Synthesis and conformational behavior of the difluoromethylene linked C-glycoside analog of β-galactopyranosyl-(1?1)-α-mannopyranoside

Article abstract of DOI:10.1016/j.carres.2007.06.012

C-Glycosides in which the pseudoglycosidic substituent is a methylene group have been advertised as hydrolytically stable mimetics of their parent O-glycosides. While this substitution assures greater stability, the lower polarity and increased conformati

Full text of DOI:10.1016/j.carres.2007.06.012

Carbohydrate Research 342 (2007) 1624–1635
Synthesis and conformational behavior of the
difluoromethylene linked C-glycoside analog of
b-galactopyranosyl-(1M1)-a-mannopyranoside
Richard W. Denton,a,b Kurissery A. Tony,a,b Jose Juan Hernandez-Gay,
c
´
´
c
c,
a,b,
*
*
´
F. Javier Canada, Jesu´s Jimenez-Barbero and David R. Mootoo
˜
aDepartment of Chemistry, Hunter College, 695 Park Avenue, New York, NY 10021, United States
bThe Graduate Center, CUNY, 365 5th Avenue, New York, NY 10016, United States
cCentro de Investigaciones Biolo´gicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
Received 14 March 2007; received in revised form 6 June 2007; accepted 7 June 2007
Available online 13 June 2007
Abstract—C-Glycosides in which the pseudoglycosidic substituent is a methylene group have been advertised as hydrolytically stable
mimetics of their parent O-glycosides. While this substitution assures greater stability, the lower polarity and increased conforma-
tional flexibility in the intersaccharide linker brought about by this change may compromise biological mimicry. In this regard, C-
glycosides, in which the pseudoanomeric methylene is replaced with a difluoromethylene group, are interesting because the CF2
group is more of an isopolar replacement for oxygen than CH2. In addition, the CF2 residue is expected to instill conformational
bias into the intersaccharide torsions. Herein is described the synthesis and conformational behavior of the difluoromethylene linked
C-glycoside of b-D-galactopyranosyl-(1M1)-a-D-mannopyranoside. The synthesis centers on the formation of the galactose residue
via an oxocarbenium ion–enol ether cyclization. Conformational analysis, using a combination of molecular mechanics, dynamics,
and NMR spectroscopy, suggests that the difluoro-C-glycoside populates the non-exo-Gal/exo-Man conformer to a major extent
(ca 50%), with a minor contribution (ꢀ15%) from the exo-Gal/exo-Man conformer that corresponds to the ground sate of the par-
ent O-glycoside.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Keywords: Glycomimetic; Oxocarbenium ion; Cyclization; De novo
1. Introduction
interested in the mimicry of C-glycosides in which the
methylene linker is replaced with a CHF or CF2 residue.
The design of these mimetics was guided by two tenets.
First, the electronegativity of the fluorine substituents
could make the intersaccharide linker more isopolar to
the glycosidic oxygen.6 Second, based on the unusual
conformational properties of 2-fluoroethanols and re-
lated structures, such fluoro-C-glycosides are expected
to have a more well defined conformational bias than
the exact C-glycoside with respect to the intersaccharide
linker, such that they may more closely mimic the
conformational properties of O-glycoside.7,8 Indeed,
the use of CHF and CF2 as isosteres of oxygen has been
examined in other molecules of biological interest, and
examples of CF2 linked C-furanosides have been
The replacement of the glycosidic oxygen in O-glycoside
with a methylene substituent leads to an analogue with
greater hydrolytic stability than the parent O-glycoside.1
Such compounds often referred to as exact C-glycosides,
may function as biological mimetics of their parent O-
glycosides, but the extent of this mimicry could be com-
promised by the lower polarity and greater flexibility of
the intersaccharide linker.2–5 In this vein, we have been
*
Corresponding authors. Tel.: +34 918373112x4370; fax: +34
915531706 (J.J.-B.); tel.: +1 212 772 4356; fax: +1 212 772 5332
(D.R.M.); e-mail addresses: jjbarbero@cib.csic.es; dmootoo@
hunter.cuny.edu
0008-6215/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.06.012

R. W. Denton et al. / Carbohydrate Research 342 (2007) 1624–1635
1625
HO
for hydroxymethyl linked C-glycosides (e.g., 10: X/
Y = H/OH), we envisaged an initial synthesis of 5 that
was based on fluorination of the ketone derived from
10.17 Not surprisingly, given the highly substituted nat-
ure of this precursor, this strategy was unsuccessful.
Therefore, a revised plan in which the CF2 group was
introduced in a less complex precursor (i.e., 7: X/
Y = F/F) was adopted. A key question with this ap-
proach was the feasibility of the oxocarbenium ion cycli-
zation on the difluorinated enol ether thioacetal (i.e., 8,
X/Y = F/F) in light of the noted deactivation of related
difluorinated enol ethers to electrophilic reagents.18 In
addition, while the thioacetal precursor 5 was available
from earlier investigations, a synthesis of an a,a-diflu-
oroacid like 7 had to be devised (Scheme 1).
OH
OH
OH
OH
HO
RO
O
O
X
OH
1 X = O; R = NaO2CCH2
2 X = CH2; R = NaO2CCH2
HO
OH
OH
OH
OH
HO
RO
O
Y
O
X
OH
3 X = F; Y = H; R = NaO2CCH2
4 X = H; Y = F; R = NaO2CCH2
5 X = Y = F; R = H
Figure 1. O- and C-disaccharides.
prepared.9–11 We have previously reported the synthesis
and conformational behavior of 2–4,12,13 the exact and
the CHF linked analogues of 1, a known O-disaccharide
mimetic of sialyl Lewis X (Fig. 1).14 In this series the
fluoro-C-glycoside 3 was found to be the closest confor-
mational mimic of 1. Herein, as an extension of this
study, we describe the synthesis and conformational
properties of the CF2 linked analogue 5.15
Initial attempts at the synthesis of a,a-difluoroacid
through treatment of an a-ketoester precursor with
DAST17 led to intractable mixture of products. A suc-
cessful plan originated in the reaction of the Reformat-
sky-like reagent from methyl bromodifluoroacetate and
the known aldehyde 11 (Scheme 2).19,20 This led to an
inseparable mixture of epimeric (R)- and (S)-alcohols
O
OTBDPS
OH
OTBDPS
OTBDPS
O
O
R
R
O
O
O
2. Results and discussion
2.1. Synthesis
Y
Y
O
O
Y
X
X
SPh
SPh
9
6
8
PGO
OPG
X/Y = H/H, H/OR
OTBDPS
OPG
O
We have been developing a de novo synthesis of com-
plex C-disaccharides 10, in which the key step is the
formation of a C1 substituted glycal 9 via an enol
ether–oxocarbenium ion cyclization.16 C-Glycoside 10
is then obtained by the stereoselective hydroboration
of 9. Because this method was previously successful
O
Y
R
PGO
O
5
O
HOOC
HO
X
X
7
10
Scheme 1. Retrosynthesis of the difluoromethylene linked C-
disaccharide.
OBn
OH
OR' OBn
O
OBn
e
RO2C
F
MeO2C
d
OHC
a, b
c
F
F
OBn OBn
F
OBn
OBn
OBn
OBn
(S)-12/ (R)-12 R = Et, R' = Ac
(S)-13/ (R)-13 R = Me, R' = H
11
14
BnO
BnO
3 OBn
OBn
OBn
F
BnO
O
f
OBn
+
OBn
OH
F
O
O
5
MeO2C
OTBDPS
F
RO2C1'
g
F
F
OBn
TBDPSO
MeO2C
F
15
+
19
17 R = Me
18 R = H
OBn
BnO
H
H
H
OBn
OH
AcO
H
O
OAc
AcO
F
OAc
OAc
OTBDPS
F
F
O
H
MeO2C
O
MeO2C
F
H
F
F
16
OAc
MeO2C
AcO
20
21
J1,2 = J2,3 = 3.4;
J4,5 = 8.3 Hz
J1,2 = 10.1; J2,3 = 3.2;
J4,5 = 1.5 Hz
Scheme 2. Synthesis of difluoroacid 18. Reagents: (a) BrCF2CO2Et, Zn, THF, reflux then 11; (b) Ac2O, DMAP, EtOAc, two steps, 35%; (c) NaOMe,
MeOH, 83%; (d) mCPBA, CH2Cl2, aq NaH2PO4/Na2HPO4, 74%; (e) (i) NaOMe, MeOH then HCl in ether; (ii) TMSCHN2, MeOH, 15 (52%) + 16
(22%); (f) TBDPSCl, imidazole, DMF, 50 ꢁC, 17 (59%) + 19 (39%); (g) 3 M NaOH, EtOH then 2 M HCl, 94%.

