Stereocontrolled synthesis of four diastereomeric C-aryl manno- and talofuranosides

Article abstract of DOI:10.1016/j.carres.2012.08.023

In a chiral-pool synthesis starting from d-mannono-1,4-lactone 1a, the four diastereomeric C-aryl furanosides (1S,4R)-4a, (1S,4S)-4b, (1R,4R)-4c, and (1R,4S)-4d were obtained in a stereocontrolled manner. The key steps of the synthetic pathway comprise a

Full text of DOI:10.1016/j.carres.2012.08.023

Carbohydrate Research 361 (2012) 162–169
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Stereocontrolled synthesis of four diastereomeric C-aryl manno- and
talofuranosides
Elisa Ravarino a, Sunit Kumar Jana a, Roland Fröhlich b, Ralph Holl a,
⇑
a Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany
b Organisch-Chemisches Institut der Westfälischen Wilhelms-Universität Münster, Corrensstr. 40, 48149 Münster, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 June 2012
Received in revised form 30 August 2012
Accepted 31 August 2012
Available online 10 September 2012
In a chiral-pool synthesis starting from D-mannono-1,4-lactone 1a, the four diastereomeric C-aryl furano-
sides (1S,4R)-4a, (1S,4S)-4b, (1R,4R)-4c, and (1R,4S)-4d were obtained in a stereocontrolled manner. The
key steps of the synthetic pathway comprise a stereoselective reduction of the diastereomeric hemiketals
(4R)-2a and (4S)-2b as well as a stereospecific cycloetherification of the resulting diols (1R,4R)-5a,
(1S,4R)-5c, and (1S,4S)-5d. This ring closure which led to the desired C-glycosides was achieved by a Mits-
unobu reaction or by preparing the 1-O-benzoyl-4-O-methylsulfonyl derivative 7 which was then treated
with sodium methoxide. Final hydrolysis of the 5,6-O-isopropylidene protecting group led to the diaste-
reomeric diols (1S,4R)-4a, (1S,4S)-4b, (1R,4R)-4c, and (1R,4S)-4d, representing versatile building blocks
for further synthetic transformations.
Keywords:
C-Gylcosides
Diastereoselective reduction
Cycloetherification
Carbohydrate mimetics
Chiral-pool synthesis
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Alternatively, C-aryl glycosides can be obtained by establishing
the sugar ring via intramolecular cyclization reactions, like electro-
C-glycosides, compounds in which the anomeric oxygen has
been substituted with a carbon atom, are considered to be less
prone to chemical and enzymatic hydrolysis and represent an
important class of carbohydrate mimetics.1,2 These structures are
prevalent in many pharmacologically active compounds and natu-
ral products.3–6 Therefore, the synthesis of C-glycosides has at-
tracted considerable attention and was extensively reviewed in
the literature.7–10
phile-induced cyclizations of carbohydrate-derived alkenols27 or
intramolecular Mitsunobu cycloetherifications of diols.28
In this paper we wish to report the stereocontrolled preparation
of the four diastereomeric C-phenyl furanosides (1S,4R)-4a,
(1S,4S)-4b, (1R,4R)-4c, and (1R,4S)-4d serving as versatile building
blocks, for example, for the synthesis of potential antibiotics and
other pharmacologically active compounds.14,29
Searching for C-glycosidic LpxC inhibitors11–14 we were inter-
ested in the synthesis of C-aryl furanosides. In the literature many
synthetic strategies toward C-aryl glycosides are described. For
example, sugars bearing an activating group at the anomeric center
like glycosyl halides,15,16 glycosyl acetates17,18 and glycosyl trichlo-
roacetimidates19 can undergo electrophilic aromatic substitutions
giving access to C-aryl glycosides. This class of compounds can also
be obtained by reacting metallated aryl compounds with glycosyl
halides,20,21 1,2-anhydro sugars22 and sugar lactones. In case of
the addition of organometallic reagents to lactones, the resulting
lactols need to be reduced by the Lewis acid-trialkylsilane method
or by the use of sodium cyanoborohydride in the presence of
dichloroacetic acid in order to yield the desired C-glycosides.23,24
Another strategy toward C-aryl glycosides is the transformation
of glycal derivatives in Pd-mediated Heck-type couplings.25,26
2. Results and discussion
First, the known C-phenyl b-
sized according to a literature procedure:29 After a nucleophilic at-
tack of phenyllithium to -mannono-1,4-lactone 1a, the resulting
D-mannofuranoside 3a was synthe-
D
hemiketal 2a was reduced with Et3SiH in the presence of BF3ꢀOEt2.
Due to the presence of the Lewis acid BF3ꢀOEt2 a partial cleavage of
the 5,6-isopropylidene acetal occurred. Therefore, in addition to
the bisacetonide 3a the diol 4a was also isolated from the reaction
mixture (Scheme 1).
The stereochemistry in position 1 of the C-phenyl b-D-manno-
furanoside 3a was confirmed by NOE experiments: Irradiation with
the resonance frequency of 4-H (3.70 ppm) reinforces the signal of
1-H (4.61 ppm), while the signals of the aromatic protons are not
influenced. This indicates the cis-orientation of 1-H relative to
4-H in the tetrahydrofuran ring.
In order to gain access to the (4S)-configured C-phenyl b-
furanoside 3b, the same strategy which led to the C-phenyl
D-talo-
⇑
Corresponding author. Tel.: +49 251 8333372; fax: +49 251 8332144.
E-mail address: hollr@uni-muenster.de (R. Holl).
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.08.023

