Stereoselective synthesis of nonsymmetrical difructose dianhydrides from xylylene-tethered d-fructose precursors

Article abstract of DOI:10.1016/j.tet.2008.01.054

Nonsymmetrical furanose-pyranose difructose dianhydrides (DFAs), a class of cyclic disaccharides present in foodstuffs, have been prepared in high yield by connecting the reacting monosaccharide moieties through a xylylene bridge prior to triflic acid-pro

Full text of DOI:10.1016/j.tet.2008.01.054

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2792e2800
www.elsevier.com/locate/tet
Stereoselective synthesis of nonsymmetrical difructose dianhydrides
from xylylene-tethered D-fructose precursors
a,y
a
Farida Louis , M. Isabel Garcıa-Moreno , Patricia Balbuena , Carmen Ortiz Mellet
a
a,
*
´
Jose M. Garcıa Fernandez
,
b,
*
´
´
´
a Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad de Sevilla, Profesor Garc´ıa Gonza´lez 1, E-41012 Sevilla, Spain
b Instituto de Investigaciones Qu´ımicas, CSICdUniversidad de Sevilla, Ame´rico Vespucio 49, Isla de la Cartuja, E-41092 Sevilla, Spain
Received 12 November 2007; received in revised form 31 December 2007; accepted 10 January 2008
Available online 16 January 2008
Abstract
Nonsymmetrical furanoseepyranose difructose dianhydrides (DFAs), a class of cyclic disaccharides present in foodstuffs, have been prepared
in high yield by connecting the reacting monosaccharide moieties through a xylylene bridge prior to triflic acid-promoted bis-spiroketalization.
The reaction can then proceed either intra- or intermolecularly, both the regio- and the stereoselectivity being strongly dependent on the spacer
length. Noteworthy, the longer m- and p-xylylene positional isomers led to the thermodynamic a-D-fructofuranose b-D-fructopyranose
1,20:2,10-dyanhydride 1, the major DFA in commercial caramel, in a stereoselective manner. The shorter o-xylylene tether afforded preferentially
the elusive contra-thermodynamic b-D-fructofuranose a-D-fructopyranose diastereomer 2, a trace constituent of caramel. The results have been
rationalized in terms of stereoelectronic and conformational properties and offer new perspectives for the preparation of pure DFA standards for
analytical and nutritional studies.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Spiroketals; Difructose dianhydrides; Fructose; Prebiotics; Xylylene; Spiro-sugars
1. Introduction
diastereoisomers are formed during the acid or thermal-pro-
moted dimerizationespiroketalization of fructose-containing
materials (sucrose, glycosyl fructoses, inulin), being present
in dietary foods such as caramel, chicory, fructose syrups, or tor-
refacted coffee.3 The implications of this discovery in human
nutrition have strongly stimulated research in these and related
spiro-sugars.4
The structural and stereochemical diversity of DFAs makes
these compounds ideal targets for evaluating new spiroketal
synthetic methodologies. Almost quantitative conversions of
D-fructose and oligosaccharides thereof into DFAs have been
achieved by using anhydrous hydrogen fluoride (HF) or pyri-
dinium poly(hydrogen fluoride) complexes as solvents and
catalysts.5 Separation of pure compounds from these multi-
component mixtures becomes, however, extremely difficult,
making this approach unsuitable for the preparation of single
isomers in most cases.
The stereocontrolled construction of polyfunctional tricyclic
bis-spiroketals, especially the control of the stereochemistry at
the two spiroketal centers, continues to present a stimulating
challenge in target and diversity oriented synthesis.1 This sub-
structure is present in a wide range of interesting natural prod-
ucts, including several marine toxins and ionophore antibiotics,
and is also the underlying structural element of a unique class of
spirodisaccharides isolated from microorganisms and higher
plants recently identified as prebiotic food products, namely
di-D-fructose dianhydrides (DFAs).2 Up to 13 different DFA
* Corresponding authors. Tel.: þ34 954551519; fax: þ34 954624960
(C.O.M.); tel.: þ34 954489559; fax: þ34 954460565 (J.M.G.F.).
E-mail addresses: mellet@us.es (C.O. Mellet), jogarcia@iiq.csic.es (J.M.
´
´
Gyarcıa Fernandez).
Fueled by the need of pure DFA standards for the investiga-
tion of their impact in the human diet,6 we recently developed
Present address: Department of Chemistry, Faculty of Sciences, University
of Alexandria, PO Box 426, Ibrahimia, 21321 Alexandria, Egypt.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.054

F. Louis et al. / Tetrahedron 64 (2008) 2792e2800
2793
a new strategy for the stereoselective synthesis of DFAs based
on the insertion of an appropriate spacer between the reacting
fructose moieties.7 The methodology takes advantage of the
conformational differences at the central 1,4-dioxane ring
(chair or boat) in DFA diastereomers as a function of the rel-
ative stereochemistry at the spiroketal centers and proved very
successful for accessing difuranose (type I) and dipyranose
(type III) DFAs (Fig. 1, n¼m¼1 or 2, respectively).
spiroketal centers is discussed and rationalized in terms of
stereoelectronic and conformational properties.
2. Results and discussion
2.1. Synthesis of xylylene-tethered D-fructose precursors
In order to install the xylylene tether between ring-size an-
chored D-fructopyranose and D-fructofuranose scaffolds, the
reaction sequence depicted in Scheme 1 was implemented.11
(R,S) or (S,R)
O
(R,R) or (S,S)
HO
OH
HO
O
H+
O
O
n
O
m
n
O
O
O
O
O
mOH
O
OH
"boat" DFAs
O
"chair" DFAs
O
O
NaH
DMF
O
O
O
Figure 1. Preferred conformations of bis-spiroketal difructose dianhydrides as
a function of the relative configuration at the spiroketal centers.
5
O
O
Br
AcOH-H2O
(70%)
Br
Br
meta: 9
para: 10
ortho: 11
The situation is much more complicated in the case of fur-
anoseepyranose (n¼1, m¼2 in Fig. 1; type II) DFAs. The four
diastereomeric possibilities are encountered in food products
in this case, namely the a,b-, b,a-, di-a-, and di-b-1,20:2,10-
dianhydrides (1e4; Fig. 2).8 Examination of the interatomic
distances in 3D molecular models suggested that the chair
compounds 1 (thermodynamic) and 2 (contra-thermody-
namic9) could be obtained selectively by restraining the dis-
tance between positions O-6 and O-30 in appropriately
tethered furanoseepyranose precursors.
meta: 6
para: 7
ortho: 8
O
O
NaH, BnBr, DFM
(m or p; 65%)
O
O
ref. 14 (o)
OH
HO
O
meta: 12
para: 13
ortho: 14
O
O
O
Br
OBn
BnO
OH
O
O
meta: 15
para: 16
ortho: 17
O
Br
BnO
(51-62%)
OBn
NaH
DMF
18
O
O
OH
6
O
O
O
6.0 Å
HO
OH
5.5 Å
1'
O
6
OBn
BnO
O
5
O
O
5
HO
2
HO
O
2
4
HO
O
4'
BnO
OBn
1
3'
O
O
2'
3
4
OH
3'
HO
OH
meta: 19
para: 20
ortho: 21
2'
6'
1
3
O
5'
1'
O
4'
HO
6'
OH
OH
O
5'
1 (α,β)
2 (β,α)
chair conformers
Scheme 1. Tethering reaction sequence for fructofuranoseefructopyranose
derivatives.
OH
OH
O
8.0 Å
Etherification of 1,2:4,5-di-O-isopropylidene-b-D-fructo-
pyranose12 (5) by reaction with excess of commercial a,a0-
dibromoxylene (6e8) afforded the corresponding monobro-
mobenzyl derivatives 9e11. The meta and para positional
isomers 9 and 10 were transformed into the 4,5-di-O-benzyl
derivatives 15 and 16, respectively, through a two-step reac-
tion sequence that involved selective hydrolysis of the nonano-
meric isopropylidene group with aq acetic acid (/12 and 13)
and conventional benzylation with excess of benzyl bromide.
The ortho isomer 14 affords a cyclic 3,4-O-(o-xylylene) deriva-
tive, resulting from intramolecular etherification reaction,
under these conditions.13 Preparation of the requested bromo-
benzyl-armed derivative 17 was achieved after transient
replacement of the bromo group by chloro following a previ-
ously reported procedure.7a Nucleophilic displacement of the
halogen atom by 3,4-di-O-benzyl-1,2-O-isopropylidene-b-
D-fructofuranose14 (18) provided the target xylylene-bridged
precursors 19e21.
8.1 Å
O
OH
HO
HO
O
OH
HO
HO
O
O
OH
OH
OH
O
O
O
HO
3 (β,β)
4 (α,α)
boat conformers
Figure 2. Conformations of the different type II DFA diastereomers with indi-
cation of the O-6eO-30 interatomic distance.