1626
R. W. Denton et al. / Carbohydrate Research 342 (2007) 1624–1635
in an approximate 1:3 ratio. Acetylation of the mixture
allowed separation of the respective acetates (R)- and
(S)-12 which were individually treated with sodium
methoxide in methanol to give (R)- and (S)-13, the cor-
responding methyl ester derivatives of the original alco-
hols. The configuration at the newly formed stereogenic
center in these products was tentatively assigned by
NMR comparison with closely related diastereomeric
pairs19 and the stereochemistry of the desired isomer
(S)-12 eventually confirmed in the tetrahydropyran
derivatives 20 and 21 (vide infra). Alkene (S)-13 was
treated with m-CPBA and the resulting 2:1 mixture of
epoxides exposed to sodium methoxide in methanol to
give a product that exhibited partial ester hydrolysis.
The crude material was therefore treated with TMS–dia-
zomethane, following which chromatography afforded
two fractions in an approximate ratio of 5:2, an unsep-
arated mixture of two isomeric tetrahydropyrans 15,
and another component that was presumed to be a se-
ven-membered ring isomer 16. Silylation of the mixture
of primary alcohols 15 gave 17, C-pyranoside with an ‘a-
D-manno’ configuration and the ‘b-L-gulo’ isomer 19 in a
3:2 ratio. The stereochemistry of 17 and 19 was assigned
ester 22 in 76% yield.21 Takai methylenation on 22
afforded the difluoro enol ether 23 in 63% yield based
on recovered 22.22 The reactivity of the difluoro ester
and enol ether under acidic and basic conditions is note-
worthy. Thus, the acid sensitivity of the methylene
linked enol ethers that were prepared in our earlier study
called for chromatography on basic alumina.16 While
the difluoro derivative 23 was also stable under these
conditions, it was discovered, during the purification
of the mixture of 22 and 23, that the a,a-difluoro ester
was not. In comparison, both ester 22 and enol ether
23 were stable to chromatography on silica gel. The
key cyclization reaction on 23 was promoted by methyl
triflate in the presence of 2,6-di-tert-butyl-4-methyl-
pyridine (DTBMP), giving the difluoromethylene linked
glycal 24 in 82% yield. Thus, as initially feared, the diflu-
oromethylene moiety did not have an adverse effect on
the oxocarbenium ion cyclization. Hydroboration of
24 provided difluoromethylene linked C-disaccharide
25 as a single diastereomer in 86% yield. The straightfor-
ward removal of the alcohol protecting groups provided
the title C-disaccharide 5.
1
by H NMR analysis of the acetylated derivatives 20
2.2. Conformational analysis
and 21. Thus, the J values for the ring protons of 20
and the appearance of an NOE between H1 and H4 sug-
gested a distorted chair-like conformation. This trans-
lates to syn relationships between H1 and H4 and H2
and H3, and confirms the configuration at C1 and C2,
the two new stereogenic centers that were introduced
in the reaction leading to (S)-12. Similarly, J data and
an NOE between H1 and H5 pointed to the stereochem-
istry indicated in 21. That the configuration at C1 in 20
and 21 was determined to be opposite is consistent with
synthetic logic. Finally, saponification of 17 provided
18, the required precursor for C-disaccharide 5.
The potential energy surfaces for 5 was calculated using
the MM3*23 force field, as previously described
(Fig. 2).12,24,25 These maps are useful to delimit the
low-energy regions that are accessible to rotation
around the glycosidic torsion angles UGal (H1Gal
–
C1Gal–X–C1Man) and UMan (H1Man–C1Man–X–C1Gal).
The different conformers have been dubbed, exo, non-
exo and anti with respect to glyconic torsions UGal and
U
Man, by analogy with the exo-anomeric notation for
O-glycosides. Thus exo-UGal and exo-UMan correspond
to values of ca +60ꢁ and ꢁ60ꢁ, non-exo-UGal and non-
exo-UMan to ꢁ60ꢁ and +60ꢁ, and anti-UGal and anti-
Thioacetal 6 and difluoro acid 18 were next subjected
to the C-glycosidation sequence (Scheme 3). The Yam-
aguchi esterification procedure on 6 and 18 provided
BnO
BnO
OBn
OBn
OR
OBn
OR
OR
OBn
OR
O
O
O
O
c
6
a
O
O
F
F
O
+
O
b
F
F
X
18
SPh
22 X = O
23 X = CH2
24 R = TBDPS
d
R = TBDPS
e, f
BnO
OBn
OR
OBn
OR
O
O
O
F
5
O
F
OH
25 R = TBDPS
Scheme 3. Synthesis of difluoro-C-disaccharide 5. Reagents: (a) 18,
2,4,6-trichlorobenzoyl chloride, Et3N, THF then 6, DMAP, toluene,
76% based on 18; (b) Takai reagent, 63%; (c) MeOTf, DTBMP,
CH2Cl2, MS 4A, 82%; (d) BH3, Me2S, THF; then Na2O2, 86%; (e) HCl
in ether, CH3OH, 63%; (f) Pd/C, HCOOH, CH3OH, 93%.
Figure 2. Steric energy map (UMan,UGal) calculated by MM3* with
e = 80 for 5. Contours are given every 2.5 kJ molꢁ1
.

R. W. Denton et al. / Carbohydrate Research 342 (2007) 1624–1635
1627
Figure 3. Stereoviews of the global and local minima A–D of 5 according to MM3* calculations. See Table 1 for UGal and UMan for the different
conformers.
UMan to 180ꢁ, respectively. Four principal low-energy
conformer types were obtained, but with very different
specific conformation.27 Exclusive NOEs are shown in
bold in Table 1.
populations: (A) exo-UGal/non-exo-UMan, (B) exo-UGal
exo-UMan, (C) non-exo-UGal/exo-UMan, and (D) anti-
Gal/non-exo-UMan. These conformations are shown in
/
2.3. Experimental confirmation of modeling data by NMR
U
Fig. 3, and their geometries and relative energies sum-
marized in Table 1.
In addition, the conformational stability of the differ-
ent conformers was checked by using MD simulations
also with the MM3* force field.26 Some of the computed
In order to deduce the final conformational distribution
for 5, the predictions from the force field calculations
were compared with the experimental data as deter-
mined from NMR. The chemical shifts in D2O are listed
in Table 2. Assignment of resonances was made through
a combination of COSY, TOCSY, 1D and 2D-NOESY/
ROESY, and HSQC experiments.
U
Man/UGal distributions are displayed in Figure 4.
