Synthesis and solution conformational analysis of 2,3-anhydro-3-C-[(1R)-2, 6-anhydro-1-deoxy-1-fluoro-D-glycero-D-guloheptitol-1-C-yl]-β -D-gulo-furanose: First example of a monofluoromethylene-linked C-disaccharide

Article abstract of DOI:10.1021/jo0102462

Condensation of 2,3,4,6-tetra-O-benzyl-β-D-glucopyranosylcarbaldehyde with isolevoglucosenone induced by Et₂AlI, followed by epoxidation, gave an aldol that was fluorinated into a monofluoromethylene C-glucopyranoside that was converted into the title C-disaccharide 1. Its conformational behavior in water has been studied by using a combination of NMR spectroscopy (J and NOE data) and molecular mechanics calculations.

Full text of DOI:10.1021/jo0102462

5132
J . Org. Chem. 2001, 66, 5132-5138
Syn th esis a n d Solu tion Con for m a tion a l An a lysis of
2,3-An h yd r o-3-C-[(1R)-2,6-a n h yd r o-1-d eoxy-1-flu or o-D-glycer o-D-gu lo-
h ep titol-1-C-yl]-â-D-gu lo-fu r a n ose: F ir st Exa m p le of a
Mon oflu or om eth ylen e-Lin k ed C-Disa cch a r id e
J esu´s J ime´nez-Barbero,* Raynald Demange, Kurt Schenk, and Pierre Vogel*
Section de Chimie, Universite´ de Lausanne, BCH, CH-1015 Lausanne-Dorigny, Switzerland,
Instituto de Quı´mica Orga´nica, CSIC, J uan de la Cierva 3, E 28006 Madrid, Spain, and
Institut de Cristallographie de l’Universite´, BSP, CH-1015-Lausanne-Dorigny, Switzerland
pierre.vogel@ico.unil.ch
Received March 6, 2001
Condensation of 2,3,4,6-tetra-O-benzyl-â-D-glucopyranosylcarbaldehyde with isolevoglucosenone
induced by Et2AlI, followed by epoxidation, gave an aldol that was fluorinated into a monofluoro-
methylene C-glucopyranoside that was converted into the title C-disaccharide 1. Its conformational
behavior in water has been studied by using a combination of NMR spectroscopy (J and NOE data)
and molecular mechanics calculations.
In tr od u ction
anomeric-syn disposition can be adopted (4-50%), which
depends on the strength of 1,3-type syn-diaxial interac-
tions and the particular bond distance and angle values.
Regarding the recognition of these analogues by proteins
and enzymes, we have also reported that thiocellobiose
is bound by Streptomyces sp. â-glucosidase in the con-
formation usually found for regular O-glycosides (syn-
Φ,Ψ).7 However, we also have described that the C-gly-
cosyl analogue of lactose is bound by Escherichia coli
â-galactosidase in an unusual high energy conformation.8
Moreover, this derivative, C-lactose, is recognized by two
lectins, namely, ricin-B and galectin-1, in other distinct
conformations.9,10 These results have prompted us to
extend our studies to determine which is the degree of
similarity between other sugars and their analogues,
with different glycosidic linkages, in the free and in the
protein-bound state.11
On this basis, we report here on the synthesis and
conformational study of a new C-disaccharide, 1, in which
â-D-glucopyranose is linked by a monofluoromethylene
bridge at position C3 of 2,3-anhydro-D-gulofuranose. The
conformation analysis of 1 will use a combination of NMR
spectroscopy and molecular mechanics calculations.12,13
Compound 1 represents the first example of a new class
The quest for glycosidase and glycosyl transferase
inhibitors, as well as for stable glycomimetics, has led to
different groups of oligosaccharide analogues with the
glycosidic and endocyclic oxygens substituted by other
atoms.1 Thus, carbon-, thio-, and imino-linked glycosides,
carbasugars, and other derivatives have been employed,
with different degrees of success.2,3 For these pseudosac-
charides to be biologically useful, one of the requirements
probably concerns that their conformational behavior
should be analogous to that of the natural compound, to
minimize the entropic costs of the recognition process
with the receptor.4 It should be stressed that, in principle,
the substitution of the exo- or endocyclic oxygens by other
atoms will result in a change in both the size and/or the
electronic properties of the glycosidic linkage, particularly
in the conformational anomeric effects.5 Therefore, it is
relevant to determine how the three-dimensional struc-
tures of the synthetically prepared derivatives are af-
fected by such modifications, in relation to those of the
corresponding O-glycosides. In this context, we have
recently reported that for the C-glycosyl, S-glycosyl, and
carba analogues of lactose,6 in the absence of the stereo-
electronic stabilization provided by the anomeric effect,
conformations which are not consistent with the exo-
(6) Montero, E.; Garc´ıa, A.; Asensio, J . L.; Hirai, K.; Ogawa, S.;
Santoyo-Gonza´lez, F.; Can˜ada, F. J .; J ime´nez-Barbero, J . Eur. J . Org.
Chem. 2000, 1945.
(1) (a) Gabius, H. J .; Gabius, S. In Glycosciences: Status and
Perspectives; Chapman
&
Hall: London, 1997. (b) Chemistry of
(7) Montero, E.; Vallmitjana, M.; Perez-Pons, J . A.; Querol, E.;
J ime´nez-Barbero, J .; Can˜ada, F. J . FEBS Lett. 1998, 421, 243.
(8) Espinosa, J . F.; Montero, E.; Vian, A.; Garcia, J . L.; Dietrich,
H.; Mart´ın-Lomas, M.; Schmidt, R. R.; Imberty, A.; Can˜ada, F. J .;
J ime´nez-Barbero, J . J . Am. Chem. Soc. 1998, 120, 10862.
(9) (a) Espinosa, J . F.; Can˜ada, F. J .; Asensio, J . L.; Dietrich, H.;
Mart´ın-Lomas, M. Schmidt, R. R.; J ime´nez-Barbero, J . Angew. Chem.,
Int. Ed. Engl. 1996, 35, 303. (b) Espinosa, J . F.; Can˜ada, F. J .; Asensio,
J . L.; Mart´ın-Pastor, M.; Dietrich, H.; Mart´ın-Lomas, M.; Schmidt, R.
R.; J ime´nez-Barbero, J . J . Am. Chem. Soc. 1996, 118, 10862.
