, J6a,6b
¼
0
0
0
0
4.38 (d, 1H, H-1b), 4.42 (d, 1H, H-10b), 4.50 (ddd, 1H,
12.6 Hz, H-6a), 3.66 (dd, 1H, J5 ,6 a¼3.7 Hz, J6 a,6 b¼11.0
0
0
0
0
J4 ,5 ¼4.9 Hz, J5 ,6 a¼3.5 Hz, J5,6b¼4.3 Hz, H-50), 4.63
(m, 1H, H-5), 4.67 (dd, 1H, J5,6a¼4.5 Hz, J6a,6b¼12.1 Hz,
H-6a), 4.74 (dd, 1H, J5,6b¼3.4 Hz, H-6b), 4.82 (dd, 1H,
Hz, H-60a), 3.71 (d, 1H, J1a,1b¼11.6 Hz, H-1a), 3.73 (m, 1H,
0
0
0
0
0
0
0
0
H-5), 3.77 (d, 1H, J3 ,4 ¼9.8 Hz, H-3 ), 3.77 (d, 1H, H-1 a),
3.79 (m, 2H, H-3, H-4), 3.82 (dd, 1H, J5,6b¼1.8 Hz, H-6b),
J6 a,6 b¼10.5 Hz, H-60a), 4.84 (dd, 1H, H-60b), 5.52 (dd, 1H,
J3,4¼1.1 Hz, J4,5¼4.9 Hz, H-4), 5.66 (d, 1H, H-3), 5.69 (1H,
3.87 (m, 1H, H-50), 3.97 (dd, 1H, J5 ,6 b¼2.3 Hz, H-60b), 4.02
0
0
0
0
0
0
0
0
(dd, 1H, J4 ,5 ¼3.1 Hz, H-4 ), 4.18 (1H, d, H-1 b), 4.44–5.02
(m, 12H, CH2Ph), 7.24–7.37 (m, 30H, Ph); 13C NMR
(75.5 MHz, CDCl3) d 58.9 (C-60), 60.6 (C-6), 61.2 (C-1),
61.3 (C-10), 72.3 (C-50), 71.3, 71.4, 72.1, 72.3, 73.5, 75.4
(CH2Ph), 73.7 (C-4), 73.9 (C-3), 76.1 (C-30), 77.6 (C-5),
78.3 (C-40), 94.5 (C-20), 95.8 (C-2), 127.5–138.5 (Ph);
FABMS: m/z 887 (100%, [MþNa]þ). Anal. Calcd for
C54H56O10: C, 74.98; H, 6.52; found: C, 74.86; H, 6.54.
0
0
0
0
0
0
d, J3 ,4 ¼6.8 Hz, H-3 ), 6.03 (1H, dd, J4 ,5 ¼4.9 Hz, H-4 ),
7.10–8.10 (m, 30H, Ph); 13C NMR (75.5 MHz, CDCl3) d
61.7 (C-1), 63.1 (C-10), 63.6 (C-6), 70.1 (C-60), 77.3 (C-4),
78.9 (C-5), 80.2 (C-50), 81.9 (C-3), 83.6 (C-40), 88.2 (C-30),
99.9 (C-20), 102.1 (C-2), 128.0–133.5 (Ph), 164.5–166.0
(CO); FABMS: m/z 971 (100%, [MþNa]þ). Anal. Calcd for
C54H44O16: C, 68.35; H, 4.67; found: C, 68.52; H, 4.86.
3.2.7. 3,4,5,30,40,50-Hexa-O-benzyl-di-b-D-fructopyra-
nose 1,20:2,10-dianhydride (7a). Rf¼0.47 (1:2 EtOAc–
3.2.11. 3,4,5-Tri-O-allyl-a-D-fructopyranose 3,4,5-tri-O-
allyl-b-D-fructopyranose 1,20:2,10-dianhydride (8b).
Rf¼0.40 (1:2 EtOAc–petroleum ether); [a]D¼234.6 (c
1
petroleum ether); [a]D¼288.0 (c 1.0, CHCl3); H NMR
1
(500 MHz, CDCl3) d 3.59 (d, 2H, J1a,1b¼12.1 Hz, H-1a),
3.67 (dd, 2H, J5,6a¼0.5 Hz, J6a,6b¼11.6 Hz, H-6a), 3.75 (dd,
2H, J5,6b¼1.8 Hz, H-6b), 3.77 (m, 2H, H-5), 3.85 (d, 2H,
H-1b), 3.91 (d, 2H, J3,4¼9.8 Hz, H-3), 4.02 (d, 2H,
J4,5¼3.0 Hz, H-4), 4.63–4.95 (m, 12H, CH2Ph), 7.20–
7.35 (m, 30H, Ph); 13C NMR (125.7 MHz, CDCl3) d 62.8
(C-6), 63.3 (C-1), 68.7 (C-4), 70.3 (C-5), 71.6 (C-3), 71.7,
72.5, 74.6 (CH2O), 97.3 (C-2), 127.2–138.9 (Ph). Anal.
