Carbohydrate-derived spiroketals: Stereoselective synthesis of di-D-fructose dianhydrides via intramolecular aglycon delivery

Article abstract of DOI:10.1021/ol034022c

(Matrix presented) A one-pot synthesis of C₂-symmetric di-D-fructose dianhydrides having the 1,6,9,13-tetraoxadispiro [4.2.4.2]tetradecane skeleton has been accomplished via intramolecular aglycon delivery from (6 → 6) xylylene-tethered fructof

Full text of DOI:10.1021/ol034022c

ORGANIC
LETTERS
2003
Vol. 5, No. 6
873-876
Carbohydrate-Derived Spiroketals:
Stereoselective Synthesis of
Di-D-fructose Dianhydrides via
Intramolecular Aglycon Delivery
,‡
,†
Enrique M. Rubio,† Carmen Ortiz Mellet,* and Jose´ M. Garc´ıa Ferna´ndez*
Instituto de InVestigaciones Qu´ımicas, CSIC, Ame´rico Vespucio s/n, Isla de la Cartuja,
E-41092 SeVilla, Spain, and Departamento de Qu´ımica Orga´nica, Facultad de
Qu´ımica, UniVersidad de SeVilla, Aptdo. 553, E-41071 SeVilla, Spain
jogarcia@cica.es; mellet@us.es
Received January 7, 2003
ABSTRACT
A one-pot synthesis of C -symmetric di-D-fructose dianhydrides having the 1,6,9,13-tetraoxadispiro [4.2.4.2]tetradecane skeleton has been
2
accomplished via intramolecular aglycon delivery from (6 f 6) xylylene-tethered fructofuranose precursors. The stereochemical outcome of
the glycosylation−spiroketalization process is governed by the geometrical constraints imposed by the rigid tetracyclic structure of the final
compound.
The widespread occurrence of highly substituted and func-
tionalized spiroketal subunits in many biologically significant
natural products and the increasing pharmacological impor-
tance of some representatives have promoted considerable
interest in the development of synthetic routes to these
compounds.1,2 Of special interest is the tricyclic dispiro
arrangement, which appears in nature in a number of
polyether ionophores such as narasin, salinomycin, nobori-
tomycin, the antibiotics CP44 661 and X 14766A, and other
substances isolated from marine organisms.3,4 This structural
element is also present in several diketose dianhydrides,5,6
a
unique class of cyclic disaccharides of which di-D-fructose
† Istituto de Investigaciones Qu´ımicas, CSIC.
J. Org. Lett. 2002, 4, 489-492 (e) Keller, V. A.; Martinelli, J. R.; Streiter,
E. R.; Burke, S. D. Org. Lett. 2002, 4, 467-470. (f) Smith, A. B.; Corbett,
R. M.; Pettit, G. R.; Chapuis, J.-C.; Schmidt, J. M.; Hamel, E.; Jung, M. K.
Bioorg. Med. Chem. Lett. 2002, 12, 2039-2042. (g) Crimmins, M. T.; Katz,
J. D.; Washburn, D. G.; Allwein, S. P.; McAtee, L. F. J. Am. Chem. Soc.
2002, 124, 5661-5663.
‡ Universidad de Sevilla.
(1) For reviews, see: (a) Perron, F.; Albizati, K. F. Chem. ReV. 1989,
89, 1617-1661. (b) Imanishi, T.; Iwata, C. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1994; Vol. 14, pp
517-550. (c) Ichihara, A.; Oikawa, H.; Toshima, H. In Studies in Natural
Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1996; Vol.
18, pp 269-313. (d) Pietruszka, J. Angew. Chem., Int. Ed. 1998, 37, 2629-
2636. (e) Tu, Y. Q.; Hu¨bener, A.; Zhang, H.; Moore, C. J.; Fletcher, M. T.;
Hayes, P.; Dettner, K.; Francke, W.; McErlean, C. S. P.; Kitching, W.
Synthesis 2000, 1956-1978.
(2) Selected recent syntheses: (a) Izquierdo, I.; Plaza, M. T.; Rodr´ıguez,
M.; Tamayo, J. A. Eur. J. Org. Chem. 2002, 309-317. (b) Holson, E. B.;
Roush, W. R. Org. Lett. 2002, 4, 3719-3722. (c) Holson, E. B.; Roush,
W. R. Org. Lett. 2002, 4, 3723-3725. (d) Wardrop, D. J.; Zhang, W.; Fritz,
(3) For a review, see: Brimble, M. A.; Fare`s, F. A. Tetrahedron 1999,
55, 7661-7706.
(4) Selected recent syntheses: (a) Sugimoto, T.; Ishihara, J.; Murai, A.
Synlett 1999, 541-544. (b) Dorta, R. L.; Mart´ın, A.; Salazar, J. A.; Sua´rez,
E. J. Org. Chem. 1998, 63, 2251-2261. (c) Kocienski, P. J.; Brown, R. C.
D.; Pommier, A.; Procter, M.; Schmidt, B. J. Chem. Soc., Perkin Trans. 1
1998, 9-40.
(5) For a review, see: Manley-Harris, M.; Richards, G. N. AdV.
Carbohydr. Chem. Biochem. 1997, 52, 207-266.
10.1021/ol034022c CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/21/2003