(10) Asensio, J . L.; Espinosa, J . F.; Dietrich, H.; Can˜ada, F. J .;
Schmidt, R. R.; Mart´ın-Lomas, M.; Andre´, S.; Gabius, H. J .; J ime´nez-
Barbero, J . J . Am. Chem. Soc. 1999, 121, 8995.
(11) Ravishankar, R.; Surolia, A.; Vijayan, M.; Lim, S.; Kishi, Y. J .
Am. Chem. Soc. 1998, 120, 11297.
(12) (a) Peters, T.; Pinto, B. M. Curr. Opin. Struct. Biol. 1996, 6,
710. (b) Imberty, A. Curr. Opin. Struct. Biol. 1997, 7, 617. (c) J ime´nez-
Barbero, J .; Asensio, J . L.; Can˜ada, J .; Poveda, A. Curr. Opin. Struct.
Biol. 1999, 9, 549.
C-glycosides; Levy, W., Chang, D., Eds.; Elsevier: Cambridge, 1995.
(c) C-Glycoside synthesis; Postema, M. D. H., Ed.; CRC Press: Boca
Raton, FL, 1995. (d) Driguez, H. Top. Curr. Chem. 1997, 187, 85. (e)
Andrews, J . S.; Pinto, B. M. Carbohydr. Res. 1995, 270, 51. (f) Yuasa,
H.; Hashimoto, H. Rev. Heteroat. Chem. 1999, 19, 35.
(2) (a) J ohns, B. A.; Pan, Y. T.; Elbein, A. D.; J ohnson, C. R. J . Am.
Chem. Soc. 1997, 119, 4856. (b) Gabius, H. J ., Sinowatz, F., Eds. Special
volume on glycosciences. Acta Anat. 1998, 161, 1.
(3) Ogawa, S.; Hirai, K.; Odagiri, T.; Matsunaga, N.; Yamazaki, T.
A.; Nakajima, A. Eur. J . Org. Chem. 1936, 1, 1099, and references
therein.
(4) Searle, M. S.; Williams, D. H. J . Am. Chem. Soc. 1992, 114,
10690.
(5) (a) Asensio, J . L.; Can˜ada, F. J .; Garc´ıa, A.; Murillo, M. T.;
Ferna´ndez-Mayoralas, A.; J ohns, B. A.; Kozak, J .; Zhu, Z.; J ohnson,
C. R.; J ime´nez-Barbero, J . J . Am. Chem. Soc. 1999, 121, 11318. (b)
Asensio, J . L.; Can˜ada, F. J .; Kahn, N. Mootoo, D. A.; J ime´nez-Barbero,
J . Chem. Eur. J . 2000, 6, 1035.
10.1021/jo0102462 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/04/2001

Monofluoromethylene-Linked C-Disaccharide
J . Org. Chem., Vol. 66, No. 15, 2001 5133
Sch em e 1
of C-disaccharides. The few fluorinated C-disaccharides
reported so far are difluoromethylene-linked C-furano-
sides.14,15 As we shall see, the monosubstitution of the
methylene linker in â-C-glucopyranoside allows for un-
usual conformations to exist in equilibrium with “normal”
conformations of the C-glycosides.
C1′-C3 of 7 is probably due to hydrogen bonding involv-
ing one of the 4-hydroxy groups and the ethereal oxygen
center at C7′ of the C-â-D-glucopyranoside unit of 7. The
structure of 7 confirms an SN2-type displacement (no
intervention of participating groups in the heterolytic
process) for the fluorination of aldol (+)-5 into the
â-fluoroketone (+)-6. The (1′S) configuration of the hy-
droxymethylene linker of C-disaccharide (+)-5 has been
established unambiguously by conversion of (+)-5 into
1,6:2,3-dianhydro-3-C-[(1S)-2,6-anhydro-D-glycero-D-gulo-
heptitol-1-C-yl]-â-D-gulo-pyranose-1′,4-acetonide.18
Reduction of ketone (+)-6 with NaBH4 in MeOH was
highly stereoselective and gave (+)-8 quantitatively.
Debenzylation of (+)-8 with metallic sodium in am-
monia20 afforded the fully deprotected dianhydro-C-
disaccharide (+)-9 in 95% yield. Peracetylation under
standard conditions (Ac2O, pyridine, DMAP) gave the
pentaacetate (+)-10 (96%) that reacted with trifluoro-
acetic acid in acetic anhydride, giving rise to the 2,3-
anhydro-D-gulose derivative (+)-11 in 73% yield. The
structure of (+)-11 was deduced from its coupling con-
Resu lts a n d Discu ssion
Syn th esis. The synthesis of the fluoromethylene-
linked C-disaccharide 1 starts with a Baylis-Hillmann
type of condensation of the â-D-glucopyranose-derived
carbaldehyde 216 with isolevoglucosenone 317 induced by
Et2AlI. The enone (+)-4 so obtained is epoxidized ste-
reospecifically into (+)-5.18 Fluorination of (+)-5 with
DAST (Et2NSF3)19 in CH2Cl2 afforded (+)-6 in 73% yield
(Scheme 1). The stucture of (+)-6 was established un-
ambiguously by single-crystal X-ray radiocrystallography
of its hydrate 7 obtained when crystalline (+)-6 was left
in the air. Interestingly, 7 adopts about its C1′-C2′ bond
an unusual conformation. Indeed, the O-C2′ and C1′-
C3 bonds of 7 are nearly synperiplanar (dihedral angle:
+8.49(26)° and -6.47(27)° for the two forms found in the
monocrystal). The quasi eclipsing of bonds O-C2′ and
3
stant J (H-1,H-2) ) 3.0 Hz.21 Ammonolysis of (+)-11 in
1
MeOH liberated 1 in 77% yield. Its H NMR spectrum
showed a 7:1 mixture of the R-furanose form 1 and
R-pyranose form 12 (Scheme 2).
Molecu la r Mech a n ics a n d Dyn a m ics Ca lcu la -
tion s. C-Disaccharide 1 shows two torsional degrees of
freedom (Φ, Ψ) for the glycosidic linkage and two more
for the corresponding lateral chains. Therefore, in a first
step, the population of the different staggered rotamers
around the Φ/Ψ linkages was estimated (Figure 1) by
using the MM3* force field.22 Glycosidic torsion angles
are defined as Φ (H-C2′/C1′-C3) (rotamers about C2′-
C1′ bond), Ψ (C2′-C1′/C3-C4) (rotamers about C1′-C3
bond), ω1 as dihedral angle (O4-C4/C5-C6), ω2 as (C4-
C5/C6-O6), and ω3 as (C5′-C6′/C7′-O). The results are
shown in Table 1.
