Spacer-mediated synthesis of bis-spiroketal disaccharides: Nonsymmetrical furanose-pyranose difructose dianhydrides

Article abstract of DOI:10.1055/s-2007-991055

The stereochemical outcome of the dimerization reaction of D-fructose, leading to tricyclic bis-spiroketal systems, can be tuned by inserting a xylylene template between the reacting moieties. Spirocyclization becomes then an intramolecular process, the a

Full text of DOI:10.1055/s-2007-991055

2738
LETTER
Spacer-Mediated Synthesis of Bis-spiroketal Disaccharides: Nonsymmetrical
Furanose–Pyranose Difructose Dianhydrides
Difructose Diaa
nhydrides rida Louis,a,1 M. Isabel García-Moreno,a Patricia Balbuena,a Carmen Ortiz Mellet,*a José M. García Fernández*b
a
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Profesor García González 1, 41012 Sevilla, Spain
Fax +34(954)624960; E-mail: mellet@us.es
b
Instituto de Investigaciones Químicas, CSIC, Universidad de Sevilla, Américo Vespucio 49, Isla de la Cartuja, 41092 Sevilla, Spain
Fax +34(954)460565; E-mail: jogarcia@iiq.csic.es
Received 19 March 2007
has proven very useful for accessing difuranose (type I;
1–3) and dipyranose (type III; 8, 9) DFAs. High diaste-
reomeric excesses in favor of compounds having different
stereochemistry (a,b) at both spiroketal centers (1 and 8,
Abstract: The stereochemical outcome of the dimerization reaction
of D-fructose, leading to tricyclic bis-spiroketal systems, can be
tuned by inserting a xylylene template between the reacting
moieties. Spirocyclization becomes then an intramolecular process,
the available conformational space depending on the nature of the respectively), which are thermodynamically more stable,
tether. The methodology is here illustrated by the stereoselective
were achieved by performing the spiroketalization reac-
synthesis of two nonsymmetrical di-D-fructose dianhydrides
present in commercial caramel.
tion in organic solvents under irreversible reaction condi-
tions.8 This strategy is, however, unsuitable for the
Key words: acetals, difructose dianhydrides, spiroacetals, oligo-
saccharides, spiro compounds
preparation of DFAs incorporating fructofuranose and
fructopyranose moieties in the tricyclic core (type II
DFAs; 4–7), which can exist in four different diastereo-
meric combinations. Thus, initial attempts to prepare
The bis-spiroketal unit is present in a wide range of inter-
esting natural products, including several marine toxins
and ionophore antibiotics.2 This complex architectural
arrangement is also the underlying structural motif of a
unique family of cyclic disaccharides isolated from
microorganisms and higher plants, namely di-D-fructose
dianhydrides (DFAs).3 During the last decade, DFAs have
been recognized as the major products of acidic and
thermal activation of fructose and fructose-containing
oligosaccharides (sucrose, glycosyl fructoses, inulin),
being present in dietary foods such as caramel, chicory, or
torrefacted coffee.4 The implications of this discovery in
human nutrition and the promising prebiotic properties of
DFAs have strongly stimulated research in these and
related spiro-sugars.5
these compounds from binary mixtures of fructofuranose
and fructopyranose precursors led invariably to the simul-
taneous formation of all type I, type II, and type III DFAs
1–9 (Figure 1).
type I
O
OH
OH
type II
O
O
O
O
O
OH
OH
O
O
HO
OH
O
HO
OH
HO
HO
OH
OH
4 α,β
5 β,α
6 α,α
7 β,β
1 α,β
2 α,α
3 β,β
type III
O
O
OH
HO
O
Up to thirteen different diastereomeric DFAs have been
identified in commercial foodstuffs, making the synthesis
of individual isomers a very difficult issue. Almost quan-
titative conversions of D-fructose, inulin, sucrose, and iso-
meric glucosylfructoses into structurally diverse DFAs
have been achieved by using anhydrous hydrogen fluoride
(HF) as solvent and catalyst.6 Separation of pure com-
pounds from these multicomponent mixtures, however,
becomes extremely hard. Although the use of pyridinium
poly(hydrogen fluoride) complexes, a soft form of HF, let
establish some kinetic and thermodynamic relationships,7
the low interconversion barriers and the reversibility of
the reaction make this approach unsuitable for the prepa-
ration of single isomers in most cases. Anchoring the
cyclic form of D-fructose by suitable protecting groups
HO
OH HO
OH
8 α,β
9 β,β
Figure 1 Structures of the bis-spiroketal difructose dianhydrides
present in commercial caramel and other foodstuffs
We have recently reported9 a new approach for the syn-
thesis of bis-spiroketal systems based on the ‘rigid spacer
between non-reactive centers’ concept previously intro-
duced in oligosaccharide synthesis.10 By connecting
homologous positions in the reacting moieties through an
appropriate tether, stereoselective syntheses of contra-
thermodynamic11 C2-symmetric type I and type III DFAs,
namely the b,b-diastereomers 3 and 9, were accom-
plished. The success of the approach relies on the confor-
mational dissimilarities between derivatives having
different or identical configuration at the anomeric posi-
tions, which adopt chair or boat arrangements, respective-
ly, at the central dioxane ring to comply with the anomeric
SYNLETT 2007, No. 17, pp 2738–2742
1
6
.1
0
.