Preliminary results supported the above hypothesis and in-
dicated the possibility of further discriminating between both
chair isomers by using xylylene positional isomers as distance
restriction elements.10 We now report the synthesis of the
whole series of m-, p-, and o-xylylene-tethered fructose pre-
cursors and a complete comparative study of their reactivity.
The structure and relative proportions of the products resulting
from intra- and intermolecular spiroketalization, as well as the
influence of the tether in the stereochemistry at the new

2794
F. Louis et al. / Tetrahedron 64 (2008) 2792e2800
19-21
2.2. Synthesis of fructofuranoseefructopyranose bis-
spiroacetals (type II DFAs)
TfOH,
62-78%
(see Table)
CH2Cl2
Activation of the xylylene-tethered fructofuranoseefructo-
pyranose derivatives 19 and 20 with trifluoromethanesulfonic
acid (TfOH) in dichloromethane promoted the tandem isopro-
pylidene cleavageeglycosylationespiroketalization transfor-
mation. In both cases the intramolecular process led to
a single bis-spiroacetal, namely the thermodynamic a,b type
II DFA derivative 22 or 24, respectively. Intermolecular spiro-
cyclization, leading to oligomeric material, was an expected
competing reaction. Double bis-spirocyclization leading to
macrocyclic dimers was strongly favored as compared to the
formation of linear or higher order cyclic oligomers, as seen
from mass spectrometry data. The corresponding C2-symmet-
ric bis-a,b diastereomer 23 or 25 was by far the major com-
pound in this fraction, which is in agreement with the high
thermodynamic stability of the a-D-fructofuranose b-D-fructo-
pyranose 1,20:2,10-dianhydride basic structure. In fact, the first
bis-spiroacetal formed in the intermolecular reaction acts as
a tether-like template to control the stereochemical issues of
the next intramolecular bis-spirocyclization process during
macrocyclic ring formation,15 which further favors the forma-
tion of the C2-symmetric derivative. Not surprisingly, the more
rigid p-xylylene bridge resulted in higher macrocyclization
rates. Nevertheless, simultaneous removal of the xylylene
spacer and the benzyl protecting groups could be accom-
plished in quantitative yield by catalytic hydrogenolysis in
both the intramolecular (22 and 24) and the intermolecular
derivatives (23 or 25), leading exclusively to the fully unpro-
tected thermodynamic DFA 1. Combining these fractions to-
gether, the methodology allows accessing 1 (18% in the
DFA fraction of commercial caramels) in 71 and 58% yields,
respectively, with 100% de (Scheme 2).
O
O
O
OBn
OBn
O
OBn
O
O
O
O
+
OBn
O
O
BnO
OBn
O O
BnO
OBn
OBn
α,β
β,α
meta: 22
para: 24
ortho: 26
H2/Pd
100%
H2/Pd
99%
2
1
ortho: 27
BnO
O
O
O
BnO
O
O
BnO
O
isomeric cyclic
dimers
+
+
O
O
OBn
OBn
O
O
O O
BnO
OBn
bis- α,β
meta: 23
para: 25
ortho: 28
H2/Pd
99%
1
Starting
material
Products (%)
isomeric cyclic
dimers
α,β
β,α
bis-α,β
(10)
(14)
(6)
19
20
22 (59)
24 (25)
n.d.
n.d.
23 (12)
25 (33)
26 (30)
27 (42)
21
28 (7)
Scheme 2. Stereoselective synthesis of type II DFAs.
We hypothesized that shortening the O-6eO-30 distance in
˚
1 and 2 (5.5e6.0 A; Fig. 2), by inserting an o-xylylene tether
1
and 2, is remarkable. Examination of the H NMR data re-
˚
(w3 A), would provoke a substantial steric constrain in their
chair ground state conformation upon intramolecular spiro-
cyclization. This situation should be better accommodated
by the less rigid contra-thermodynamic b,a isomer 2. Actu-
ally, the thermodynamic (a,b) and contra-thermodynamic
(b,a) DFA diastereomers 26 and 27 were now formed in
1:1.5 relative proportion, which represents a 90-fold increase
in the selectivity toward the contra-thermodynamic structure
as compared with the thermodynamic equilibrium for the un-
protected bis-spiroacetals 1 and 2 (the 1/2 relative proportion
reaches 60:1 after thermodynamic equilibration). Compound 2
(less than 1% in commercial caramel) was obtained in quan-
titative yield by hydrogenolysis of 27. No significant differ-
ences were observed, however, in the composition of the
dimer fraction as a function of the xylylene positional isomer,
the bis-a,b macrocycle 28 being the privileged structure
(Scheme 2).
vealed that the o-xylylene-tethered a,b-derivative 26 keeps
the same conformation at the six-membered rings as compared
with the m- or p-positional isomers 22 and 24 or the unpro-
tected derivative 1, that is, the central 1,4-dioxane ring in chair
2
conformation and the fructopyranose ring in the C5 confor-
mation. Partial steric release can only be achieved at the
expenses of conformational distortion of the furanose ring.
In contrast, the vicinal protoneproton coupling constants
around the a-fructopyranose ring in 27 evidenced a profound
conformational change as compared with reported data for
DFAs incorporating this structural subunit, including 2.
Thus, the presence of the o-xylylene bridge provokes the flip
5
0
0
of the C2 conformation (J3 ,4 ¼3.2 Hz for 2) to the reverse
2C5 disposition (J3 ,4 ¼7.9 Hz for 27). Simultaneously, the
central 1,4-dioxane ring shifts to a skeweboat arrangement,
as seen by NOE contacts, thereby bringing closer the
0
0
˚
0
The switch in the stereochemical outcome of the spirocyc-
lization process by acting on the spacer length, in spite of the
almost identical interatomic distances between the concerned
oxygens in the ground state of both diastereomeric DFAs 1
bridged positions (dO-6eO-3 ¼3.2 A). The energetic cost of
loosing an anomeric effect stabilization is then overcome by
the release in the steric constrain imposed by the spacer
(Fig. 3).

F. Louis et al. / Tetrahedron 64 (2008) 2792e2800
2795
for water (1e4) or chloroform (27). 1,2:4,5-Di-O-isopropyl-
idene-b-D-fructopyranose (5), 3,4-di-O-benzyl-1,2-O-isopro-
pylidene-b-D-fructofuranose7a (18), and 4,5-di-O-benzyl-3-O-
(2-bromomethylbenzyl)-1,2-O-isopropylidene-b-D-fructopyra-
nose14 (17) were prepared according to described procedures.
3.2 Å
O
O
O
O
H
J
3',4' = 7.4 Hz
O
H
O
OBn
BnO
H
OBn
H
BnO
2
C
NOE
5
4.2. 3-O-(3-Bromomethylbenzyl)-1,2:4,5-di-O-
isopropylidene-b-D-fructopyranose (9)
27 (β,α)
Figure 3. Conformation of 27 as determined by NMR in chloroform-d solution
with indication of diagnostic data.
To a solution of 1,3-bis(bromomethyl)benzene (6, 1.99 g,
7.56 mmol, 2 equiv) in dry DMF (50 mL), NaH (60% in mineral
oil, 378 mg, 9.45 mmol) was added and the suspension was
stirred at room temperature for 15 min. 1,2:4,5-Di-O-isopropyl-
idene-b-D-fructopyranose (5, 1.0 g, 3.78 mmol) was then added
and the reaction mixture was further stirred for 24 h. Et2O
(15 mL) and water (15 mL) were added, the organic layer was
separated, washed with water (5ꢂ10 mL), dried (MgSO4), fil-
tered, and concentrated. The resulting residue was purified by
column chromatography (1:10 EtOAcepetroleum ether) to
yield 9 (955 mg, 57%); Rf¼0.56 (1:3 EtOAcepetroleum ether);
[a]D ꢁ88.1 (c 1.0, CH2Cl2); IR: nmax¼3030, 2986, 1512, 1454,
1375, 1217, 1080, 885, 698 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d¼7.40e7.26 (m, 4H, Ph), 4.97, 4.65 (2d, 2H, 2JH,H¼12.1 Hz,
CHPh), 4.48 (s, 2H, CH2Br), 4.38 (dd, 1H, J3,4¼7.3 Hz,
J4,5¼6.0 Hz, H-4), 4.22 (dd, 1H, J5,6a¼2.6 Hz, H-5), 4.15
(dd, 1H, J6a,6b¼13.4 Hz, H-6a), 4.10 (d, 1H, J1a,1b¼8.5 Hz,
H-1a), 4.00 (d, 1H, H-6b), 3.91 (d, 1H, H-1b), 3.49 (d, 1H,
H-3), 1.54, 1.50, 1.43, 1.38 (4s, 12H, CMe2); 13C NMR
(125.7 MHz, CDCl3): d¼139.0e127.5 (Ph), 112.2, 109.0
(CMe2), 104.3 (C-2), 77.7 (C-4), 76.2 (CH2Ph), 73.8 (C-5),
72.5 (C-1), 71.9 (C-3), 60.1 (C-6), 33.3 (CH2Br), 28.2, 26.8,
26.2, 26.0 (CMe2); FABMS: m/z 445, 443 (20%, [MþH]þ).