(13) A general survey of conformation of carbohydrates and ana-
logues is presented in the following: French, A. D.; Brady, J . W.
Computer Modelling of Carbohydrate Molecules; American Chemical
Society: Washington, DC, 1990. For carba sugars, besides ref 6, see:
(a) Duus, J . O.; Bock, K.; Ogawa, S. Carbohydr. Res. 1994, 252, 1. (b)
Duus, J . O.; Guzma´n, J . F.; Bock, K.; Ogawa, S.; Yokoi, F. Carbohydr.
Res. 1991, 209, 51. (c) Bock, K.; Guzma´n, J . F.; Ogawa, S. Carbohydr.
Res. 1988, 174, 354. (d) Bock, K.; Ogawa, S.; Orihara, M. Carbohydr.
Res. 1989, 191, 357.
(14) (a) Motherwell, W. B.; Ross, B. C.; Tozer, M. J . Synlett 1989,
68. (b) Herpin, T. F.; Motherwell, W. B.; Tozer, M. J . Tetrahedron:
Asymmetry 1994, 5, 2269.
(15) (a) Kovensky, J .; Burrieza, D.; Colliou, V.; Ferna´ndez-Cirelli,
A.; Sinay¨, P. J . Carbohydr. Chem. 2000, 19, 1. (b) Plantier-Royon, R.;
Portella, C. Carbohydr. Res. 2000, 327, 119.
For Ψ and ω2,3, the rotamers are defined as g+ (60°),
g- (-60°), and anti (180°), while for Φ, conformers in
agreement with the exo-anomeric orientation (Φ ca. +60°)
and in disagreement (Φ ca. -60°) are denoted as exo and
(16) (a) Wang, Y.; Babirad, S. A.; Kishi, Y. J . Org. Chem. 1992, 57,
468. (b) Haneda, T.; Kim, S. H.; Kishi, Y. J . Org. Chem. 1992, 57, 490.
(17) Horton, D.; Roski, J . P.; Norris, P. J . Org. Chem. 1996, 61, 3783.
(18) Zhu, Y.-H.; Demange, R.; Vogel, P. Tetrahedron: Asymmetry
2000, 11, 263.
(19) Shellhamer, D. F.; Briggs, A. A.; Miller, B. M.; Prince, J . M.;
Scott, D. H.; Heasley, V. L. J . Chem. Soc., Perkin Trans. 2 1996, 973.
(20) (a) Cheney, L. C.; Piening, J . R. J . Am. Chem. Soc. 1945, 67,
2252. (b) Procter, G.; Genin, D.; Challenger, S. Carbohydr. Res. 1990,
202, 81.
(21) (a) Buss, D. H.; Hough, L.; Hall, L. D.; Manville, J . F.
Tetrahedron 1965, 21, 69. (b) Chmielewski, M.; Mieczkowski, J .; Priebe,
W.; Zamojski, A. Tetrahedron 1978, 34, 3325. (c) Abdel-Malik, M. M.;
Peng, Q.-J .; Perlin, A. S. Carbohydr. Res. 1987, 159, 11.

5134 J . Org. Chem., Vol. 66, No. 15, 2001
J ime´nez-Barbero et al.
Sch em e 2
Ta ble 1. Su m m a r y of th e Molecu la r Mech a n ics Ca lcu la tion s Ca r r ied ou t for 1 (MM3*, MACROMODEL)
conformer
(Φ, ψ)
∆E,
relative
populations
J 1′,2′
(hertz)
H-2′,
H-4
H-2′,
H-2
H-3′,
H-4′
H-3′,
H-2
H-1′,
H-3′
H-1′,
H-2
H-1′,
H-4
kJ mol-1
anti-Φ/g-
178, -49
anti-Φ/anti
180, 161
exo-Φ/anti
61, 165
0.0
2.4
42.5b
16.2b
13.9b
24.3b
1.2
2.8
2.7
9.6
9.6
0.7
0.4
9.6
1.0
0.6
5.4
4.1
5.0
4.7
2.4
4.9
4.7
3.6
4.5
2.8
3.0
4.5
4.2
2.1
4.2
2.9
4.1
4.9
4.9
2.8
2.9
2.7
4.7
5.4
5.1
5.0
5.3
4.0
2.3
4.1
3.1
2.5
4.2
5.3
4.4
5.2
3.1
6.6
5.1
5.4
2.9
3.1
3.1
2.5
2.5
3.7
3.7
2.6
2.9
3.6
2.6
2.8
4.0
4.0
2.8
2.9
4.0
3.8
2.8
2.8
3.0
4.0
2.9
3.0
4.2
2.7
2.8
2.9
2.9
4.0
3.0
2.8
exo-Φ/g-
60, -51
1.4
non- exo-Φ/g+
-40, 156
non- exo-Φ/anti
-40, 156
exo-Φ/g+
49, 49
8.9
15.9
10.0
9.9
0.1
0.8
anti-Φ/g-
0.8
58
non- exo-Φ/g-
-26, -59
ensemble
average
14.3
0.2
100.0
a
Expected coupling constants (J in hertz) and expected distances (r, Å) for every conformer are also given. Distances smaller than 2.5
b
Å that correspond to strong NOEs are in bold type. Distances smaller than 3 Å are detected experimentally and are in italic type. See
Figure 1 for representations of these conformations.
From the calculated energy values (Table 1), it is
obvious that only four conformers (anti-Φ/a, anti-Φ/g-,
exo-syn-Φ/a, and exo-syn-Φ/g-) have appreciable popula-
tion according to a Boltzmann function (Table 1). There-
fore, two rotamers around Φ (anti-Φ (60%) and syn-exo-Φ
(39%)) and two around Ψ are favored (g- (67%) and anti
(30%)). Nevertheless, it can be observed that, although
destabilized by more than 2.5 kcal/mol, non-exo conform-
ers around Φ were local minima (ca. 2% population), as
well as the exo and anti conformers. This result is in
contrast to usual O-glycosides, for which these non-exo
conformers are not local minima. In fact, molecular
mechanics calculations carried out for the putative O-
analogue (13) of 1 confirmed this point, and the non-exo
conformers converged to the corresponding exo-syn
geometries.
F igu r e 1. Representation of major conformers of 1 and
significant vicinal coupling constants.
For the torsional Φ/Ψ combinations, the four conform-
ers are within an energy range of only 0.5 kcal/mol.