Examination of the four different conformational
families revealed several proton–proton distances of
close to 2.5 A that are unique to a particular conforma-
tion of 5. An NOE corresponding to any of these proton
pairs is deemed an exclusive NOE, and is diagnostic of a
The J values for the ring protons indicate that all the
pyranose chairs adopt the usual 4C1 chair (Table 2). The
intermediate observed values for the C5–C6 lateral
chains are in agreement with equilibria between the tg:gt
˚
Table 1. Comparison between the inter-residue proton–proton distances calculated by MM3* for the conformers A–D (approximated UGal and UMan
angles in brackets), of 5 and the observed NOEs in the 1D-NOESY spectrum at 350 ms mixing time for 5
Conformer
(UGal/UMan
A(60/60)
exo/non-exo
B(50/ꢁ50)
exo/exo
C(ꢁ70/ꢁ70) D(ꢁ170/60)
Ensemble
non-exo/exo anti/non-exo average
Best fit
A:B:C:D
)
DE (kJ/mol)
Population (%)
2.0
22.5%
1.6
26.5%
0
12.8
0.3%
Calc
50.7%
25:15:50:10
˚
˚
NOE exp
(%)/distance (A)
Calc distance (A) Calc distance (A) Calc
Ensemble average
˚
˚
˚
˚
distance (A) distance (A) distance (A)
2.55
˚
1M–2M (internal 4.7%/2.55 A
2.55
2.55
2.55
reference)
˚
1G–1M
1G–2M
1G–5M
1M–2G
2M–G2
1.9%/3.0 A
3.0
2.1
4.5
4.3
4.9
2.4
4.3
4.2
4.7
5.2
3.2
4.7
2.5
3.2
4.8
3.7
3.8
4.5
2.2
2.7
2.8
2.7
—
3.5
4.8
2.9
2.6
—
3.0
3.8
˚
3.9%/2.6 A
Overlap
˚
1.7%/3.0 A
˚
<0.4%/>3.8 A
In all cases, NOEs or ROEs were positive; that is, the cross peaks showed different sign to diagonal peaks, as expected for small molecules. Relative
steric energies for (DE, kJ/mol) are also given. Interproton distances corresponding to exclusive NOEs are shown in bold.

1628
R. W. Denton et al. / Carbohydrate Research 342 (2007) 1624–1635
180
120
60
180
120
60
180
120
60
0
0
0
ΦMan
-60
-120
-180
-60
-60
-120
-180
-120
-180
-180 -120 -60
0
60
120 180
-180 -120 -60
0
60
120 180
-180 -120 -60
0
60
120 180
ΦGal
Figure 4. Frequency of sampling of UMan/UGal torsion angles from the MD simulations (MM3*) for 5, starting from the different local minima. From
left to right, starting from minima A, B, and C, respectively. Transitions from B to A (central panel) and from C to B (right panel) are observed.
Table 2. 1H NMR chemical shifts (d, ppm) and vicinal coupling
constants (J, Hz) for compound 5
tained as described in the experimental section and com-
pared to those estimated by the MM3* molecular
Atom
d, ppm (J, Hz)
mechanics and dynamics calculations (Table 1).
The ensemble averaged distances computed on the
basis of the population ratios obtained from MM3* agree
reasonably well with those experimentally deduced from
the NOE values (see Section 4). Both sets of data sup-
port the presence of a conformational equilibrium
among several conformers. However, some experimental
distances are slightly different from those calculated
from the MM3 distribution. Thus, the relative weakness
of the 1Man–2Gal NOE and the very small intensity
of 2Man–2Gal, which is exclusive for conformer D, indi-
cates that a major contribution from conformer D is un-
likely. However, the fact that this NOE is at all observed
suggests that the 0.3% deduced from MM3* is underesti-
mated. The presence of conformers A and B is also
granted since the 1Gal–2Man and 1Gal–1Man NOEs
are exclusive for these geometries. In this case the
MM3* prediction appears to be somewhat high. The
presence of the global minimum C is only grounded
on the MM3* calculations and cannot be directly demon-
strated by NMR because its exclusive NOE cannot be
determined, due to overlapping between the two key
protons (H1 Gal and H5 Man show the same chemical
shift). Thus, although the experimental data was quali-
tatively consistent with the calculated trends, it was
not definitive, as the experimental NOE values could
also fit other population distributions. To examine this
possibility, a systematic variation of the populations of
the four conformers was then performed and the com-
puted distances were compared to the experimental
ones.31 Using this protocol, it was deduced that the rel-
ative percentages of the observable NOEs can only be
accounted for when a significant population of C is con-
sidered. Attempts to fit all the observable NOEs (see
Table 1) when minimum C was not considered did not
succeed. In fact, the best fit to the experimental NOEs
is obtained when a 25:15:50:10 distribution of A:B:C:D
H1M
H2M
H3M
H4M
H5M
H6aM
H6bM
F1
4.51 (2.3, 14.3, 19.4)
4.33 (2.3, 3.4)
3.92 (3.8, 9.1)
3.62 (9.0, 9.0)
3.66 (9.0, 2.2, not meas.)
3.89 (12.2)
3.74
(14.3, 14.3)
(14.3, 19.4)
3.84 (14.3, 14.3, 10.0)
3.93 (9.8, 9.6)
3.70 (9.6, 3.4)
4.00 (3.4, 0.5)
3.79 (0.5, 3.5, 6.8)
3.76
F2
H1G
H2G
H3G
H4G
H5G
H6aG
H6bG
3.74 (6.8, 12.2)
conformers for the Gal ring and the gg:gt conformers
for the Man moiety.28 The anomeric protons of both
Gal and Man residues show scalar couplings to the fluo-
rine atoms at the pseudoglycosidic linkage. The ob-
served couplings vary between only 15 and 20 Hz,
which are intermediate values for vicinal H/F arrange-
ments. In previous studies, we have used the vicinal H/
F couplings as additional data to assess the conforma-
tional equilibrium around the intersaccharide torsions.13
Unfortunately, it is well known that the presence of
additional electronegative substituents along the cou-
pling pathway strongly modify the relationship between
torsion angles and coupling constants and, thus, the
available Karplus-like equation for vicinal H/F cou-
plings is not valid for this molecule. Therefore, the con-
formational analysis with respect to the intersaccharide
linker has to rely exclusively on the NOE data.29,30
Accordingly, NOESY and ROESY experiments were
carried out to determine the intensities of the observed
NOEs. Experimental proton–proton distances were ob-

R. W. Denton et al. / Carbohydrate Research 342 (2007) 1624–1635
1629
is considered. Therefore, compound 5 exists predomi-
nantly as a conformational equilibrium between natural
and non-natural conformers4 with substantial (ca. 50%)
non-exo-anomeric conformations around the UGal gly-
cosidic linkage, and detectable, ꢀ35%, contribution of
the non-exo-anomeric conformer for UMan. Thus, over-
all, the MM3* simulations within MACROMODEL32
agree reasonably well with the observed populations.
nium(VI) molybdate tetrahydrate (12.5 g) and
cerium(IV) sulfate tetrahydrate (5.0 g) in 10% aqueous
sulphuric acid (500 mL). Flash column chromatography
(FCC) was performed using silica gel 60 (230–400 mesh)
and employed a stepwise solvent polarity gradient, cor-
related with TLC mobility.
4.2. (3S) Ethyl 3-acetoxy-4,5,6-tris(benzyloxy)-2,2-di-
fluorooct-7-enoate [(S)-12] and (3R) ethyl 3-acetoxy-
4,5,6-tris(benzyloxy)-2,2-difluorooct-7-enoate [(R)-12]
3. Conclusion
To a solution of activated zinc dust (13.2 g, 0.21 mol) in
dry THF at reflux (30 mL) was added ethyl bromodiflu-
oroacetate (19.1 mL, 0.15 mol). After 10 min, a solution
of 1120 (20.0 g, 0.05 mmol) in THF (60 mL) was intro-
duced dropwise over 30 min. The mixture was then
heated at reflux for 3 h, cooled to rt and carefully
poured into 1 N HCl (40 mL) and ice (40 g), and
extracted with EtOAc (3 · 150 mL). The organic layer
was washed with saturated aqueous NaHCO3, and
brine, dried (Na2SO4), and concentrated in vacuo.
FCC of the residue gave a mixture of epimeric alcohols
(13.9 g, 54%) in a 3:1 ratio; colorless oil; Rf = 0.29 (10%
As described in earlier studies, the conformational dis-
tributions around the glycosidic linkages of the parent
O-glycoside 1 and its C-glycoside analogue, 2, are rather
different. The O-glycoside populates almost entirely
(>93%) the natural exo-Gal/exo-Man (B) conformation,
whereas the C-glycoside exists in this conformation in
only 30%, with four other conformational families A
(42%), C (6%), D (10%), and E (12%).12 The monofluo-
rinated analogue 3 shows a high preference for A (90%).