dianhydrides (DFAs) are paradigmatic examples. DFAs have
been isolated from microorganisms7 and higher plants8 and
have also been identified in food materials such as caramel
and chicory.9
the thermodynamically favored diastereomer, since it can
accommodate the oxygen substituents in an axial orientation
and the carbon substituents in an equatorial disposition with
the central 1,4-dioxane ring in a chair conformation. Such a
situation does not prevail for the C2-symmetric di-R- and
di-â-D-fructofuranose 1,2′:2,1′-dianhydrides 2 and 3, respec-
tively, which must adopt a boat conformation at the central
ring in order to accommodate the anomeric effect at both
anomer centers, a less favorable arrangement (Figure 1).5
Despite the variety of general methods existing for the
construction of the spiroketal moiety, the control of the
stereochemistry at the anomeric center is, almost exclusively,
based on the relative thermodynamic stability of the different
isomers in the acid-catalyzed spiroketalization. When all
factors that control spirocyclization, i.e., a maximum ano-
meric effect and minimum steric interactions, are reinforcing,
a major isomer is produced. The stereoselectivity is lower
when these factors are in conflict. In tricyclic systems,
however, such general statements must be applied carefully.
A range of structures can usually accommodate the basic
requirements with rather small differences in energy and low
interconversion barriers. Actually, the dimerization reaction
of D-fructose under acidic conditions leads to a complex
mixture of up to 13 DFA isomers that differ in the ring size,
linking position, and stereochemistry at the acetal stereo-
centers, seven of which possess a tetraoxadispiro core with
either the [4.2.4.2]-, [5.2.4.2]-, or [5.2.5.2]tetradecane ar-
rangement (Figure 1, types I-III, respectively).5
We have previously devised a stereoselective synthesis of
2, having a trans relative disposition between the anomeric
oxygen atoms and the vicinal hydroxyl groups, by taking
advantage of the participating character of O-acyl groups
during the Lewis acid-catalyzed glycosylation-spirocycliza-
tion reaction of 1,2-O-isopropylidene-â-D-fructofuranose
precursors.10 We now report the highly diastereoselective
preparation of the di-â-isomer 3 by implementing the concept
of intramolecular aglycon delivery (IAD),11 originally in-
troduced by Hindsgaul12 and Stork13 for the synthesis of
â-mannosides, to the control of the stereochemical outcome
in spiroketalization processes.
Our strategy relies on the significant differences in the
through-space distance between the primary hydroxyl groups
of the nonsymmetric 1 and the C2-symmetric DFA isomers
2 and 3 in their most stable conformations. The restriction
of this parameter by incorporation of an appropriate tether
should favor the latter compounds by fixing the boat
conformation. In a first approach, the m-xylylene spacer,
previously used by Schmidt in oligosaccharide synthesis,14
was considered. Thus, the dimeric 1,2-O-isopropylidene-â-
D-fructofuranose derivative 8 was prepared by a reaction
sequence involving selective protection of the primary
(7) (a) Tanaka, K.; Uchiyama, T.; Ito, A. Biochim. Biophys. Acta 1972,
284, 248-256. (b) Tanaka, K.; Sonobe, K.; Uchiyama, T.; Matsuyama, T.
Carbohydr. Res. 1979, 75, 340-344. (c) Matsuyama, T.; Tanaka, K.;
Mashiko, M.; Kanamoto, M. J. Biochem. 1982, 92, 1325-1328. (d)
Haraguchi, K.; Kishimoto, M.; Seki, K.; Hayashi, K.; Kobayashi, S.;
Kainuma, K. Agric. Biol. Chem. 1988, 52, 291-292. (e) Kawamura, M.;
Takahashi, S.; Uchiyama, T. Agric. Biol. Chem. 1988, 52, 3209-3210. (f)
Matsuyama, T.; Tanaka, K.; Uchiyama, T. Agric. Biol. Chem. 1991, 55,
1413-1414.
(8) Li, H.; Zhu, W.; Yokoyama, C.; Harada, N. Carbohydr. Res. 1997,
299, 301-305.
(9) (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. (c) Manley-Harris, M.; Richards, G. N. Carbohydr. Res. 1996, 287,
183-202. (d) Ratsimba, V.; Garc´ıa Ferna´ndez, J. M.; Defaye, J.; Nigay,
H., Voilley, A, J. Chromatogr. A 1999, 844, 283-293.
Figure 1. Tricyclic dispiroketal frameworks present in di-D-fructose
dianhydrides: tetraoxadispiro [4.2.4.2]tetradecane (I), tetraoxa-
dispiro [5.2.4.2]tetradecane (II), and tetraoxadispiro [5.2.5.2]-
tetradecane core (III). The three possible type I DFA diastereomers
1-3 are also shown.
(10) Benito, J. M.; Go´mez-Garc´ıa, M.; Ortiz Mellet, C.; Garc´ıa Ferna´n-
dez, J. M.; Defaye, J. Org. Lett. 2001, 3, 549-552.
(11) Here we are using the notion of intramolecular aglycon deliVery in
a broad sense, to refer to transformations involving an intramolecular
glycosylation reaction in which the acceptor and the donor moieties are
linked through a tether that controls the stereochemical outcome, to produce
product distributions different from those obtained in the intermolecular
process, and that can be further removed. It should be noted, however, that
classical IAD glycosylation reactions proceed to give, preferentially, the
kinetic product, which is not necessary true in the present case.
(12) (a) Barresi, F.; Hindsgaul, O. Can. J. Chem. 1994, 72, 1447-1465.
(b) Barresi, F.; Hindsgaul, O. Synlett 1992, 72, 759-761. (c) Barresi, F.;
Hindsgaul, O. J. Am. Chem. Soc. 1991, 113, 9376-9377.
(13) (a) Stork, G.; La Clair, J. J. J. Am. Chem. Soc. 1996, 118, 247-
248. (b) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114, 1087-1088.
(14) (a) Mu¨ller, M.; Schmidt, R. R. Eur. J. Org. Chem. 2001, 2055-
2066. (b) Mu¨ller, M.; Huchel, U.; Geyer, A.; Schmidt, R. R. J. Org. Chem.
1999, 64, 6190-6201. (c) Huchel, U.; Schmidt, R. R. Tetrahedron Lett.
1998, 39, 7693-7694.
The stereoselective synthesis of DFAs of type I is
particularly challenging due to the presence of two five-
membered rings, for which the anomeric effect is consider-
ably reduced as compared with six-membered rings. Of the
three possible type-I diastereomers, the nonsymmetrical R-D-
fructofuranose â-D-fructofuranose 1,2′:2,1′-dianhydride 1 is
(6) Recent syntheses: (a) Li, X.; Takahashi, H.; Ohtake, H.; Shiro, M.,
Ikegami, S. Tetrahedron 2001, 57, 8053-8066. (b) Dondoni, A.; Marra,
A.; Scherrmann, M.-C.; Bertolasi, V. Chem. Eur. J. 2001, 7, 1371-1382.
874
Org. Lett., Vol. 5, No. 6, 2003