Anal. Calcd for C20H27BrO6: C, 54.18; H, 6.14. Found: C,
54.26; H, 6.03.
3. Summary and conclusions
In summary, the above results broaden the concept of rigid
spacer-mediated spirocyclization by taking advantage not only
of distance restrictions but also of subtle molecular flexibility
differences. Limiting the conformational space during the in-
tramolecular reaction leading to the bis-spiroketal framework,
by judicious choice of the spacer and of the linking positions
on the reactive subunits, allows discrimination between DFA
diastereomers depending on their chair or boat ground state
conformation. By additionally introducing steric constrains,
the more flexible contra-thermodynamic structures are privi-
leged. The combination of both aspects provides alternative
opportunities for the preparation of complex bis-spiroketal
frameworks, as illustrated by the rational design of stereose-
lective syntheses for the nonsymmetrical difructose dianhy-
drides 1 and 2.
4. Experimental
4.1. General methods
All solvents and reagents were purchased from commercial
sources and used without further purification, except for di-
chloromethane, which was distilled under Ar stream over
CaH2 and DMF, which was dried over BaO, distilled and kept
4.3. 3-O-(4-Bromomethylbenzyl)-1,2:4,5-di-O-
˚
over 4 A molecular sieves. Optical rotations were measured at
isopropylidene-b-D-fructopyranose (10)
20 ꢀC in 1-cm or 1-dm tubes. IR spectra were recorded on an
FTIR. 1H (and 13C NMR) spectra were recorded at 500
(125.7) or 300 (75.5) MHz. 2D COSY, 2D NOESY, 1D TOCSY,
HMQC, and HSQC experiments were used to assist on NMR as-
signments. Thin-layer chromatography (TLC) was carried out
on aluminum sheets coated with Kieselgel 60 F254 (E. Merck),
with visualization by UV light and by charring with 10% H2SO4.
The operating conditions for FAB mass spectra were the follow-
ing: 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 po-
tential of 7 keV; NaI was added as cationizing agent. For ESI
mass spectra, 0.1 pM sample concentrations were used, the
Compound 10 (402 mg, 48%) was obtained from 5 (0.5 g,
1.89 mmol) and 1,4-bis(bromomethyl)benzene (7, 1.06 g,
7.56 mmol) following the procedure above described for 9;
Rf¼0.42 (1:3 EtOAcepetroleum ether); [a]D ꢁ68.0 (c 1.0,
CH2Cl2); IR: nmax¼3035, 2986, 1651, 1514, 1454, 1379, 1219,
1
1090, 874 cmꢁ1; H NMR (500 MHz, CDCl3): d¼7.37e7.26
2
(m, 4H, Ph), 4.96, 4.65 (2d, 2H, JH,H¼12.1 Hz, CHPh), 4.49
(s, 2H, CH2Br), 4.37 (dd, 1H, J3,4¼7.5 Hz, J4,5¼6.0 Hz, H-4),
4.22 (dd, 1H, J5,6a¼2.5 Hz, H-5), 4.14 (dd, 1H, J6a,6b¼13.5 Hz,
H-6a), 4.08 (d, 1H, J1a,1b¼8.5 Hz, H-1a), 4.00 (d, 1H, H-6b),
3.90 (d, 1H, H-1b), 3.49 (d, 1H, H-3), 1.53, 1.49, 1.41, 1.38
(4s, 12H, CMe2); 13C NMR (125.7 MHz, CDCl3): d¼138.9e
127.8 (Ph), 112.2, 109.0 (CMe2), 104.3 (C-2), 77.6 (C-4), 76.3
(CH2Ph), 73.7 (C-5), 72.5 (C-1), 71.9 (C-3), 60.1 (C-6), 33.2
(CH2Br), 28.1, 26.8, 26.1, 26.0 (CMe2); FABMS: m/z 467, 465
(20%, [MþNa]þ). Anal. Calcd for C20H27BrO6: C, 54.18; H,
6.14. Found: C, 54.14; H, 6.16.
mobile phase consisting of 50% aq acetonitrile at 0.1 L minꢁ1
Elemental analyses were performed at the Instituto de
.
´
Investigaciones Quımicas (Sevilla, Spain). Calculations were
performed with the MACROMODEL 6.0 package using the
MM2* force field and the GB/SA continuous solvent model

2796
F. Louis et al. / Tetrahedron 64 (2008) 2792e2800
4.4. 3-O-(3-Bromomethylbenzyl)-1,2-O-isopropylidene-b-D-
fructopyranose (12)
EtOAcepetroleum ether) to give 15 (303 mg, 65%); Rf¼0.57
(1:3 EtOAcepetroleum ether); [a]D ꢁ9.9 (c 1.0, CH2Cl2); IR:
nmax¼3030, 2986, 1645, 1516, 1366, 1244, 1072, 748,
Compound 9 (400 mg, 0.9 mmol) was dissolved in 60% aq
acetic acid (2.4 mL) and stirred at 45 ꢀC for 2 h. The reaction
mixture was then diluted with water (5 mL) and extracted
with EtOAc (4ꢂ4 mL). The combined organic phase was
washed with saturated aq NaHCO3 (6 mL), dried (MgSO4), fil-
tered, and concentrated. The resulting residue was purified by
column chromatography (2:1 EtOAcepetroleum ether) to give
12 (254 mg, 70%); Rf¼0.44 (2:1 EtOAcepetroleum ether);
[a]D ꢁ81.4 (c 0.98, CH2Cl2); IR: nmax¼3428, 2936, 1458,
698 cmꢁ1
;
1H NMR (500 MHz, CDCl3): d¼7.31e7.23 (m,
14H, Ph), 5.01, 4.63 (2d, 2H, 2JH,H¼11.7 Hz, CHPh), 4.74, 4.68
(2d,2H, 2JH,H¼12.5 Hz, CHPh), 4.59(s, 2H, CH2Ph), 4.43(s, 2H,
CH2Br), 4.01 (d, 1H, J1a,1b¼8.5 Hz, H-1a), 3.97 (d, 1H, H-1b),
3.92 (dd, 1H, J3,4¼9.8 Hz, J4,5¼2.1 Hz, H-4), 3.90 (d, 1H, H-3),
3.81 (m, 1H, H-5), 3.80 (dd, 1H, J6a,6b¼13.0 Hz, J5,6a¼1.9 Hz,
H-6a), 3.75 (dd, 1H, J5,6b¼1.4 Hz, H-6b), 1.47, 1.42 (2s, 6H,
CMe2); 13C NMR (127.5 MHz, CDCl3): d¼139.3e127.6 (Ph),
111.9 (CMe2), 105.9 (C-2), 80.1 (C-4), 75.5 (C-3), 74.9
(CH2Ph), 73.3 (C-5), 72.0 (C-1), 71.9, 71.5 (CH2Ph), 61.3 (C-
6), 33.5 (CH2Br), 27.1, 26.3 (CMe2); FABMS: m/z 607, 605
(35%, [MþNa]þ), 527 (25%, [MþNaꢁBr]þ). Anal. Calcd for
C31H35BrO6: C, 63.81; H, 6.05. Found: C, 63.80; H, 5.84.
1379, 1220, 1077, 887, 690 cmꢁ1 1H NMR (500 MHz,
;
CDCl3): d¼7.42e7.26 (m, 4H, Ph), 4.83, 4.73 (2d, 2H,
2JH,H¼11.6 Hz, CHPh), 4.48 (s, 2H, CH2Br), 4.06 (d, 1H,
J1a,1b¼8.7 Hz, H-1a), 4.03 (dd, 1H, J3,4¼9.5 Hz, J4,5¼5.0 Hz,
H-4), 3.99 (d, 1H, H-1b), 3.98 (m, 1H, H-5), 3.96 (d, 1H,
J6a,6b¼12.4 Hz, H-6a), 3.77 (dd, 1H, J5,6b¼1.5 Hz, H-6b),
3.67 (d, 1H, H-3), 2.58, 2.52 (2br s, 2H, 2OH), 1.49, 1.44 (2s,
6H, CMe2); 13C NMR (125.7 MHz, CDCl3): d¼138.7e127.7
(Ph), 111.9 (CMe2), 105.5 (C-2), 76.6 (C-3), 74.8 (CH2Ph),
71.8 (C-1), 71.3 (C-4), 69.7 (C-5), 63.6 (C-6), 33.2 (CH2Br),
26.7, 26.2 (CMe2); FABMS: m/z 427, 425 (90%, [MþNa]þ),
347 (95%, [MþNaꢁBr]þ). Anal. Calcd for C17H23BrO6: C,
50.63; H, 5.75. Found: C, 50.69; H, 5.67.
