Spacer-mediated synthesis of contra-thermodynamic spiroacetals: Stereoselective synthesis of C2-symmetric difructose dianhydrides

Article abstract of DOI:10.1021/jo052184b

The xylylene moiety (ortho, meta, and para) was employed as a rigid tether in the spacer-mediated synthesis of difructose dianhydrides (DFAs), a unique class of bis-spiroacetal derivatives present in food products. The synthetic methodology exploits the s

Full text of DOI:10.1021/jo052184b

Spacer-Mediated Synthesis of Contra-Thermodynamic Spiroacetals:
Stereoselective Synthesis of C2-Symmetric Difructose Dianhydrides
Enrique M. Rubio,† M. Isabel Garc´ıa-Moreno,‡ Patricia Balbuena,† Fernando J. Lahoz,§
Eleuterio AÄ lvarez,† Carmen Ortiz Mellet,*,‡ and Jose´ M. Garc´ıa Ferna´ndez*,†
Instituto de InVestigaciones Qu´ımicas, CSIC, Ame´rico Vespucio 49, Isla de la Cartuja,
E-41092 SeVilla, Spain, Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica,
UniVersidad de SeVilla, Aptdo. 553, E-41071 SeVilla, Spain, and
Departamento de Qu´ımica Inorga´nica - I.C.M.A. Facultad de Ciencias,
UniVersidad de Zaragoza - CSIC, 50009 Zaragoza, Spain
jogarcia@iiq.csic.es; mellet@us.es
ReceiVed October 20, 2005
The xylylene moiety (ortho, meta, and para) was employed as a rigid tether in the spacer-mediated synthesis
of difructose dianhydrides (DFAs), a unique class of bis-spiroacetal derivatives present in food products.
The synthetic methodology exploits the suitability of triflic acid to promote spirocyclization in organic
solvents under irreversible reaction conditions, using anomeric isopropylidene fructose derivatives as
precursors. Advantage was taken of the strong dependence of the conformational properties of DFAs on
the relative configuration of the spiroketal centers. Highly stereoselective syntheses of the contra-
thermodynamic difructofuranose and difructopyranose diastereomers, namely the C2-symmetric derivatives
having the â-configuration at both anomeric centers, have been accomplished by judicious choice of the
xylylene positional isomer and of the linking position to the fructose building blocks. Interestingly, the
rigid spacer concept has also been implemented to favor intermolecular processes leading to higher
macrocyclic architectures that incorporate the bis-spiro fructodisaccharide subunit.
1. Introduction
interactions, are reinforcing, a major isomer is produced. In a
number of natural products, however, these factors are in
conflict, and these contra-thermodynamic acetals have been
more difficult to access.3 The difficulty is exacerbated for
polyfunctional tricyclic bis-spiroacetal systems, since then a
range of structures can usually accommodate the basic require-
ments, that is, oxygen substituents at spiroacetal centers in axial
orientation and carbon substituents in equatorial disposition, with
small differences in energy and low interconversion barriers.
This basic framework is the prevalent underlying structural
element of a unique class of spirodisaccharides isolated from
microorganisms and higher plants, namely di-D-fructose dian-
hydrides (DFAs).4 The identification of DFAs as the major
oligosaccharide components in some food products, such as
caramel or chicory,5 and their promising prebiotic properties4,6
have provided a further impetus to the synthesis of these and
related spirosugars.7
Spiroacetal substructures are widely distributed in natural
compounds with diverse origins, including plants, fungi, marine
organisms, and insects.1 Many of these compounds exhibit
important biological activities, and consequently, there is a
sustained interest in the stereocontrolled construction of these
moieties.2 Most methods rely on the acid-catalyzed cyclization
of a ketodiol intermediate and thus lead to a thermodynamic
mixture of spiroacetals. When all factors that control spiroket-
alization, i.e., a maximum anomeric effect and minimum steric
† Instituto de Investigaciones Qu´ımicas, CSIC.
‡ Universidad de Sevilla.
§ Universidad de Zaragoza - CSIC.
(1) For reviews, see: (a) Mead, K. T.; Brewer, B. N.Curr. Org. Chem.
2003, 7, 227-256. (b) M. A. Brimble, D. P. Furkert, Curr. Org. Chem.
2003, 7, 1-24. (c) Brimble, M. A.; Fare`s, F. A. Tetrahedron 1999, 55,
7661-7706. (d) Pietruszka, J. Angew. Chem., Int. Ed. 1998, 37, 2629-
2636. (e) Perron, F.; Albizati, K. F. Chem. ReV. 1989, 89, 1617-1661.
10.1021/jo052184b CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/18/2006
J. Org. Chem. 2006, 71, 2257-2266
2257

Rubio et al.
SCHEME 1. Spiroacetal Disaccharide Cores (Types I-V)
Formed by Acid Treatment of D-Fructose
DFAs are formed during protonic activation of fructose-
containing materials. Under such conditions, a fructosyl oxo-
carbenium cation is generated, which undergoes in situ glyco-
sylation to the corresponding ketodisaccharide. Further spiro-
acetalization is a reversible process that leads to a complex
mixture of spirodisaccharides in which the two D-fructose
constituents are joined through a central 1,4-dioxane ring. Up
to five different tricyclic cores and 13 DFA isomers that differ
in the ring size, linking position, and stereochemistry of the
acetal stereocenters have been identified from reaction mixtures
(Scheme 1).8 This structural and stereochemical diversity makes
DFAs ideal targets for evaluating new synthetic methodologies.
Thermodynamic DFAs have different configurations (R,â)
at the acetal centers and can position all oxygens to favor double
anomeric stabilization at each of them with the central 1,4-
dioxane ring in a chair conformation (Figure 1a). These DFAs
have been previously prepared by setting up an equilibrium and
then separating the major isomers.4,8 Such a scenario does not
(2) For selected recent references, see: (a) Halim, R.; Brimble, M. A.;
Merten, J. Org. Lett. 2005, 7, 2659-2662. (b) Ball, M.; Gaunt, M. J.; Hook,
D. F.; Jessiman, A. S.; Kawahara, S.; Orsini, P.; Scolaro, A.; Talbot, A.
C.; Tanner, H. R.; Yamanoi, S.; Ley, S. V. Angew. Chem., Int. Ed. 2005,
44, 5433-5438. (c) Tursun, A.; Canet, I.; Aboab, B.; Sinibaldi, M.-E.
Tetrahedron Lett. 2005, 46, 2291-2294. (d) Lopez, R.; Poupon, J.-C.;
Prunet, J.; Fe´re´zou, J.-P.; Ricard, L. Synlett 2005, 644-661. (e) Barun, O.;
Sommer, S.; Waldmann, H. Angew. Chem., Int. Ed. 2004, 43, 3195-3199.
(f) van Hooft, P. A. V.; Oualid, F. E.; Overkleeft, H. S.; van der Marel, G.
A.; van Boom, J. H.; Leeuwenbourg, M. A. Org. Biomol. Chem. 2004, 2,
1395-1403. (g) Sous, M. E.; Ganame, D.; Tregloan, P. A.; Rizzacasa, M.
A. Org. Lett. 2004, 6, 3001-3004. (h) Zanatta, S. D.; White, J. M.;
Rizzacasa, M. A. Org. Lett. 2004, 6, 1041-1044. (i) Yin, B.-L.; Hu, T.-S.;
Yue, H.-J.; Gao, Y.; Wu, W.-M.; Wu, Y.-L. Synlett 2004, 306-310. (j)
Caputo, R.; Ciriello, U.; Festa, P.; Guaragna, A.; Palumbo, G.; Petadella,
S. Eur. J. Org. Chem. 2003, 2617-2621. (k) Hubbs, J. L.; Heathcock, C.
H. J. Am. Chem. Soc. 2003, 125, 12836-12843. (l) Gaunt, M. J.; Jessiman,
A. S.; Orsini, P.; Tanner, H. R.; Hook, D. F.; Ley, S. V. Org. Lett. 2003,
5, 4819-4822. (m) Crimmins, M. T.; Katz, J. D.; Washburn, D. G.; Allwein,
S. P.; McAtee, L. F. J. Am. Chem. Soc. 2002, 124, 5661-5663. (n) Betancor,
C.; Freire, R.; Pe´rez-Mart´ın, I.; Prange´, T.; Sua´rez, E. Org. Lett. 2002, 4,
1295-1297. (o) Izquierdo, I.; Plaza, M. T.; Rodr´ıguez, M.; Tamayo, J. A.
Eur. J. Org. Chem. 2002, 309-317.
(3) The term “contra-thermodynamic” designates diastereomers that are
energetically strongly disfavored and, consequently, cannot be access under
reversible kinetics or thermodynamic conditions. For remarkable recent
examples of stereoselective syntheses of contra-thermodynamic spiroacetal
frameworks, see: (a) Takaoka, L. R.; Buckmelter, A. J.; LaCruz, T. E.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2005, 127, 528-529. (b) LaCruz, T.
E.; Rychnovsky, S. D. Org. Lett. 2005, 7, 1873-1875.
(4) For a review, see: Manley-Harris, M.; Richards, G. N. AdV.
Carbohydr. Chem. Biochem. 1997, 52, 207-266.
(5) (a) Defaye, J.; Garc´ıa Ferna´ndez, J. M. Carbohydr. Res. 1994, 256,
C1-C4. (b) Defaye, J.; Garc´ıa Ferna´ndez, J. M. Zuckerindustrie 1995, 120,
700-704. (c) Manley-Harris, M.; Richards, G. N. Carbohydr. Res. 1996,
287, 183-202. (d) Christian, T. J.; Manley-Harris, M.; Field, R. J.; Parker,
B. A. J. Agric. Food Chem. 2000, 48, 1823-1837.
prevail in the case of DFAs having identical configurations at
both acetal centers (R,R or â,â), for which full anomeric and
steric stabilization is not possible because one of the ring
oxygens would be necessarily equatorial in the chair arrange-
ment (Figure 1b). These contra-thermodynamic DFAs tend to
adopt instead a boat or skew-boat conformation at the central
ring, the gain on steric energy being compensated by a more
efficient anomeric effect stabilization (Figure 1c).9
(6) For selected recent reports, see: (a) Minamida, K.; Shiga, K.; Sujaka,
I. N.; Sone, T.; Yokota, A.; Hara, H.; Asano, K.; Tomita, F. J. Biosci.
Bioeng. 2005, 99, 230-236. (b) Hara, H.; Kondo, K. Biosci. Biotechnol.