The present investigation indicates that the difluoro-
C-glycoside 5 populates the non-exo-Gal/exo-Man
conformer C to a major extent (ca 50%), with additional
contributions (ꢀ10–25%) from A, B, and D. Thus 5
might not be an accurate biological mimetic of the
O-glycoside 1, if the active conformation corresponds
to the ground state of 1. Difluoro-C-glycosides mimics
like 5 could be more effective in cases where the glyco-
sidic oxygen of the parent O-glycoside interacts directly
with the receptor. This relative activity of 5 with respect
to different carbohydrate receptors is an avenue for
future investigation.
1
EtOAc/petroleum ether); H NMR (CDCl3) d 1.74 (t,
J = 7.1 Hz, 2.3H), 1.32 (t, J = 7.1 Hz, 0.7H), 3.38 (dd,
J = 3.2, 10.0 Hz, 0.3H), 3.58 (m, 0.7H) 3.77 (m, 0.3H),
3.86 (m, 1.7H), 3.94–4.08 (m, 1.7H), 4.11–4.22 (m,
0.7H), 4.31 (q, J = 7.1 Hz, 0.6H), 4.40–4.87 (m, 7H),
5.37–5.50 (m, 2H), 5.92 (m, 0.7H), 6.03 (m, 0.3H),
7.27–7.39 (m, 15H); 13C NMR (CDCl3) major isomer:
d 13.8, 62.5, 70.4, 75.2, 78.9 (d, J = 3.9 Hz), 81.6, 82.9,
114.8 (dd, J = 257.3, 257.4 Hz), 120.0, 127.9, 128.1–
128.6 (several resonances), 135.3, 137.4, 138.01, 138.4,
163.4 (t, J = 30.8 Hz). Minor isomer: d 14.0, 63.2,
70.4, 70.6, 73.9 (d, J = 3.4 Hz), 74.3, 75.3, 80.0, 81.7,
119.5, 127.0–129.0 (several resonances) 135.8, 137.6,
137.99, 138.2, 163.6 (dd, J = 30.0, 33.1 Hz). ESIMS
calcd for C31H38O6F2N [M+NH4]+: 558.2662. Found:
558.2651.
4. Experimental
4.1. Synthetic general methods
Unless otherwise stated, all reactions were carried out
under a nitrogen atmosphere in oven-dried glassware
using standard syringe and septa technique. 1H and
13C NMR spectra were obtained on a Varian Unity Plus
500 (500 MHz) spectrometer. Chemical shifts are rela-
tive to the deuterated solvent peak or the tetramethylsi-
lane (TMS) peak at (d 0.00) and are in parts per million
(ppm). Assignments for selected nuclei were determined
from 1H COSY experiments. High-resolution mass spec-
trometry (HRMS) was performed on an Ultima Micro-
mass Q-Tof instrument at the Mass Spectrometry
Laboratory of the University of Illinois, Urbana-Cham-
paign. Thin layer chromatography (TLC) was done on
0.25 mm thick precoated silica gel HF254 aluminum
sheets. Chromatograms were observed under UV (short
and long wavelength) light, and were visualized by heat-
ing plates that were dipped in a solution of ammo-
A portion of the above mixture (0.52 g, 1.09 mmol)
was dissolved in EtOAc (30 mL) and treated with acetic
anhydride (0.52 mL, 5.45 mmol) and DMAP (26.6 mg,
0.22 mmol) for 30 min. MeOH (1 mL) was added and
the volatiles were removed under reduced pressure.
FCC of the residue afforded (S)-12 (0.40 g, 64%) and
(R)-12 (0.13 g, 21%) as colorless oils.
For (S)-12: Rf = 0.38 (10% EtOAc/petroleum ether);
[a]D ꢁ21.0 (c 1.5, CHCl3); IR (film) 1767 (s) cmꢁ1
;
1H NMR (CDCl3) d 1.08 (t, J = 7.1 Hz, 3H), 2.20,
(s, 3H), 3.74 (d, J = 8.1 Hz, 1H), 3.92 (q, J = 7.1 Hz,
1H), 4.06 (m, 3H), 4.41 (A of ABq, J = 10.8 Hz, Dd =
0.15 ppm, 1H), 4.44 (A of ABq, J = 12.2 Hz, Dd =
0.25 ppm, 1H), 4.56 (B of ABq, J = 10.8 Hz, Dd =
0.15 ppm, 1H), 4.68 (B of ABq, J = 12.2 Hz, Dd =
0.25 ppm, 1H), 4.87 (ABq, J = 12.0 Hz, Dd = 0.04 ppm,
2H), 5.39 (d, J = 17.1 Hz, 1H), 5.46 (dd, J = 1.2,

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R. W. Denton et al. / Carbohydrate Research 342 (2007) 1624–1635
1
10.5 Hz, 1H), 5.81 (ddd, J = 7.8, 10.5, 17.4 Hz, 1H), 6.00
(ddd, J = 3.2, 10.5, 20.8 Hz, 1H), 7.19–7.44 (m, 15H);
ether); H NMR (CDCl3) d 2.47 (dd, J = 2.7, 4.9 Hz,
0.6H), 2.60 (t, J = 4.5 Hz, 0.6H), 2.68 (dd, J = 2.6,
4.9 Hz, 0.4H), 2.84 (t, J = 4.6 Hz, 0.4H), 3.09 (m, 0.4H),
3.36 (m, 0.6H), 3.30 (m, 0.6H), 3.53–3.60 (m, 3.8H),
3.68 (m, 0.6H), 3.91 (m, 1.6H), 4.01 (d, J = 5.9 Hz,
0.4H), 4.45–4.90 (m, 7H), 7.18–7.40 (m, 15H); 13C
NMR (CDCl3) major isomer: d 43.9, 52.7, 53.1, 70.6 (t,
J = 22.5 Hz), 73.9, 74.4, 78.9 (d, J = 3.3 Hz), 80.8, 80.9,
114.9 (dd, J = 250.0, 258.1 Hz), 122.9–128.7 (several res-
onances), 137.4, 137.9, 1381, 138.4, 138.8, 163.8 (dd,
J = 30.2, 32.3 Hz). Minor isomer: d 47.2, 51.1, 53.0,
70.1 (t, J = 25.1 Hz), 73.4, 75.2, 78.8 (d, J = 3.4 Hz),
79.5, 81.5, 115.0, (dd, J = 250.0, 256.9 Hz), 137.2, 137.7,
138.3, 163.7 (t, J = 31.3 Hz). ESIMS calcd for
C30H36O7F2N [M+NH4]+: 560.2454. Found: 560.2452.
13C NMR (CDCl3)
d 13.7, 20.6, 62.8, 69.4 (t,
J = 22.0 Hz), 70.5, 73.0, 75.0, 77.3 (d, J = 2.7 Hz), 81.2,
81.8, 113.3 (dd, J = 251.1, 257.5 Hz), 120.4, 127.9–
128.7 (several resonances), 135.0, 137.1, 138.4, 138.8,
162.3 (dd, J = 28.9, 33.1 Hz), 168.4. ESIMS calcd for
C33H40O7F2N [M+NH4]+: 600.2767. Found: 600.2761.
For (R)-12: Rf = 0.28 (10% EtOAc/petroleum ether);
1H NMR (CDCl3) d 1.23 (t, J = 7.1 Hz, 3H), 2.07 (s,
3H), 3.78 (dd, J = 4.2, 6.5 Hz, 1H), 4.20 (m, 4H),
4.38–4.25 (m, 2H), 4.64–4.80 (m, 4H), 5.42 (d,
J = 10.4 Hz, 1H), 5.48 (d, J = 17.3 Hz, 1H), 5.80 (ddd,
J = 2.2, 12.7, 19.9 Hz, 1H), 6.01 (ddd, J = 7.8, 10.4,
17.6 Hz, 1H), 7.28–7.43 (m, 15H); 13C NMR (CDCl3)
d 13.9, 20.7, 63.3, 70.0 (dd, J = 24.6, 28.6 Hz) 73.2,
74.2, 75.1, 80.6, 81.8, 113.2 (dd, J = 255.2, 257.4 Hz),
119.4, 127.7–128.5 (several resonances), 135.9, 138.1,
138.4, 138.5, 162.8 (dd, J = 30.3, 32.9 Hz), 168.5.