Therefore, the calculations predict a high amount of
conformational freedom. exo-Anomeric anti and syn
conformers in Φ, together with anti or g- conformers
around Ψ, are predicted to be the most stable combina-
non-exo, respectively. For ω1, the rotamers are dubbed
gg, gt, and tg. The first letter g or t considers the torsion
O4-C4/C5-C6 and the second one C3-C4/C5-C6.

Monofluoromethylene-Linked C-Disaccharide
J . Org. Chem., Vol. 66, No. 15, 2001 5135
Ta ble 2. Su m m a r y of Exp er im en ta l 1H NMR (500 MHz)
Ch em ica l Sh ifts (δ, p p m ), Cou p lin g Con sta n ts (J in
h er tz), a n d NOEs (%) for a Solu tion of 1 in D2O a t 25 °C
expected J values were calculated for each conformer,
weighted according to its particular population, and
averaged, producing, in all cases, a satisfactory agree-
ment with the experimental values. The torsion angle
around the C4-C5 linkage should be in the vicinity of
the gt and gg conformers, since the corresponding cou-
pling constant (J 4,5 < 2 Hz) agrees with the values
predicted for both conformers (2.0-2.8 Hz). A similar
agreement is produced for the C5-C6 linkage Therefore,
the MM3* values seem to correctly reproduce the con-
formational behavior around these torsions.
proton
δH (ppm)
J (hertz)
NOE with
H-1
H-2
H-4
H-5
5.43 (5.49)a 1.7
3.88 (3.78) 1.7
4.58 (4.22) 1.9
H-2
H-1′
2′S H-2′ (s)b H-1′ (s)
4.19
3.67
3.68
5.0 (5.0)a
H-6a
H-6b
H-1′
H-2′
H-3′
H-4′
H-5′
H-6′
H-7′a
H-7′b
-
-
4.95 (5.18) 4.0
H-4 (w) H-2 (s), H-2′ (s) H-3′ (s)
H-1′, H-4′ (s), H-6 (s)
3.85
3.53
3.49
3.40
3.44
3.74
3.75
4.0 (8.5) H-4 (s)
8.6
8.8
8.7
2.8 (5.5)
-
-
The key conformational information around the Φ
angle was obtained from the J (4.0 Hz) value and NOE
3
experiments. The J H,H value is between those expected
for the exo-anomeric anti (2.5 Hz) and exo (9.8 Hz)
geometries (Figure 1), showing evidence of the confor-
mational equilibrium around Φ, with a higher proportion
of anti geometries (ca. 75:25) than that predicted from
MM3* calculations25 (60:38). In all four major conformers
calculated for 1 (Figure 1), the dihedral angle between
H-C2′ and C1′-F approaches 60°. For deoxyfluoropyra-
a
Values in parentheses are those observed for the minor
b
pyranose 12 at equilibrium with 1. s ) strong NOE, w ) weak
NOE.
tions. Minor populations of non-exo conformers around
Φ (1-2%) and g+ (3%) conformers around Ψ are pre-
dicted. Regarding ω1, similar energy values were found
for the three rotamers for basically all Φ/Ψ combinations,
with preference for the gt and gg rotamers.
3
nosides, the J H,F coupling constant in such a geometry
is expected to vary between 12 and 15 Hz.26 The value of
3
13 Hz measured for J (H-C2′, F-C1′) of 1 is in perfect
agreement with the predictions given by our molecular
mechanics calculations and corroborates the other 1H
NMR data. Additional information came from NOEs. A
close inspection to the 3D models for the basic exo-
anomeric and non-exo-anomeric conformations around
this linkage indicated that there are exclusive27 inter-
residue NOEs that unequivocally characterize the dif-
ferent conformations. Thus, 2D-NOESY and 1D-DPFGSE
NOESY28 spectra were acquired (see Supporting Infor-
mation).
Additional information on the conformational stability
of the different minima was obtained from MD simula-
tions with the MM3* force field using the continuum GB/
SA (generalized Born solvent-accessible surface area)
solvent model for water.23 Independently from the start-
ing minimum, the calculated trajectories showed several
interconversions among the different regions and pre-
sented a clear resemblance to the conformer populations
described above (Figure 1). In particular, exo-anomeric
and anti conformers were major for Φ, and no excursions
to non-exo-anomeric regions were detected (data not
shown). Ψ angle is always between within the g- and
anti regions. Interconversions around ω1-ω3 were very
frequently found, in agreement with the molecular
mechanics energy values and the experimental J values
(see below).
NMR Stu d ies. The validity of the predictions obtained
through the molecular mechanics calculations was tested
using 1H NMR measurements, especially NOE and J
values. In a first step, the assignment of the resonances
was made through a combination of COSY, HSQC, and
TOCSY experiments at 500 MHz. The results are shown
in Table 2. The proton-proton coupling constants (J 4,5
) 1.9, J 5,6a ) 5.0, J 5,6b ) 5.0 Hz) for the furanose lateral
chain and for Φ torsion angle (J 1′,2′ ) 4.0 Hz) agree with
a conformational equilibrium among several conformers.
Expected couplings were calculated from the molecular
mechanics-based conformational distribution using the
Altona modification of the Karplus equation.24 The
The exo/g- conformation is characterized by short H4-
H2′ distances of 2.4 Å. In addition, H-1′/H-3′ and H-1′/
H-2 are 2.5 and 2.8 Å, respectively. The exo/anti con-
former is characterized by a short H-2′/H-2 distance (only
2.1 Å). H-1′/H-3′ and H-1′/H-4 are 2.5 and 3.0 Å, respec-
tively. The anti/g- conformer places H-3′ and H-4 and
H-3′ and H-2 at 2.7 and 2.5 Å, respectively, while the
H-1′ of the C linker is 2.8 Å apart of H-2. No exclusive
NOE does exist for the anti/anti conformer. Therefore,
the unambiguous presence of either conformer can be
detected by focusing on the existence of these. Indeed,
this is the case. Many of these NOEs are seen in water
solution. Indeed, strong to medium H-4/H-2′, H-4/H-3′,
H-1′/H-3′, and H-1′/H-2 NOEs may be observed unam-
biguously, indicating the presence of a major conforma-
tional equilibrium around both glycosidic linkages. On
top with this, a weak NOE between H-1′/H-4 proton pairs
is also observed. Therefore, these data indicate that the
expected syn exo-anomeric conformer is in equilibrium
in solution with the anti-Φ conformer, in agreement with
(22) The MM3* force field (Allinger, N. L.; Yuh, Y. H.; Lii, J . H. J .