4.7. 4,5-Di-O-benzyl-3-O-(4-bromomethylbenzyl)-1,2-O-
isopropylidene-b-D-fructopyranose (16)
Compound 16 (204 mg, 65%) was obtained from 13
(203 mg, 0.50 mmol) following the procedure above described
for 15; Rf¼0.26 (1:3 EtOAcepetroleum ether); [a]D ꢁ106.5
(c 1.0, CH2Cl2); IR: nmax¼3030, 2988, 1645, 1516, 1454,
1
1370, 1223, 1072, 880 cmꢁ1; H NMR (300 MHz, CDCl3):
d¼7.40e7.26 (m, 14H, Ph), 5.04, 4.66 (2d, 2H, 2JH,H¼11.8 Hz,
CHPh), 4.77, 4.70 (2d, 2H, 2JH,H¼12.0 Hz, CHPh), 4.61 (s, 2H,
CH2Ph), 4.50 (s, 2H, CH2Br), 4.02 (d, 1H, J1a,1b¼8.5 Hz, H-1a),
3.98 (d, 1H, H-1b), 3.94 (m, 1H, H-4), 3.90 (d, 1H, J3,4¼9.5 Hz,
H-3), 3.82 (dd, 1H, J6a,6b¼13.0 Hz, J5,6a¼2.0 Hz, H-6a), 3.78
(m, 1H, H-5), 3.76 (dd, 1H, J5,6b¼1.7 Hz, H-6b), 1.49, 1.43
(2s, 6H, CMe2); 13C NMR (75.5 MHz, CDCl3): d¼138.9e
127.4 (Ph), 111.7 (CMe2), 105.7 (C-2), 79.9 (C-4), 75.2 (C-3),
74.7 (CH2Ph), 73.1 (C-5), 71.8 (CH2Ph), 71.7 (C-1), 71.3
(CH2Ph), 61.2 (C-6), 33.3 (CH2Br), 26.9, 26.1 (CMe2); FABMS:
m/z 606, 604 (30%, [MþNa]þ). Anal. Calcd for C31H35BrO6: C,
63.81; H, 6.05. Found: C, 64.10; H, 6.03.
4.5. 3-O-(4-Bromomethylbenzyl)-1,2-O-isopropylidene-b-D-
fructopyranose (13)
Compound 13 (253.9 mg, 70%) was obtained from 10
(400 mg, 0.9 mmol) following the procedure above described
for 12; Rf¼0.44 (2:1 EtOAcepetroleum ether); [a]D ꢁ9.9 (c
1.0, CH2Cl2); IR: nmax¼3422, 2988, 1651, 1514, 1454, 1377,
1225, 1090, 876 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d¼7.45e7.26 (m, 4H, Ph), 4.82, 4.72 (2d, 2H, 2JH,H¼11.7 Hz,
CHPh), 4.48 (s, 2H, CH2Br), 4.04 (d, 1H, J1a,1b¼8.7 Hz,
H-1a), 4.01 (m, 1H, H-4), 3.98 (d, 1H, H-1b), 3.96 (dd, 1H,
H-5), 3.95 (dd, 1H, J6a,6b¼12.9 Hz, J5,6a¼1.5 Hz, H-6a),
3.76 (dd, 1H, J5,6b¼1.8 Hz, H-6b), 3.66 (d, 1H, J3,4¼9.3 Hz,
H-3), 2.61, 1.72 (2br s, 2H, 2OH), 1.49, 1.42 (2s, 6H, CMe2);
13C NMR (75.5 MHz, CDCl3): d¼138.1e128.0 (Ph), 111.8
(CMe2), 105.4 (C-2), 76.4 (C-3), 74.6 (CHPh), 71.7 (C-1),
71.2 (C-4), 69.6 (C-5), 63.5 (C-6), 33.0 (CH2Br), 26.6, 26.0
(CMe2); FABMS: m/z 427, 425 (40%, [MþNa]þ). Anal. Calcd
for C17H23BrO6: C, 50.63; H, 5.75. Found: C, 50.40; H, 5.67.
4.8. General procedure for the preparation of (O-6/O-30)-
xylylene-tethered fructofuranoseefructopyranose derivatives
(19e21)
To a solution of 2,3-di-O-benzyl-1,2-O-isopropylidene-b-D-
fructofuranose 18 (188 mg, 0.47 mmol) in dry DMF (3 mL),
NaH (60% in mineral oil, 46 mg, 0.98 mmol) was added and
the reaction mixture was stirred at room temperature for 1 h.
A solution of 15, 16, or 17 (225 mg, 0.39 mmol) in dry DMF
(4 mL) was then added, the reaction mixture was further stirred
at room temperature for 3 h, quenched by addition of H2O
(2 mL), concentrated, and the resulting residue was purified by
column chromatography using the eluent indicated in each case.
4.6. 4,5-Di-O-benzyl-3-O-(3-bromomethylbenzyl)-1,2-O-
isopropylidene-b-D-fructopyranose (15)
To a suspension of NaH (60% in mineral oil, 154 mg,
4.0 mmol) and benzyl bromide (1.9 mL, 16 mmol) in dry DMF
(5 mL), a solution of 12 (323 mg, 0.80 mmol) in dry DMF
(3 mL) was added. The reaction mixture was stirred for 1 h at
room temperature, then quenched with H2O (5 mL), extracted
with Et2O (5ꢂ10 mL), the combined organic layer was washed
with water (3ꢂ15 mL), dried (MgSO4), and concentrated. The
resulting residue was purified by column chromatography (1:6
4.8.1. 3,4-Di-O-benzyl-1,2-O-isopropylidene-b-D-
fructofuranose 40,50-di-O-benzyl-10,20-O-isopropylidene-b-
D-fructopyranose 6,30-O-(m-xylylene) (19)
Eluent: 1:6 EtOAcetoluene; yield: 190 mg (54%); Rf¼0.47
1
(1:6 EtOAcetoluene); [a]D ꢁ62.0 (c 1.0, CHCl3); H NMR

F. Louis et al. / Tetrahedron 64 (2008) 2792e2800
2797
(500 MHz, CDCl3): d¼7.31e7.22 (m, 24H, Ph), 5.02, 4.62 (2d,
1H, 2JH,H¼11.5 Hz, CHPh), 4.74, 4.67 (2d, 1H, 2JH,H¼12.5 Hz,
CHPh), 4.68 (s, 2H, CH2Ph), 4.60, 4.57 (2d, 1H, 2JH,H¼13.3 Hz,
CHPh), 4.60, 4.54 (2d, 1H, 2JH,H¼12.0 Hz, CHPh), 4.52 (s, 2H,
J5,6b¼6.5 Hz, H-6b), 1.48e1.38 (m, 12H, CMe2); 13C NMR
(125.7 MHz, CDCl3): d¼138.5e127.6 (Ph), 111.7, 111.5
(CMe2), 109.0 (C-2), 105.9 (C-20), 84.6 (C-4), 83.1 (C-3), 80.2
(C-5), 80.0 (C-40), 75.0 (C-30), 73.3 (C-50), 72.4 (C-6, CH2Ph),
72.3, 72.2, 72.1 (CH2Ph), 71.9 (C-10), 71.5 (C-1), 71.3, 70.6
(CH2Ph), 61.4 (C-60), 26.9e26.4 (CMe2); FABMS: m/z 926
(20%, [MþNa]þ). Anal. Calcd for C54H62O12: C, 71.82; H,
6.92. Found: C, 71.55; H, 6.84.
CH2Ph), 4.10 (m, 2H, H-4, H-5), 4.01 (d, 1H, J1a,1b¼9.0 Hz,
0
0
0
H-1a), 3.99 (d, 1H, J1a ,1b ¼8.5 Hz, H-1 a), 3.98 (d, 1H, J3,4
¼
5.0 Hz, H-3), 3.95 (d, 1H, H-10b), 3.92 (d, 1H, H-1b), 3.91 (d,
0
0
0
0
0
0
1H, J3 ,4 ¼9.5 Hz, H-3 ), 3.88 (dd, 1H, J4 ,5 ¼2.8 Hz, H-4 ),
0
0
0
0
0
3.79 (dd, 1H, J6a ,6b ¼12.8 Hz, J5 ,6a ¼2.3 Hz, H-6 a), 3.78 (m,
1H, H-50), 3.74 (dd, 1H, J5 ,6b ¼1.8 Hz, H-6 b), 3.61 (m, 1H,
H-6a), 3.55 (m, 1H, H-6b), 1.45, 1.42, 1.40 (3s, 12H, CMe2);
13C NMR (125.7 MHz, CDCl3): d¼138.8e126.9 (Ph), 111.8,
111.5 (CMe2), 109.0 (C-2), 105.9 (C-20), 84.5 (C-4), 83.1
(C-3), 80.2 (C-5), 80.1 (C-40), 75.4 (C-30), 75.3 (CH2Ph), 73.5
(CH2Ph), 73.4 (C-50), 72.4 (C-6), 72.3, 72.2, 72.0 (CH2Ph),
72.0 (C-10), 71.5 (CH2Ph), 71.3 (C-1), 61.4 (C-60), 27.1, 26.4,
26.2 (CMe2); FABMS: m/z 926 (20%, [MþNa]þ). Anal. Calcd
for C54H62O12: C, 71.82; H, 6.92. Found: C, 71.92; H, 7.04.