hydroxyl group in the known acetonide 415 as the corre-
sponding tert-butyl dimethyl silyl ether 5, benzylation of the
secondary hydroxyl groups (f 6), fluorolysis of the silyl
ether group (f 7), and reaction of the resulting alcohol with
R,R′-dibromo-m-xylene (Scheme 1).
Scheme 2. Stereoselective Synthesis of Type-I DFAs via IAD
Using the p- and o-Xylylene Tethers
Scheme 1. Stereoselective Synthesis of Type-I DFAs via IAD
Using the m-Xylylene Tether
Cleavage of the acetal protecting groups in dimer 8,
intramolecular glycosylation, and subsequent spirocyclization
were effected in a one-pot manner by using trifluoromethane-
sulfonic acid as the catalyst in dichloromethane solution. An
inseparable mixture of the R,â- and R,R-isomers 9 and 10,
respectively, in a 1:2 relative proportion was thus obtained
in 75% yield. Hydrogenolysis of the benzyl groups led to
the fully unprotected DFAs 1 and 2 (Scheme 1).16
The above result is in agreement with a destabilization of
the chair conformation of the 1,4-dioxane ring in difuranose
DFA isomers upon tethering of the primary hydroxyl groups.
Actually, under identical reaction conditions, the monomeric
3,4,6-tri-O-benzyl-1,2-isopropylidene-â-D-fructofuranose10 af-
forded the analogous hexa-O-bezyl R,â- and R,R-DFAs in a
3:1 relative proportion, as expected from the already
discussed relative thermodynamic stabilities. It seems, how-
ever, that the m-xylylene linker is still too flexible to avoid
formation of the thermodynamically favored nonsymmetrical
diastereomer, and this situation prevents isolation of the
elusive di-â-diastereomer.
To further limit the flexibility of the system, the dimeric
p- and o-xylylene-tethered fructofuranose derivatives 11 and
14, respectively, were prepared by reaction of the selectively
protected acetonide 7 with R,R′-dibromo-p- and o-xylene,
respectively. After treatment with trifluoromethanesulfonic
acid, compound 11 afforded a mixture of the C2-symmetric
DFA diastereomers 12 and 13 in a 4:1 ratio, although in
(15) Chittenden, G. J. F. J. Chem. Soc., Chem. Commun. 1980, 882-
883.
(16) Typical IAD-Spirocyclization Procedure. To a solution of the
corresponding xylylene-tethered D-fructofuranose derivative 8, 11, or 14
(80 mg, 0.088 mmol) in dry CH2Cl2 (14 mL) at -78 °C was added
trifluoromethanesulfonic acid (12 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 1 h. Et3N (3 drops) was added, and the resulting
solution was stirred for 10 min and then concentrated. Column chroma-
tography (silica gel, 1:3 EtOAc-petroleum ether) afforded the corresponding
two-component mixtures of DFAs (9, 10 and 12, 13, respectively) in the
case 8 and 11 or the individual DFAs (15 and 16) in the case of 14.
Conventional hydrogenation of the benzyl xylylene derivatives with H2 (1
atm) over 10% Pd/C in 2:1 EtOAc-MeOH for 24 h afforded the
corresponding fully unprotected DFAs 1-3 whose relative proportions were
stablished by GC following the procedure reported in ref 9d. In all cases,
the physical and spectroscopic properties of the unprotected isomers were
identical to those previously reported (cf. ref 5).
Org. Lett., Vol. 5, No. 6, 2003
875