Biochem. 2005, 69, 839-841. (c) Tamura, A.; Shiomi, T.; Tamaki, N.;
Shigematsu, N.; Tomita, F.; Hara, H. Biosci. Biotechnol. Biochem. 2004,
68, 1882-1887.
(7) (a) 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, 2632-2636. (b) Li, X.; Takahashi, H.; Ohtake, H.; Shiro, M.;
Ikegami, S. Tetrahedron 2001, 57, 8053-8066. (c) Garc´ıa Ferna´ndez, J.
M.; Ortiz Mellet, C.; Defaye, J. J. Org. Chem. 1998, 63, 3572-3580. (d)
Bextermo¨ller, R.; Redlich, H.; Schnieders, K.; Thrma¨hlen, S.; Fro¨lich, R.
Angew. Chem., Int. Ed. 1998, 37, 2496-2500. (e) Garc´ıa Ferna´ndez, J.
M.; Schnelle, R.-R.; Defaye, J. Aust. J. Chem. 1996, 49, 319-325. (f) Rubio,
E. M.; Garc´ıa-Moreno, M. I.; Balbuena, P.; Ortiz Mellet, C.; Garc´ıa
Ferna´ndez, J. M. Org. Lett. 2005, 7, 729-731.
(8) (a) Defaye, J.; Garc´ıa Ferna´ndez, J. M. Carbohydr. Res. 1994, 251,
1-15. (b) Defaye, J.; Garc´ıa Ferna´ndez, J. M. Carbohydr. Res. 1994, 251,
17-31. (c) Defaye, J.; Garc´ıa Ferna´ndez, J. M. Carbohydr. Res. 1992, 237,
223-247.
FIGURE 1. Chair (a and b) and boat (c) conformational arrangements
at the central 1,4-dioxane ring in thermodynamic (R,â; up) and contra-
thermodynamic DFAs (R,R or â,â; down).
We have previously reported the stereoselective preparation
of some R,â-thermodynamic and R,R-contra-thermodynamic
DFAs by using participating or nonparticipating protecting group
(9) Bock, K.; Pedersen, C.; Defaye, J.; Gadelle, A. Carbohydr. Res. 1991,
216, 141-148.
2258 J. Org. Chem., Vol. 71, No. 6, 2006

Spacer-Mediated Synthesis of Spiroacetals
motifs that shift the reaction outcome in the desired direction
under irreversible reaction conditions.10 A main limitation of
this approach was, however, its unsuitability to access the â,â-
contra-thermodynamic bis-spiroacetals. We speculated that the
above-mentioned conformational differences could be exploited
in the design of stereoselective syntheses of the elusive
thermodynamically unfavored DFA diastereomers. In this paper,
we utilize an approach that employs a rigid spacer judiciously
installed between the ketose moieties under reaction for the
remote control of the stereochemistry at the newly formed
spirocenters.11 Two conceptually different strategies have been
explored and compared, namely the use of xylylene positional
isomer spacers to promote intramolecular or, conversely,
intermolecular glycosylation-bis-spiroketalization. The syn-
thesis of the precursors, the influence of the tether structure on
the reaction outcome, and the scope and limitations of the
methods to access C2-symmetric bis-spiroacetals with the
1,6,9,13-tetraoxadispiro[4.2.4.2]tetradecane and 1,7,10,15-
tetraoxadispiro[5.2.5.2]hexadecane cores (type I and type III
DFAs) are discussed.
FIGURE 2. Conformations of the known type I (1-3) and type III (4
and 5) DFAs with indication of the O-6-O-6′ and O-3-O-3′
interatomic distances, respectively.
2. Results and Discussion
2.1. Retrosynthetic Analysis. Our strategy for the stereose-
lective synthesis of D-fructose-derived bis-spiroacetal derivatives
stems from the analysis of the particular conformational
properties of these compounds as dictated by stereoelectronic
factors. Three difuranoid type I DFAs, namely the nonsymmetric
R,â and the C2-symmetric R,R and â,â isomers (1-3), and two
dipyranoid type III DFAs, the R,â and â,â isomers (4 and 5,
respectively), are known. Examination of the respective mo-
lecular models revealed remarkable differences in the atomic
distances between homologous hydroxyl groups at the two
D-fructose subunits as a function of the relative stereochemistry
of the spiroacetal centers, assuming the limit chair and boat
arrangements at the central 1,4-dioxane ring. Thus, the primary
hydroxyl groups must be significantly closer in 2 and 3 as
compared with the thermodynamic DFA 1, while the distance
between the hydroxyl groups at positions C-3 and C-3′ should
be above 2 Å shorter in the contra-thermodynamic dipyranose
isomer 5 as compared with 4 (Figure 2). Consequently, the
introduction of a distance restriction between these nonreacting
hydroxyls was contemplated as a means for configurational
control.
FIGURE 3. Interatomic distances between the benzylic methylene
carbon atoms in the R,R′-dibromoxylene positional isomers 6-8.
alization reaction must be carried out under irreversible reaction
conditions. Following our previous work on the activation of
anomeric isopropylydene groups in benzyl-protected fructose
derivatives with trifluoromethanesulfonic acid,10b we conceived
the use of xylylene positional isomer spacers to comply with
those requirements.11
Preliminary calculations indicated that m- and o-xylylene
bridges might provide the appropriate distance to favor the boat
arrangement upon intramolecular bis-spirocyclization (Figure
3). The p-xylylene positional isomer would give rise to rather
constrained intramolecular bis-spiroacetals, both in the case of
chair or boat arrangements. Consequently, the intermolecular
reaction, leading initially to a linear dimer, was expected to occur
to a much greater extent. Interestingly, the molecular models
suggested that further macrocyclization would be strongly
favored in the case of the C2-symmetric contra-thermodynamic
derivatives, featuring a concave shape, while the nonsymmetric
thermodynamic derivatives would rather tent to oligomerize.
A comparative study of the reactivity of the m-, o-, and
p-xylylene-bridged precursors seemed, therefore, intriguing.
2.2. Synthesis of Xylylene-Tethered D-Fructose Precursors.
To install the xylylene tether onto the D-fructofuranose scaffold,
the reaction sequence depicted in Scheme 2 was implemented.
Regioselective tert-butyldimethylsilylation of the primary hy-
droxyl in the 1,2-O-isopropylidene derivative 9 (f 10), available
in one step from the commercial monosaccharide,12 followed
by protection of the secondary hydroxyls as benzyl ethers
(f 11), fluorolysis of the silyl group (f 12), and nucleophilic
substitution reaction of the resulting alcohol with the corre-
To check this concept, some prior considerations are impor-
tant. First, the ring size of the fructose precursors must be
preserved during the glycosylation-spiroketalization process.
Second, both the protecting groups and the tether group must
be stable under the acidic conditions needed for spiroacetal
formation and easily removable in a later step. Third, since
contra-thermodynamic spiroacetals have a strong tendency to
isomerize to give the thermodynamic derivatives, the spiroket-
(10) (a) Benito, J. M.; Go´mez-Garc´ıa, M.; Ortiz Mellet, C.; Garc´ıa
Ferna´ndez, J. M.; Defaye, J. Org. Lett. 2001, 3, 549-552. (b) Benito, J.
M.; Rubio, E. M.; Go´mez-Garc´ıa, M.; Ortiz Mellet, C.; Garc´ıa Ferna´ndez,
J. M. Tetrahedron 2004, 60, 5899-5906.
(11) The rigid spacer concept has been previously exploited in anomeric
configuration control during glycosidic bond-forming reactions. See: (a)
Mu¨ller, M.; Huchel, U.; Geyer, A.; Schmidt, R.-R. J. Org. Chem. 1999,
64, 6190-6201. (b) Jung, K.-H.; Mu¨ller, M.; Schmidt, R.-R. Chem. ReV.
2000, 100, 4423-4442. (c) Mu¨ller, M.; Schmidt, R.-R. Eur. J. Org. Chem.
2001, 2055-2066. For a preliminary communication on the extension of
this concept to the synthesis of C2-symmtric carbohydrate-derived spiroac-
etals, see: (d) Rubio, E. M.; Ortiz Mellet, C.; Garc´ıa Ferna´ndez, J. M. Org.
Lett. 2003, 5, 873-876.
(12) Chittenden, G. J. F. J. Chem. Soc., Chem. Commun. 1980, 882-
883.
J. Org. Chem, Vol. 71, No. 6, 2006 2259

Rubio et al.
SCHEME 2. Tethering Reaction Sequence for
Difructofuranose Derivativesa
bis-spirocylization (28, 31, and 34, respectively), as seen from
mass spectrometry data. In the case of the m-xylylene derivative,
the intramolecular fraction (78%) consisted of an inseparable
1:2 mixture of the tetracyclic spiro-disaccharides having the R,â
(26) and R,R (27) configuration at the new stereogenic centers.
The thermodynamic R,â isomer was not detected in the
corresponding fraction obtained from the o- and p-xylylene-
tethered derivatives, which contained exclusively the contra-
thermodynamic C2-symmetric bis-spirocetals with R,R (29 and
32) and â,â (30 and 33) anomeric configurations. Compounds
29 and 30 (88% yield, 1:9 relative proportion) could be separated
and characterized in pure form. In the case of the p-xylylene
derivative, the intramolecular reaction was actually disfavored
(19% yield), affording a 4:1 mixture of 32 and 33 (Scheme 4).
Simultaneous removal of the xylylene spacer and the benzyl
protecting groups was accomplished in quantitative yield by
catalytic hydrogenolysis. The identity and the relative propor-
tions of isomeric DFAs were established by gas chromatography
after trimethylsilylation of the mixtures of the unprotected
compounds 1-3 and comparison with authentic standards.14 The
pure spirodisaccharides could be obtained by column chroma-
tography of the corresponding peracetylated products and further
deacetylation as previously reported.15-17 Hydrogenation of 29
and 30 separately afforded exclusively the pure bis-spirodisac-
charides 2 and 3, respectively, discarding any possible isomer-
ization reaction during the deprotection step. Upon treatment
with mineral acid in water solution, both 2 and 3 rapidly
isomerized to give mixtures where the thermodynamic bis-
spiroacetals, having R,â configuration at anomeric centers, were
the predominating structures, thus confirming their contra-
themodynamic character.
a Reagents and conditions: (i) TBDMSCl, imidazole, DMF, rt, 16 h;
(ii) BnBr, NaH, DMF, rt, 5 h; (iii) TBAF, THF, 0 °C, 3 h; (iv) NaH, DMF,
6-8, rt, 1 h.