2
0
0
7
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-991055; Art ID: D08307ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Difructose Dianhydrides
2739
effect (Figure 2). We speculated that this methodology
could be extended to the preparation of type II DFAs by
tethering furanose and pyranose building blocks through
judiciously chosen bridges. This has now been translated
into efficient syntheses of the thermodynamic a,b-deriva-
tive 4 and the contra-thermodynamic b,a counterpart 5.
Br
Br
O
O
~6 Å
O
+
OH
O
O
10
NaH
DMF
57%
O
O
O
O
O
aq AcOH
70%
(a)
HO
O
O
O
O
O
O
OR
Br
Br
O
O
RO
BnBr, 65%
12 R = H
11
(c)
O
rigid spacer
OH
OH
13 R = Bn
O
(b)
O
HO
O
O
O
O
O
O
OH
( )n
O
( )n
NaH
DMF
O
O
O
O
O
O
OBn
O
O
BnO
54%
n = 4, 5
15
BnO
OBn
O
Figure 2 Schematic representation of the chair (a) and boat (b) con-
formations for DFAs having different or identical configuration at the
spiroketal centers. The application of the ‘rigid spacer concept’ to trap
the boat isomers is depicted (c).
14
O
O
TfOH
CH2Cl2
59%
O
BnO
OBn
O
6
OH
Examination of the interatomic relationships for 4–7 in
their more stable conformations by computer-generated
molecular models revealed that the primary position O-6
in the furanose moiety and position O-3¢ in the pyranose
ring lie much closer in the chair conformers 4 (6.0 0.5
Å) and 5 (6.5 0.5 Å) than in the boat DFAs 6 and 7 (8.1
1 Å). Consequently, the introduction of an m-xylylene
tether (ca. 6 Å) between these nonreacting hydroxyls was
contemplated as a mean for configurational control. Ther-
modynamic considerations should then result in the
predominance of the a,b-isomer 4, which is the major
compound in thermodynamic mixtures containing the 13
DFA isomers.
6.0 ± 0.5 Å
O
5
4
O
BnO
1'
HO
2
O
3'
HO
H2, Pd
99%
O
O
O
3
O
1
BnO
OBn
HO
OH
OH
2'
4'
O
O
OBn
5'
4 (α,β)
16
6'
Scheme 1 m-Xylylene-mediated stereospecific synthesis of DFA 4.
The key interatomic distances for the synthetic design are indicated.
The stereospecificity induced by the m-xylylene template
in the above spirocyclization reaction deserves a further
comment. In the intermolecular dimerization, the relative
proportion of compounds 4–7 was found to be 60:1:1:10.
Therefore, the incorporation of the O-6–O-3¢ distance re-
striction fully prevented the formation of the boat diaste-
reomers 6 and 7 and further selected the thermodynamic
a,b-chair DFA 4 (18% in the DFA fraction of commercial
caramels).