disappointingly low yield (Scheme 2). In the case of 14,
having the shorter spacer, the IAD glycosylation-spiro-
cyclization reaction led to the di-â-DFA 16 in 90% de over
the di-R-isomer 15 and 85% total yield, which could be
separated by silica gel column chromatography. Further
hydrogenolysis afforded the fully unprotected di-R- and di-
â-DFAs 2 and 3 (Scheme 2). To the best of our knowledge,
this is the first synthesis of the latter compound, a minor
component of the disaccharide fraction of sucrose and
D-fructose caramels,9 in good yield.
NMR, and molecular modeling data.5 In spiroketalic â-linked
D-fructofuranosyl moieties, O-2 and O-3 would be unfavor-
ably eclipsed in certain conformations, which results in
skewed conformations around Eo being favored over con-
formations in which C-2 and C-3 are in the same plane.5 As
a consequence, the hydroxymethyl groups in C2-symmetric
difuranose DFA derivatives are taken apart in the case of
the di-R-isomer 2 and drawn nearer in the case of the di-â
counterpart 3. This is in agreement with the later isomer
being favored for the shorter o-xylylene spacer.
The remarkable differences in the stereoselectivity of the
above spirocyclization reactions as a function of the substitu-
tion pattern of the xylylene spacer deserve a further comment.
No traces of the R,â-diastereomer were detected in the last
two cases, probably due to the interplay of stereoelectronic
effects at the 1,4-dioxane ring and the geometrical constraints
imposed by the rigid tether, in agreement with molecular
mechanics calculations.17 Stereoelectronic effects also influ-
ence the conformations of the five-membered rings in DFAs.
Thus, R-D-fructofuranose rings in DFA derivatives have been
shown to adopt a rather rigid 3E conformation by X-ray, 1H
In summary, we have demonstrated that the IAD approach
represents a powerful tool for the control of the stereochem-
istry in spirocyclization reactions leading to complex
dispiroketal derivatives. Extension of this strategy to the
preparation of other systems is currently in progress in our
laboratories.
Acknowledgment. We thank the DGESIC for financial
support, Contracts PPQ200-1341 and BCM2001-2366-CO3-
03. E. M. Rubio thanks the CSIC and the Institut fu¨r
Technologie der Kohlenhydrate e.V. for a Ph.D. fellowship.
(17) Molecular mechanics calculations for derivatives of DFAs 1-3
bearing xylylene tethers between the primary oxygen atoms were performed
using MM2* as integrated in MACROMODEL 6.0 and the GBSA
continuum solvent model for chloroform. The three-dimensional geometries
obtained were in agreement with the discussed conformational and relative
stability data.
Supporting Information Available: Experimental pro-
cedures and data for compounds 8, 11, and 14. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL034022C
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