Am. Chem. Soc. 1989, 111, 8551) implemented in MACROMODEL
(Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.; Caufield,
C.; Chang, G.; Hendrickson, T.; Still, W. C. J . Comput. Chem. 1990,
11, 440) differs of the regular MM3 force field in the treatment of the
electrostatic term since it uses charge-charge instead of dipole-dipole
interactions. The MM3* force field was used since it has provided a
satisfactory agreement between experimental and theoretical data for
a variety of saccharides and carba sugars.6 For specific cases, see: (a)
Espinosa, J . F.; Dietrich, H. M.; Mart´ın-Lomas, M.; Schmidt, R. R.;
J ime´nez-Barbero, J . Tetrahedron Lett 1996, 37, 1467. (b) Mart´ın-
Pastor, M.; Espinosa, J . F.; Asensio, J . L.; J imenez-Barbero, J .
Carbohydr. Res. 1997, 298, 15.
(24) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C.
Tetrahedron, 1980, 36, 2783.
(25) Perez, S.; Imberty, A.; Engelsen, S.; Gruza, J .; Mazeau, K.;
J imenez-Barbero, J .; Poveda, A.; Espinosa, J . F. Carbohydr. Res. 1998,
314, 141.
(26) See, for example: (a) San Fabia´n, J .; Guilleme, J .; D´ıez, E. J .
Magn. Reson. 1998, 133, 255. (b) Thibaudeau, C.; Plavec, J .; Chatto-
padhyaya, J . J . Org. Chem. 1998, 63, 4967. (c) San Fabia´n, J .;
Guilleme, J . Chem. Phys. 1996, 206, 325. (d) Emsley, J . W.; Phillips,
L.; Wray, V. Prog. NMR Spectrosc. 1976, 10, 83.
(27) Dabrowski, J .; Kozar, T.; Grosskurth, H.; Nifant’ev, N. E. J .
Am. Chem. Soc. 1995, 117, 5534.
(23) Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. J .
Am. Chem. Soc. 1990, 112, 6127.
(28) Stott, K.; Stonehouse, J .; Keeler, J .; Hwang, T.-L.; Shaka, A.
J . J . Am. Chem. Soc. 1995, 117, 4199.

5136 J . Org. Chem., Vol. 66, No. 15, 2001
J ime´nez-Barbero et al.
the J data and the molecular mechanics calculations. The
observed NOEs are averaged among all the rotamers
present in solution. Along this reasoning, it can be
observed that the experimental values are in good
agreement with those estimated from the MM3* calcu-
lated distribution.
lecular mechanics calculations.33 Our observations with
the fluoromethylene-linked C-disaccharide 1, along with
those previously obtained for other glycomimetics, are
relevant for drug design. The flexibility of these mimetics
may limit use them as therapeutic agents: an entropy
penalty has to be paid and minima other than the global
minimum could be bound by biological receptors.34 Nev-
ertheless, the small energy barriers between the different
energy regions might allow for the global minimum
conformation of the glycoside to be bound by a protein
without a major energy conflict. In addition, these
compounds may be excellent probes to study the com-
bining sites of proteins and enzymes and they may also
serve as test compounds to compare conformational
properties of oligosaccharides.35,36 Our work suggests that
stereospecific monofluorination of the methylene linker
of a C-glycoside can be used to favor “unnatural” confor-
mations of the glycomimetic.
All the experimental and theoretical data prove that
there are internal motions around the glycosidic link-
ages.29 The presence of non-exo-anomeric conformers for
the glycomimetic is probably smaller than 5%. Thus, the
molecular mechanics and NMR results have allowed us
to demonstrate the participation of at least two conform-
ers around Φ of the fluoromethylene-linked C-disaccha-
ride 1.30 The exo-anomeric31 preference for it should
mainly reside in steric effects, probably 1,3-type interac-
4
tions.5 In fact, for the regular C1(D) chairs of the gluco
series, there is a 1,3-type interaction between the equa-
torially substituted C-2, as in 1, and the aglycon when
the non-exo-anomeric (non-exo) conformation is consid-
ered (Figure 1). There are not such steric interactions
for the exo-anomeric (exo) and the anti conformations.
Therefore, this interaction is probably at the origin of the
strong preference of the exo-anomeric orientation in 1.5,31
For O-glycosides, the stereoelectronic effect will be ad-
ditionally superimposed, with a subsequent further
stabilization of the exo-anomeric orientation, thus provid-
ing an explanation for the basically unique conformation
around the Φ angle of the O-disaccharides.31 Indeed,
MM3* calculations for the O-glycosyl analogue 13 point
to the major existence of the syn-exo conformer (>70%),
which corresponds to the minor geometries around Φ of
the C-disaccharide 1. Our observation that 1 adopts
preferred anti-Φ conformations can be interpreted in
terms of a stabilizing gauche effect32 involving the
fluorine atom and the ethereal oxygen atom of the
glucopyranosyl moiety. Regarding Ψ (rotamers about
C1′-C3 bond) of the O-glucopyranoside 13, the calcula-
tions predict that the g- conformers are highly destabi-
lized and that only the anti conformers are possible. The
shortening of the C-O bonds with respect to the C-C
ones is probably responsible for this fact.
Exp er im en ta l Section
Gen er a l Rem a r k s. See ref 37. None of the procedures were
optimized. Flash column chromatography (FC) was performed
on Merk silica gel (230-400 mesh). Thin-layer chromatography
(TLC) was carried out on silica gel (Merk aluminum foils).
NMR Sp ectr oscop y. 1H NMR signal assignments were
confirmed by double irradiation experiments and, when re-
quired, by 2D-NOESY and COSY spectra. J values are given
in hertz. The 600 MHz 1H NMR spectra were recorded on a
Bruker AMX-600 FR spectrometer. The 500 MHz 1H NMR
spectra in D2O were recorded on a Varian Unity 500 spec-
trometer, using an approximately 2 mg/mL solution at differ-
ent temperatures (299-313 K). Chemical shifts are reported
in ppm, using external TMS (0 ppm) as reference. The double
quantum filtered COSY spectrum was performed with a data
matrix of 256 × 1K to digitize a spectral width of 2000 Hz. A
total of 16 scans were used with a relaxation delay of 1 s. The
2D TOCSY esperiment was performed using a data matrix of
256 × 2K to digitize a spectral width of 2000 Hz; 4 scans were
used per increment with a relaxation delay of 2 s. MLEV 17
was used for the 100 ms isotropic mixing time. The one-bond
proton-carbon correlation experiment was collected in the 1H-
detection mode using the HSQC sequence and a reverse probe.
