Carbohydrate-derived spiroketals. Stereoselective synthesis of Di-d-fructose dianhydrides by boron trifluoride promoted glycosylation-spiroketalization of acetal precursors

Article abstract of DOI:10.1021/ol006953j

(Matrix presented) Di-D-fructose 1,2′:2,1′-dianhydrides, dispiro-tricyclic disaccharides widely found in food materials, have been stereoselectively prepared in one-pot reaction from O-protected D-fructose 1,2-acetonide precursors by treatment with boron

Full text of DOI:10.1021/ol006953j

ORGANIC
LETTERS
2001
Vol. 3, No. 4
549-552
Carbohydrate-Derived Spiroketals.
Stereoselective Synthesis of
Di-D-fructose Dianhydrides by Boron
Trifluoride Promoted
Glycosylation−Spiroketalization of
Acetal Precursors†
,‡,
Juan M. Benito,‡ Marta Go´mez-Garc´ıa,§ Carmen Ortiz Mellet,*
,§
|
Jose´ M. Garc´ıa Ferna´ndez,* and Jacques Defaye
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad de SeVilla,
Aptdo. 553, E-41071 SeVilla, Spain, Instituto de InVestigaciones Qu´ımicas, CSIC,
Ame´rico Vespucio s/n, Isla de la Cartuja, E-41092 SeVilla, Spain, and CNRS and
UniVersite´ Joseph Fourier-Grenoble I (UMR 5063), De´partement de Pharmacochimie
Mole´culaire-Glucides, BP 138, F-38243 Meylan, France
jogarcia@cica.es
Received December 4, 2000
ABSTRACT
Di-D-fructose 1,2′:2,1′-dianhydrides, dispiro-tricyclic disaccharides widely found in food materials, have been stereoselectively prepared in
one-pot reaction from O-protected D-fructose 1,2-acetonide precursors by treatment with boron trifluoride diethyl etherate. The dimerization
sequence involves (i) cleavage of the anomeric acetal linkage, (ii) autoglycosylation, and (iii) final spiroketalization, the stereochemical outcome
being strongly dependent on the nature of the hydroxyl protecting groups.
The spiroketal unit is a widespread substructure in many
biologically active natural products, including steroidal
saponins, polyether ionophores, macrolide antibiotics, insect
pheromones, and toxic metabolites from algae and fungi.1,2
A main strategy for its elaboration relies on the acid-catalyzed
intramolecular cyclization of the corresponding dihydroxy-
keto precursors or their equivalents. Since such a basic
skeleton is present in ketoses, it was anticipated that
† Dedicated to Professor Ge´rad Descotes on the occasion of his retirement.
‡ Universidad de Sevilla.
(2) For selected recent examples of spiroketal syntheses, see: (a)
Crimmins, M. T.; Katz, J. D. Org. Lett. 2000, 2, 957-960. (b) Balachari,
D.; O’Doherty, G. A. Org. Lett. 2000, 2, 863-866. (c) Zuev, D,; Paquette,
L. A. Org. Lett. 2000, 2, 679-682. (d) Drouet, K. E.; Ling, T.; Tran, H.
V.; Theodorakis, E. A. Org. Lett. 2000, 2, 207-210. (e) Barret, A. G. M.;
Braddock, D. C.; de Koning, P. D.; White, A. J.; Williams, D. J. J. Org.
Chem. 2000, 65, 375-380. (f) Brimble, M. A.; Caprio, V. E.; Johnston, A.
D.; Sidford, M. H. Tetrahedron Lett. 2000, 41, 3955-3958. (g) Arterburn,
J. B.; Perry, M. C. Org. Lett. 1999, 1, 769-771. (h) Dounay, A. B.; Forsyth,
C. J. Org. Lett. 1999, 1, 451-453. (i) Trost, B. M.; Corte, J. R. Angew.
Chem., Int. Ed. 1999, 38, 3664-3666. (j) Carretero, J. C.; de Diego, J. E.;
Hamdouchi, C. Tetrahedron 1999, 55, 15159-15166. (k) Bueno, A. B.;
Hegedus, L. S. J. Org. Chem. 1998, 63, 684-690.
§ Instituto de Investigaciones Qu´ımicas, CSIC.
E-mail: mellet@cica.es
| CNRS and Universite´ Joseph Fourier-Grenoble I.
(1) For general and specialized reviews on the synthesis of spiroketals
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) Brimble, M. A.; Fare`s, F. A. Tetrahedron 1999, 55, 7661-7706.
10.1021/ol006953j CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/24/2001