Calcd for C30H44O10: C, 74.98; H, 6.53; found: C, 74.84; H,
6.36.
0.7, CHCl3); H NMR (500 MHz, CDCl3) d 3.39 (d, 1H,
0
J1 a,1 b¼11.4 Hz, H-10a), 3.47 (d, 1H, J3 ,4 ¼9.8 Hz, H-3 ),
3.55 (d, 1H, J3,4¼3.0 Hz, H-3), 3.56 (d, 1H, J1a,1b¼12.1 Hz,
H-1a), 3.59 (dd, 1H, J5,6a¼4.0 Hz, J6a,6b¼11.1 Hz, H-6a),
3.64 (dd, 1H, J4,5¼5.0 Hz, H-4), 3.73 (m, 4H, H-5, H-50,
0
0
0
0
H-60a, H-60b), 3.78 (d, 1H, H-1b), 3.79 (dd, 1H, J4 ,5
¼
0
0
2.7 Hz, H-40), 3.87 (dd, 1H, J5,6b¼4.0 Hz, H-6b), 3.99–4.15
(m, 11H, CH2O), 4.21 (d, 1H, H-10b), 4.35 (ddt, 1H, 2JH,H
¼
3
4
12.6 Hz, JH,H¼5.3 Hz, JH,H¼1.3 Hz, CH2O), 5.09–5.17
(m, 12H, CH2vCH), 5.80–5.95 (m, 6H, CH2vCH); 13C
NMR (125.7 MHz, CDCl3) d 58.8 (C-6), 60.8 (C-1), 61.1
(C-60), 61.4 (C-10), 72.1 (C-50), 73.7 (C-30), 74.1 (C-5), 70.4,
70.9, 71.4, 71.6, 72.6, 74.6 (6CH2O), 76.2 (C-4), 77.6 (C-3,
C-40), 94.3 (C-20), 95.8 (C-2), 116.8, 116.9, 117.0, 117.2,
117.3, 117.4 (6CHvCH2), 134.5, 134.9, 135.0, 135.1,
135.2, 135.3 (6CHvCH2). Anal. Calcd for C30H44O10: C,
63.81; H, 7.85; found: C, 63.98; H, 7.90.
3.2.8. 3,4,5,30,40,50-Hexa-O-allyl-di-b-D-fructopyranose
1,20:2,10-dianhydride (7b). Rf¼0.50 (1:2 EtOAc–petro-
leum ether); [a]D¼2138.1 (c 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3) d 3.58 (d, 2H, J3,4¼9.8 Hz, H-3), 3.60
(d, 2H, J1a,1b¼11.8 Hz, H-1a), 3.68 (dd, 2H, J6a,6b¼13.2 Hz,
J5,6a¼1.9 Hz, H-6a), 3.72 (m, 2H, H-5), 3.73 (dd, H, J5,6b
¼
1.9 Hz, H-6b), 3.81 (d, 2H, J4,5¼3.1 Hz, H-4), 4.00 (d, 2H,
2
H-1b), 4.09–4.18 (m, 11H, CH2O), 4.35 (ddt, 1H, JH,H
¼
3.2.12. 3,4,5-Tri-O-benzoyl-a-D-fructopyranose 3,4,5-
tri-O-benzoyl-b-D-fructopyranose 1,20:2,10-dianhydride
(8c). Rf¼0.31 (1:2 EtOAc–petroleum ether); [a]D¼
2119.4 (c 0.6, CHCl3); 1H NMR (500 MHz, CDCl3) d
3
4
12.4 Hz, JH,H¼2.5 Hz, JH,H¼1.3 Hz, CH2O), 5.08–5.31
(m, 12H, CH2vCH), 5.85–5.97 (m, 6H, CH2vCH); 13C
NMR (125.7 MHz, CDCl3) d 61.6 (C-6), 64.5 (C-1), 71.0,
71.2, 74.0 (CH2O), 73.8 (C-5), 77.8 (C-4), 78.7 (C-3), 97.0
(C-2), 116.7, 116.8, 117.3 (CHvCH2), 135.1, 135.2, 135.3
(CHvCH2). Anal. Calcd for C30H44O10: C, 63.81; H, 7.85;
found: C, 63.81; H, 7.88.