ESIMS calcd for C33H40O7F2N [M+NH4]+: 600.2767.
Found: 600.2753.
4.5. Methyl 3,7-anhydro-4,5,6-tri-O-benzyl-2,2-difluoro-
D-glycero-D-talo-octosonate and methyl 3,7-anhydro-
4,5,6-tri-O-benzyl-2,2-difluoro-L-glycero-D-talo-
octosonate (15)
A solution of 14 (4.19 g, 7.73 mmol) in dry MeOH
(400 mL) was treated with 1 M MeONa in MeOH
(23.2 mL, 23.2 mmol). After stirring for 23 h at rt, the
reaction was acidified to pH 2 with a solution of HCl
in ether and the solvent evaporated under reduced pres-
sure. The residue was dissolved in MeOH (20 mL) and
toluene (60 mL) then treated with TMSCHN2 (5.8 mL,
11.6 mmol, 2 M solution in ether) at 0 ꢁC. After
30 min, acetic acid (1 mL) was added to the reaction
and the volatiles were removed under reduced pressure.
FCC of the residue yielded 15 (2.16 g, 52%), as an insep-
arable mixture, and 16 (0.95 g, 22%).
4.3. (3S)-Methyl 4,5,6-tris(benzyloxy)-2,2-difluorooct-7-
enoate (S)-13
A
solution of ethyl ester–acetate (S)-12 (1.11 g,
1.90 mmol) in dry MeOH (20 mL) was treated with
1 M MeONa in MeOH (5.7 mL, 5.7 mmol). After stir-
ring for 1 h at rt, the reaction was neutralized with
2 N HCl and the solvent evaporated under reduced pres-
sure. FCC of the residue afforded (S)-13 (0.79 g, 83%) as
a colorless oil; Rf = 0.54, (10% EtOAc/petroleum ether);
1H NMR (CDCl3) d 3.50 (s, 3H), 3.52 (m, 1H), 3.84 (m,
2H), 4.11 (t, J = 7.1 Hz, 1H), 4.36–4.73 (m, 5H), 4.83 (s,
2H), 5.37 (d, J = 18.6 Hz, 1H), 5.41 (d, J = 18.6 Hz,
1H), 5.90 (ddd, J = 8.3, 10.0, 17.6 Hz, 1H), 7.14–7.46
For 15: colorless oil, Rf = 0.49 (30% EtOAc/petro-
1
leum ether); H NMR (CDCl3) d 1.66 (d, J = 8.9 Hz,
D2O exchange, 0.5H), 1.87 (t, J = 6.2 Hz, D2O ex-
change, 0.5H), 3.42 (dd, J = 1.2, 3.3 Hz, 0.5H), 3.50
(m, 0.5H), 3.65 (m, 2H), 3.75–3.98 (m, 5.5H), 4.08 (dd,
J = 3.2, 5.2 Hz, 0.5H), 4.28–4.72 (m, 7H), 7.15–7.38
(m, 15H); 13C NMR (CDCl3) d 53.0, 53.4, 61.7, 62.0,
71.4, 71.9, 72.0, 72.4, 72.5, 72.7–73.2 (several reso-
nances), 73.4, 74.3, 74.8, 75.7, 76.9, 114.0 (t,
J = 254.7 Hz), 114.9 (dd, J = 256.3, 260.3 Hz), 127.7–
128.6 (several resonances), 137.4, 137.6, 137.9, 138.0,
163.37 (t, J = 30.9 Hz), 163.40 (dd, J = 27.0, 31.8 Hz).
ESIMS calcd for C30H36O7F2N [M+NH4]+: 560.2454.
Found: 560.2489.
(m, 15H); 13C NMR (CDCl3)
d 52.9, 70.7 (t,
J = 22.9 Hz), 70.8, 72.9, 75.3, 77.3 (d, J = 2.7 Hz),
81.2, 81.8, 113.3 (dd, J = 251.1, 257.5 Hz), 120.4,
127.9–128.7 (several resonances), 135.0, 137.1, 138.4,
138.8, 163.8 (dd, J = 30.2, 32.1 Hz). ESIMS calcd for
C30H36O6F2N [M+NH4]+: 544.2505. Found: 544.2505.
4.4. Epoxide mixture 14
To a solution of (S)-13 (0.79 g, 1.50 mmol) in CH2Cl2
(20 mL) was added a mixture of m-CPBA (2.61 g,
15.1 mmol), CH2Cl2 (20 mL), NaH2PO4 (4.30 g,
30.3 mmol), Na2HPO4 (4.14 g, 30.0 mmol) and water
(40 mL). The suspension was stirred for 26 h at rt then
poured into 10% Na2SO3 in saturated aqueous
NaHCO3. After stirring for 1 h, the organic layer was sep-
arated, washed with brine, dried (Na2SO4) and
evaporated under reduced pressure. FCC of the residue
afforded 14 (0.50 g, 74% based on recovered alkene) as a
2:1 mixture; clear oil; Rf = 0.30 (15% EtOAc/petroleum
For 16: colorless oil, Rf = 0.60 (30% EtOAc/petro-
1
leum ether); H NMR (CDCl3) d 3.13 (d, J = 8.3 Hz,
D2O exchange, 1H), 3.62 (s, 3H), 3.71 (m, 1H), 3.77
(dd, J = 4.9, 12.6 Hz, 1H), 3.83 (t, J = 5.2, 1H), 4.02
(d, J = 6.0 Hz, 1H), 4.06 (d, J = 12.7 Hz, 1H), 4.33–
4.44 (m, 4H), 4.60 (s, 2H), 4.70 (ABq, J = 11.8 Hz,
Dd = 0.03 ppm, 2H), 7.25–7.37 (m, 15H); 13C NMR
(CDCl3) d 53.3, 66.5, 67.2, 72.0, 72.5, 73.3, 74.1, 75.2,
80.1, 115.7 (t, J = 255.7 Hz), 127.1–128.8 (several reso-

R. W. Denton et al. / Carbohydrate Research 342 (2007) 1624–1635
1631
nances), 137.5, 137.7, 138.0, 163.8 (t, J = 31.5 Hz).
ESIMS calcd for C30H36O7F2N [M+NH4]+: 560.2454.
Found: 560.2451.
organic phase washed with water, dried (Na2SO4) and
evaporated under reduced pressure to provide 18
(1.60 g, 94%); colorless oil, Rf = 0.34 (20% MeOH/
1
CHCl3); H NMR (CDCl3) d 1.05 (s, 9H, (CH3)3CSi),
4.6. Methyl 3,7-anhydro-4,5,6-tri-O-benzyl-8-O-t-butyl-
diphenylsilyl-2,2-difluoro-D-glycero-D-talo-octosonate
(17) and methyl 3,7-anhydro-4,5,6-tri-O-benzyl-8-O-t-
butyldiphenylsilyl-2,2-difluoro-L- glycero-D-talo-octoson-
ate (19)
3.87–4.05 (m, 5H, H-4, 6, 7, 8a, 8b), 4.14 (dd, J = 2.9,
6.2 Hz, 1H, H-5), 4.48–4.66 (m, 7H, H-3, 3 · PhCH2),
7.24–7.48 (m, 21H, Ph), 7.71 (m, 4H, Ph); 13C NMR
(CDCl3) d 27.0, 27.2 ((CH3)3CSi), 62.6 (C-8), 72.1 (t,
J = 24.1 Hz) (C-4), 72.37, 72.43, 72.9, 73.1, 73.8, 76.2,
77.5 (7C, C-4, 5, 6, 3 · PhCH2), 114.6 (t, J = 257.0 Hz)
(C-2), 127.7–129.9 (several resonances), 133.4, 133.6,
135.8, 135.9, 137.6, 138.0, 138.2 (Ph), 166.4 (t,
J = 31.7 Hz) (C-1). ESIMS calcd for C45H52O7SiF2N
[M+NH4]+: 784.3476. Found: 784.3464.