spiroketalization might occur more universally in carbohy-
drate transformation schemes. In fact, spirodioxanyl disac-
charides have long been known as the dimerization products
arising from the acid treatment of ketoses.3 Some members
of this family derived from D-fructose, termed generically
di-D-fructose dianhydrides (DFAs), have also been isolated
from microorganisms4 and higher plants.5 Their potential use
as sweetners,6 bifidogenic agents,7 or polyhydroxylated
spiroketal chiral templates8 has triggered intense interest in
the synthesis of these and related spiro sugars.9 The
identification of DFAs as the major components of the
thermolysis product of sucrose- and D-fructose-containing
food materials, such as caramel or chicory,10 and the need
for pure standards for their analytical evaluation11 has
provided a further impetus.
Scheme 1. Protic Acic Catalyzed Dimerization of Ketoses
High yielding preparations of DFAs have been previously
achieved by protonic activation of D-fructose, sucrose, or
inulin with anhydrous hydrogen fluoride (HF) or its complex
with pyridine.12 Under such conditions, a fructosyl oxocar-
benium cation is generated, which undergoes in situ glyco-
sylation into the corresponding keto-disaccharide. Further
spiroketalization is a reversible process governed mainly by
stereoelectronic factors, i.e., maximum anomeric effect and
minimum steric interactions (Scheme 1).13
In tricyclic systems such general principles must be applied
carefully. A range of structures can usually accommodate
the basic requirementssoxygen substituents at anomeric
centers in axial disposition, carbon substituents in equatorial
dispositionswith rather small differences in energy and low
(3) For a recent review, see: Manley-Harris, M.; Richards, G. N. AdV.
Carbohydr. Chem. Biochem. 1997, 52, 207-266.
(4) (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,, Uchiyama, T. Agric. Biol. Chem. 1988, 52, 3209-3210. (f)
Matsuyama, T.; Tanaka, K.; Uchiyama, T. Agric. Biol. Chem. 1991, 55,
1413-1414.
interconversion barriers. Consequently, a complex distribu-
tion of isomers that differ on the ring size, linking position,
and stereochemistry at the acetal stereocenters is generally
obtained. Up to five different tricyclic cores (Types I to V)
and 12 DFA isomers may be present in the reaction mixtures.
Although their relative proportions can be varied to some
extent by modulation of the acid strength, isolation of pure
samples from these isomeric mixtures remains a difficult
task.3
(5) Li, H.; Zhu, W.; Yokoyama, C.; Harada, N. Carbohydr. Res. 1997,
299, 301-305.
(6) Uchiyama, T. In Science and Technology of Fructans; Suzuki, M.,
Chatterton, N. J., Eds.; CRC: Boca Raton, FL, 1993; pp 170-190.
(7) (a) Manley-Harris, M.; Richards, G. N. Zuckerindustrie 1994, 119,
924-928. (b) Tanaka, M.; Nakajima, Y.; Nisio, K. J. Carbohydr. Chem.
1993, 12, 49-61.
(8) (a) Garc´ıa Ferna´ndez, J. M.; Gadelle, A.; Defaye, J. Carbohydr. Res.
1994, 265, 249-269. (b) Defaye, J.; Garc´ıa Ferna´ndez, J. M. Tetrahedron:
Asymmetry 1994, 5, 2241-2250.
(9) (a) Garc´ıa Ferna´ndez, J. M.; Ortiz Mellet, C.; Defaye, J. J. Org. Chem.
1998, 63, 3572-3580. (b) Bextermo¨ller, R.; Redlich, H.; Schnieders, K.;
Thrma¨hlen, S.; Fro¨lich, R. Angew. Chem., Int. Ed. Engl. 1998, 37, 2496-
2500. (c) Regelin, H.; Sunghwa, F.; Zwanenburg, B.; Gelder, R.; Chittenden,
G. J. F. Carbohydr. Polymers 1998, 37, 323-333. (d) Mart´ın, A.; Salazar,
J. A.; Sua´rez, E. J. Org. Chem. 1996, 61, 3999-4006. (e) Garc´ıa Ferna´ndez,
J. M.; Schnelle, R.-R.; Defaye, J. Aust. J. Chem. 1996, 49, 319-325.
(10) (a) Defaye, J.; Garc´ıa Ferna´ndez, J. M. Carbohydr. Res. 1994, 256,
C1. (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.
We have previously reported the stereospecific synthesis
of a Type III DFA, namely, di-â-D-fructopyranose 1,2′:2,1′-
dianhydride, by use of an acetal-protected D-fructopyranose
precursor and HF as promotor.14 The rather severe reaction
conditions prevent, however, extension of this approach to
other selectively protected derivatives. On the other hand,
boron trifluoride diethyl etherate has been widely used for
the cleavage of acetal protecting groups,15 as promoter in
glycosylation reaction,s16 and as catalyst in spiroketalization
processes.1a We assumed that these three transformations
might proceed in a tandem manner for ketoses bearing
acetonide groups at the anomeric position, taking advantage
(11) Ratsimba, V.; Garc´ıa Ferna´ndez, J. M.; Defaye, J.; Nigay, H.,
Voilley, A, J. Chromatogr. A 1999, 844, 283-293.
(12) (a) Defaye, J.; Garc´ıa Ferna´ndez, J. M. Carbohydr. Res. 1994, 251,
17-31. (b) Defaye, J.; Garc´ıa Ferna´ndez, J. M. Carbohydr. Res. 1994, 251,
1-15. (a) Defaye, J.; Garc´ıa Ferna´ndez, J. M. Carbohydr. Res. 1992, 237,
223-247 and references therein.
(13) Bock, K.; Pedersen, C.; Defaye, J.; Gadelle, A. Carbohydr. Res.
1991, 216, 141-148.
(14) Garc´ıa Ferna´ndez, J. M.; Schnelle, R.-R.; Defaye, J. Tetrahedron:
Asymmetry 1995, 6, 307-312.
(15) Ishihara, K. In Lewis Acids in Organic Synthesis; Yamamoto, H.,
Ed.; Wiley-VCH: Weinheim, 2000; Vol.1, pp 89-133.
(16) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531.
550
Org. Lett., Vol. 3, No. 4, 2001