4.9. General procedure for the xylylene-mediated
stereoselective synthesis of type II DFA derivatives (22e28)
0
0
0
To a solution of the corresponding m-, p-, or o-xylylene-
tethered precursor 19, 20, or 21 (280 mg, 0.31 mmol) in
CH2Cl2 (20 mL) at ꢁ78 ꢀC under Ar, trifluoromethanesulfonic
acid (41 mL) was added. The reaction mixture was allowed to
reach room temperature and stirred for 1 h, then quenched by
addition of Et3N (0.1 mL), and concentrated. Column chroma-
tography of the resulting residue (1:3/1:1 EtOAcepetroleum
ether for 19 and 20; 1:5/1:2 EtOAcepetroleum ether for 21)
afforded first the intramolecular reaction products 22, 24 or 26
and 27, respectively. A second fraction contained the pure
bis(a,b) macrocyclic dimer 23, 25, or 28. A third fraction con-
sisted in an inseparable mixture of isomeric macrocyclic
dimers, as seen from mass spectrometry data (see Scheme 2
for relative proportions and isolated yields).
4.8.2. 3,4-Di-O-benzyl-1,2-O-isopropylidene-b-D-
fructofuranose 40,50-di-O-benzyl-10,20-O-isopropylidene-b-
D-fructopyranose 6,30-O-(p-xylylene) (20)
Eluent: 1:8 EtOAcetoluene; yield: 216 mg (51%); Rf¼0.41
1
(1:4 EtOAcetoluene); [a]D ꢁ80.6 (c 1.0, CH2Cl2); H NMR
(500 MHz, CDCl3): d¼7.31e7.24 (m, 24H, Ph), 5.01, 4.63 (2d,
2H, 2JH,H¼11.5 Hz, CHPh), 4.74, 4.67 (2d, 2H, 2JH,H¼12.5 Hz,
CH2Ph), 4.68 (s, 2H, CH2Ph), 4.60 (m, 4H, CH2Ph), 4.55 (s, 2H,
CH2Ph), 4.10 (m, 2H, H-4, H-5), 4.02 (d, 1H, J1a,1b¼9.3 Hz,
4.9.1. 3,4-Di-O-benzyl-a-D-fructofuranose 4,5-di-O-benzyl-
b-D-fructopyranose 6,30-O-(m-xylylene) 1,20:2,10-
dianhydride (22)
0
0
0
H-1a), 4.00 (d, 1H, J1a ,1b ¼8.6 Hz, H-1 a), 3.99 (d, 1H,
J3,4¼6.2 Hz, H-3), 3.95 (d, 1H, H-10b), 3.92 (m, 2H, H-1b,
0
H-30), 3.89 (dd, 1H, J3 ,4 ¼9.9 Hz, J4 ,5 ¼2.7 Hz, H-4 ), 3.79 (m,
Yield: 142 mg (59%); Rf¼0.51 (1:2 EtOAcepetroleum
ether); [a]D þ10.1 (c 0.9, CHCl3); 1H NMR (500 MHz,
CDCl3): d¼7.32e6.96 (m, 24H, Ph), 5.18, 4.52 (2d, 2H,
0
0
0
0
2H, H-50, H-60a), 3.74 (dd, 1H, J6 a,6 b¼12.9 Hz, J5 ,6 b¼1.0 Hz,
0
0
0
0
H-60b), 3.61 (dd, 1H, J6a,6b¼9.9 Hz, J5,6a¼6.2 Hz, H-6a), 3.56
(dd, 1H, J5,6b¼6.1 Hz, H-6b), 1.53e1.39 (m, 12H, CMe2); 13
C
2JH,H¼13.0 Hz, CHPh), 4.75, 4.64 (2d, 2H, JH,H¼12.7 Hz,
2
2
NMR (125.7 MHz, CDCl3): d¼138.5e127.6 (Ph), 111.8, 111.5
(CMe2), 109.0 (C-2), 105.9 (C-20), 84.5 (C-4), 83.1 (C-3), 80.2
(C-5, C-40), 75.3 (C-30), 75.2 (CH2Ph), 73.4 (C-50), 73.3
(CH2Ph), 72.3e71.9 (3CH2Ph, C-6, C-10), 71.5 (CH2Ph), 71.3
(C-1), 61.4 (C-60), 27.1e26.2 (CMe2); ESIMS: m/z 925.5
([MþNa]þ). Anal. Calcd for C54H62O12: C, 71.82; H, 6.92.
Found: C, 71.86; H, 7.11.
CHPh), 4.68, 4.60 (2d, 2H, JH,H¼11.5 Hz, CHPh), 4.67 (s,
2H, CH2Ph), 4.47 (s, 2H, CH2Ph), 4.51, 4.41 (2d, 2H,
2
0
0
0
JH,H¼12.0 Hz, CHPh), 4.16 (d, 1H, J1a ,1b ¼11.6 Hz, H-1 a),
4.14 (m, 1H, H-5), 4.00 (d, 1H, J3,4¼2.5 Hz, H-3), 3.99 (m,
1H, H-6a), 3.96 (d, 1H, J1a,1b¼11.8 Hz, H-1a), 3.94 (dd, 1H,
0
0
0
0
0
0
0
J3 ,4 ¼9.5 Hz, J4 ,5 ¼3.2 Hz, H-4 ), 3.83 (d, 2H, J6a ,6b ¼12.0 Hz,
H-60a, H-1b), 3.74 (m, 1H, H-6b), 3.72 (m, 1H, H-50), 3.61 (d,
1H, H-30), 3.60 (d, 1H, H-60b), 3.54 (dd, 1H, J4,5¼7.5 Hz,
H-4), 3.39 (d, 1H, H-10b); 13C NMR (125.7 MHz, CDCl3):
d¼140.5e124.9 (Ph), 102.3 (C-2), 95.9 (C-20), 89.0 (C-3),
85.1 (C-4), 80.1 (C-5), 78.9 (C-30), 78.6 (C-40), 73.5 (C-50),
75.8 (CH2Ph), 74.8 (C-6), 74.3, 72.5, 72.3, 71.2 (CH2Ph), 62.5
(C-10), 62.0 (C-1), 60.3 (C-60); FABMS: m/z 809 (60%,
[MþNa]þ). Anal. Calcd for C48H50O10: C, 73.26; H, 6.40.
Found: C, 73.07; H, 6.07.
4.8.3. 3,4-Di-O-benzyl-1,2-O-isopropylidene-b-D-
fructofuranose 40,50-di-O-benzyl-10,20-O-isopropylidene-b-
D-fructopyranose 6,30-O-(o-xylylene) (21)
Eluent: 1:8/1:6 EtOAcetoluene; yield: 220 mg (62%);
Rf¼0.47 (1:6 EtOAcetoluene); [a]D ꢁ74.3 (c 1.1, CH2Cl2);
1H NMR (500 MHz, CDCl3): d¼7.31e7.22 (m, 24H, Ph),
5.08, 4.69 (2d, 2H, 2JH,H¼12.0 Hz, CHPh), 4.73, 4.68 (2d, 2H,
2JH,H¼12.5 Hz, CHPh), 4.67 (s, 2H, CH2Ph), 4.59, 4.55 (2d,
2H, 2JH,H¼12.0 Hz, CHPh), 4.58, 4.53 (2d, 2H, 2JH,H¼12.0 Hz,
CHPh), 4.58 (s, 2H, CH2Ph), 4.09 (m, 2H, H-4, H-5), 4.01 (d,
4.9.2. Macrocyclic dimer (23)
Yield: 28.4 mg (12%); Rf¼0.24 (1:2 EtOAcepetroleum
ether); [a]D ꢁ27.5 (c 0.6, CH2Cl2); 1H NMR (500 MHz,
CDCl3): d¼7.16e7.09 (m, 48H, Ph), 4.98, 4.56 (2d, 4H,
1H, J1a,1b¼9.0 Hz, H-1a), 3.97 (d, 1H, J3,4¼6.5 Hz, H-3), 3.90
0
0
0
0
0
(dd, 1H, J3 ,4 ¼9.5 Hz, J4 ,5 ¼3.0 Hz, H-4 ), 3.90 (d, 1H,
2
H-1b), 3.89 (d, 1H, H-30), 3.88 (d, 1H, J1a ,1b ¼9.0 Hz, H-1 a),
3.83 (d, 1H, H-10b), 3.75 (m, 3H, H-50, H-60a, H-60b), 3.57
(dd, 1H, J6a,6b¼10.0 Hz, J5,6a¼6.0 Hz, H-6a), 3.54 (dd, 1H,
2JH,H¼11.4 Hz, CH2Ph), 4.74, 4.67 (2d, 4H, JH,H¼12.7 Hz,
0
0
0
CHPh), 4.63 (s, 2H, CH2Ph), 4.64, 4.59 (2d, 4H, 2JH,H¼11.7 Hz,
CHPh), 4.52, 4.48 (2d, 4H, 2JH,H¼12.4 Hz, CHPh), 4.41, 4.36

2798
F. Louis et al. / Tetrahedron 64 (2008) 2792e2800
(2d, 4H, 2JH,H¼11.8 Hz, CH2Ph), 4.33 (d, 2H, J1a,1b¼11.4 Hz,
([MþNa]þ). Anal. Calcd for C48H50O10: C, 73.26; H, 6.40.