The synthesis of the nonsymmetrical O-6→O-3¢ m-xy-
lylene-bridged precursor is illustrated in Scheme 1. Reac-
tion of 1,2:4,5-di-O-isopropylidene-b-D-fructopyranose
(10)12 (one step from D-fructose) with an excess of a,a¢-
dibromo-m-xylene led to the corresponding 3-O-bromo-
methylbenzyl ether 11. Selective removal of the nonano-
meric isopropylidene group (→12) and subsequent
standard benzylation provided the fructopyranose build-
ing block 13.13 Incorporation of the fructofuranose moiety
149a (four steps from D-fructose) at the remaining reactive
bromobenzyl position afforded the required tethered de-
rivative 15.14 Treatment of 15 with trifluoromethane-
sulfonic acid (triflic acid, TfOH) in dichloromethane
promoted the intramolecular tandem glycosylation–spiro-
cyclization reaction,15 zipping up the tricyclic bis-
spiroketal core to give exclusively the a,b-configured
DFA derivative 16 (59% isolated yield).16 Simultaneous
removal of the xylylene and benzyl groups by catalytic
hydrogenolysis afforded the target fully unprotected dian-
hydride 4 in quantitative yield,17 whose structure was con-
firmed by comparison of its spectroscopic and
chromatographic properties with an authentic sample2,4d
(Scheme 1).
The synthesis of the contra-thermodynamic b,a-isomer 5
(less than 1% in the DFA fraction of commercial cara-
mels) represents a much more difficult challenge. The
configurational differences between 4 and 5 are not
associated with significant conformational changes, with
virtually identical inter-residue distances. Recent crystal-
lographic evidence,9a however, suggested that contra-
thermodynamic DFAs exhibit a relatively high conforma-
tional flexibility, whereas thermodynamic derivatives are
much more rigid. This intrinsic difference could be used
with advantage to achieve further diastereoselection. We
hypothesized that shortening the O-6–O-3¢ distance, e.g.
by inserting an o-xylylene tether (ca. 3 Å), would provoke
a substantial steric constrain in the chair ground-state
conformation that would be better accommodated by the
b,a-isomer 5.
Synlett 2007, No. 17, 2738–2742 © Thieme Stuttgart · New York

2740
F. Louis et al.
LETTER
Replacing the 3-O-(3-bromomethylbenzyl) fructopyra- incorporating this structural subunit,2 including 5. Thus,
nose monomer 13 into the 2-bromomethylbenzyl posi- the presence of the o-xylylene bridge causes the flip of the
tional isomer 1718 in the bridging reaction provided the 5C2 conformation (J3¢,4¢ = 3.2 Hz for 5) to the reverse 2C5
corresponding nonsymmetrical o-xylylene-tethered pre- disposition (J3¢,4¢ = 7.9 Hz for 19). Simultaneously, the
cursor 18.14 Activation of 18 with triflic acid likewise re- central 1,4-dioxane ring shifts to a skew-boat arrange-
sulted in bis-spiroketal ring-closing reaction15 to give, in ment, as seen by NOE contacts, thereby bringing closer
this case, a 1:1.5 binary mixture of the thermodynamic the bridged positions (dO-6–O-3¢ = 3.2 Å). The energetic
a,b-isomer 1919 and the contra-thermodynamic b,a-DFA cost of losing an anomeric effect stabilization is then over-
derivative 2020 (Scheme 2). Their structures were con- come by the release in the steric constrain imposed by the
firmed after transformation into the respective unpro- spacer.
tected compounds17 4 and 5 and comparison of their
In summary, the above results broaden the concept of
rigid-spacer-mediated spirocyclization by taking advan-
tage not only of distance restrictions but also of subtle
spectroscopic and gas-chromatographic data with authen-
tic samples.2,4d
molecular flexibility differences. The combination of both
aspects provides alternative opportunities for the stereose-
lective synthesis of complex bis-spiroketal frameworks.
O
O
O
The potential of the approach is illustrated by the rational
O
O
design of efficient syntheses for the nonsymmetrical
furanose–pyranose difructose dianhydrides 4 and 5.
O
OBn
BnO
Br
NaH
DMF
O
O
O
9
O
OBn
O
BnO
62%
O
18
17
Acknowledgment
BnO
OBn
We thank the Spanish Ministerio de Educación y Ciencia (contract
numbers CTQ2004-05854/BQU and CTQ2006-15515-C02-01/
BQU) and the Junta de Andalucía (P06-AGR-02115) for financial
support.
TfOH
CH2Cl2
52%
(1:1.5)
3.2 Å
O
6
O
6
5
4
O
O
BnO
5
O
2
O
References and Notes
2
3'
OBn
O
1
O
2'
O
3'
OBn
O
3
+
BnO
4
4'
1
(1) Permanent address: Department of Chemistry, Faculty of
Sciences, University of Alexandria, P.O. Box 426 Ibrahimia,
21321 Alexandria, Egypt.
BnO
3
2'
6'
1'
O
6'
4'
OBn
O
BnO
19
5'
20
OBn
5'
H2, Pd
99%
H2, Pd 99%
(2) For reviews, see: (a) Brimble, M. A.; Furkert, D. P. Curr.