The mixture of 15 (213 mg, 0.39 mmol), TBDPSCl
(0.03 mL, 1.18 mmol), and imidazole (106 mg, 1.56
mmol) in anhydrous DMF (5 mL) was stirred at 50 ꢁC
for 2.5 h. The reaction was then quenched by the addi-
tion of MeOH (1 mL) and extracted with ether. The
combined organic phase was washed with brine, dried
(Na2SO4), filtered, and evaporated under reduced pres-
sure. The residue was purified by gravity column chro-
matography to give 17 (180 mg, 59%) and 19 (119 mg,
39%).
4.8. Methyl 4,5,6-tri-O-acetyl-3,7-anhydro-8-O-t-butyl-
diphenylsilyl-2,2-difluoro-D-glycero-D-talo-octosonate
(20)
Colorless oil; Rf = 0.44 (30% EtOAc/petroleum ether);
1H NMR (CDCl3) d 1.08 (s, 9H, (CH3)3–), 1.99, 2.00,
2.12 (all s, 9H, CH3CO · 3), 3.71 (dd, J = 3.2,
11.7 Hz, 1H, H-6a), 3.75 (dd, J = 4.7, 11.7 Hz, 1H, H-
6b), 3.82 (s, 3H, CH3O–), 3.98 (m, 1H, H-5), 4.42
(ddd, J = 3.6, 6.6, 23.4 Hz, 1H, H-1), 5.38 (dd,
J = 3.6, 8.3 Hz, 1H, H-3), 5.43 (t, J = 8.3 Hz, 1H, H-
4), 5.65 (t, J = 3.4 Hz, 1H, H-2), 7.36–7.42 (m, 6H),
7.64–7.71 (m, 4H); 13C NMR (CDCl3) d 20.8 (two reso-
nances), 20.9, 26.9, 53.9, 62.5, 65.7, 66.1, 69.4 (d, J =
4.3 Hz), 74.3 (dd, J = 22.0, 30.0 Hz), 76.4, 114.5 (dd,
J = 258.1, 262.1 Hz), 127.9 (two resonances), 128.5,
130.0, 133.2, 133.4, 135.8, 135.9, 162.9 (dd, J = 29.2,
32.7 Hz), 169.5, 169.7, 169.9. ESIMS calcd for C31H42-
O10SiF2N [M+NH4]+: 654.2541. Found: 654. 2537.
For 17: colorless oil, Rf = 0.68 (10% EtOAc/petro-
1
leum ether); IR (film) 1770 (s) cmꢁ1; H NMR (CDCl3)
d 1.11 (s, 9H), 3.69 (s, 3H), 3.91 (dd, J = 6.4, 12.5 Hz,
1H), 3.94–4.00 (m, 3H), 4.07 (t, J = 5.9 Hz, 1H), 4.13
(dd, J = 3.2, 5.6 Hz, 1H), 4.51 (dd, J = 5.6, 10.5,
19.0 Hz, 1H), 4.60–4.71 (m, 6H), 7.26 (m, 2H), 7.34–
7.50 (m, 19H), 7.72 (m, 4H); 13C NMR (CDCl3) d
26.9, 53.4, 62.8. 72.3, 72.87, 72.94 (dd, J = 22.3,
27.0 Hz), 73.5, 74.1, 77.4, 115.2 (dd, J = 256.5,
258.8 Hz), 127.8–129.8 (several resonances), 133.5,
133.8, 135.8, 136.0, 137.9, 138.3, 138.4, 163.6 (t, J =
31.4 Hz).
ESIMS
calcd
for
C46H54O7SiF2N
[M+NH4]+: 798.3632. Found: 798.3637.
For 19: colorless oil, Rf = 0.62 (10% EtOAc/petroleum
ether); 1H NMR (CDCl3) d 1.09 (s, 9H), 3.61 (s, 3H), 3.67
(dd, J = 1.1, 3.7 Hz, 1H), 3.75 (t, J = 2.7 Hz, 1H), 3.81
(m, 2H), 3.96 (dd, J = 2.6, 10.0 Hz, 1H), 4.03 (t,
J = 6.8 Hz, 1H), 4.32–4.70 (m, 5H), 4.48 (A of ABq,
J = 12.1 Hz, Dd = 0.21 ppm, 1H), 4.69 (B of ABq, J =
12.1 Hz, Dd = 0.21 ppm, 1H), 7.16 (m, 2H), 7.28–7.47
(m, 19H), 7.67 (m, 4H); 13C NMR (CDCl3) d 27.0,
53.2, 62.3. 72.0, 72.1, 73.1, 73.2, 73.4 (two resonances,
a singlet and an apparent t, J = 23.0 Hz), 74.8, 75.7,
114.3 (t, J = 254.5 Hz), 127.9–128.8 (several resonances),
133.4, 133.7, 135.7, 135.8, 137.8, 138.4 (two resonances),
163.7 (t, J = 31.3 Hz). ESIMS calcd for C46H54O7SiF2N
[M+NH4]+: 798.3632. Found: 798.3630.
4.9. Methyl 4,5,6,8-tetra-O-acetyl-3,7-anhydro-2,2-di-
fluoro-L-glycero-D-talo-octosonate (21)
Colorless oil; Rf = 0.42 (40% EtOAc/petroleum ether);
1H NMR (C6D6) d 1.98, 2.06, 2.20 (all s, 12H,
CH3CO · 4), 3.91 (s. 3H, CH3O–), 4.14–4.16 (m, 2H,
H-5, 6a), 4.17 (t, J = 5.9 Hz, 1H, H-6b), 4.34 (ddd,
J = 7.8, 8.3, 14.4 Hz, 1H, H-1), 5.00 (dd, J = 1.5,
3.9 Hz, 1H, H-4), 5.40 (dd, J = 3.2, 10.3 Hz, 1H, H-2),
5.43 (t, J = 3.2 Hz, 1H, H-3); 13C NMR (CDCl3) d
20.6, 20.8 20.9 (two resonances), 53.6, 61.9, 63.9 (d,
J = 4.2 Hz), 66.6, 67.8, 72.9 (dd, J = 23.8, 28.4 Hz),
73.0, 113.6 (dd, J = 252.0, 261.5 Hz), 163.2 (dd,
J = 30.2, 32.2 Hz), 169.0 (two resonances), 169.7,
170.5. ESIMS calcd for C17H26O11F2N [M+NH4]+:
458.1468. Found: 458.1467.
4.7. 3,7-Anhydro-4,5,6-tri-O-benzyl-8-O-t-butyldiphenyl-
silyl-2,2-difluoro-D-glycero-D-talo-octosonic acid (18)
Methyl ester 17 (1.70 g, 2.18 mmol) was treated with a
mixture of 3 N NaOH (2.2 mL, 6.54 mmol) and ethanol
(40 mL). After 1 h the reaction mixture was concen-
trated in vacuo and acidified with 2 N HCl (20 mL).
The mixture was then extracted with EtOAc and the
4.10. Ester (22)
A mixture of acid 18 (43 mg, 0.06 mmol), 2,4,6-trichlo-
robenzoyl chloride (0.01 mL, 0.06 mmol) and triethyl-

1632
R. W. Denton et al. / Carbohydrate Research 342 (2007) 1624–1635
amine (0.02 mL, 0.12 mmol) in THF (3 mL) was stirred
for 3.5 h at 0 ꢁC. DMAP (10.0 mg, 0.08 mmol) and a
solution of alcohol 6 (31 mg, 0.06 mmol) in toluene
was added, and stirring continued for 1 h. The mixture
was then diluted with ether (10 mL), washed with satu-
rated aqueous NaHCO3 and brine, dried (Na2SO4),
filtered, and evaporated under reduced pressure. The
residue was purified by FCC to give ester 22 (54 mg,
91% based on recovered 6, 76% based on consumed
18); colorless oil; Rf = 0.33 (10% EtOAc/petroleum
ether); [a]D ꢁ32.2 (c 1.0, CHCl3); IR (film) 1780 (s)
Dd = 0.14 ppm, 1H, PhCH), 4.75 (d, J = 3.7 Hz, 1H,
H-9b), 4.79 (dd, J = 2.7, 5.6 Hz, 1H, H-20), 4.87 (d,
J = 11.3 Hz, 1H, PhCH), 5.08 (ddd, J = 1.7, 7.6,
26.7 Hz, 1H, H-1), 6.22 (d, J = 5.6 Hz, 1H, H-10),
6.89–7.43 (m, 30H, Ph), 7.65–7.88 (m, 10H, Ph); 13C
NMR (C6D6) d 27.3, 27.4, 27.6, 27.9, 62.1, 65.2, 72.6,
73.0, 73.5, 74.7 (dd, J = 22.0, 32.1 Hz), 75.0, 75.2, 78.9
(d, J = 4.6 Hz), 81.0, 84.9, 88.3 (t, J = 4.6 Hz), 113.1,
119.8 (dd, J = 248.4, 253.9 Hz), 127.3–129.5 (several res-
onances), 130.2 (two resonances), 130.6 (two reso-
nances), 131.6, 133.6, 133.8, 134.5, 134.6, 135.5, 136.4,
136.5, 139.1, 139.5, 139.7, 154.3 (dd, J = 23.8,
31.2 Hz). ESIMS calcd for C75H88O9SSi2F2N
[M+NH4]+: 1272.5681. Found: 1272.5671.