H-1a), 4.27 (m, 2H, H-5), 4.00 (d, 2H, J3,4¼1.9 Hz, H-3), 3.99
Found: C, 72.99; H, 6.28.
0
0
0
0
0
(dd, 2H, J3 ,4 ¼9.4 Hz, J4 ,5 ¼3.2 Hz, H-4 ), 3.96 (dd, 2H,
0
J4,5¼5.4 Hz, H-4), 3.92 (d, 2H, J1a ,1b ¼11.9 Hz, H-1 a), 3.83
4.9.5. 3,4-Di-O-benzyl-a-D-fructofuranose 40,50-di-O-
benzyl-b-D-fructopyranose 6,30-O-(o-xylylene) 1,20:2,10-
dianhydride (26)
0
0
0
0
0
0
0
(dd, 2H, J6a ,6b ¼12.6 Hz, J5 ,6a ¼1.7 Hz, H-6 a), 3.79 (dd, 2H,
J6a,6b¼10.0 Hz, J5,6a¼3.4 Hz, H-6a), 3.78 (d, 2H, H-10b), 3.74
(m, 2H, H-50), 3.71 (d, 2H, H-30), 3.67 (dd, 2H, J5,6b¼6.1 Hz,
H-6b), 3.56 (d, 2H, H-60b), 3.39 (d, 2H, H-1b); 13C NMR
(125.7 MHz, CDCl3): d¼138.6e127.1 (Ph), 102.4 (C-2), 96.1
(C-20), 88.9 (C-3), 84.3 (C-4), 81.4 (C-5), 78.3 (C-40), 77.0
(C-30), 75.4 (CH2Ph), 73.8 (C-50, CH2Ph), 72.5, 72.0, 71.7,
71.3 (CH2Ph), 70.6 (C-6), 62.1 (C-10), 62.0 (C-1), 60.5 (C-60);
ESIMS: m/z 1596.5 ([MþNa]þ). Anal. Calcd for C96H100O20:
C, 73.26; H, 6.40. Found: C, 73.13; H, 6.42.
Yield: 70.3 mg (30%); Rf¼0.66 (1:1 EtOAcepetroleum
ether); [a]D þ4.9 (c 0.8, CHCl3); 1H NMR (500 MHz, CDCl3):
d¼7.32e7.16 (m, 24H, Ph), 5.53, 4.91 (2d, 2H, 2JH,H¼14.6 Hz,
2
CHPh), 4.97, 4.63 (2d, 2H, JH,H¼12.0 Hz, CHPh), 4.74, 4.68
2
(2d, 2H, JH,H¼12.7 Hz, CHPh), 4.68, 4.61 (2d, 2H,
2
2JH,H¼10.0 Hz, CHPh), 4.48, 4.40 (2d, 2H, JH,H¼11.7 Hz,
2
CHPh), 4.47, 4.41 (2d, 2H, JH,H¼11.8 Hz, CHPh), 4.06 (d,
1H, J6a,6b¼12.6 Hz, H-6a), 4.01 (br d, 1H, J4,5¼8.7 Hz, H-5),
0
0
0
0
0
3.98 (dd, 1H, J3 ,4 ¼9.7 Hz, J4 ,5 ¼3.1 Hz, H-4 ), 3.88 (d, 1H,
J3,4¼3.7 Hz, H-3), 3.86 (d, 1H, J1a,1b¼13.7 Hz, H-1a), 3.84
4.9.3. 3,4-Di-O-benzyl-a-D-fructofuranose 4,5-di-O-benzyl-
b-D-fructopyranose 6,30-O-(p-xylylene) 1,20:2,10-
dianhydride (24)
0
0
0
0
(m, 1H, H-6b), 3.72 (dd, H, J6a ,6b ¼11.5 Hz, J5 ,6a ¼3.0 Hz,
H-60a), 3.71 (m, 1H, H-50), 3.70 (d, 1H, H-1b), 3.65 (d, 1H,
H-60b), 3.61 (dd, 1H,0 H-4), 3.55 (d, 1H, H-30), 3.39 (d, 1H,
Yield: 60.2 mg (25%); Rf¼0.5 (2:3 EtOAcepetroleum
ether); [a]D þ29.0 (c 1.0, CH2Cl2); 1H NMR (500 MHz,
CDCl3): d¼7.72e7.03 (m, 24H, Ph), 4.84, 3.97 (2d, 2H,
J1a ,1b ¼12.0 Hz, H-1 a), 3.05 (d, 1H, H-1 b); 13C NMR
(125.7 MHz, CDCl3): d¼140.6e126.7 (Ph), 102.0 (C-2), 95.2
(C-20), 88.8 (C-3), 86.2 (C-4), 79.6 (C-5), 78.9 (C-40), 74.5
(C-30), 73.4 (C-50), 72.9, 72.5, 72.4, 72.0, 71.4 (CH2Ph), 71.2
(C-6), 68.5 (CH2Ph), 62.6 (C-10), 62.4 (C-1), 60.6 (C-60);
ESIMS: m/z 809 [MþNa]þ, 825 [MþK]þ. Anal. Calcd for
C48H50O10: C, 73.26; H, 6.40. Found: C, 73.13; H, 6.48.
0
0
0
2
2JH,H¼12.0 Hz, CHPh), 4.74, 4.69 (2d, 2H, JH,H¼12.7 Hz,
2
CHPh), 4.64, 4.56 (2d, 2H, JH,H¼12.1 Hz, CHPh), 4.56 (s,
2
2H, CH2Ph), 4.55, 3.67 (2d, 2H, JH,H¼12.2 Hz, CHPh), 4.53
0
0
0
00
(s, 2H, CH2Ph), 3.96 (m, 1H, J5 ,6b ¼9.8 Hz, J4 ,5 ¼6.8 Hz,
H-50), 3.90 (t, 1H, J3 ,4 ¼7.2 Hz, H-4 ), 3.78 (m, 2H, H-5, H-6a),
3.73 (m, 1H, J3,4¼2.6 Hz, H-4), 3.62 (d, 1H, J1a,1b¼11.0 Hz, H-
1a), 3.59 (d, 1H, H0-30), 3.55 (m, 1H, H-6b), 3.44 (d, 1H,
0
0
4.9.6. 3,4-Di-O-benzyl-b-D-fructofuranose 40,50-di-O-
benzyl-a-D-fructopyranose 6,30-O-(o-xylylene) 1,20:2,10-
dianhydride (27)
0
0
J6a ,6b ¼10.0 Hz, H-6 a), 3.31 (d, 1H, H-3), 3.12 (d, 1H, H-1b),
3.09 (d, 1H, H-60b), 2.79 (d, 1H, J1a ,1b ¼12.5 Hz, H-1 a), 1.14
(d, 1H, H-10b); 13C NMR (125.7 MHz, CDCl3): d¼138.6e
127.4 (Ph), 99.6 (C-2), 92.9 (C-20), 83.5 (C-3), 83.2 (C-4), 80.6
(C-5), 76.8 (C-40), 73.4 (C-30), 72.8, 72.7, 72.6, 72.3 (CH2Ph),
71.9 (C-50), 71.2 (CH2Ph), 70.9 (C-6), 63.3 (C-10), 61.7 (C-1),
57.3 (C-60); ESIMS: m/z 809.37 ([MþNa]þ). Anal. Calcd for
C48H50O10: C, 73.26; H, 6.40. Found: C, 73.24; H, 6.62.