of their propensity to develop tertiary glycosyl oxocabenium
cations. We now report on the application of this strategy to
the stereoselective preparation of DFAs having the 1,6,9,13-
tetraoxadispiro[4.2.4.2]tetradecane (Type I) and 1,7,10,15-
tetraoxadispiro[5.2.5.2]hexadecane (Type III) dispiroketal
frameworks.
Treatment of 3,4,6-tri-O-benzyl-1,2-O-isopropylidene-â-
D-fructofuranose 1, readily accessible from D-fructose in two
steps via the corresponding fructofuranose 1,2-O-acetonide,17
with 1 equiv of boron trifluoride diethyl etherate in toluene
afforded a 1:2.5 mixture of the hexa-O-benzylated di-R-D-
fructofuranose (3) and R-D-fructofuranose â-D-fructofuranose
(6) 1,2′:2,1′-dianhydrides,18 which were separated and depro-
tected to the known cyclic disaccharides 5 and 8, respec-
tively.3 Replacement of the benzyl groups by benzoyl groups
likewise preserved the furanose form of fructose while
reversing the stereochemical outcome of the spiroketalization
reaction. Thus, upon treatment of 2 with the Lewis acid
promoter the C2 symmetric dianhydride 4 was obtained in
96% de over the asymmetric diastereomer 7 (Scheme 2).18
D-fructose templates. The dimerization process proceeded
more slowly in these cases as compared with the furanose
counterparts, in agreement with the expected lower stability
of the six-membered cyclic oxocarbenium ion intermediate.
Nevertheless, satisfactory yields in the corresponding hexa-
O-benzyl (11 and 14) and hexa-O-benzoyl (12 and 15)
difructopyranose dianhydrides were obtained within 16 h by
using 2.5 equiv of BF3‚Et2O.18 The relative proportion
between the C2 symmetric (di-â-D) and the asymmetric
diastereomer (R,â-D) was, as in the furanose series, strongly
dependent upon the nature of the hydroxyl protecting groups.
Whereas the benzyl-protected acetonide 9 resulted almost
exclusively in the R-D-fructopyranose â-D-fructopyranose
1,2′:2,1′-dianhydride derivative 14 (11:14, 1:25), the triben-
zoate 10 gave a 1:1 mixture of 12 and 15. The structural
assignment was confirmed by transformation into the known
fully unprotected DFAs 16 and 17 (Scheme 3).3
Scheme 3. Stereoselective Synthesis of Type III DFAs
Scheme 2. Stereoselective Synthesis of Type I DFAs
To implement this approach for the stereoselective prepa-
ration of dispiro-difructopyranose dianhydrides, 3,4,5-tri-O-
benzyl- and 3,4,5-tri-O-benzoyl-1,2-O-isopropylidene-â-D-
fructopyranose (9 and 10, respectively), available in three
steps from D-fructose,19 were used as pyranose-anchored
The possibility to control not only the ring size but also
the stereochemistry at the spiroketal centers is noteworthy.
In contrast to the protic acid catalyzed reaction, spiroketal-
ization occurs now under irreversible conditions. The prefer-
ence for asymmetric dispiroketal structures in the case of
nonparticipating benzyl substituents (i.e., 6 and 14) agrees
with a preferred chair conformation at the incipient 1,4-
dioxane ring, analogous to that encountered in the final
(17) Chittenden, G. J. F. J. Chem. Soc., Chem. Commun. 1980, 882-
883.
(18) Typical Dimerization Procedure. To a solution of the corre-
sponding D-fructose 1,2-O-acetonide derivative 1, 2, 9, or 10 (0.3 mmol)
in dry toluene (2 mL) at -20 °C was added BF3‚Et2O (1 equiv for 1 and
9; 2.5 equiv for 2 and 10) under Ar. The reaction mixture was allowed to
reach room temperature and stirred for 4 h (1 and 9) or overnight (2 and
10). MeOH (1.5 mL) and CH2Cl2 (10 mL) were then added, and the resulting
solution was washed with 5% aqueous NaHCO3 (2 × 10 mL), dried
(MgSO4), and concentrated. Column chromatography (silica gel, 1:5
EtOAc-hexanes) afforded the corresponding two-component mixtures of
DFAs in 60-85% yield. Conventional hydrogenation of the benzylated
derivatives (3, 6 or 11, 13) with H2 (1 atm) over 10% Pd/C in 2:1 EtOAc-
MeOH for 24 h or debenzoylation (4, 7 or 14, 16) with 0.1 M NaOMe in
MeOH afforded the corresponding mixtures of fully unprotected DFAs 5,
8 or 17, 19 whose relative proportions were stablished by GC following
the procedure reported in ref 10. The hexabenzyl derivatives 3, 6 and 11,
13 could also be separated by column chormatography using the above
eluent. Alternatively, the mixtures of unprotected DFAs were separated as
their corresponding hexaacetates using 1:3 EtOAc-hexanes as the eluent.
In all cases, the physical and spectroscopic properties of the separated
unprotected isomers were identical to those previously reported (cf. ref 3).
(19) Brady, R. F., Jr. AdV. Carbohydr. Chem. Biochem. 1971, 26, 197-
278.
Org. Lett., Vol. 3, No. 4, 2001
551