A data matrix was used to digitize a spectral width of 2000
Hz in F2 and 10000 Hz in F1; 4 scans were used per increment
with a relaxation delay of 1 s and a delay corresponding to a
J value of 145 Hz. A BIRD pulse was used to minimize the
proton signals bonded to 12C. 13C decoupling was achieved by
the WALTZ scheme.
Con clu sion
The results presented herein clearly show that the Φ
glycosidic linkages (rotation about C1′-C2′ bond) of
C-glycosyl analogues are more flexible than those of the
natural O-glycosides, as determined by NMR and mo-
NOESY experiments were performed with the selective 1D
double pulse field gradient spin echo module, using three
different mixing times, namely, 250, 500, and 750 ms. 2D
NOESY experiments were also performed with the same
mixing times and using 256 × 2K matrixes.
(29) For a detailed description of conformational analysis of carbo-
hydrates using MD simulations, see: Woods, R. J . Curr. Opin. Struct.
Biol. 1995, 5, 591.
(30) Neuhaus, D.; Williamson, M. P. The Nuclear Overhauser Effect
in Structural and Conformational Analysis; VCH Publishers: New
York, 1989.
NOE Ca lcu la tion s. NOESY spectra were simulated ac-
cording to a complete relaxation matrix approach, following
the protocol previously described, using three different mixing
times (between 250 and 750 ms). The spectra were simulated
(31) (a) Lemieux, R. U.; Koto, S.; Voisin, D. Am. Chem. Soc. Symp.
Ser. 1979, 87, 17. (b) Thatcher, G. R. J . The Anomeric Effect and
Associated Stereoelectronic Effects; American Chemical Society: Wash-
ington, DC, 1993. (c) Tvaroska, I.; Bleha, T. Adv. Carbohydr. Chem.
Biochem. 1989, 47, 45. (d) Kirby, A. J . The Anomeric Effect and Related
Stereoelectronic Effects at Oxygen; Springer-Verlag: Heidelberg, Ger-
many, 1983.
(32) (a) Allen, L. C. Chem. Phys. Lett. 1968, 2, 597. (b) Wolfe, S.
Acc. Chem. Res. 1972, 5, 102. (c) Olson, W. K. J . Am. Chem. Soc. 1982,
104, 278. (d) Wiberg, K. B.; Murko, M. A.; Laidig, K. E.; MacDougall,
P. J . J . Phys. Chem. 1990, 94, 6956. (e) Thibaudeau, C.; Plavec, J .;
Garg, N.; Papchikhin, A.; Chattopadhyaya, J . J . Am. Chem. Soc. 1994,
116, 4038. (f) Bakke, J . M.; Bjerkeseth, L. H.; Ronnow, T. E. C. L.;
Steinsvoll, K. J . Mol. Struct. 1994, 321, 205. (g) Abraham, R. J .;
Chambers, E. J .; Thomas, W. A. J . Chem. Soc., Perkin Trans. 2 1994,
949. (h) Rablen, P. R.; Hoffmann, R. W.; Hrovat, D. A.; Borden, W. T.
J . Chem. Soc., Perkin Trans. 2 1999, 1719.
(33) Poveda, A.; Asensio, J . L.; Bazin, H.; Polat, T.; Lindhardt, R.
J .; J imenez-Barbero, J . Eur. J . Org. Chem. 2000, 1805.
(34) For different implications of conformational restriction of the
ligand upon protein binding, see: Bundle, D. R.; Alibe´s, R.; Nilar, S.;
Otter, A.; Warwas, M.; Zhang, P. J . Am. Chem. Soc. 1998, 120, 5317.
(35) For a different conclusion, see: Navarre, N.; Amiot, N.; Van
Oijen, A. H.; Imberty, A.; Poveda, A.; J imenez-Barbero, J .; Cooper, A.;
Nutley, M. A.; Boons, G. J . Chem. Eur. J . 1999, 5, 2281.
(36) For conformational selection in carbohydrate recognition by
proteins, see refs 9-12 and Gilleron, M.; Siebert, H.-C.; Kaltner, H.;
Von der Lieth, C. W.; Kozar, T.; Halkes, K. M.; Korchagina, E. Y.;
Bovin, N. V.; Gabius, H.-J .; Vliegenthart, J . F. G. Eur. J . Biochem.
1998, 249, 27.
(37) (a) Sevin, A. F.; Vogel, P. J . Org. Chem. 1994, 59, 5920. (b)
Kraehenbuehl, K.; Picasso, S.; Vogel, P. Helv. Chim. Acta 1998, 81,
1439.

Monofluoromethylene-Linked C-Disaccharide
J . Org. Chem., Vol. 66, No. 15, 2001 5137
from the average distances r-6 calculated from the popula-
47.0, 5.0, 1H), 4.35 (ddd, J ) 6.2, 5.1, 1.8, 1H), 4.24 (d, J )
5.1, 1H), 4.18 (dd, J ) 8.1, 1.8, 1H), 3.88 (dd, J ) 12.1, 2.1,
1H), 3.79-3.71 (m, 3H), 3.48 (dd, J ) 8.9, 8.8, 1H), 3.41 (dd,
J ) 8.9, 8.85, 1H), 3.36 (dd, J ) 8.9, 8.85, 1H), 3.33 (m, 1H),
3.25 (dd, J ) 1.2, 1.1, 1H).
kl
tion distribution at 303 K. Isotropic motion and external
relaxation of 0.1 s-1 were assumed. A τc of 50 ps was used to
obtained the best match between experimental and calculated
NOEs for the intraresidue proton pairs (Fuc H1/H2). All NOE
calculations were automatically performed by a homemade
program, available from the authors upon request.