SCHEME 3. Tethering Reaction Sequence for
Difructopyranose Derivativesa
No pure compounds could be isolated from the respective
macrocyclic fractions 28 (16%), 31 (6%), and 34 (68%).
Catalytic hydrogenation of the crude mixtures provided the R,â
(1) and R,R (2) diastereomers in 1:2 relative proportion in the
three cases (Scheme 4).
It is worth mentioning that, using the above reaction condi-
tions, the intermolecular dimerization of the unbridged tri-O-
benzylated derivative of 1 afforded the corresponding R,â and
R,R diastereomers in 3:1 relative proportion.10b In the intramo-
lecular transformation, the xylylene spacer favors first the
construction of a large ring upon the glycosylation step and then
a boat conformation in the dioxane central ring during spiroac-
etalization, resulting in a reverse diastereoselection. In the
intermolecular process, the second bis-spirocyclization reaction
leading to macrocyclic derivatives is favored in the case of
symmetric arrangements, which also result in the contra-
thermodynamic R,R framework being the major substructure.
The differences in the stereoselectivity of the above spiro-
cyclization reactions as a function of the substitution pattern of
the xylylene spacer are remarkable and must be ascribed to the
interplay of stereoelectronic effects at the 1,4-dioxane ring and
the geometrical constraints imposed by the rigid tether. It is
known that stereoelectronic effects do also influence the
conformations of the five-membered rings in DFAs. Thus, R-D-
a Reagents and conditions: (i) NaH, DMF, 6-8, rt, 1 h; (ii) 60% aq
AcOH, 45 °C, 2 h; (iii) BnBr, NaH, DMF, rt, 4 h.
sponding R,R′-dibromoxylene 6-8 afforded the target dimers
13-15. The preparation of the D-fructopyranose analogues 23-
25 started by the tethering reaction of the readily available 1,2:
4,5-diacetonide 1613 (f 17-19). Regioselective hydrolysis of
the nonanomeric acetal group (f 21-23) and subsequent
benzylation provided the desired C2-symmetric precursors
(Scheme 3).
2.3. Synthesis of Fructofuranosyl Bis-spiroacetals (Type
I DFAs). Activation of the xylylene-tethered difuranose deriva-
tives 13-15 with trifluoromethanesulfonic acid (TfOH) in
dichloromethane promoted the tandem isopropylidene cleav-
age-glycosylation-spiroketalization transformation. In the three
cases, two groups of products, accounting for 82-94% of the
total reaction mixture, were formed, corresponding to the
intramolecular reaction compounds (26 and 27; 29 and 30; and
32 and 33) and the macrocyclic derivatives resulting from double
(14) Ratsimba, V.; Garc´ıa Ferna´ndez, J. M.; Defaye, J.; Nigay, H.,
Voilley, A. J. Chromatogr. A 1999, 844, 283-293.
(15) Defaye, J.; Gadelle, A.; Pedersen, C. Carbohydr. Res. 1985, 136,
53-65.
(16) Defaye, J.; Gadelle, A.; Pedersen, C. Carbohydr. Res. 1988, 174,
323-329.
(17) Manley-Harris, M.; Richards, G. N. Carbohydr. Res. 1996, 287,
183-202.
(13) (a) Brady, Jr., R. F. AdV. Carbohydr. Chem. Biochem. 1971, 26,
197-278. (b) Lichtenthaler, F. W. Carbohydr. Res. 1998, 313, 69-89.
2260 J. Org. Chem., Vol. 71, No. 6, 2006

Spacer-Mediated Synthesis of Spiroacetals
SCHEME 4. Synthesis of Type I DFAsa
a Reagents and conditions: (i) TfOH, CH2Cl2, rt, 1 h (see table inset for yields; n.d.: not detected); (ii) 10% Pd/C, H2, 1:1 EtOAc-MeOH, 10% HCOOH.
fructofuranose rings in DFA derivatives have been shown to
The lower yield, but higher stereoselectivity, of the intramo-
lecular reactions in dipyranose derivatives, in comparison with
the difuranose series, is probably due to the higher rigidity of
the resulting tetracyclic systems as a consequence of the
attachment of the xylylene segment to secondary hydroxyl
groups. Noteworthy, a strong preference was also observed for
the contra-thermodynamic â,â-structure in the macrocyclic
fractions (37, 39, and 40). Thus, after catalytic hydrogenation
the unprotected spiro-disaccharides 4 and 5 were obtained in
1:6 relative proportion. That strongly suggests that the first bis-
spiroacetal formed in the intermolecular reaction acted as a
tether-like template to control the stereochemical issues of the
next intramolecular bis-spirocyclyzation process during mac-
rocyclic ring formation.19 Although no pure compounds could
be isolated from the m- and o-xylylene-bridged macrocyclic
fractions, in the case of the p-xylylene positional isomer the
main reaction product could be separated by crystallization (35%
yield). Single crystal X-ray diffraction let ascribe unequivocally
the all-â,â 40 structure. Consequently, after catalytic hydrogena-
tion the di-â-fructopyranose DFA 5 was the only reaction
product (Scheme 5).
3
1
adopt a rather rigid E conformation by X-ray, H NMR and
molecular modeling data.4 In â-linked D-fructofuranosyl moi-
eties, however, skewed conformations around EO are privileged.4
As a consequence, the hydroxymethyl groups in C2-sym-
metric difuranose DFA derivatives are further apart in the case
of the di-R isomer 2 and drawn nearer in the case of the di-â
counterpart 3, which is in agreement with the later isomer being
strongly favored for the shorter o-xylylene spacer. This
represents the first stereoselective synthesis of this particu-
lar DFA, a minor constituent of fructose and sucrose cara-
mel.14
2.4. Synthesis of Fructopyranosyl Bis-spiroacetals (Type
III DFAs). Treatment of the m-xylylene-bridged difructopyra-
nose derivative 23 with trifluoromethanesulfonic acid in dichlo-
romethane led to a mixture of the corresponding bis-spirodis-
accharides 35 (R,â) and 36 (â,â) in 1:4 relative proportion (59%
yield), together with an inseparable mixture of macrocyclic
products 37 (24% yield), resulting from double bis-spirocy-
clization reaction. Considering that the dimerization reaction
of 3,4,5-tri-O-benzyl-1,2-O-isopropylydene-â-D-fructopyranose,
an untethered analogue of 23, led to a 25:1 ratio in favor of the
R,â-diastereomer,10b the selectivity toward the C2-symmetric â,â
counterpart in the intramolecular reaction is increased by a factor
of 100. Further shortening the intermonosaccharide distance by
using the o-xylylene tether (24) afforded the di-â DFA derivative
38 as the sole intramolecular reaction product (42% yield)
together with the corresponding macrocyclic compounds 39
(35%). Conversely, the larger p-xylylene bridge (25) totally
prevented intramolecular spirocyclization, leading exclusively
to the formation of the macrocyclic compounds 40 in 72% yield.
Catalytic hydrogenolysis of 35 quantitatively yielded the fully
deprotected thermodynamic type III DFA 4, while 36 and 38
provided exclusively the contra-thermodynamic diastereomer
5 (Scheme 5).18
Interestingly, the crystal structure of the all-â,â 40 derivative
(Figure 3) evidenced a significantly distorted chair conformation
at the 1,4-dioxane rings (Figure 4), instead of the skew-boat
conformation previously observed in the crystal structure of the
complex of the parent DFA 5 with Sr2+ 20
Most probably,
.
(18) A stereospecific synthesis of 5, via a transient fructosyl fluoride
intermediate, has previously been reported. See: Garc´ıa Ferna´ndez, J. M.;
Schnelle, R.-R.; Defaye, J. Tetrahedron: Asymmetry 1995, 6, 307-312.
(19) 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, 8260-8261.
(20) (a) Angyal, S. J.; Craig, D. C.; Defaye, J.; Gadelle, A. Can. J. Chem.
1990, 68, 1140-1144. (b) Gattuso, G.; Nepogodiev, S. A.; Stoddart, J. F.
Chem. ReV. 1998, 98, 1919-1958.
J. Org. Chem, Vol. 71, No. 6, 2006 2261

Rubio et al.
SCHEME 5. Synthesis of Type III DFAsa
FIGURE 4. Structure of all-â,â 40 in the crystal. Hydrogens are
omitted for clarity. One of the benzyl groups, showing disorder, is
depicted in the two different positions apparently observed.
for the preparation of a new type of spiroacetal-arene hybrid
polycyclic receptors. On the whole, a powerful methodology
for spiroacetal synthesis in general can be based on this new
conceptual approach.
3. Experimental Section
6-O-tert-Butyldimethylsilyl-1,2-O-isopropylidene-â-D-fructo-
furanose (10). To a solution of 1,2-O-isopropylidene-â-D-fructo-
furanose12 9 (1.288 g, 5.8 mmol) and imidazole (596 mg, 8.8 mmol)
in DMF (25 mL) was added tert-butylchlorodimethylsilane (970
mg, 6.44 mmol), and the reaction mixture was stirred overnight.
The solvent was removed under reduced pressure, the residue was
partitioned between CH2Cl2 and water, and the organic layer was
washed with water, dried (MgSO4), filtered, and concentrated.
Yield: 1.878 g (96%). Rf ) 0.70 (3:1 EtOAc-petroleum ether).
a Reagents and conditions: (i) TfOH, CH2Cl2, rt, 1 h (see table inset for
yields; n.d.: not detected); (ii) 10% Pd/C, H2, 1:1 EtOAc-MeOH, 10%
HCOOH.
1
[R]D ) -27.0 (c 1.2, CH2Cl2). H NMR (500 MHz, CDCl3): δ
contra-thermodynamic DFAs exibit a conformational equilib-
rium in solution rather than a defined conformation at the central
ring. It any case, the barrier on going from the chair to the boat
conformation must be much lower in the contra-thermodynamic
DFAs as compared with the thermodynamic counterparts. Our
results show that these differences in conformational barriers
can be put forward in the design of stereoselective syntheses of
tricyclic bis-spiroacetal systems.