Org. Chem. 2003, 7, 1. (b) Brimble, M. A.; Farès, F. A.
Tetrahedron 1999, 55, 7661. For selected recent references,
see: (c) Georgiu, T.; Tofi, M.; Montagnon, T.;
OH
OH
6.0 ± 0.5 Å
O
6.5 ± 0.5 Å
Vassilikogiannakis, G. Org. Lett. 2006, 8, 1945. (d) Zhou,
X.-T.; Carter, R. G. Angew. Chem. Int. Ed. 2006, 45, 1787.
(e) Fürstner, A.; Fenster, M. D. B.; Fasching, B.; Godbout,
C.; Radkowski, K. Angew. Chem. Int. Ed. 2006, 45, 5510.
(f) Liu, J.; Yang, J. H.; Ko, C.; Hsung, R. P. Tetrahedron
Lett. 2006, 47, 6121. (g) Meilert, K.; Brimble, M. A. Org.
Biomol. Chem. 2006, 4, 2184. (h) Paterson, I.; Anderson, E.
A.; Dalby, S. M.; Lim, J. H.; Maltas, P.; Moessner, C. Chem.
Commun. 2006, 4186. (i) Halim, R.; Brimble, M. A.;
Merten, J. Org. Lett. 2005, 7, 2659. (j) Sofikiti, N.;
Montagnon, T.; Vassilikogiannakis, G.; Stratakis, M. Org.
Lett. 2005, 7, 2357. (k) Paterson, I.; Anderson, E. A.; Dalby,
S. M.; Loiseleur, O. Org. Lett. 2005, 7, 4121.
HO
HO
O
HO
O
O
HO
O
OH
OH
HO
OH
OH
O
O
HO
5 (β,α) O
4 (α,β)
Scheme 2 o-Xylylene-mediated synthesis of DFA 5. The key
interatomic distances for the synthetic design are indicated.
The outstanding enhancement in the 5:4 relative propor-
tion (90-fold as compared with the nontemplated reaction)
by acting on the spacer length is remarkable. Examination
of the 1H NMR data revealed that the o-xylylene-tethered
a,b-derivative 19 keeps the same conformation at the six-
membered rings as compared with the m-positional iso-
mer 16 or the unprotected derivative 4, that is, the central
1,4-dioxane ring is in a chair conformation and the fructo-
(3) For a review, see: Manley-Harris, M.; Richards, G. N. Adv.
Carbohydr. Chem. Biochem. 1997, 52, 207.
(4) (a) Defaye, J.; García Fernández, J. M. Carbohydr. Res.
1994, 256, C1. (b) Defaye, J.; García Fernández, J. M.
Zuckerindustrie 1995, 120, 700. (c) Manley-Harris, M.;
Richards, G. N. Carbohydr. Res. 1996, 287, 183.
(d) Ratsimba, V.; García Fernández, J. M.; Defaye, J.;
Nigay, H.; Voilley, A. J. Chromatogr., A 1999, 844, 283.
(e) Christian, T. J.; Manley-Harris, M.; Field, R. J.; Parker,
B. A. J. Agric. Food Chem. 2000, 48, 1823. (f) Montilla,
A.; Ruiz-Matute, A. I.; Martínez-Castro, I.; del Castillo, M.
D. Food Res. Int. 2006, 39, 801. (g) Böhm, A.; Klessen, B.;
Henle, T. Eur. Food Res. Technol. 2006, 222, 737.
2
pyranose ring is in the C5 conformation. Partial steric
release can only be achieved at the expense of conforma-
tional distortion of the furanose ring. In contrast, the vici-
nal proton-proton coupling constants around the a-
fructopyranose ring in 19 evidenced a profound confor-
mational change as compared with reported data for DFAs
Synlett 2007, No. 17, 2738–2742 © Thieme Stuttgart · New York

LETTER
Difructose Dianhydrides
2741
(5) (a) Enderlin, G.; Taillefumier, C.; Didierjean, C.; Chapleur,
Y. Tetrahedron: Asymmetry 2005, 16, 2459. (b)vant Hooft,
P. A. V.; Oualid, F. E.; Overkleeft, H. S.; van der Marel, G.
A.; van Boom, J. H.; Leeuwenburgh, M. A. Org. Biomol.