0
0
0
Yield: 98 mg (42%); Rf¼0.65 (1:1 EtOAcepetroleum ether);
[a]D þ18.1 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d¼7.31e7.13 (m, 24H, Ph), 5.34, 4.53 (2d, 2H, 2JH,H¼10.9 Hz,
CHPh), 4.69, 4.64 (2d, 2H, 2JH,H¼11.1 Hz, CHPh), 4.68, 4.51
2
(2d, 2H, JH,H¼10.0 Hz, CHPh), 4.68 (s, 4H, CH2Ph), 4.60,
2
4.32 (2d, 2H, JH,H¼12.2 Hz, CHPh), 4.59 (d, 1H, J1a,1b
¼
12.5 Hz, H-1a), 4.24 (dt, 1H, J5,6b¼10.5 Hz, J5,6a¼J4,5¼4.5 Hz,
0
0
0
H-5), 4.19 (d, 1H, J1a ,1b ¼11.4 Hz, H-1 a), 4.15 (d, 1H,
0
0
0
4.9.4. Macrocyclic dimer (25)
J3 ,4 ¼7.9 Hz, H-3 ), 4.13 (dd, 1H, J3,4¼6.3 Hz, H-4), 4.05 (dd,
0
0
0
0
0
Yield: 79.5 mg (33%); Rf¼0.44 (1:1 EtOAcepetroleum
ether); [a]D ꢁ7.0 (c 1.0, CH2Cl2); 1H NMR (500 MHz,
CDCl3): d¼7.50e7.07 (m, 48H, Ph), 5.01, 4.55 (2d, 4H,
1H, J6a ,6b ¼12.2 Hz, J5 ,6a ¼5.8 Hz, H-6 a), 3.87 (d, 1H, H-3),
0
0
0
0
0
3.74 (dt, 1H, J4 ,5 ¼J5 ,6b ¼3.0 Hz, H-5 ), 3.70 (d, 1H, H-1b),
3.65 (dd, 1H, J6a,6b¼10.5 Hz, H-6a), 3.60 (t, 1H, H-6b), 3.52
(d, 1H, H-10b), 3.45 (dd, 1H, H-60b), 3.41 (dd, 1H, H-40); 13C
NMR (125.7 MHz, CDCl3): d¼138.6e127.2 (Ph), 101.4 (C-2),
97.7 (C-20), 85.1 (C-4), 84.7 (C-3), 79.0 (C-5), 78.0 (C-30), 76.3
(C-40), 72.9, 72.7, 72.0 (CH2Ph), 71.9 (C-6), 71.6 (C-50), 71.2,
70.9, 70.2 (CH2Ph), 63.8 (C-10), 61.0 (C-60), 59.8 (C-1); ESIMS:
m/z 809 [MþNa]þ, 825 [MþK]þ. Anal. Calcd for C48H50O10:
C, 73.26; H, 6.40. Found: C, 73.13; H, 6.06.
2
2JH,H¼12.2 Hz, CHPh), 4.73, 4.66 (2d, 4H, JH,H¼12.3 Hz,
CHPh), 4.66, 4.60 (2d, 4H, 2JH,H¼12.4 Hz, CHPh), 4.60, 4.56
2
2
(2d, 4H, JH,H¼12.6 Hz, CHPh), 4.56, 4.51 (2d, 4H, JH,H
¼
2
12.2 Hz, CHPh), 4.42, 4.37 (2d, 4H, JH,H¼11.7 Hz, CHPh),
4.23 (d, 2H, J1a,1b¼11.7 Hz, H-1a), 4.20 (m, 1H, H-5), 3.99 (dd,
0
0
0
0
0
2H, J3 ,4 ¼9.6 Hz, J4 ,5 ¼3.1 Hz, H-4 ), 3.96 (d, 2H, J3,4¼2.1 Hz,
0
0
0
H-3), 3.89 (d, 2H, J1a ,1b ¼11.7 Hz, H-1 a), 3.83 (dd, 2H,
J6a,6b¼12.4 Hz, H-6a), 3.76 (d, 2H, H-1b), 3.74 (dd, 2H,
J4,5¼7.8 Hz, H-4), 3.73 (m, 4H, H-50, H-60a), 3.67 (d, 2H,
4.9.7. Macrocyclic dimer (28)
H-30), 3.59 (d, 2H, J6a ,6b ¼10.7 Hz, J5 ,6b ¼5.1 Hz, H-6 b), 3.55
(d, 1H, H-6b), 3.26 (d, 1H, H-10b); 13C NMR (125.7 MHz,
CDCl3): d¼138.6e127.5 (Ph), 102.4 (C-2), 96.0 (C-20), 88.7
(C-3), 84.8 (C-4), 81.3 (C-5), 78.4 (C-40), 76.8 (C-30), 75.2
(CH2Ph), 73.7 (C-50), 73.3, 72.4, 71.9, 71.8, 71.3 (CH2Ph),
71.3 (C-6), 62.1 (C-1, C-10), 60.5 (C-60); ESIMS: m/z 1595.76
Yield: 31.8 mg (7%); Rf¼0.47 (1:1 EtOAcepetroleum ether);
[a]D ꢁ2.0(c1.0,CHCl3);1HNMR(500 MHz, CDCl3):d¼7.30e
7.11 (m, 48H, Ph), 4.98, 4.89 (2d, 4H, 2JH,H¼12.9 Hz, CHPh),
4.97, 4.70 (2d, 4H, 2JH,H¼11.7 Hz, CHPh), 4.75, 4.68 (2d, 4H,
0
0
0
0
0
2
2JH,H¼12.5 Hz, CHPh), 4.71, 4.63 (2d, 4H, JH,H¼11.7 Hz,
CHPh), 4.52 (s, 4H, CH2Ph), 4.34, 4.23 (2d, 4H, 2JH,H¼11.9 Hz,

F. Louis et al. / Tetrahedron 64 (2008) 2792e2800
2799
2006, 8, 1945e1948; (f) Zhou, X.-T.; Carter, R. G. Angew. Chem., Int. Ed.
2006, 45, 1787e1790;(g)Furstner, A.;Fenster, M. D. B.;Fasching, B.;Godb-
CHPh), 4.27 (m, 2H, J5,6b¼6.3 Hz, J5,6a¼4.2 Hz, H-5), 4.01 (dd,
0
¨
0
0
0
0
2H, J3 ,4 ¼9.8 Hz, J4 ,5 ¼3.1 Hz, H-4 ), 3.95 (dd, 2H, J6a,6b
¼
out, C.; Radkowski, K. Angew. Chem., Int. Ed. 2006, 45, 5510e5515; (h) Liu,
J.; Yang, J. H.; Ko, C.; Hsung, R. P. Tetrahedron Lett. 2006, 47, 6121e6123;
(i) Meilert, K.; Brimble, M. A. Org. Biomol. Chem. 2006, 4, 2184e2192; (j)
Paterson, I.; Anderson, E. A.; Dalby, S. M.; Lim, J. H.; Maltas, P.; Moessner,
C. Chem. Commun. 2006, 4186e4188.
9.8 Hz, H-6a), 3.92 (m, 4H, H-3, H-4), 3.87 (d, 2H, J1a,1b
¼
0
0
0
12.0 Hz, H-1a), 3.79 (d, 4H, J6a ,6b ¼12.3 Hz, H-6 a, H-1b),
3.76 (d, 2H, H-10a), 3.73 (m, 2H, H-50), 3.70 (dd, 2H, H-6b),
3.68 (d, 2H, H-30), 3.51 (d, 2H, H-60b), 2.94 (d, 1H, H-10b); 13C
NMR (125.7 MHz, CDCl3): d¼138.9e126.8 (Ph), 102.6 (C-2),
95.6 (C-20), 88.5 (C-3), 84.8 (C-4), 82.3 (C-5), 79.0 (C-40), 74.1
(C-30), 73.7 (C-50), 73.1, 72.7, 72.0 (CH2Ph), 71.3 (CH2Ph),
71.1 (C-6), 70.1 (CH2Ph), 61.9 (C-10), 61.5 (C-1), 60.6 (C-60);
ESIMS: m/z 1596 [MþNa]þ, 1612 [MþK]þ. Anal. Calcd for
C48H50O10: C, 73.26; H, 6.40. Found: C, 73.22; H, 6.29.
2. For a review, see: Manley-Harris, M.; Richards, G. N. Adv. Carbohydr.
Chem. Biochem. 1997, 52, 207e266.
´
´
3. (a) Defaye, J.; Garcıa Fernandez, J. M. Carbohydr. Res. 1994, 256, C1e
´
C4; (b) Defaye, J.; Garcıa Fernandez, J. M. Zuckerindustrie 1995, 120,
´
700e704; (c) Manley-Harris, M.; Richards, G. N. Carbohydr. Res.
´
´
1996, 287, 183e202; (d) Ratsimba, V.; Garcıa Fernandez, J. M.; Defaye,
J.; Nigay, H.; Voilley, A. J. Chromatogr., A 1999, 844, 283e293; (e)
Christian, T. J.; Manley-Harris, M.; Field, R. J.; Parker, B. A. J. Agric.
Food Chem. 2000, 48, 1823e1837; (f) Bohm, A.; Kaiser, I.; Trebstein,
¨
A.; Henle, T. Eur. Food Res. Technol. 2005, 220, 466e471; (g) Montilla,
4.10. a-D-Fructofuranose b-D-fructopyranose 1,20:2,10-
dianhydride (1)
´
A.; Ruiz-Matute, A. I.; Martınez-Castro, I.; del Castillo, M. D. Food Res.