cmꢁ1 1H NMR (CDCl3) d 1.04 (two singlets, 18H,
;
2 · (CH3)3CSi), 1.31, 1.43, (both s, 6H, C(CH3)2),
3.77–3.89 (m, 5H, H-40a, 40b, 5, 8a, 8b), 3.91 (q,
J = 5.1 Hz, 1H, H-7), 3.99 (t, J = 5.9 Hz, 1H, H-6),
4.07 (dd, J = 3.0, 5.6 Hz, 1H, H-4), 4.39–4.60 (m, 8H,
H-20, 3, 3 · PhCH2), 5.22 (m, 1H, H-30), 5.42 (d,
J = 6.6 Hz, 1H, H-10), 7.16–7.42 (m, 30H, Ph), 7.52
(m, 2H, Ph ), 7.65 (m, 8H, Ph); 13C NMR (CDCl3) d
26.7, 26.9, 27.0, 27.2, 61.6, 62.8, 72.5, 72.6, 72.7, 72.9,
73.2, 74.0, 74.5, 77.1, 77.6, 78.7, 84.7, 112.1, 114.9 (t,
J = 257.4 Hz), 127.8–129.8 (several resonances), 130.0,
132.6, 132.9, 133.0, 133.4, 133.5, 133.8, 135.8 (three res-
onances), 135.9, 136.0, 137.8, 138.4, 138.5, 162.4 (t,
J = 31.8 Hz). ESIMS calcd for C74H86O10SSi2F2N
[M+NH4]+: 1274.5474. Found: 1274.5476.
4.12. Glycal (24)
Enol ether 23 (200 mg, 0.16 mmol), 2,6-di-tert-butyl-4-
methylpyridine (163 mg, 1.59 mmol), and freshly acti-
vated, powdered 4A molecular sieves (400 mg) in anhy-
drous CH2Cl2 (15 mL) were stirred for 15 min at rt
under an argon atmosphere and then cooled to 0 ꢁC.
Methyl triflate (0.18 mL, 0.80 mmol) was then intro-
duced, and the mixture was warmed to rt and stirred
for an additional 2 d, at which time triethylamine
(0.2 mL) was added. The mixture was diluted with ether,
washed with saturated aqueous NaHCO3 and brine,
dried (Na2SO4), filtered and evaporated under reduced
pressure. The residue was purified by FCC to give glycal
24 (124 mg, 82% based on recovered 23), clear oil,
Rf = 0.54 (10% EtOAc/petroleum ether); 1H NMR
(C6D6) d 1.16, 1.18 (both s, 18H), 1.27, 1.28, (both s,
6H), 3.86 (t, J = 6.9 Hz, 1H), 4.03–4.17 (m, 7H), 4.30
(t, J = 2.9 Hz, 1H), 4.38 (m, 1H), 4.50–4.60 (m, 5H),
4.72 (A of ABq, J = 11.5 Hz, Dd = 0.23 ppm, 1H),
4.79 (apparent ddd, J = 2.9, 10.0, 22.7 Hz, 1H), 4.98
(B of ABq, J = 11.5 Hz, Dd = 0.23 ppm, 1H), 5.41 (d,
J = 2.7 Hz, 1H), 7.08–7.38 (m, 27H), 7.70–7.87 (m,
8H); 13C NMR (C6D6) d 27.4, 27.5, 28.8, 63.7, 63.8,
69.3, 72.2, 73.0, 73.3, 74.0, 74.9, 75.2 (dd, J = 24.7,
30.2 Hz), 77.5, 78.5, 80.3 (d, J = 2.7 Hz), 102.7 (t,
J = 5.5 Hz), 111.3, 118.8 (dd, J = 247.4, 252.0 Hz),
127.9–128.9 (several resonances), 133.9, 134.1 (two reso-
nances), 136.2, 136.3, 136.4, 136.7, 139.2, 139.5, 139.9,
148.5 (dd, J = 26.6, 31.2 Hz). ESIMS calcd for C69H82-
O9Si2F2N [M+NH4]+: 1162.5491. Found: 1162.5497.
4.11. Enol ether (23)
TMEDA (1.20 mL, 7.96 mmol) was added at 0 ꢁC to a
mixture of 1 M titanium tetrachloride in CH2Cl2
(4.98 mL, 4.98 mmol) and THF (6 mL). The resulting
yellow-brown suspension was allowed to warm to rt
and stirred for 30 min. At this point freshly activated
zinc dust (546 mg, 8.36 mmol) and lead(II) chloride
(28 mg, 0.10 mmol) were added in one portion and stir-
ring was continued for 10 min. To the resulting bluish-
green mixture was added a solution of ester 22
(257 mg, 0.20 mmol) and dibromomethane (0.28 mL,
3.98 mmol) in THF (6 mL). The mixture was stirred at
60 ꢁC for 3.5 h then diluted with brine, and cooled to
rt over 30 min. Ether (20 mL) was then added and vigor-
ous stirring continued for 20 min. The suspension was
filtered through neutral alumina and the residue washed
with ether. The ethereal extract was concentrated in
vacuo and gravity chromatography of the residue over
silica gel afforded enol ether 23 (101 mg, 63%, based
on recovered 22); colorless oil; Rf = 0.53 (5% EtOAc/
4.13. 2,6:8,12-Dianhydro-9,10,11-tri-O-benzyl-1,13-di-O-
tert-butyldiphenylsilyl-3,4-O-isopropylidene-7-deoxy-7,7-
difluoro-D-erythro-L-allo-L-galacto-tridecitol (25)
1
petroleum ether); H NMR (C6D6) d 1.15, 1.17 (both
s, 18H, 2 · (CH3)3CSi), 1.47, 1.55, (both s, 6H,
C(CH3)2), 3.81 (dd, J = 5.9, 11.0 Hz, 1H, H-8a), 4.01–
4.15 (m, 5H, H-30, 40a, 6, 7, 8b), 4.18 (dd, J = 7.3,
11.0 Hz, 1H, H-40b), 4.31 (apparent t, J = 2.5 Hz, 1H,
H-6), 4.35 (t, J = 3.7 Hz, 1H, H-9a), 4.43–4.49 (m, 4H,
H-4, 3 · PhCH), 4.62 (A of ABq, J = 11.9 Hz, Dd =
0.14 ppm, 1H, PhCH), 4.69 (B of ABq, J = 11.9 Hz,
Borane dimethyl sulfide complex (0.11 mL, 1.10 mmol)
was added at 0 ꢁC to a solution of glycal 24 (0.12 g,
0.11 mmol) in anhydrous THF (10 mL) under an atmo-
sphere of argon. The mixture was warmed to rt and stir-
red for an additional 2 h at this temperature. The

R. W. Denton et al. / Carbohydrate Research 342 (2007) 1624–1635
1633
solution was then cooled to 0 ꢁC and treated with a mix-
4.15. Molecular modeling
ture of 3 N NaOH (6 mL) and 30% aqueous H2O2
(6 mL) for 30 min. The mixture was diluted with ether,
washed with saturated aqueous NaHCO3 and brine,
dried (Na2SO4), filtered and evaporated under reduced
pressure. The residue was purified by FCC to give 25
(0.11 g, 86%) as a colorless oil; Rf = 0.48 (20% EtOAc/
Potential energy surfaces and population maps were
calculated using the MM3* force field,23 as implemented
in MACROMODEL 7.1.32 Torsion angle UMan is defined
as H1Man–C1Man–CF2–C1Gal and UGal as H1Gal–
C1Gal–CF2 –C1Man. In a first step, a rigid UMan/UGal
map was calculated by using a grid step of 18ꢁ at each
torsion coordinate.33,34 The corresponding 400 con-
formers were optimized by fixing UMan/UGal at each cor-
responding value to generate the relaxed energy map.