Chem. 2004, 2, 1395. (c) Tatibouët, A.; Lawrence, S.;
Rollin, P.; Holman, G. D. Synlett 2004, 1945. (d) 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, 2632. (e) Li, X.; Takahashi, H.; Ohtake, H.;
Shiro, M.; Ikegami, S. Tetrahedron 2001, 57, 8053.
(f) García Fernández, J. M.; Ortiz Mellet, C.; Defaye, J. J.
Org. Chem. 1998, 63, 3572. (g) Bextermöller, R.; Redlich,
H.; Schnieders, K.; Thormählen, S.; Fröhlich, R. Angew.
Chem. Int. Ed. 1998, 37, 2496. (h) García Fernández, J. M.;
Schnelle, R.-R.; Defaye, J. Aust. J. Chem. 1996, 49, 319.
(i) García Fernández, J. M.; Schnelle, R.-R.; Defaye, J.
Tetrahedron: Asymmetry 1995, 6, 307.
(MgSO4), filtered, and concentrated. The resulting residue
was purified by column chromatography (EtOAc–PE, 2:1)
to give 12 (254 mg, 70%). Conventional benzylation of 12
(323 mg, 0.80 mmol) with NaH/BnBr afforded 13 (303 mg,
65%).
(14) General Procedure for the Preparation of (O-6→O-3¢)-
Xylylene-Tethered Fructofuranose–Fructopyranose
Derivatives (15 and 18)
To a solution of 2,3-di-O-benzyl-1,2-O-isopropylidene-b-D-
fructofuranose 149a (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 r.t. for 1 h. A
solution of 13 or 1713 (225 mg, 0.39 mmol) in anhyd DMF
(4 mL) was then added, the reaction mixture was further
stirred at r. t. for 3 h, quenched by addition of H2O (2 mL),
concentrated and the resulting residue was purified by
column chromatography using EtOAc–toluene (1:6) as
eluent to give 15 (190 mg, 54%) or 18 (220 mg, 62%).
(15) General Procedure for Xylylene-Mediated Synthesis of
Type II DFA Derivatives (16, 19, and 20)
(6) (a) Defaye, J.; Gadelle, A.; Pedersen, C. Carbohydr. Res.
1985, 136, 53. (b) Defaye, J.; García Fernández, J. M.
Carbohydr. Res. 1994, 251, 1. (c) Defaye, J.;
García Fernández, J. M. Carbohydr. Res. 1994, 251, 17.
(7) Defaye, J.; García Fernández, J. M. Carbohydr. Res. 1992,
237, 223.
To a solution of the corresponding m- or o-xylylene-tethered
precursor 15 or 18 (280 mg, 0.31 mmol) in CH2Cl2 (20 mL)
at –78 °C under Ar, TfOH (41 mL) was added. The reaction
mixture was allowed to reach r.t. and stirred for 1 h, then
quenched by addition of Et3N (0.1 mL) and concentrated.
Column chromatography of the resulting residue (1:3 → 1:1
EtOAc–PE for 15; 1:5 → 1:2 EtOAc–PE for 18) afforded 16
(142 mg, 59%) or 19 (48.7 mg, 20.8%) and 20 (72.8 mg,
31.2%), respectively, as the only intramolecular reaction
products.
(8) (a) Benito, J. M.; Gómez-García, M.; Ortiz Mellet, C.;
García Fernández, J. M.; Defaye, J. Org. Lett. 2001, 3, 549.
(b) Benito, J. M.; Rubio, E. M.; Gómez-G arcía, M.;
Ortiz Mellet, C.; García Fernández, J. M. Tetrahedron 2004,
60, 5899. (c) Balbuena, P.; Rubio, E. M.; Ortiz Mellet, C.;
García Fernández, J. M. Chem. Commun. 2006, 2610.