2.5. Summary and Conclusions. The results here reported
demonstrate that the rigid spacer concept can be successfully
applied to the control of the stereochemistry in the preparation
of bis-spiroacetals. This is particularly noteworthy for fructose
derivatives because two (intramolecular reaction) or four
(intermolecular macrocyclization) quaternary stereogenic centers
are formed with high anomeric control, which is generally not
observed for fructosyl donors. Limiting the conformational space
during the intramolecular reaction leading to the bis-spiroketal
framework, by judicious choice of the spacer and of the linking
positions on the reactive subunits, allows access to the ther-
modynamically less stable C2-symmetric diastereomers with
high stereoselectivity. On the other hand, the spacer can be tuned
to prevent the intramolecular process, then favoring the forma-
tion of higher macrocycles while still controlling the stereo-
chemical outcome, which may represent an original strategy
(ppm) 4.07 (d, 1 H, J1a,1b ) 9.2 Hz, H-1a), 4.03 (dd, 1 H, J3,4
)
7.8 Hz, J4,5 ) 6.3 Hz, H-4), 4.01 (d, 1 H, H-1b), 3.92 (d, 1 H,
H-3), 3.76 (dd, 1 H, H-5), 3.76 (d, 1 H, J6a,6b ) 12.1 Hz, J5,6a
)
5.3 Hz, H-6a), 3.65 (dd, 1 H, J5,6b ) 7.8 Hz, H-6b), 2.77 (bs, 2 H,
2 OH), 1.38, 1.47 (2 s, each 3 H, CMe2), 0.88 (s, 9 H, SiCMe3),
0.06 (s, 6 H, SiMe2). 13C NMR (125.7 MHz, CDCl3): δ (ppm)
111.3 (CMe2), 108.6 (C-2), 80.6 (C-5), 77.4 (C-3, C-4), 70.9 (C-
1), 64.6 (C-6), 26.2, 26.5 (CMe2), 25.8 (SiCMe3), 18.3 (SiCMe3),
-5.5 (SiMe2). FABMS: m/z 357 (100, [M + Na]+). Anal. Calcd
for C15H30O6Si: C, 55.14; H, 9.25. Found: C, 55.24; H, 9.40.
3,4-Di-O-benzyl-6-O-tert-butyldimethylsilyl-1,2-O-isopropyl-
idene-â-D-fructofuranose (11). To a solution of 10 (760 mg, 2.2
mmol) in dry DMF (30 mL) were added NaH (360 mg, 9 mmol)
and benzyl bromide (1.40 mL, 11 mmol). The reaction mixture
was stirred for 5 h at room temperature, MeOH (10 mL) was added,
and the solvent was evaporated. The resulting residue was extracted
with Et2O (30 mL), washed with water (10 mL), dried (MgSO4),
concentrated, and purified by column chromatography (1:8 EtOAc-
petroleum ether) to yield 11 (1.07 g, 95%). Rf ) 0.58 (1:5 EtOAc-
1
petroleum ether). [R]D ) -37.2 (c 1.0, CH2Cl2). H NMR (300
MHz, CDCl3): δ (ppm) 7.39-7.43 (m, 10 H, 2 Ph), 4.62-4.80
(m, 4 H, 2 CH2), 4.25 (dd, 1 H, J3,4 ) 6.3 Hz, J4,5 ) 4.4 Hz, H-4),
4.11 (d, 1 H, J1a,1b ) 9.2 Hz, H-1a), 4.07 (d, 1 H, H-3), 4.02 (m,
1 H, H-5), 3.98 (d, 1 H, H-1b), 3.81 (m, 2 H, H-6a, H-6b), 0.17 (s,
6 H, SiMe2), 1.53, 1.56 (2 s, each 3 H, CMe2), 0.98 (s, 9 H,
SiCMe3). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 127.6-139.5
2262 J. Org. Chem., Vol. 71, No. 6, 2006

Spacer-Mediated Synthesis of Spiroacetals
(Ph), 111.3 (CMe2), 108.8 (C-2), 84.9 (C-5), 83.0 (C-4), 81.9 (C-
3), 72.1, 72.2 (CH2), 71.2 (C-1), 64.8 (C-6), 26.3, 26.4 (CMe2),
25.9 (SiCMe3), 18.3 (SiCMe3), -5.5 (SiMe2). FABMS: m/z 537
(10, [M + Na]+), 457 (20, [M - tBu]+). Anal. Calcd for C29H42O6-
Si: C, 67.66; H, 8.22. Found: C, 67.69; H. 8.03.
J1a,1b ) 9.0 Hz, H-1a), 3.99 (d, 2 H, J3,4 ) 6.0 Hz, H-3), 3.92 (d,
2 H, H-1b), 3.62 (dd, 2 H, J6a,6b ) 10.0 Hz, J5,6a ) 6.5 Hz, H-6a),
3.56 (dd, 2 H, J5,6b ) 6.0 Hz, H-6b), 1.46, 1.43 (2 s, each 6 H, 2
CMe2). 13C NMR (125.7 MHz, CDCl3): δ (ppm) 138.0-127.7 (Ph),
111.5 (CMe2), 109.0 (C-2), 84.4 (C-4), 83.1 (C-3), 80.2 (C-5), 73.3,
72.2, 72.0 (CH2Ph), 72.3 (C-6), 71.3 (C-1), 26.5 (CMe2). FABMS:
m/z 925 (10, [M + Na]+). Anal. Calcd for C54H62O12: C, 71.82;
H, 6.92. Found: C, 71.84; H, 6.67.
General Procedure for the Preparation of (O-3fO-3′)-
Xylylene-Tethered Fructopyranose Derivatives 17-19. To a
solution of 1,2:4,5-di-O-isopropylidene-â-D-fructopyranose13 16
(490 mg, 1.88 mmol) in dry DMF (20 mL) was added NaH (188
mg, 4.71 mmol), and the suspension was stirred at room temperature
for 15 min. A solution of the corresponding bis(bromomethyl)-
benzene 6-8 (249 mg, 0.94 mmol) was then added, and the reaction
mixture was further stirred for 1 h at room temperature. The reaction
was quenched by addition of Et2O (8 mL) and water (4 mL), and
the organic layer was separated and washed with water (5 × 5
mL), dried (MgSO4), concentrated, and purified by column chro-
matography (1:3 EtOAc-petroleum ether).
3,4-Di-O-benzyl-1,2-O-isopropylidene-â-D-fructofuranose (12).
To a stirred solution of 11 (590 mg, 1.14 mmol) in THF (25 mL)
under Ar was added TBAF (1 m in THF, 114 µL, 1.0 equiv) at 0
°C. The reaction mixture was stirred for 3 h until dissappearance
of the starting material, diluted with Et2O (25 mL), washed with
water (2 × 10 mL), dried (MgSO4), filtered, and concentrated.
Purification of the residue by column chromatography (1:2 EtOAc-
petroleum ether) gave 12 (521 mg, 92%). Rf ) 0.10 (1:5 EtOAc-
1
petroleum ether). [R]D ) -77.0 (c 1.0, CH2Cl2). H NMR (500
MHz, CDCl3): δ (ppm) 7.30-7.38 (m, 10 H, 2 Ph), 4.74-4.57
(m, 4 H, 2 CH2), 4.41 (dd, 1 H, J3,4 ) 7.1 Hz, J4,5 ) 9.3 Hz, H-4),
4.06 (dd, 1 H, J1a,1b ) 11.2 Hz, H-1a), 4.05 (d, 1 H, H-3), 4.04
(ddd, 1 H, J5,6a ) 3.0 Hz, J5,6b ) 3.8 Hz, H-5), 3.97 (d, 1 H, H-1b),
3.75 (dd, 1 H, J6a,6b ) 12.1 Hz, H-6a), 3.59 (dd, 1 H, H-6b), 2.53
(bs, 1 H, OH), 1.53, 1.47 (2 s, each 3 H, CMe2). 13C NMR (125.7
MHz, CDCl3): δ ) 111.7 (CMe2), 127.6-139.6 (Ph), 108.5 (C-
2), 83.2 (C-5), 81.8 (C-4), 81.7 (C-3), 72.2, 72.8 (CH2), 71.1 (C-
1), 63.4 (C-6), 26.1, 26.4 (CMe2). FABMS: m/z 423 (100, [M +
Na]+). Anal. Calcd for C23H28O6: C, 68.98; H, 7.05. Found: C,
68.94; H, 6.99.
1,3-Bis[(1,2:4,5-di-O-isopropylidene-â-D-fructopyranos-3-O-
yl)methyl]benzene (17). Yield: 489 mg (84%). Rf ) 0.41 (2:5
EtOAc-petroleum ether). [R]D ) -110.7 (c 1.05, CHCl3). 1H NMR
(400 MHz, CDCl3): δ (ppm) 7.29-7.24 (m, 4 H, Ph), 4.93, 4.61
2
(2 d, 2 H, JH,H ) 12.0 Hz, CHPh), 4.35 (dd, 2 H, J3,4 ) 7.2 Hz,
General Procedure for the Preparation of (O-6fO-6′)-
Xylylene-Tethered Fructofuranose Derivatives 13-15. To a
solution of 12 (450 mg, 1.123 mmol) in dry DMF (10 mL) was
added NaH (60 mg, 2.81 mmol). The suspension was stirred for 5
min, and then the corresponding bis(bromomethyl)benzene 6-8
(148.5 mg, 0.56 mmol) was added. The reaction mixture was stirred
for 1 h at room temperature, and the reaction was quenched by
addition of saturated aqueous NH4Cl. The solvents were evaporated,
and the residue was partitioned between Et2O (20 mL) and water
(20 mL). The organic phase was separated, washed with water (2
× 10 mL), dried (Na2SO4), filtered, and concentrated. The resulting
residue was purified by column chromatography (1:3 EtOAc-
petroleum ether).
J4,5 ) 5.6 Hz, H-4), 4.20 (dd, 2 H, J5,6a ) 2.4 Hz, H-5), 4.12 (dd,
2 H, J6a,6b ) 13.6 Hz, H-6a), 4.05 (d, 2 H, J1a,1b ) 8.4 Hz, H-1a),
3.93 (d, 2 H, H-6b), 3.86 (d, 2 H, H-1b), 3.47 (d, 2 H, H-3), 1.51,
1.47, 1.36, 1.25 (4 s, 24 H, CMe2). 13C NMR (100.6 MHz,
CDCl3): δ (ppm) 138.3-126.9 (Ph), 112.1, 109.0 (CMe2), 104.4
(C-2), 77.7 (C-4), 76.2 (C-3), 73.8 (C-5), 73.0 (C-1), 71.9 (CH2-
Ph), 60.2 (C-6), 28.2, 26.9, 26.2, 26.1 (CMe2); FABMS: m/z 645
(30, [M + Na]+). Anal. Calcd for C32H46O12: C, 61.72; H, 7.45.