compounds, with the oxygen substituents in axial disposition
and the carbon substituents in equatorial disposition (Figure
1, B).3 Such situation does not prevail for the symmetric
Figure 1. Conformations at the central dioxane ring for C2
symmetric (A) and asymmetric (B) dispiroketals.
isomers, which must adopt a boat conformation at the central
ring in order to accommodate the anomeric effect at both
anomeric centers, a less favorable arrangement (Figure 1,
A).3
Figure 2. Probable structure of the acyloxocarbenium cations
involved in the BF3-catalyzed glycosylation-spiroketalization of
benzoylated D-fructose precursors.
For derivatives bearing participating acyl substituents, the
reaction probably proceeds through 2,3-acyloxonium entities
(18 and 19). In the furanose series, this situation leads with
high stereoselectivity to the expected di-R dianhydride 4,
having the oxygen substituents at C-2 and C-3 in trans
relative disposition. In the pyranose series, however, pyra-
midalization of the anomeric carbon likely increases the
crowding of the already hindered R-face. Glycosylation at
this stage may then compete with the attack by the axially
disposed benzoate group at C-5 to give a 2,5-acyloxonium
intermediate (20) that, at its turn, will undergo glycosyla-
tion-spiroketalization through the â-face to give 12 (Figure
2).
dispiro-cyclic disaccharides. Both the ring size and the
stereochemistry at the spiroketal centers can be controlled
by judicious choice of the protecting groups in the monosac-
charide template. Extension of this procedure to the prepara-
tion of other spiroketal frameworks is currently in progress
in our laboratories.
Acknowledgment. We thank the FEDER program for
financial support, contract no. 1FD-0893-CO3-03. M. Go´-
mez-Garc´ıa thanks the CSIC and the Institut fu¨r Technologie
der Kohlenhydrate e.V. for a PhD fellowship.
In summary, we have demonstrated that boron trifluoride
is a suitable reagent to promote dimerization of ketoses to
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