4-O-Acetyl-1,6:2,3-d ia n h yd r o-3-C-[(1R)-3,4,5,7-tetr a -O-
a ce t yl-2,6-a n h yd r o-1-d e oxy-1-flu or o-D-glycer o-D-gu lo-
h ep titol-1-C-yl]-â-D-gu lo-p yr a n ose ((+)-10). A mixture of
(+)-9 (480 mg, 1.42 mmol), Ac2O (5.4 mL), pyridine (9 mL),
and 4-(dimethylamino)pyridine (0.5 mg) was stirred at 20 °C
for 15 h. Solvent evaporation in vacuo gave a residue that was
taken up in toluene (10 mL), and the solvent was evaporated
to dryness in vacuo. The latter operation was repeated and
the residue purified by flash chromatography on silica gel (1:2
light petroleum ether/EtOAc), affording 751 mg (96%) of a
white solid: mp 63 °C; [R]25D ) +32 (c ) 0.08, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 5.62 (s, 1H), 5.24 (dd, J ) 9.3, 9.25, 1H),
5.22 (d, J ) 4.7, 1H), 5.16 (dd, J ) 9.3, 9.25, 1H), 5.04 (dd, J
) 45.0, 7.8, 1H), 5.00 (dd, J ) 9.3, 9.25, 1H), 4.51 (ddd, J )
6.3, 4.7, 1.7, 1H), 4.17, (dd, J ) 12.6, 5.2, 1H), 4.05 (dd, J )
12.6, 5.2, 1H), 3.99 (dd, J ) 8.3, 1.7, 1H), 3.79-3.70 (m, 3H),
3.29 (s, 1H), 2.13, 2.10, 2.03, 2.02, 2.01 (5s, 15H).
1,4,6-Tr i-O-a cet yl-2,3-a n h yd r o-3-C-[(1R)-3,4,5,7-t et r a -
O-a cetyl-2,6-a n h yd r o-1-d eoxy-1-flu or o-D-glycer o-D-gu lo-
h ep titol-1-C-yl]-r-D-gu lo-p yr a n ose ((+)-11). A mixture of
(+)-10 (387 mg, 0.71 mmol), Ac2O (3 mL), and CF3COOH (2
mL) was stirred at 20 °C for 2.5 h. It was poured into ice (10
mL) and neutralized with a saturated aqueous solution of
NaHCO3 (pH 8). The mixture was extracted with EtOAc (10
mL, 3 times). The combined organic extracts were washed with
brine (30 mL) and dried (MgSO4). Solvent evaporation and
flash chromatography on silica gel (1:2 light petroleum ether/
Molecu la r Mech a n ics a n d Dyn a m ics Ca lcu la tion s.
Molecular mechanics and dynamics calculations were per-
formed using the MM3* force field as implemented in MAC-
ROMODEL 4.5. Glycosidic torsion angles are defined as Φ
(H2′-C2′/C1′-C3), Ψ (C2′-C1′/C3-C4), ω1 as (O4-C4/C5-
C6), ω2 as (C4-C5/C6-O6), and ω3 as (C5′-C6′/C7′-O). The
results are shown in Table 1. For Ψ and ω, the rotamers are
defined as g+ (60°), g- (-60°), and anti (180°), while for Φ,
conformers in agreement with the exo-anomeric orientation (Φ
ca. +60) and in disagreement (Φ ca. -60) are denoted as exo
and non-exo, respectively. The dielectric constant ꢀ ) 80 and
the continuum GB/SA solvent model were performed. Eighty-
one initial geometries were considered, by combining the
stagerred orientations for Φ, Ψ, and ω. From the energy
values, probability distributions were calculated for each
conformer, according to a Boltzmann function at 300 K.
The global energy minimum structure was used as starting
geometry for molecular dynamics (MD) simulations at 300 K,
with the GB/SA solvent model and a time step of 1 fs. The
equilibration period was 100 ps. After this period, structures
were saved every 0.5 ps. The total simulation time was 3 ns.
Average distances between intraresidue and interresidue
proton pairs were calculated from the dynamics simulations.
1,6:2,3-Dia n h yd r o-3-C-[(1R)-2,6-a n h yd r o-3,4,5,7-tetr a -
O-ben zyl-1-d eoxy-1-flu or o-D-glycer o-D-gu lo-h ep titol-1-C-
yl]-â-D-r ibo-h ex-4-u lop yr a n ose ((+)-6). A solution of (+)-
518 (1.61 g, 2.3 mmol) in CH2Cl2 (30 mL) was added to a stirred
solution of DAST (0.84 mL, 6.4 mmol) in CH2Cl2 (30 mL) cooled
to -95 °C. The reaction mixture was allowed to warm to room
temperature overnight. Then H2O (50 mL) was added. The
aqueous layer was extracted with CH2Cl2 (50 mL, 3 times).
The combined organic extracts were washed with brine (50
mL) and dried (MgSO4). Solvent evaporation and flash chro-
matography on silica gel (3:1 light petroleum ether/EtOAc)
afforded 1.17 g (73%) of a white solid which was crystallized
(4:1 hexane/EtOAc): mp 91 °C; [R]25D ) +5.3 (c ) 0.22, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.33-7.09 (m, 20H), 5.46 (br s,
1H), 5.03 (dd, J ) 44.0, 2.6, 1H), 4.8-4.51 (m, 6H), 4.40-4.38
(m, 3H), 3.86 (dd, J ) 8.6, 1.6, 1H), 3.72 (ddd, J ) 17.0, 9.3,
2.6, 1H), 3.68 (dd, J ) 10.7, 2.9, 1H), 3.63-3.55 (m, 5H), 3.39
(br s, 1H), 3.27 (m, J ) 9.3, 1H).
EtOAc) afforded 336 mg (73%) of a white solid: mp 137 °C;
1
[R]25 ) +16 (c ) 0.08, CHCl3); H NMR (400 MHz, CDCl3) δ
D
6.34 (d, J ) 3.0, 1H), 5.55 (br s, 1H), 5.25-5.18 (m, 2H), 5.04
(dd, J ) 9.5, 9.45, 1H), 4.72 (dd, J ) 46.0, 6.7, 1H), 4.27 (dd,
J ) 12.4, 2.2, 1H), 4.25 (ddd, J ) 7.2, 5.5, 1.4, 1H), 4.09 (dd,
J ) 11.6, 5.5, 1H), 4.08, (dd, J ) 12.4, 5.5, 1H), 3.93, (dd, J )
11.6, 7.2, 1H), 3.77 (m, 1H), 3.75 (d, J ) 3.0, 1H), 3.71 (ddd, J
) 9.5, 5.5, 2.2, 1H), 2.18, 2.15, 2.11, 2.05, 2.045, 2.02, 2.015
(7s, 21H).