Found: C, 61.46; H, 7.27.
1,2-Bis[(1,2:4,5-di-O-isopropylidene-â-D-fructopyranos-3-O-
yl)methyl]benzene (18). Yield: 437 mg (75%). Rf ) 0.41 (2:5
EtOAc-petroleum ether). [R]D ) -73.9 (c 1.05, CHCl3). 1H NMR
(400 MHz, CDCl3): δ (ppm) 7.31-7.22 (m, 4 H, Ph), 5.30 (s, 2
2
1,3-Bis[(3,4-di-O-benzyl-1,2-O-isopropylidene-â-D-fructofura-
H, CH2Ph), 5.09, 4.64 (2 d, 2 H, JH,H ) 12.0 Hz, CHPh), 4.33
nos-6-O-yl)methyl]benzene (13). Yield: 441 mg (87%). Rf ) 0.47
(dd, 2 H, J3,4 ) 7.2 Hz, J4,5 ) 6.4 Hz, H-4), 4.18 (ddd, 2 H, J5,6b
) 5.6 Hz, J5,6a ) 1.2 Hz, H-5), 4.11 (dd, 2 H, J6a,6b ) 13.2 Hz,
H-6a), 3.98 (dd, 2 H, H-6b), 3.93 (d, 2 H, J1a,1b ) 8.4 Hz, H-1a),
3.82 (d, 2 H, H-1b), 3.48 (d, 2 H, H-3), 1.64, 1.54, 1.36, 1.35 (4 s,
24 H, CMe2). 13C NMR (100.6 MHz, CDCl3): δ (ppm) 136.2-
127.6 (Ph), 112.1, 109.0 (CMe2), 104.4 (C-2), 77.7 (C-4), 76.4 (C-
3), 73.8 (C-5), 72.0 (C-1), 70.5 (CH2Ph), 60.2 (C-6), 28.2, 26.8,
26.2 (CMe2). FABMS: m/z 645 (30, [M + Na]+). Anal. Calcd for
C32H46O12: C, 61.72; H, 7.45. Found: C, 61.88; H, 7.59.
1
(2:5 EtOAc-petroleum ether). [R]D ) -30.3 (c 0.6, CHCl3). H
NMR (500 MHz, CDCl3): δ (ppm) 7.31-7.22 (m, 24 H, 5 Ph),
4.70-4.56 (m, 12 H, 6 CH2Ph), 4.13 (m, 4 H, H-4, H-5), 4.04 (d,
2 H, J1a,1b ) 9.5 Hz, H-1a), 4.01 (d, 2 H, J3,4 ) 6.0 Hz, H-3), 3.94
(d, 2 H, H-1b), 3.64 (dd, 2 H, J6a,6b ) 10.0 Hz, J5,6a ) 6.0 Hz,
H-6a), 3.58 (dd, 2 H, J5,6b ) 6.0 Hz, H-6b), 1.48, 1.44 (2 s, each
6 H, 2 CMe2). 13C NMR (125.7 MHz, CDCl3): δ (ppm) 138.5-
127.0 (Ph), 111.8 (CMe2), 109.1 (C-2), 84.5 (C-4), 83.0 (C-3), 80.2
(C-5), 73.5, 72.2, 72.0 (CH2Ph), 72.1 (C-6), 71.2 (C-1), 27.4 (CMe2).
FABMS: m/z 925 (70, [M + Na]+). Anal. Calcd for C54H62O12:
C, 71.82; H, 6.92. Found: C, 71.83; H, 6.63.
1,4-Bis[(1,2:4,5-di-O-isopropylidene-â-D-fructopyranos-3-O-
yl)methyl]benzene (19). Yield: 527 mg, 83%. Rf ) 0.41 (2:5
EtOAc-petroleum ether). [R]D ) -108.3 (c 0.62, CHCl3). 1H NMR
(500 MHz, CDCl3): δ (ppm) 7.30-7.21 (m, 4 H, Ph), 4.93, 4.62
1,2-Bis[(3,4-di-O-benzyl-1,2-O-isopropylidene-â-D-fructofura-
nos-6-O-yl)methyl]benzene (14). Yield: 416 mg (82%). Rf ) 0.50
(2:5 EtOAc-petroleum ether). [R]D ) -26.7 (c ) 0.7 in CHCl3).
1H NMR (500 MHz, CDCl3): δ ) 7.31-7.22 (m, 24 H, 5 Ph),
4.70-4.54 (m, 12 H, 6 CH2Ph), 4.09 (m, 4 H, H-4, H-5), 4.02 (d,
2 H, J1a,1b ) 9.5 Hz, H-1a), 3.98 (d, 2 H, J3,4 ) 6.5 Hz, H-3), 3.92
(d, 2 H, H-1b), 3.61 (dd, 2 H, J6a,6b ) 9.5 Hz, J5,6a ) 6.0 Hz, H-6a),
3.58 (dd, 2 H, J5,6b ) 6.0 Hz, H-6b), 1.45, 1.41 (2 s, each 6 H, 2
CMe2). 13C NMR (125.7 MHz, CDCl3): δ ) 137.9-127.7 (Ph),
111.5 (CMe2), 109.0 (C-2), 84.4 (C-4), 83.1 (C-3), 80.1 (C-5), 72.4,
72.3, 72.0 (CH2Ph), 72.1 (C-6), 71.3 (C-1), 26.4 (CMe2). FABMS:
m/z 925 (20%, [M + Na]+). Anal. Calcd for C54H62O12: C, 71.82;
H, 6.92. Found: C, 71.74; H, 7.00.
2
(2 d, 4 H, JH,H ) 11.9 Hz, CHPh), 4.36 (dd, 2 H, J3,4 ) 7.2 Hz,
J4,5 ) 5.8 Hz, H-4), 4.20 (dd, 2 H, J5,6a ) 2.1 Hz, H-5), 4.12 (dd,
2 H, J6a,6b ) 13.4 Hz, H-6a), 4.05 (d, 2 H, J1a,1b ) 8.5 Hz, H-1a),
3.97 (d, 2 H, H-6b), 3.86 (d, 2 H, H-1b), 3.47 (d, 2 H, H-3), 1.56,
1.52, 1.38, 1.36, (4 s, 24 H, CMe2). 13C NMR (125.7 MHz,
CDCl3): δ (ppm) 137.6-127.7 (Ph), 112.2, 109.0 (CMe2), 104.4
(C-2), 77.8 (C-4), 76.1 (C-3), 73.8 (C-5), 72.8 (C-1), 71.9 (CH2-
Ph), 60.2 (C-6), 28.2, 26.9, 26.2, 26.0 (CMe2). FABMS: m/z 645
(100, [M + Na]+). Anal. Calcd for C32H46O12: C, 61.72; H, 7.45.
Found: C, 61.50; H, 7.20.
General Procedure for the Preparation of Selectively Pro-
tected Bis(fructopyranose) Derivatives 20-22. A solution of the
fully protected derivative 17, 18, or 19 (380 mg, 0.61 mmol) was
dissolved in 60% aq AcOH (2 mL) and stirred at 45 °C for 2 h.
The reaction mixture was then diluted with water (5 mL) and
extracted with EtOAc (4 × 4 mL). The organic phase was washed
with saturated aqueous NaHCO3 (6 mL), dried (MgSO4), filtered,
1,4-Bis[(3,4-di-O-benzyl-1,2-O-isopropylidene-â-D-fructofura-
nos-6-O-yl)methyl]benzene (15). Yield: 452 mg (90%). Rf ) 0.52
1
(2:5 EtOAc-petroleum ether). [R]D ) -25.4 (c 0.6, CHCl3). H
NMR (500 MHz, CDCl3): δ ) 7.31-7.24 (m, 24 H, 5 Ph), 4.68-
4.55 (m, 12 H, 6 CH2Ph), 4.11 (m, 4 H, H-4, H-5), 4.02 (d, 2 H,
J. Org. Chem, Vol. 71, No. 6, 2006 2263

Rubio et al.
and concentrated. The resulting residue was purified by column
chromatography (45:5:3 EtOAc-EtOH-H2O).
CHCl3). 1H NMR (500 MHz, CDCl3): δ (ppm) 7.49-7.21 (m, 24
2
H, Ph), 5.04, 4.72 (2 d, 4 H, JH,H ) 12.5 Hz, CHPh), 4.67, 4.61
(2 d, 4 H, 2JH,H ) 13.0 Hz, CHPh), 4.55 (s, 4 H, CHPh), 3.88 (m,
4 H, H-3, H-4), 3.81 (d, 2 H, J1a,1b ) 8.5 Hz, H-1a), 3.73 (m, 8 H,
H-1b, H-5, H-6a, H-6b), 1.43, 1.41 (2 s, 12 H, CMe2). 13C NMR
(125.7 MHz, CDCl3): δ (ppm) 138.5-127.4 (Ph), 111.6 (CMe2),
105.9 (C-2), 80.3 (C-4), 75.1 (C-3), 73.4 (C-5), 72.0, 71.9, 71.6
(CH2Ph), 71.9 (C-1), 61.6 (C-6), 26.9, 26.4 (CMe2). FABMS: m/z
925 (100, [M + Na]+). Anal. Calcd for C54H62O12: C, 71.82; H,
6.92. Found: C, 71.60; H, 6.80.
1,3-Bis[(1,2-O-isopropylidene-â-D-fructopyranos-3-O-yl)meth-
yl]benzene (20). Yield: 260 mg (69%). Rf 0.50 (45:5:3 EtOAc-
EtOH-H2O). [R]D ) -111.7 (c 1.25, CHCl3). 1H NMR (500 MHz,
CD3OD): δ (ppm) 7.31-7.29 (m, 4 H, Ph), 4.96, 4.63 (2 d, 2 H,
2JH,H ) 11.4 Hz, CHPh), 4.82 (s, 2 H, CHPh), 3.94 (d, 2 H, J1a,1b
) 8.0 Hz, H-1a), 3.91 (dd, 2 H, J3,4 ) 9.6 Hz, J4,5 ) 3.5 Hz, H-4),
3.89 (dd, 2 H, J6a,6b ) 12.4 Hz, J5,6a ) 1.2 Hz, H-6a), 3.84 (m, 2
H, H-5), 3.81 (d, 2 H, H-1b), 3.66 (d, 2 H, H-3), 3.61 (dd, 2 H,
J5,6b ) 1.9 Hz, H-6b), 1.40, 1.32 (2 s, 12 H, CMe2). 13C NMR
(125.7 MHz, CD3OD): δ (ppm) 138.7-126.9 (Ph), 111.5 (CMe2),
105.9 (C-2), 75.7 (C-3), 74.7 (CH2Ph), 71.6 (C-1), 71.5 (C-4), 70.1
(C-5), 64.2 (C-6), 25.9, 25.2 (CMe2); FABMS: m/z 565 (100, [M
+ Na]+). Anal. Calcd for C26H38O12: C, 57.56; H, 7.06. Found:
C, 57.51; H, 6.85.