E. Ravarino et al. / Carbohydrate Research 361 (2012) 162–169
163
O
O
O
HO
HO
H3C
H3C
H3C
OH
O
O
O
O
O
H
H
O
O
O
(a)
(b)
H3C
H3C
H3C
H
H
H
H
+
O
O
O
O
O
O
O
O
H3C
CH3
H3C
CH3
H3C
CH3
H3C
CH3
1a
2a
3a
4a
(c)
O
O
O
H3C
H
H3C
H
H3C
OH
H
O
O
O
O
(e)
H
O
O
O
(d)
H3C
H3C
H3C
O
O
O
O
O
O
H3C
CH3
H3C
CH3
H3C
CH3
1b
2b
3b
Scheme 1. Reagents and conditions: (a) PhLi, THF, ꢁ78 °C, 1 h, 95%; (b) Et3SiH, BF3ꢀEt2O, ACN, ꢁ40 °C, 24% 3a and 46% 4a;29 (c) (1) piperidine, EtOAc, (2) MsCl, NEt3, DMAP,
EtOAc, 66%;30 (d) PhLi, THF, ꢁ78 °C, 1 h, 53%; (e) Et3SiH, BF3ꢀEt2O, ACN, ꢁ40 °C.
b-
-talono-1,4-lactone 1b. Therefore, the
was transformed into the -talono-1,4-lactone 1b according to a
D
-mannofuranoside 3a should be followed starting from the
OH OH
O
D
D-mannono-1,4-lactone 1a
H3C
D
O
CH3
O
O
reported one-pot sequence, which proceeded via opening of the
lactone ring with piperidine, followed by mesylation and intramo-
H3C
CH3
(a)
(b)
lecular SN2-type O-alkylation.30 Then,
D-talono-1,4-lactone 1b was
5a
O
H3C
OH
treated with phenyllithium to give hemiketal 2b.
O
The inversion of the stereocenter in position 4 led to changes in
the 1H NMR spectrum of 2b compared to 2a. As 4-H is trans-
oriented relative to 3-H, a smaller coupling constant (J = 2.1 Hz)
can be observed for the coupling between these protons in the
1H NMR spectrum of 2b compared to the same coupling in the
spectrum of 2a (J = 3.9 Hz).
However, the subsequent reduction of 2b with Et3SiH in the
presence of BF3ꢀOEt2, which was performed under various condi-
tions, did not yield the desired C-glycoside 3b but gave a complex
mixture of products.
O
H3C
H
O
O
CH3
H3C
OH OH
O
2a
H3C
O
CH3
O
O
H3C
CH3
5c
As the reduction of hemiketal 2b did not afford the desired
compound, another strategy for the synthesis of 3b had to be
followed. Therefore, for the synthesis of the (1S,4S)-, the (1R,4R)-,
and the (1R,4S)-configured C-glycosides 3b, 3c, and 3d a stereose-
lective reduction of a hemiketal and subsequent cycloetherification
was envisaged.28,31,32
O
H3C
H
OH
OH OH
O
O
O
(c)
H3C
H3C
O
O
H3C
O
CH3
CH3
O
O
H3C
CH3
The reduction of the (4R)-configured hemiketal 2a with
L-Selectride in THF at ꢁ78 °C yielded diastereoselectively the
(1R,4R)-configured diol 5a. (Scheme 2) In contrast, when reducing
2a with L-Selectride in CH2Cl2 at ꢁ78 °C in the presence of ZnCl2,
the (1S,4R)-configured diastereomer 5c was obtained.33
The configuration of the stereocenter in position 1 of 5a and 5c
was assigned from their subsequent cyclization products taking
into account an inversion of configuration at that position.
In case of the L-Selectride reduction of the (4S)-configured
hemiketal 2b the (1S,4S)-configured diol 5d was obtained both,
in the presence and the absence of ZnCl2. Recrystallization of 5d
gave colorless crystals that were suitable for X-ray crystal structure
analysis. As the configuration of all the other chiral centers is given
from the chiral-pool synthesis, the configuration in position 1 was
confirmed by the X-ray structure to be (1S). (Fig. 1)
2b
5d
Scheme 2. Reagents and conditions: (a) L-Selectride, THF, ꢁ78 °C, then rt, 16 h,
82%; (b) ZnCl2, CH2Cl2, ꢁ78 °C, L-Selectride, then rt, 16 h, 66%; (c) L-Selectride, THF,
ꢁ78 °C, then rt, 16 h, 75%.
yielded the syn(1,2-threo)-isomers 5c and 5d can be explained by
the formation of the intermediate 7-membered cyclic chelate A
involving the c-hydroxy groups of the compounds (Fig. 2). Hydride
delivery from the exo-face of this metallocycle would give the ob-
served syn-isomers. By contrast, the outcome of the reductions in
the absence of added ZnCl2 was dependent on the substitution pat-
tern of C-4 bearing the c-hydroxy group: While the 3,4-threo deriv-
ative 2a yielded the anti(1,2-erythro)-isomer 5a, the 3,4-erythro
derivative 2b gave the syn-isomer 5d. When 2a is reduced with
L-Selectride in the absence of ZnCl2, the less strongly coordinating
lithium ion might form the chelate B (R1 = H, R2 = 2,2-dimethyl-
1,3-dioxolan-4-yl). As in this complex the Re-face of the carbonyl
The different stereochemical outcomes of the reductions of
hemiketals 2a and 2b can be rationalized taking into account
models for the reduction of
The fact that the reduction of both lactols in the presence of ZnCl2
c
-lactols described in the literature:33