7:1 Mixtu r e of 2,3-An h yd r o-3-C-[(1R)-2,6-a n h yd r o-1-
d eoxy-1-flu or o-D-glycer o-D-gu lo-h ep titol-1-C-yl]-â-D-gu lo-
fu r a n ose (1) a n d 2,3-An h yd r o-3-C-[(1R)-2,6-a n h yd r o-1-
d eoxy-1-flu or o-D-glycer o-D-gu lo-h ep titol-1-C-yl]-â-D-gu lo-
p yr a n ose (12). A mixture of (+)-11 (97 mg, 0.15 mmol) and a
saturated solution of NH3 in MeOH (7 mL) was stirred at 20
°C for 3.5 h. Solvent evaporation in vacuo afforded pure 1, 12,
and acetamide (by 1H NMR). Chromatography on silica gel
(1.7:1 CHCl3/MeOH) afforded 38 mg (72%) of a 7:1 mixture of
1 and 12 as a hygroscopic white solid: [R]25D ) -7.4 (c ) 0.15,
1,6:2,3-Dia n h yd r o-3-C-[(1R)-2,6-a n h yd r o-3,4,5,7-tetr a -
O-ben zyl-1-d eoxy-1-flu or o-D-glycer o-D-gu lo-h ep titol-1-C-
yl]-â-D-gu lo-p yr a n ose ((+)-8). NaBH4 (96 mg, 2.6 mmol) was
added portionwise to a stirred solution of (+)-6 (1.1 g, 1.6
mmol) in MeOH (40 mL) cooled to 0 °C. After stirring at 0 °C
for 2 h, CH2Cl2 (50 mL), H2O (50 mL), and 1 M aqueous HCl
(5 mL) were added. The aqueous layer was extracted with CH2-
Cl2 (50 mL, 3 times), and the combined organic extracts were
washed with brine (50 mL) and dried (MgSO4). Solvent
evaporation afforded 1.1 g (100%) of a white solid pure enough
1
MeOH); H NMR (600 MHz, CD3OD) of 1, δ 5.34 (d, J ) 2.8,
1H), 4.83 (dd, J ) 46.0, 4.2, 1H), 4.70 (d, J ) 2.4, 1H), 4.12
(br.d, J ) 2.4, 1H), 3.88 (dd, J ) 12.3, 2.2, 1H), 3.75 (ddd, J )
13.0, 9.4, 4.2, 1H), 3.72 (d, J ) 2.8, 1H), 3.68 (dd, J ) 12.3,
5.6, 1H), 3.66-3.62 (m, 2H), 3.51 (dd, J ) 9.4, 9.35, 1H), 3.41
(dd, J ) 9.4, 9.35, 1H), 3.36 (dd, J ) 9.45, 9.4, 1H), 3.28 (dd,
J ) 9.45, 5.6, 2.2, 1H); 19F NMR (376.4 MHz, CD3OD) of 1, δ
-193.0 (dd, J ) 46.0, 13.0, 1F); 13C NMR (100.6 MHz, CD3-
OD) of 1, δ 95.5 (d, 1J (C,H) ) 173), 94.2 (dd, 1J (C,F) ) 174,
1J (C,H) ) 155), 82.2 (d, 1J (C,H) ) 142), 79.9 (dd, 1J (C,H) )
for the next steps: mp 38 °C; [R]25 ) +23 (c ) 0.24, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 7.36-7.13 (m, 20H), 5.55 (br s,
1H), 5.07 (dd, J ) 45.0, 8.2, 1H), 4.85-4.67 (m, 5H), 4.47-
4.41 (m, 3H), 4.28 (ddd, J ) 6.3, 4.5, 1.8, 1H), 4.14 (d, J ) 4.5,
1H), 4.08 (dd, J ) 8.2, 1.8, 1H), 3.86-3.53 (m, 8H), 3.24 (s,
1H).
2
1
1
142, J (C,F) ) 21), 79.6 (d, J (C,H) ) 143), 75.6 (d, J (C,H) )
1
3
1
148), 72.9 (dd, J (C,H) ) 145, J (C,F) ) 5), 72.1 (d, J (C,H) )
1
1
144), 71.2 (d, J (C,H) ) 145), 64.2 (t, J (C,H) ) 142), 63.6 (d,
2J (C,F) ) 26), 62.7 (t, 1J (C,H) ) 141), 61.3 (dd, 1J (C,H) ) 193,
3J (C,F) ) 6).
1,6:2,3-Dia n h yd r o-3-C-[(1R)-2,6-a n h yd r o-1-d eoxy-1-flu -
or o-D-glycer o-D-gu lo-h ep t it ol-1-C-yl]-â-D-gu lo-p yr a n ose
((+)-9). Metallic Na (1 g, 43 mmol) was added to liquid NH3
(30 mL, condensed at -78 °C). A solution of (+)-8 (1.07 g, 1.5
mmol) in anhydrous THF (12 mL) was added dropwise with
stirring. After stirring at -78 °C for 50 min, solid NH4Cl (4 g)
was added and the cooling bath removed. Once at 20 °C, the
residue was taken up in MeOH and purified by flash chroma-
tography on silica gel (3:1 CH2Cl2/MeOH), affording 0.5 g (95%)
X-r a y Cr ysta l Str u ctu r e An a lysis. Crystallographic data
(excluding structure factors) for 1,6:2,3-dianhydro-3-C-[(1R)-
2,6-anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-1-fluoro-D-glycero-
D-gulo-heptitol-1-C-yl]-â-D-ribo-pyranose (7, hydrate of (+)-6)
have been deposited with the Cambridge Data Centre as
supplementary publication under no. CCDC. 155696. Copies
of these data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: +41
1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
of a hygroscopic white solid: [R]25 ) +5.6 (c ) 0.45, MeOH);
D
1H NMR (400 MHz, CD3OD) δ 5.57 (br s, 1H), 4.97 (dd, J )

5138 J . Org. Chem., Vol. 66, No. 15, 2001
J ime´nez-Barbero et al.
1
Su p p or tin g In for m a tion Ava ila ble: Detailed H and 13C
Ack n ow led gm en t . We thank the Swiss National
Science Foundation, the Fonds Herbette (Lausanne), the
Office Fe´de´ral de l'Enseignement et de la Science (Bern,
european COST D13/0001/99 action), and the DGICYT
(Madrid, grant BQU2000-1501-C02-01) for financial
support. We thank also Mr. Martial Rey and Franscisco
Sepu´lveda for technical help.
NMR spectra and signal assignments, further rotations data,
and UV, IR, and MS spectra; 1H NMR NOESY, 1H NMR
DPFGNOE, and 1H NMR TOCSY spectra of 1; ORTEP
representation of 7; superimposition of 100 snapshots from one
of the MD simulations for 1. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0102462