1,4-Bis[(4,5-di-O-benzyl-1,2-O-isopropylidene-â-D-fructopy-
ranos-3-O-yl)methyl]benzene (25). Yield: 184 mg (82%). Rf )
0.46 (1:2 EtOAc-petroleum ether). [R]D ) -97.3 (c 0.84, CHCl3).
1H NMR (500 MHz, CDCl3): δ (ppm) 7.31-7.24 (m, 24 H, Ph),
5.02, 4.62 (2 d, 4 H, 2JH,H ) 11.4 Hz, CHPh), 4.74, 4.68 (2 d, 4 H,
2
2JH,H ) 12.6 Hz, CHPh), 4.61, 4.59 (2 d, 4 H, JH,H ) 11.7 Hz,
CHPh), 3.99 (d, 2 H, J1a,1b ) 8.5 Hz, H-1a), 3.95 (d, 2 H, H-1b),
3.91 (m, 4 H, H-3, H-4), 3.77 (m, 6 H, H-5, H-6a, H-6b), 1.45,
1.39 (2 s, 12 H, CMe2). 13C NMR (125.7 MHz, CDCl3): δ (ppm)
138.5-127.6 (Ph), 111.8 (CMe2), 105.9 (C-2), 80.1 (C-4), 75.2 (C-
3, CH2Ph), 73.4 (C-5), 72.0 (CH2Ph), 71.5 (C-1), 61.3 (C-6), 27.1,
26.2 (CMe2). FABMS: m/z 925 (50, [M + Na]+). Anal. Calcd for
C54H62O12: C, 71.82; H, 6.92. Found: C, 71.74; H, 6.71.
1,2-Bis[(1,2-O-isopropylidene-â-D-fructopyranos-3-O-yl)meth-
yl]benzene (21). Yield: 230 mg (70%). Rf ) 0.50 (45:5:3 EtOAc-
EtOH-H2O). [R]D ) -171.1 (c 0.61, CHCl3). 1H NMR (300 MHz,
CD3OD): δ (ppm) 7.51-7.30 (m, 4 H, Ph), 5.19, 4.75 (2 d, 2 H,
2JH,H ) 11.7 Hz, CHPh), 4.90 (s, 2 H, CH2Ph), 3.95 (dd, 2 H, J3,4
) 9.8 Hz, J4,5 ) 3.4 Hz, H-4), 3.91 (m, 2 H, H-6a), 3.88 (dd, 2 H,
H-5), 3.85 (d, 2 H, J1a,1b ) 8.7 Hz, H-1a), 3.81 (d, 2 H, H-1b),
3.73 (d, 2 H, H-3), 3.64 (dd, 2 H, J6a,6b ) 12.3 Hz, J5,6b ) 1.7 Hz,
H-6b), 1.43, 1.35 (2 s, 12 H, CMe2). 13C NMR (75.5 MHz, CD3-
OD): δ (ppm) 138.1-129.0 (Ph), 112.8 (CMe2), 107.2 (C-2), 77.0
(C-3), 73.6 (CH2Ph), 73.0 (C-1), 72.7 (C-4), 71.5 (C-5), 65.6 (C-
6), 27.2, 26.6 (CMe2); FABMS: m/z 565 (100, [M + Na]+). Anal.
Calcd for C26H38O12: C, 57.56; H, 7.06. Found: C, 57.64; H, 7.09.
1,4-Bis[(1,2-O-isopropylidene-â-D-fructopyranos-3-O-yl)meth-
yl]benzene (22). Yield: 237 mg (72%). Rf ) 0.50 (45:5:3 EtOAc-
EtOH-H2O). [R]D ) -159.5 (c 1.01, CHCl3). 1H NMR (500 MHz,
m-Xylylene-Mediated Synthesis of Type I DFA Derivatives
26-28. To a solution of the m-xylylene-tethered bis(D-fructofura-
nose) 13 (400 mg, 0.44 mmol) in dry CH2Cl2 (60 mL) at -78 °C
under Ar was added trifluoromethanesulfonic acid (60 µL). The
reaction mixture was stirred for 1 h, allowed to reach room
temperature, and then stirred for an additional 1 h. Et3N (10 drops)
was added, and the resulting solution was stirred for 10 min and
then concentrated. Column chromatography (1:3 EtOAc-petroleum
ether) of the residue afforded first the two-component inseparable
mixture of intramolecular reaction products 26 and 27 (1:2, 270
mg, 78%). A second fraction contained the corresponding macro-
cyclization compounds 28 (55 mg, 16%), as seen from FABMS
data. Removal of the xylylene and benzyl groups in the mixture of
26 and 27 by catalytic hydrogenation afforded the corresponding
DFAs 1 and 2 in quantitative yield, whose relative proportions and
identities were confirmed by GC, using authentic standards. The
macrocyclic fraction 28 quantitatively yielded the spirodisaccharides
1 and 2 in 1:2 ratio after catalytic hydrogenation. The binary
mixtures of 1 and 2 could be separated by conventional acetylation,
column chromatography and Zemple´n deacetylation as previously
reported. The individual DFAs exhibited spectroscopic properties
identical to those in the literature.4
o-Xylylene-Mediated Synthesis of Type I DFA Derivatives
29-31. To a solution of the o-xylylene-tethered bis(D-fructofura-
nose) 14 (400 mg, 0.44 mmol) in dry CH2Cl2 (60 mL) at -78 °C
under Ar was added trifluoromethanesulfonic acid (60 µL). The
reaction mixture was stirred for 1 h, allowed to reach room
temperature, and then stirred for an additional 1 h. Et3N (10 drops)
was added, and the resulting solution was stirred for 10 min and
then concentrated. Column chromatography (1:3 EtOAc-petroleum
ether) of the residue afforded the pure tetracyclic spirodisaccharides
29 (30 mg, 9%) and 30 (275 mg, 79%) and the macrocyclic fraction
31 (20 mg, 6%). Removal of the xylylene and benzyl groups in 29
and 30 by catalytic hydrogenation afforded the corresponding pure
DFAs 2 and 3 in quantitative yield. The macrocyclic fraction 28
quantitatively yielded the spirodisaccharides 1 and 2 in 1:2 ratio
after catalytic hydrogenation.
CD3OD): δ (ppm) 7.38 (m, 4 H, Ph), 4.97, 4.63 (2 d, 2 H, 2JH,H
)
11.4 Hz, CHPh), 4.85 (s, 2 H, CH2Ph), 3.94 (d, 2 H, J1a,1b ) 8.5
Hz, H-1a), 3.92 (dd, 2 H, J3,4 ) 9.8 Hz, J4,5 ) 3.0 Hz, H-4), 3.90
(dd, 2 H, J6a,6b ) 12.4 Hz, J5,6a ) 1.2 Hz, H-6a), 3.85 (m, 2 H,
H-5), 3.81 (d, 2 H, H-1b), 3.67 (d, 2 H, H-3), 3.62 (dd, 2 H, J5,6b
) 1.8 Hz, H-6b), 1.42, 1.32 (2 s, 12 H, CMe2). 13C NMR (125.7
MHz, CD3OD): δ (ppm) 139.4-129.1 (Ph), 112.9 (CMe2), 107.2
(C-2), 77.0 (C-3), 76.0 (CH2Ph), 72.9 (C-1), 72.8 (C-4), 71.5 (C-
5), 65.6 (C-6), 25.9, 25.2 (CMe2). FABMS: m/z 565 (100, [M +
Na]+). Anal. Calcd for C26H38O12: C, 57.56; H, 7.06. Found: C,
57.53; H, 6.73.
General Procedure for the Preparation of Benzylated Bis-
(fructopyranose) derivatives 23-25. To a solution of 20, 21, or
22 (88 mg, 0.16 mmol) in dry DMF (3 mL) was added NaH (65
mg, 1.62 mmol), and the suspension was stirred at room temperature
for 15 min. Benzyl bromide (81 µL, 0.65 mmol, 4 equiv) was then
added, and the mixture was further stirred for 15 min. The reaction
was quenched by addition of Et2O (10 mL) and water (5 mL), and
the organic phase was separated, washed with water (5 × 5 mL),
dried (MgSO4), and concentrated.
1,3-Bis[(4,5-di-O-benzyl-1,2-O-isopropylidene-â-D-fructopy-
ranos-3-O-yl)methyl]benzene (23). Yield: 110 mg (75%). Rf )
0.46 (1:2 EtOAc-petroleum ether). [R]D ) -66.8 (c 1.6, CHCl3).
1H NMR (500 MHz, CDCl3): δ (ppm) 7.38-7.23 (m, 24 H, Ph),
2
5.01, 4.56 (d, 4 H, JH,H ) 11.6 Hz, CHPh), 4.73, 4.67 (d, 4 H,
2
2JH,H ) 12.6 Hz, CHPh), 4.61, 4.57 (d, 4 H, JH,H ) 12.5 Hz,
CHPh), 3.98 (d, 2 H, J1a,1b ) 8.5 Hz, H-1a), 3.93 (d, 2 H, H-1b),
3.91 (d, 2 H, J3,4 ) 9.8 Hz, H-3), 3.88 (dd, 2 H, J4,5 ) 2.5 Hz,
H-4), 3.75 (m, 6 H, H-5, H-6a, H-6b), 1.44, 1.37 (2 s, 12 H, CMe2).
13C NMR (125.7 MHz, CDCl3): δ (ppm) 138.5-126.6 (Ph), 111.8
(CMe2), 105.9 (C-2), 80.2 (C-4), 75.4 (C-3), 75.3 (CH2Ph), 73.4
(C-5), 72.0, 71.5 (CH2Ph), 71.9 (C-1), 61.3 (C-6), 27.1, 26.2 (CMe2).
FABMS: m/z 925 (80, [M + Na]+). Anal. Calcd for C54H62O12:
C, 71.82; H, 6.92. Found: C, 71.72; H, 6.84.