Int. 2006, 39, 801e806; (h) Bohm, A.; Klessen, B.; Henle, T. Eur. Food
¨
Res. Technol. 2006, 222, 737e740; (i) Ruiz-Matute, A. I.; Soria, A. C.;
Conventional catalytic hydrogenation of any of the DFA de-
rivatives 22, 24, or 26, or the corresponding dimers 23, 25, or 28
(0.038 mmol) with 10% PdeC in 1:1 EtOAceMeOH contain-
ing 10% HCOOH (0.4 mL) at 1 atm overnight, afforded the fully
unprotected bis-spiro fructodisaccharide 1 (12.2 mg, 99%) hav-
ing physicochemical and spectroscopic properties identical to
those reported; [a]D ꢁ39.5 (c 1.0, H2O); lit.2 [a]D ꢁ39 (c 4.0,
H2O). The identity of 1 was additionally confirmed by GC after
transformation into the corresponding hexa-O-trimethylsilyl
derivative, following the protocol previously reported.3d
´
Martınez-Castro, I.; Sanz, M. L. J. Agric. Food Chem. 2007, 75, 7264e
7269; (j) Tomita, K.; Shiomi, T.; Okuhara, Y.; Tamura, A.; Shigematsu,
N.; Hara, H. Biosci. Biotechnol. Biochem. 2007, 71, 681e687.
4. (a) Kaji, E.; Saiga, R.; Kurimoto, E.; Nishino, T. Heterocycles 2006, 69,
385e393; (b) Enderlin, G.; Taillefumier, C.; Didierjean, C.; Chapleur, Y.
Tetrahedron: Asymmetry 2005, 16, 2459e2474; (c) vant Hooft, P. A. V.;
Oualid, F. E.; Overkleeft, H. S.; van der Marel, G. A.; van Boom, J. H.; Leeu-
wenburgh, M. A. Org. Biomol. Chem. 2004, 2, 1395e1403; (d) Tatibouet,
¨
A.; Lawrence, S.; Rollin, P.; Holman, G. D. Synlett 2004, 1945e1948; (e)
Jang, K.-H.; Ryu, E.-J.; Park, B.-S.; Song, K.-B.; Kang, S. A.; Kim, C. H.;
Uhm, T.-B.; Park, Y.-I.; Rhee, S.-K. J. Agric. Food Chem. 2003, 51,
2632e2636; (f) Li, X.; Takahashi, H.; Ohtake, H.; Shiro, M.; Ikegami, S.
´
Tetrahedron 2001, 57, 8053e8066; (g) Garcıa Fernandez, J. M.; Ortiz
´
4.11. b-D-Fructofuranose a-D-fructopyranose 1,20:2,10-
dianhydride (2)
Mellet, C.;Defaye, J. J. Org. Chem. 1998, 63, 3572e3580;(h)Bextermoller,
¨
R.; Redlich, H.; Schnieders, K.; Thrmahlen, S.; Frolich, R. Angew. Chem.,
¨
¨
Int. Ed. 1998, 37, 2496e2500; (i) Garcıa Fernandez, J. M.; Schnelle, R.-R.;
´
´
´
´
Defaye, J. Aust. J. Chem. 1996, 49, 319e325; (j) Garcıa Fernandez, J. M.;
Schnelle, R.-R.; Defaye, J. Tetrahedron: Asymmetry 1995, 6, 307e312.
5. (a) Defaye, J.; Gadelle, A.; Pedersen, C. Carbohydr. Res. 1985, 136, 53e65;
Conventional catalytic hydrogenation of 27 (30 mg,
0.038 mmol) as above described for the preparation of 1 af-
forded 2 (12.4 mg, 100%) having physicochemical and spectro-
scopic properties identical to those reported; [a]D þ5.1 (c 1.0 in
H2O); lit.3c [a]D þ4.8 (c 2.1, H2O). The identity of 2 was addi-
tionally confirmed by GC after transformation into the corre-
sponding hexa-O-trimethylsilyl derivative, following the
protocol previously reported.3d
´
(b)Defaye, J.; GarcıaFernandez, J. M. Carbohydr. Res. 1994, 251, 1e15;(c)
´
´
´
Defaye, J.; Garcıa Fernandez, J. M. Carbohydr. Res. 1994, 251, 17e31; (d)
´
Defaye, J.; Garcıa Fernandez, J. M. Carbohydr. Res. 1992, 237, 223e247.
6. (a) Benito, J. M.; Gomez-Garcıa, M.; Ortiz Mellet, C.; Garcıa Fernandez,
´
´
´
´
´
J. M.; Defaye, J. Org. Lett. 2001, 3, 549e552; (b) Benito, J. M.; Rubio,
´
E. M.; Gomez-Garcıa, M.; Ortiz Mellet, C.; Garcıa Fernandez, J. M.
Tetrahedron 2004, 60, 5899e5906; (c) Balbuena, P.; Rubio, E. M.; Ortiz
´
´
´
´
´
Mellet, C.; Garcıa Fernandez, J. M. Chem. Commun. 2006, 2610e2612.
´
7. (a) Rubio, E. M.; Garcıa-Moreno, M. I.; Balbuena, P.; Lahoz, F. J.;
Acknowledgements
´
´
Alvarez, E.; Ortiz Mellet, C.; Garcıa Fernandez, J. M. J. Org. Chem.
´
2006, 71, 2257e2266; (b) Rubio, E. M.; Ortiz Mellet, C.; Garcıa
´
Fernandez, J. M. Org. Lett. 2003, 5, 873e876.
´
We thank the Spanish Ministerio de Educacion y Ciencia
8. For the IUPAC nomenclature recommendations to name difructose dia-
nhydrides, see: McNaught, A. D. Pure Appl. Chem. 1996, 68, 1919e2008.
9. The term ’contra-thermodynamic’ designates diastereomers that are ener-
getically strongly disfavored and, consequently, cannot be accessed under
reversible kinetics or thermodynamic conditions. For remarkable recent
examples of stereoselective syntheses of contra-thermodynamic spiroace-
tal frameworks, see: (a) Takaoka, L. R.; Buckmelter, A. J.; LaCruz, T. E.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2005, 127, 528e529; (b) LaCruz,
T. E.; Rychnovsky, S. D. Org. Lett. 2005, 7, 1873e1875.
(contract numbers CTQ2007-61180/PPQ and CTQ2006-
15515-C02-01/BQU) and the Junta de Andalucia (P06-AGR-
02115) for financial support. The Spanish Ministry of Educa-
tion and Science (M.E.C.) is also acknowledged for a doctoral
fellowship (to P.B.).
References and notes
´
10. For a preliminary communication, see: Louis, F.; Garcıa-Moreno, M. I.;
´
´
1. For reviews, see: (a) Brimble, M. A.; Furkert, D. P. Curr. Org. Chem. 2003, 7,
Balbuena, P.; Ortiz Mellet, C.; Garcıa Fernandez, J. M. Synlett 2007,
2738e2742.
`
1e24;(b)Brimble,M.A.;Fares,F. A. Tetrahedron1999, 55, 7661e7706. For
selected recent references, see: Yadav, J. S.; Joyasawal, S.; Dutta, S. K.; Kun-
war, A. C. Tetrahedron Lett. 2007, 48, 535e540; (c) Tofi, M.; Montagnon, T.;
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(e) Georgiu, T.; Tofi, M.; Montagnon, T.; Vassilikogiannakis, G. Org. Lett.
11. The m-xylylene tether has been previously exploited in anomeric configura-
tion control during glycosidic bond-forming reactions. See: (a) Muller, M.;
¨
Huchel, U.; Geyer, A.; Schmidt, R.-R. J. Org. Chem. 1999, 64, 6190e6201;
(b) Jung, K.-H.; Muller, M.; Schmidt, R.-R. Chem. Rev. 2000, 100, 4423e
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4442; (c) Muller, M.; Schmidt, R.-R. Eur. J. Org. Chem. 2001, 2055e2066.
¨

2800
F. Louis et al. / Tetrahedron 64 (2008) 2792e2800
´ ´
14. Rubio, E. M.; Garcıa-Moreno, M. I.; Balbuena, P.; Ortiz Mellet, C.; Garcıa
12. (a) Brady, R. F., Jr. Adv. Carbohydr. Chem. Biochem. 1971, 26, 197e278;
(b) Lichtenthaler, F. W. Carbohydr. Res. 1998, 313, 69e89.
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Fernandez, J. M. Org. Lett. 2005, 7, 729e731.
´
´
13. (a) Garcıa-Moreno, M. I.; Aguilar, M.; Ortiz Mellet, C.; Garcıa Fernandez,
´
15. An example of remote stereochemical control in the stereoselective
synthesis of spiroketals by a preexisting cyclic acetal functionality has
recently been reported. See: Ghosh, S.; Hsung, R. P.; Liu, J. J. Am.
Chem. Soc. 2005, 127, 8260e8261.
´
J. M. Org. Lett. 2006, 297e299; (b) Balbuena, P.; Lesur, D.; Gonzalez
ꢀ
Alvarez, M. J.; Mendicuti, F.; Ortiz Mellet, C.; Garcıa Fernandez, J. M.
´
´
Chem. Commun. 2007, 3270e3272.