(9) (a) Rubio, E. M.; García-Moreno, M. I.; Balbuena, P.;
Lahoz, F. J.; Alvarez, E.; Ortiz Mellet, C.;
(16) Selected data for 16: [a]D22 +10.1 (c 0.9, CHCl3). 1H NMR
(500 MHz, CDCl3): d = 4.16 (d, 1 H, J1a¢,1b¢ = 11.6 Hz, H-
1¢a), 4.14 (m, 1 H, H-5), 4.00 (d, 1 H, J3,4 = 2.5 Hz, H-3),
3.99 (m, 1 H, H-6a), 3.96 (d, 1 H, J1a,1b = 11.8 Hz, H-1a),
3.94 (dd, 1 H, J3¢,4¢ = 9.5 Hz, J4¢,5¢ = 3.2 Hz, H-4¢), 3.83 (d, 2
H, J6a¢,6b¢ = 12.0 Hz, H-6¢a, H-1b), 3.74 (m, 1 H, H-6b), 3.72
(m, 1 H, H-5¢), 3.61 (d, 1 H, H-3¢), 3.60 (d, 1 H, H-6¢b), 3.54
(dd, 1 H, J4,5 = 7.5 Hz, H-4), 3.39 (d, 1 H, H-1¢b). 13C NMR
(125.7 MHz, CDCl3): d = 102.3 (C-2), 95.9 (C-2¢), 89.0 (C-
3), 85.1 (C-4), 80.1 (C-5), 78.9 (C-3¢), 78.6 (C-4¢), 73.5 (C-
5¢), 75.8 (CH2Ph), 74.8 (C-6), 74.3, 72.5, 72.3, 71.2
(CH2Ph), 62.5 (C-1¢), 62.0 (C-1), 60.3 (C-6¢). MS–FAB:
m/z (%) = 809 (60) [M + Na]+. Anal. Calcd for C48H50O10: C,
73.26; H, 6.40. Found: C, 73.07; H, 6.07.
García Fernández, J. M. J. Org. Chem. 2006, 71, 2257.
(b) Rubio, E. M.; Ortiz Mellet, C.; García Fernández, J. M.
Org. Lett. 2003, 5, 873.
(10) (a) Müller, M.; Huchel, U.; Geyer, A.; Schmidt, R.-R.
J. Org. Chem. 1999, 64, 6190. (b) Jung, K.-H.; Müller, M.;
Schmidt, R.-R. Chem. Rev. 2000, 100, 4423. (c)Müller,M.;
Schmidt, R.-R. Eur. J. Org. Chem. 2001, 2055.
(11) The term ‘contra-thermodynamic’ designates diastereomers
that are energetically strongly disfavored and, consequently,
cannot be accessed under reversible kinetics or
thermodynamic conditions. For examples of stereoselective
syntheses of contra-thermodynamic spiroacetals, see:
(a) Takaoka, L. R.; Buckmelter, A. J.; LaCruz, T. E.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2005, 127, 528.
(b) LaCruz, T. E.; Rychnovsky, S. D. Org. Lett. 2005, 7,
1873.
(17) General Procedure for the Synthesis of Fully
Unprotected DFAs (4 and 5)
Catalytic hydrogenation of 16 and 19 or 20 (0.038 mmol)
with 10% Pd/C in EtOAc–MeOH (1:1) containing 10%
HCOOH (1 mL) at 1 atm overnight, afforded the fully
unprotected bis-spiro fructodisaccharide 4 or 5 in
quantitative yield having physicochemical properties
identical to those reported.2,4d
(12) (a) Brady, R. F. Jr. Adv. Carbohydr. Chem. Biochem. 1971,
26, 197. (b) Lichtenthaler, F. W. Carbohydr. Res. 1998, 313,
69.
(13) 4,5-Di-O-benzyl-3-O-(3-bromomethylbenzyl)-1,2-O-
isopropylidene-b-d-fructopyranose (13)
To a solution of 1,3-bis(bromomethyl)benzene (1.99 g, 7.56
mmol, 2 equiv) in anhyd DMF (50 mL), NaH (60% in
mineral oil, 378 mg, 9.45 mmol) was added and the
suspension was stirred at r.t. for 15 min. Compound 1012
(1.0 g, 3.78 mmol) was then added and the reaction mixture
was further stirred for 24 h. Afterwards, Et2O (15 mL) and
H2O (15 mL) were added, the organic layer was separated,
washed with H2O (5 × 10 mL), dried (MgSO4), filtered, and
concentrated. The resulting residue was purified by column
chromatography (EtOAc–PE, 1:10) to yield 11 (955 mg,
57%). Compound 11 (400 mg, 0.9 mmol) was dissolved in
60% aq AcOH (2.4 mL) and stirred at 45 °C for 2 h. The
reaction mixture was then diluted with H2O (5 mL) and
extracted with EtOAc (4 × 4 mL). The combined organic
phase was washed with sat. aq NaHCO3 (6 mL), dried
(18) Rubio, E. M.; García-Moreno, M. I.; Balbuena, P.;
Ortiz Mellet, C.; García Fernández, J. M. Org. Lett. 2005, 7,
729.