3,4,3′,4′-Tetra-O-benzyl-6,6′-O-(o-xylylene)-di-R-D-fructofura-
nose 1,2′:2,1′-Dianhydride (29). Rf ) 0.48 (1:3 EtOAc-petroleum
ether). [R]D ) +96.7 (c 0.83, CHCl3). 1H NMR (500 MHz,
CDCl3): δ (ppm) 7.28-7.24 (m, 24 H, 5 Ph), 4.70-4.54 (m, 12
H, 6 CH2), 4.14 (d, 2 H, J1a,1b ) 11.8 Hz, H-1a), 4.13 (m, 2 H,
H-5), 4.00 (d, 2 H, J3,4 ) 3.3 Hz, H-3), 3.88 (d, 2 H, H-1b), 3.77
(dd, 2 H, J6a,6b ) 12.2 Hz, J5,6a ) 2.0 Hz, H-6a), 3.61 (dd, 2 H,
H-4), 3.47 (dd, 2 H, J5,6a ) 8.4 Hz, H-6b). 13C NMR (125.7 MHz,
CDCl3): δ (ppm) 137.7-127.6 (Ph), 102.9 (C-2), 88.7 (C-3), 83.1
1,2-Bis[(4,5-di-O-benzyl-1,2-O-isopropylidene-â-D-fructopy-
ranos-3-O-yl)methyl]benzene (24). Yield: 110 mg (75%). Rf )
0.46 (1:2 EtOAc-petroleum ether). [R]D ) -48.5 (c ) 0.72,
2264 J. Org. Chem., Vol. 71, No. 6, 2006

Spacer-Mediated Synthesis of Spiroacetals
(C-4), 81.5 (C-5), 72.3, 71.9, 71.4 (CH2), 70.8 (C-6), 63.9 (C-1).
Anal. Calcd for C48H50O10: C, 73.26; H, 6.40. Found: C, 73.29;
H, 6.12.
J5,6b ) 4.1 Hz, H-6bR), 3.62 (m, 1 H, H-5â), 3.54 (d, 1 H, H-1bâ),
3.44 (d, 1 H, H-6bâ). 13C NMR (125.7 MHz, CDCl3): δ (ppm)
139.9-124.6 (Ph), 96.2 (C-2â), 94.5 (C-2R), 78.8 (C-3R), 77.2 (C-
4â), 76.7 (C-3â), 73.3 (C-5â), 72.4 (C-4R), 71.3 (C-5R), 73.7, 72.0,
71.8, 70.5 (CH2Ph), 63.5 (C-1R), 61.2 (C-1â), 60.1 (C-6â), 57.2
(C-6R). FABMS: m/z 809 (20, [M + Na]+). Anal. Calcd for
C48H50O10: C, 73.26; H, 6.40; found: C, 73.28; H, 6.32.
3,4,3′,4′-Tetra-O-benzyl-6,6′-O-(o-xylylene)-di-â-D-fructofura-
nose 1,2′:2,1′-Dianhydride (30). Rf 0.40 (1:3 EtOAc-petroleum
ether). [R]D ) +91.5 (c 0.83, CHCl3). 1H NMR (500 MHz,
3
CDCl3): δ (ppm) 7.40-7.17 (m, 24 H, 5 Ph), 4.99 (d, 2 H, JH,H
) 11.2 Hz, CH2), 4.78 (d, 2 H, 3JH,H ) 11.2 Hz, CH2), 4.61-4.52
(dd, 2 H, CH2), 4.12 (ddd, 2 H, J5,6a ) 1.8 Hz, J5,6b ) 1.3 Hz, J4,5
) 6.3 Hz, H-5), 4.02 (dd, 2 H, J3,4 ) 7.2 Hz, H-4), 3.83 (dd, 2 H,
J6a,6b ) 11.3 Hz, H-6a), 3.76 (d, 2 H, J1a,1b ) 11.2 Hz, H-1a), 3.74
(dd, 2 H, H-6b), 3.70 (d, 2 H, H-3), 3.68 (d, 2 H, H-1b); 13C NMR
(125.7 MHz, CDCl3): δ (ppm) 137.6-127.5 (Ph), 103.1 (C-2), 84.3
(C-3), 82.9 (C-4), 81.8 (C-5), 74.7 (C-6), 73.0, 72.8, 72.2 (CH2),
64.8 (C-1). Anal. Calcd for C48H50O10: C, 73.26, H, 6.40. Found:
C, 73.21; H, 6.40.
4,5,4′,5′-Tetra-O-benzyl-3,3′-O-(m-xylylene)-di-â-D-fructopy-
ranose 1,2′:2,1′-Dianhydride (36). Rf ) 0.35 (1:2 EtOAc-
1
petroleum ether). [R]D ) -110.5 (c 0.5, CHCl3). H NMR (500
MHz, CDCl3): δ (ppm) 7.39-7.12 (m, 24 H, Ph), 4.80-4.44 (m,
12 H, CHPh), 3.97 (d, 1 H, J1a,1b ) 12.1 Hz, H-1a), 3.96 (dd, 1 H,
J3,4 ) 9.9 Hz, J4,5 ) 3.1 Hz, H-4), 3.88 (d, 1 H, H-3), 3.73 (dd, 1
H, J6a,6b ) 12.5 Hz, J5,6a ) 2.0 Hz, H-6a), 3.71 (m, 1 H, H-5), 3.62
(d, 1 H, H-6b), 3.59 (d, 1 H, H-1b). 13C NMR (125.7 MHz,
CDCl3): δ (ppm) 139.9-124.6 (Ph), 97.6 (C-2), 79.2 (C-3), 77.8
(C-4), 73.9 (C-5), 73.8, 72.2, 71.6 (CH2Ph), 66.4 (C-1), 61.5 (C-
6). Anal. Calcd for C48H50O10: C, 73.26; H, 6.40. Found: C, 73.49;
H, 6.19.
p-Xylylene-Mediated Synthesis of Type I DFA Derivatives
32-34. To a solution of the p-xylylene-tethered bis(D-fructofura-
nose) 13 (400 mg, 0.44 mmol) in dry CH2Cl2 (60 mL) at -78 °C
under Ar was added trifluoromethanesulfonic acid (60 µL). The
reaction mixture was stirred for 1 h, allowed to reach room
temperature, and then stirred for an additional 1 h. Et3N (10 drops)
was added, and the resulting solution was stirred for 10 min and
then concentrated. Column chromatography (1:3 EtOAc-petroleum
ether) of the residue afforded first the two-component inseparable
mixture of intramolecular reaction products 32 and 33 (4:1, 66.5
mg, 19%). A second fraction contained the corresponding macro-
cyclization compounds 34 (217.5 mg, 63%), as seen from FABMS
data. Removal of the xylylene and benzyl groups in the mixture of
32 and 33 by catalytic hydrogenation afforded the corresponding
DFAs 2 and 3 in quantitative yield, whose relative proportions and
identities were confirmed by GC, using authentic standards. The
macrocyclic fraction 34 quantitatively yielded the spirodisaccharides
1 and 2 in 1:2 ratio after catalytic hydrogenation.
o-Xylylene-Mediated Synthesis of Type III DFA Derivatives
35-37. To a solution of the o-xylylene-tethered D-fructopyranose
derivative 24 (340 mg, 0.37 mmol) in dry CH2Cl2 (60 mL) at -78
°C was added trifluoromethanesulfonic acid (50 µL, 1.5 equiv)
under Ar. The reaction mixture was stirred for 1 h, allowed to reach
room temperature, and then stirred for an additional 4 h. Et3N (3
drops) was added, and the resulting solution was stirred for 10 min
and then concentrated. Column chromatography of the residue (1:3
EtOAc-petroleum ether) afforded the corresponding bis-spiroacetal
38 (124 mg, 42%) and the corresponding macrocyclic derivatives
39 (101.8 mg, 35%). Catalytic hydrogenolysis of 38 proceeded in
quantitative yield to give the corresponding di-â-D-fructopyranose
DFA 5, respectively. Under the same conditions, the macrocyclic
fraction 39 afforded a mixture of 4 and 5 in 1:6 relative proportion.
4,5,4′,5′-Tetra-O-benzyl-3,3′-O-(o-xylylene)-di-â-D-fructopy-
ranose 1,2′:2,1′-Dianhydride (38). Rf ) 0.36 (1:2 EtOAc-
m-Xylylene-Mediated Synthesis of Type III DFA Derivatives
35-37. To a solution of the m-xylylene-tethered D-fructopyranose
derivative 23 (340 mg, 0.37 mmol) in dry CH2Cl2 (60 mL) at -78
°C was added trifluoromethanesulfonic acid (50 µL, 1.5 equiv)
under Ar. The reaction mixture was stirred for 1 h, allowed to reach
room temperature, and then stirred for an additional 4 h. Et3N (3
drops) was added, and the resulting solution was stirred for 10 min
and then concentrated. Column chromatography of the residue (1:3
EtOAc-petroleum ether) afforded the corresponding bis-spiroac-
etals 35 (34 mg, 11.5%) and 36 (137 mg, 47.5%) and a fraction
consisting of macrocyclization products 37 (69.8 mg, 24%) arising
from double bis(spiroacetalation). Catalytic hydrogenolysis of 35
and 36 proceeded in quantitative yield to give the corresponding
difructopyranose DFAs 4 and 5, respectively. Under the same
conditions, the macrocyclic fraction 37 afforded a mixture of 4 and
5 in 1:6 relative proportion. The identity of the unprotected DFAs
4 and 5 and their relative proportions in mixtures were established
by GC and comparison with authentic samples. The individual
compounds, coming either from catalytic hydrogenolysis of 35 and
36 or from the separation of the mixtures of 4 and 5 by
peracetylation, column chromatography, and deacetylation, exhib-
ited spectroscopic properties identical to those previously reported.4
4,5-Di-O-benzyl-R-D-fructopyranose 4′,5′-Di-O-benzyl-â-D-
fructopyranose 3,3′-O-(m-Xylylene) 1,2′:2,1′-Dianhydride (35).