3.83 (d, 1H, J1 a,1 b¼11.7 Hz, H-10a), 3.89 (dd, 1H, J5,6a
¼
0
0
5.9 Hz, J6a,6b¼11.1 Hz, H-6a), 3.93 (d, 1H, J1a,1b¼11.5 Hz,
H-1a), 3.95 (d, 1H, H-1b), 4.08 (d, 1H, H-10b), 4.10 (m, 2H,
H-60a, H-60b), 4.13 (dd, 1H, J5,6b¼10.6 Hz, H-6b), 5.56 (d,
1H, J3,4¼3.7 Hz, H-3), 5.61 (ddd, 1H, J4,5¼3.3 Hz, H-5),
3.2.9. 3,4,5,30,40,50-Hexa-O-benzoyl-di-b-D-fructopyra-
nose 1,20:2,10-dianhydride (7c). Rf¼0.31 (1:2 EtOAc–
5.73 (m, 1H, H-50), 5.76 (d, 1H, J3 ,4 ¼10.5 Hz, H-3 ), 5.87
(dd, 1H, J4,5¼3.0 Hz, H-4), 7.22–8.15 (m, 30H, Ph); 13C
NMR (125.7 MHz, CDCl3) d 58.9 (C-60), 60.6 (C-6), 61.2
(C-1), 61.3 (C-10), 72.3 (C-50), 73.7 (C-4), 73.9 (C-3), 76.1
0
0
0
1
petroleum ether); [a]D¼2226.5 (c 0.38, CHCl3); H NMR
(500 MHz, CDCl3) d 3.84 (d, 2H, J1a,1b¼12.6 Hz, H-1a),

5906
J. M. Benito et al. / Tetrahedron 60 (2004) 5899–5906
(C-30), 77.6 (C-5), 78.3 (C-40), 94.5 (C-20), 95.8 (C-2),
128.1–133.6 (Ph), 164.4–171.7 (CO); FABMS: m/z 971
(100%, [MþNa]þ).
´ ´
20. Garcıa Fernandez, J. M.; Gadelle, A.; Defaye, J. Carbohydr.
Res. 1994, 265, 249–269.
´ ´
21. Defaye, J.; Garcıa Fernandez, J. M. Tetrahedron: Asymmetry
1994, 5, 2241–2250.
22. Li, X.; Takahashi, H.; Ohtake, H.; Shiro, M.; Ikegami, S.
Tetrahedron 2001, 57, 8053–8066.
Acknowledgements
23. Dondoni, A.; Marra, A.; Schermann, M.-C.; Bertolasi, V.
Chem. Eur. J. 2001, 7, 1371–1382.
´ ´
24. Garcıa Fernandez, J. M.; Ortiz Mellet, C.; Defaye, J. J. Org.
´
We thank the Spanish Ministerio de Ciencia y Tecnologıa
for financial support (contracts number BQU2003-00937
and BCM2001-2366-CO3-03). E. R. thanks the CSIC and
the Institut fu¨r Technologie der Kohlenhydrate e. V. for a
fellowship.
Chem. 1998, 63, 3572–3580.
¨ ¨
25. Bextermoller, R.; Redlich, H.; Schnieders, K.; Thrmahlen, S.;
¨
Frolich, R. Angew. Chem., Int. Ed. 1998, 37, 2496–2500.
26. Jang, K.-H.; Ryu, E.-J.; Park, B.-S.; Song, K.-B.; Kang, S.;
Kim, C. H.; Uhm, T.-B.; Park, Y.-I.; Rhee, S.-K. J. Agric.
Food Chem. 2003, 51, 2632–2636.
´ ´
27. Garcıa Fernandez, J. M.; Schnelle, R.-R.; Defaye, J. Aust.
J. Chem. 1996, 49, 319–325.
References and notes
´
28. Defaye, J.; Garcıa Fernandez, J. M. Carbohydr. Res. 1994,
´
1. Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617–1661.
2. Imanishi, T.; Iwata, C. Studies in Natural Products Chemistry;
Atta-ur-Rahman,, Ed.; Elsevier: Amsterdam, 1996; Vol. 18,
pp 517–550.
256, C1–C4.
29. Defaye, J.; Garcıa Fernandez, J. M. Zuckerindustrie 1995, 120,
´
´
700.
30. Manley-Harris, M.; Richards, G. N. Carbohydr. Res. 1996,
287, 183–202.
´ ´
31. Ratsimba, V.; Garcıa Fernandez, J. M.; Defaye, J.; Nigay, H.;
Voilley, A. J. Chromatogr. A 1999, 884, 283–293.
3. Ichiara, A.; Oikawa, H.; Toshima, H. Studies in Natural
Products Chemistry; Atta-ur-Rahman,, Ed.; Elsevier:
Amsterdam, 1996; Vol. 18, pp 269–313.