(19) Selected data for 19: [a]D22 +4.9 (c 0.8, CHCl3). 1H NMR
(500 MHz, CDCl3): d = 4.06 (d, 1 H, J6a,6b = 12.6 Hz, H-6a),
4.01 (br d, 1 H, J4,5 = 8.7 Hz, H-5), 3.98 (dd, 1 H, J3¢,4¢ = 9.7
Hz, J4¢,5¢ = 3.1 Hz, H-4¢), 3.88 (d, 1 H, J3,4 = 3.7 Hz, H-3),
3.86 (d, 1 H, J1a,1b = 13.7 Hz, H-1a), 3.84 (m, 1 H, H-6b),
3.72 (dd, H, J6a¢,6b¢ = 11.5 Hz, J5¢,6a¢ = 3.0 Hz, H-6¢a), 3.71 (m,
1 H, H-5¢), 3.70 (d, 1 H, H-1b), 3.65 (d, 1 H, H-6¢b), 3.61 (dd,
1 H, H-4), 3.55 (d, 1 H, H-3¢), 3.39 (d, 1 H, J1a¢,1b¢ = 12.0 Hz,
H-1¢a), 3.05 (d, 1 H, H-1¢b). 13C NMR (125.7 MHz, CDCl3):
d = 102.0 (C-2), 95.2 (C-2¢), 88.8 (C-3), 86.2 (C-4), 79.6 (C-
5), 78.9 (C-4¢), 74.5 (C-3¢), 73.4 (C-5¢), 72.9, 72.5, 72.4,
72.0, 71.4 (CH2Ph), 71.2 (C-6), 68.5 (CH2Ph), 62.6 (C-1¢),
Synlett 2007, No. 17, 2738–2742 © Thieme Stuttgart · New York

2742
F. Louis et al.
LETTER
62.4 (C-1), 60.6 (C-6¢). ESI-MS: m/z = 809 [M + Na]+. Anal.
Calcd for C48H50O10: C, 73.26; H, 6.40. Found: C, 73.13; H,
6.48.
3.74 (dt, 1 H, J4¢,5¢ = J5¢,6b¢ = 3.0 Hz, H-5¢), 3.70 (d, 1 H, H-
1b), 3.65 (dd, 1 H, J6a,6b = 10.5 Hz, H-6a), 3.60 (t, 1 H, H-
6b), 3.52 (d, 1 H, H-1¢b), 3.45 (dd, 1 H, H-6¢b), 3.41 (dd, 1
H, H-4¢). 13C NMR (125.7 MHz, CDCl3): d = 101.4 (C-2),
97.7 (C-2¢), 85.1 (C-4), 84.7 (C-3), 79.0 (C-5), 78.0 (C-3¢),
76.3 (C-4¢), 72.9, 72.7, 72.0 (CH2Ph), 71.9 (C-6), 71.6 (C-
5¢), 71.2, 70.9, 70.2 (CH2Ph), 63.8 (C-1¢), 61.0 (C-6¢), 59.8
(C-1). ESI-MS: m/z = 809 [M + Na]+. Anal. Calcd for
C48H50O10: C, 73.26; H, 6.40. Found: C, 73.13; H, 6.06.
(20) Selected data for 20: [a]D22 +18.1 (c 1.0, CHCl3). 1H NMR
(500 MHz, CDCl3): d = 4.59 (d, 1 H, J1a,1b = 12.5 Hz, H-1a),
4.24 (dt, 1 H, J5,6b = 10.5 Hz, J5,6a = J4,5 = 4.5 Hz, H-5), 4.19
(d, 1 H, J1a¢,1b¢ = 11.4 Hz, H-1¢a), 4.15 (d, 1 H, J3¢,4¢ = 7.9 Hz,
H-3¢), 4.13 (dd, 1 H, J3,4 = 6.3 Hz, H-4), 4.05 (dd, 1 H,
J6a¢,6b¢ = 12.2 Hz, J5¢,6a¢ = 5.8 Hz, H-6¢a), 3.87 (d, 1 H, H-3),
Synlett 2007, No. 17, 2738–2742 © Thieme Stuttgart · New York

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