Rf ) 0.40 (1:2 EtOAc-petroleum ether). [R]D ) -40.2 (c 0.5,
CHCl3). 1H NMR (500 MHz, CDCl3): δ (ppm) 7.39-7.12 (m, 24
1
petroleum ether). [R]D ) -139.7 (c 0.71, CHCl3). H NMR (500
MHz, CDCl3): δ (ppm) 7.31-7.21 (m, 24 H, Ph), 4.96, 4.78 (2 d,
4 H, 2JH,H ) 8.3 Hz, CHPh), 4.75, 4.66 (2 d, 4 H, 2JH,H ) 12.9 Hz,
CHPh), 4.64 (s, 4 H, CH2Ph), 4.51 (d, 2 H, J1a,1b ) 11.6 Hz, H-1a),
4.07 (d, 2 H, J3,4 ) 10.2 Hz, H-3), 4.05 (dd, 2 H, J4,5 ) 2.6 Hz,
H-4), 3.85 (m, 2 H, H-5), 3.80 (bd, 2 H, J6a,6b ) 12.6 Hz, H-6a),
3.76 (d, 2 H, H-6b), 3.72 (d, 2 H, H-1b). 13C NMR (125.7 MHz,
CDCl3): δ (ppm) 138.5-127.6 (Ph), 95.0 (C-2), 77.9 (C-3), 76.2
(C-4), 73.5 (C-5), 71.7, 71.4, 69.2 (CH2Ph), 66.2 (C-1), 60.8 (C-
6). FABMS: m/z 809 (100, [M + Na]+). Anal. Calcd for
C48H50O10: C, 73.26; H, 6.40. Found: C, 73.15; H, 6.12.
p-Xylylene-Mediated Synthesis of Type III DFA Derivatives
40. To a solution of the p-xylylene-tethered D-fructopyranose
derivative 25 (340 mg, 0.37 mmol) in dry CH2Cl2 (60 mL) at -78
°C was added trifluoromethanesulfonic acid (50 µL, 1.5 equiv)
under Ar. The reaction mixture was stirred for 1 h, allowed to reach
room temperature, and then stirred for an additional 4 h. Et3N (3
drops) was added, and the resulting solution was stirred for 10 min
and then concentrated. No intramolecular reaction compounds were
detected in this case. Column chromatography of the residue (1:3
EtOAc-petroleum ether) provided only the macrocyclization
derivatives 40 (209 mg, 72%). Crystallization from EtOAc yielded
the all-â,â 40 macrocyclic dimer in pure form (101.8 mg, 35%).
Catalytic hydrogenolysis of 40 afforded mixtures of 4 and 5 in 1:6
relative proportions, while the all-â,â 40 isomer yielded exclusively
the contra-thermodynamic diastereomer 5.
2
H, Ph), 4.99, 4.61 (2 d, 2 H, JH,H ) 12.0 Hz, CHPh), 4.72, 4.67
2
2
(2 d, 2 H, JH,H ) 12.5 Hz, CHPh), 4.70, 4.59 (2 d, 2 H, JH,H
)
Cyclobis[4,5,4′,5′-tetra-O-benzyl-di-â-D-fructopyranose 1,2′:
2,1′-dianhydride] 3I,3II:3′I,3′II-Di-O-(p-xylylene) (all-â,â 40). Rf
) 0.54 (1:2 EtOAc-petroleum ether). [R]D ) -138.3 (c 0.82,
CHCl3). Mp: 213.5-214.8 °C (EtOAc). 1H NMR (500 MHz,
CDCl3) δ (ppm) 7.25-7.13 (m, 48 H, Ph), 4.86, 4.68 (2 d, 8 H,
2
12.5 Hz, CHPh), 4.42, 4.35 (2 d, 2 H, JH,H ) 12.0 Hz, CHPh),
4.37 (s, 2 H, CH2Ph), 4.31, 4.24 (2 d, 2 H, 2JH,H ) 11.6 Hz, CHPh),
4.21 (d, 1 H, J1a,1b ) 11.3 Hz, H-1aâ), 4.15 (d, 1 H, J1a,1b ) 11.8
Hz, H-1aR), 3.89 (m, 3 H, H-4R, H-5R, H-6aR), 3.86 (dd, 1 H, J3,4
) 9.5 Hz, J4,5 ) 3.4 Hz, H-4â), 3.73 (d, 1 H, H-1bR), 3.72 (dd, 1
H, J6a,6b ) 11.9 Hz, J5,6a ) 3.3 Hz, H-6aâ), 3.71 (d, 1 H, J3,4 ) 3.2
Hz, H-3R), 3.69 (d, 1 H, H-3â), 3.69 (dd, 1 H, J6a,6b ) 10.2 Hz,
2
2JH,H ) 10.9 Hz, CHPh), 4.71, 4.66 (2 d, 8 H, JH,H ) 12.6 Hz,
2
CHPh), 4.53, 4.46 (2 d, 8 H, JH,H ) 11.6 Hz, CHPh), 4.01 (d, 4
H, J1a,1b ) 12.1 Hz, H-1a), 3.95 (dd, 4 H, J3,4 ) 9.9 Hz, J4,5 ) 3.0
J. Org. Chem, Vol. 71, No. 6, 2006 2265

Rubio et al.
Hz, H-4), 3.87 (d, 4 H, H-3), 3.76 (bd, 4 H, J6a,6b ) 12.8 Hz, H-6a),
3.72 (m, 4 H, H-5), 3.71 (d, 4 H, H-6b), 3.66 (d, 24 H, H-1b). 13
C20; C36/C41 and C43/C48) and one of the bridging phenyl rings
(C3, C4, C6 and C7). In all cases, two complementaryswith equal
occupancysmoieties were enough to reasonably model the detected
disorder. All disordered atoms of the terminal benzyl groups were
refined first as free isotropic atoms and then introducing anisotropy
displacement parameters despite this was strongly discouraged
considering the relative proximity of some of the disordered atoms
in the mean asymmetric unit. In the case of the central phenyl ring,
the disorder only affected four of the ring atoms (C3, C4, C6, and
C7). Anistropic thermal parameters were included for these atoms,
as their separation allows physical meaning of these values. When
observing the packing of molecules, the intermolecular contacts
clearly make evident the necessary “synchronized” presence of
disorder moieties to avoid short interatomic contacts. Hydrogen
atoms were included in calculated positions refined with positional
and thermal riding parameters. Final R factors are slightly over usual
standards, most probably as a consequence of the very weak
scattering power of the sample used and the heavy disorder present
in the crystal. Data were collected to 2θ ) 55° (completeness to
99.2%), 2515 parameters gave, R1 ) 0.0874, wR2 ) 0.2239 [for
13790 reflections with I > 2σ(I )], R1 ) 0.1122, wR2 ) 0.2532
(all data) (S ) 1.063). The final difference map displayed no
electron density higher than 0.395 e Å-3. CCDC-258519 contains
the supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; fax: (+44)-
1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk).
C
NMR (125.7 MHz, CDCl3): δ (ppm) 138.5-127.4 (Ph), 97.8 (C-
2), 79.6 (C-3), 78.1 (C-4), 73.8 (C-5), 74.6, 72.5, 71.5 (CH2Ph),
64.4 (C-1), 61.5 (C-6). FABMS: m/z 1595 (20, [M + Na]+). Anal.
Calcd for C96H100O20: C, 73.26; H, 6.40. Found: C, 73.15; H, 6.49.
X-ray Crystal Struture Analysis for all-â,â 40. C96 H100 O20,
Mr ) 1573.76, colorless block (0.07 × 0.05 × 0.04 mm3) from
AcOEt, monoclinic, space group C2 (no. 5), a ) 59.445(3) Å, b )
10.5079(5) Å, c ) 25.8107(11) Å, â ) 95.554(2)°, V ) 16046.8-
(13) Å3, Z ) 8, Fcalcd ) 1.303 g cm-3, λ(Synchrotron) ) 0.6934
Å, F(000) ) 6688, µ ) 0.091 mm-1, T ) 150 (2) K. A total of
78891 reflections collected, 20722 of which are independent for
1.92° < θ < 27.50°; 13790 [I > 2σ(I)] reflections were used for
refinement. A very weakly diffracting crystal was used for data
collection. Three runs of 600 frames each were measured with æ
values of 0, 120, and 240 degrees and scan ranges of 0.3 degrees
in ω at the Daresbury Synchrotron Radiation Source, SRS Station
9.8 (provided of a Bruker-Nonius APEXII CCD area detector).
Reflections were corrected for Lorentz polarization effects and
absorption applied by SADABS: Area-Detector Absorption Cor-
rection, Bruker-AXS within SAINT+ package, v. 7.06, 1996. The
structure was solved by direct methods (SIR-97, Giacovazzo, C.
SIR-97 Program for Crystal Structure Solution, Inst. di Ric. per lo
Sviluppo di Metodologie Cristallograpfiche, CNR, University of
Bari, Italy, 1997) and refined on F2 by full-matrix least-squares
techniques (SHELXTL-6.12 “Program for Structure Solution,
Refinement and Presentation” BRUKER AXS Inc., 5465 East
Cheryl Parkway, Madison, WI).The asymmetric unit showed the
presence of one complete molecule and two independent half
molecules. The refinement was performed stepwise, first with
isotropic thermal parameters for all atoms, and then with anisotropic
displacement parameters for all non-hydrogen atoms. Disorder
fundamentally affected some of the terminal phenyl or benzyl rings.
Geometrically constrained refinements were carried out for the
cyclic rings were high residuals evidenced some kind of disorder.
In the whole independent molecule only the terminal benzyl group
(C42A to C48A, and C42Z to C48Z) was observed disordered,
apparently in two different positions. From an initially fully
constrained refinement the different positional, thermal and oc-
cupancy parameters were successively liberated. Eventually the two
disordered moieties were refined first as free isotropic atoms, with
only the occupancy factor constrained to be equal for both moieties,
and then anisotropically refined. An identical model of disorder
was carefully detected for both half independent molecules. It
affected, in both cases, three of the terminal benzyl groups (C14/
Acknowledgment. We thank the Spanish Ministerio de
Educacio´n y Ciencia for financial support (Contract Nos.
BQU2003-00937, CTQ2004-05854/BQU, and BQU2002-1729)
and for a doctoral fellowship (to P.B.). E.M.R. thanks the CSIC
and the Institut fu¨r Technologie der Kohlenhydrate e. V. for a
fellowship. We also gratefully thank CCLRC Daresbury Labo-
ratory for allocation of synchrotron beam time (AP41) and Dr.
S. J. Teat for experimental assistance.
Supporting Information Available: General experimental
procedures, ORTEP plot for all-â,â 40 with full numbering system,
and Tables 1S-6S containing relevant crystallographic parameters,
as well as the complete X-ray crystallographic data (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO052184B
2266 J. Org. Chem., Vol. 71, No. 6, 2006