4. Pietruszka, J. Angew. Chem., Int. Ed. 1998, 37, 2629–2636.
5. Mead, K. T.; Brewer, B. N. Curr. Org. Chem. 2003, 7,
227–256.
`
32. Brimble, M. A.; Fares, F. A. Tetrahedron 1999, 55,
7661–7706, and references therein.
33. Carter, R. G.; Graves, D. E.; Gronemeyer, M. A.; Tschumper,
G. S. Org. Lett. 2002, 4, 2181–2184.
6. Zanatta, S. D.; White, J. M.; Rizzacasa, M. A. Org. Lett. 2004,
6, 1041–1044.
7. Yin, B.-L.; Hu, T.-S.; Yue, H.-J.; Gao, Y.; Wu, W.-M.; Wu,
Y.-L. Synlett 2004, 306–310.
34. McGrarvey, G. J.; Stepanian, M. W.; Bressette, A. R.; Sabat,
M. Org. Lett. 2002, 4, 3453–3456.
8. Hubbs, J. L.; Heathcock, C. H. J. Am. Chem. Soc. 2003, 125,
12836–12843.
35. Bock, K.; Pedersen, C.; Defaye, J.; Gadelle, A. Carbohydr.
Res. 1991, 216, 141–148.
´ ´
36. Defaye, J.; Garcıa Fernandez, J. M. Carbohydr. Res. 1994,
9. Tsang, K. Y.; Brimble, M. A.; Bremner, J. B. Org. Lett. 2003,
5, 4425–4427.
251, 1–15.
37. Defaye, J.; Garcıa Fernandez, J. M. Carbohydr. Res. 1994,
´
´
10. Gaunt, M. J.; Jessiman, A. S.; Orsini, P.; Tanner, H. R.; Hook,
D. F.; Ley, S. V. Org. Lett. 2003, 5, 4819–4822.
´ ´ ´ ´
11. Betancor, C.; Freire, R.; Perez-Martın, I.; Prange, T.; Suarez,
251, 17–31.
38. Defaye, J.; Garcıa Fernandez, J. M. Carbohydr. Res. 1992,
237, 223–247.
´
´
E. Org. Lett. 2002, 4, 1295–1297.
12. Crimmins, M. T.; Katz, J. D.; Washburn, D. G.; Allwein, S. P.;
McAtee, L. F. J. Am. Chem. Soc. 2002, 124, 5661–5663.
´
13. Izquierdo, I.; Plaza, M. T.; Rodrıguez, M.; Tamayo, J. A. Eur.
J. Org. Chem. 2002, 309–317.
´ ´
39. Garcıa Fernandez, J. M.; Schnelle, R.-R.; Defaye, J.
Tetrahedrom: Asymmetry 1995, 6, 307–312.
´ ´ ´
40. Benito, J. M.; Gomez-Garcıa, M.; Ortiz Mellet, C.; Garcıa
´
Fernandez, J. M.; Defaye, J. Org. Lett. 2001, 3, 549–552.
´ ´
41. Rubio, E. M.; Ortiz Mellet, C.; Garcıa Fernandez, J. M.;
14. Manley-Harris, M.; Richards, G. N. Adv. Carbohydr. Chem.
Biochem. 1997, 52, 207–266.
Defaye, J. Org. Lett. 2003, 5, 873–876.
42. Chittenden, G. J. F. J. Chem. Soc., Chem. Commun. 1980,
882–883.
15. Matsuyama, T.; Tanaka, K.; Uchiyama, T. Agric. Biol. Chem.
1991, 55, 1413–1414, and references therein.
16. Li, H.; Zhu, W.; Yokoyama, C.; Harada, N. Carbohydr. Res.
1997, 299, 301–305.
43. Ishihara, K. Lewis Acids in Organic Synthesis; Yamamoto, H.,
Ed.; Wiley: Weinheim, 2000; Vol. 1, pp 89–133.
44. Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503–1531.
45. Campbell, M. M.; Heffernan, G. D.; Lewis, T. Carbohydr. Res.
1994, 251, 243–250.
17. Uchiyama, T. In Science and Technology of Fructans; Suzuki,
M., Chatterton, N. J., Eds.; CRC: Boca Raton, FL, 1993;
pp 170–190.
18. Manley-Harris, M.; Richards, G. N. Zuckerindustrie 1994,
119, 924–928.
46. Brady, Jr. R. F. Adv. Carbohydr. Chem. Biochem. 1971, 26,
197–278.
19. Tanaka, M.; Nakajima, Y.; Nisio, K. J. Carbohydr. Chem.
1993, 12, 49–61.
47. Zhao, W.; Yang, G.; Kong, F. Carbohydr. Res. 2003, 338,
2813–2823.