The probability distribution was calculated from the
energy values according to a Boltzmann function at
300 K. In all the molecular mechanics and dynamics
calculations, the GB/SA solvation model for water
was used.
The molecular dynamics simulations were also per-
formed using the MM3* force field within MACROMODEL
7.1. For molecular dynamics simulations, several geo-
metries, corresponding to the different low energy min-
ima, were used as input. A temperature simulation of
300 K was employed with a time step of 1.5 fs and an
equilibration time of 100 ps. The total simulation times
for each compound was 3 ns.
1
petroleum ether); IR (film) 3441 (m) cmꢁ1; H NMR
(CDCl3) d 1.07 (s, 18H, 2 · (CH3)3CSi), 1.35, 1.47, (both
s, 6H, C(CH3)2), 2.93 (d, J = 5.3 Hz, 1H, D2O exchange,
–OH), 3.54 (m, 1H, H-10), 3.68 (t, J = 7.6 Hz, 1H, H-4),
3.79 (ddd, J = 2.2, 6.1, 7.8 Hz, 1H, H-50), 3.80–3.97 (m,
8H, H-20, 30, 60a, 60b, 3, 5, 6a, 6b), 4.09 (t, J = 3.4 Hz,
1H, H-2), 4.27 (dd, J = 2.5, 5.1 Hz, 1H, H-40), 4.36 (d,
J = 11.3 Hz, 1H, PhCH), 4.50–4.62 (m, 6H, H-1,
5 · PhCH), 7.06 (m, 2H, Ph), 7.22–7.42 (m, 25H, Ph),
7.65–7.73 (m, 8H, Ph); 13C NMR (CDCl3) d 26.5, 27.0,
27.3, 28.5, 62.7, 64.3, 69.7, 72.8 (two resonances), 72.9,
73.4, 74.0, 74.5, 76.6 (apparent t, J = 31.9 Hz), 78.2,
78.7, 80.2, 109.9, 121.2 (t, J = 254.2 Hz), 127.8–130.0
(several resonances), 133.2, 133.5, 133.7, 135.8, 135.9,
136.0, 138.2, 138.3, 138.5. ESIMS calcd for C69H84O10-
Si2F2N [M+NH4]+: 1180.5596. Found: 1180.5601.
4.14. 2,6:8,12-Dianhydro-7-deoxy-7,7-difluoro-D-erythro-
L-allo-L-galacto-tridecitol (5)
4.16. NMR spectroscopy
A saturated solution of HCl in ether (0.2 mL) was added
to a solution of C-glycoside 25 (87 mg, 0.07 mmol) in
anhydrous MeOH (8.0 mL) to a pH of 4. The mixture
was stirred at rt and after 2.5 h, the volatiles were
removed under reduced pressure. FCC of the crude
residue provided the pentol derivative resulting from
removal of the acetal and silyl ether protecting groups
(30 mg, 63% yield): Rf = 0.28 (95% EtOAc/petroleum
1H NMR (500 MHz) spectra were recorded at 30 ꢁC in
D2O on a Bruker AVANCE 500 spectrometer. Concen-
trations of ca. 5 mM of 5 were used. Chemical shifts are
reported in ppm, using external TMS (0 ppm) as a ref-
erence. The 2D-TOCSY experiment (70 ms mixing
time) was performed using a data matrix of 256 · 2K
to digitize a spectral width of 3000 Hz. Four scans were
used per increment with a relaxation delay of 2s. 2D-
NOESY (600, 800, and 1000 ms) and 2D-T-ROESY
experiments (300, 400, and 500 ms) used the standard
sequences. 1D-Selective NOE spectra were acquired
using the double echo sequence proposed by Shaka
and co-workers at 250, 350, 450, and 550 ms of mixing
time.35 Distances were estimated from NOESY/
ROESY experimental data as follows: NOE intensities
were normalized with respect to the diagonal peak at
zero mixing time. Selective T1 measurements were per-
formed on the anomeric and several other protons to
obtain the above-mentioned values. Experimental
NOE’s were fitted to a double exponential function,
f(t) = p0(eꢁp1t)(1 ꢁ eꢁp2t) with p0, p1, and p2 being
adjustable parameters.12 The initial slope was deter-
mined from the first derivative at time t = 0, f0(0) =
p0p2. From the initial slopes, inter-proton distances
were obtained by employing the isolated spin pair
approximation.
1
ether); H NMR (CDCl3) d 2.24 (br s, D2O exchange,
2H), 3.41 (s, 2H), 3.53 (m, 2H), 3.70 (m, 3H). 3.79 (m,
1H), 3.85 (t, J = 9.5 Hz, 1H), 3.96 (apparent t,
J = 5.0 Hz, 1H), 4.02 (s, 1H), 4.11 (m, 2H), 4.38–4.61
(m, 7H), 4.84 (br s, 1H), 7.17–7.33 (m, 15H). ESIMS
calcd for C34H40O10F2Na [M+Na]+: 669.2482. Found:
669.2480.
A mixture of material from the previous step (12 mg,
0.02 mmol), 10% Pd–C (30 mg), formic acid (0.05 mL)
and CH3OH (3 mL) was stirred under an atmosphere
of hydrogen (balloon) for 18 h. The reaction mixture
was then purged with argon, filtered through a bed of
Celite and the filtrate concentrated under reduced pres-
sure to give 5 (8 mg, 93%) as a colorless oil; Rf = 0.32
(50% MeOH/CH3Cl); [a]D +25.1 (c 0.75, H2O); 1H
NMR (see Table 2); 13C NMR (D2O) d 61.2, 61.4,
66.3, 66.7, 66.9, 68.8, 71.1 (d, J = 2.6 Hz), 73.9, 76.3
(dd, J = 22.9, 26.6 Hz), 76.9 (t, J = 22.9 Hz), 77.9,
79.3, 121.6 (dd, J = 251.1, 253.9 Hz); ESIHRMS calcd
for C13H22O10F2Na [M+Na]+: 399.1073. Found:
399.1070.
All the theoretical NOE calculations were automati-
cally performed by a home-made programme, which is
available from the authors upon request.33,34

1634
R. W. Denton et al. / Carbohydrate Research 342 (2007) 1624–1635
7. The preferred gauche conformation in 2-fluoroethyl resi-
Acknowledgments
dues attached to electronegative substituents is well
documented. For recent examples: (a) Briggs, C. R. S.;
O’Hagan, D.; Howard, J. A. K.; Yufit, D. S. J. Fluorine
Chem. 2003, 119, 9–13; (b) Briggs, C. R. S.; O’Hagan, D.;
Rzepa, H. S.; Slawin, A. M. Z. J. Fluorine Chem. 2004,
125, 19–25.
This investigation was supported by Grant R01
GM57865 from the National Institutes of Health
(NIH). ‘Research Centers in Minority Institutions’
award RR-03037 from the National Center for Research
Resources of the NIH, which supports the infrastructure
and instrumentation of the Chemistry Department at
Hunter College, is also acknowledged. The group at
Madrid thanks the Ministery of Science of Education
of Spain (Grant CTQ2006-C02-01) for funding.
8. Meier, C.; Knispel, T.; Marquez, V. E.; Siddiqui, M. A.;
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Supplementary data
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