164
E. Ravarino et al. / Carbohydrate Research 361 (2012) 162–169
indicating that the transformation was not fully stereospecific.
However, the main product of this cyclization which was isolated
in 63% yield was the (1R,4S)-configured -talofuranoside 3d, which
D
was generated via an inversion of configuration in position 1 of 5d.
The minor product 3d which was obtained in 17% yield retained
(S)-configuration in position 1.
In an alternative approach, 3d should be formed via the 1-mes-
ylate of 5d.34 Therefore, 5d was treated with methanesulfonyl
chloride in the presence of an excess of base. However, these reac-
tion conditions gave lower yields and moreover, both diastereo-
mers 3d and 3b were obtained in 30% and 10% yields, respectively.
The (1R,4S)-configuration of C-glycoside 3d was confirmed by
NOE experiments: Irradiation with the resonance frequency of 4-
H
(4.06 ppm) led to a reinforcement of the signal of 1-H
(4.88 ppm) but not of the one of 2-H (4.52 ppm). This indicates that
1-H and 4-H lie on the same side of the tetrahydrofuran ring, but
on the opposite side of 2-H.
Figure 1. Molecular structure of compound 5d.
Finally, the (1S,4S)-configured C-glycoside 3b should be synthe-
sized. As the required (1R,4S)-configured diol was not available to
perform a Mitsunobu reaction, another strategy was applied.35
Therefore, the (1S,4R)-configured diol 5c was reacted with benzoyl
chloride to yield the 1-O-benzoyl derivative 6. Its 1H NMR spec-
trum clearly indicates that the benzoylation had taken place at
the hydroxy group in position 1. Benzoylation of the sterically
more hindered hydroxy group in position 4 was not observed.
In the next step, the remaining hydroxy group of 6 was mesylat-
ed giving access to the 1-O-benzoyl-4-O-methylsulfonyl derivative
7. Treatment of 7 with methanolic sodium methoxide led to the
cleavage of the benzoate and a subsequent SN2 reaction in position
4 yielding the (1S,4S)-configured C-glycoside 3b. NOE experiments
with 3b proved the relative trans-orientation of 1-H and 4-H, as
irradiation with the resonance frequency of 1-H (5.28 ppm) did
not enhance the signal of 4-H (4.21 ppm). Therefore the phenyl
B( Bu)
B(sBu)3
H
s
H
3
O
R1
Li
M
A
O
O
O
H
O
O
H
O
H3C
O
R2
O
H3C
CH3
H3C
CH3
CH3
O
B
Figure 2. Models for the reductions of lactols 2a and 2b.
group is shielded by the axial substituent R1, reduction occurs from
the Si-face yielding the anti-diol 5a. In contrast, the formation of
complex B seems unlikely to occur in case of 2b (R1 = 2,2-di-
methyl-1,3-dioxolan-4-yl, R2 = H), as the dioxolanyl substituent
would be placed in an axial position. However, the outcome of
the reduction of 2b with L-Selectride is in agreement with the
prediction of the Felkin–Anh model.
In the next reaction step the C-glycosidic scaffolds should be
established in a stereospecific manner. Therefore, an intramolecular
cycloetherification under Mitsunobu conditions was per-
formed.28,31,32 The reaction of 5a with diisopropyl azodicarboxylate
and triphenylphosphine at ambient temperature gave the already
known (1S,4R)-configured C-glycoside 3a in 25% yield. (Scheme 3)
The stereochemical outcome of the reaction showed that the nucle-
ophilic substitution had taken place in the benzylic position and
confirmed the (R)-configuration in position 1 of 3a.
ring must be in the b-position of D-talofuranoside 3b.
The treatment of the bisacetonides 3a, 3b, 3c, and 3d with
methanol and catalytic amounts of p-toluenesulfonic acid selec-
tively led to the cleavage of the 5,6-O-isopropylidene protecting
group, while the bicyclic acetonide remained stable under these
reaction conditions. The diols (1S,4R)-4a, (1S,4S)-4b, (1R,4R)-4c,
and (1R,4S)-4d and were obtained in 36–73% yields. As the cleav-
age of the 2,3-O-isopropylidene protecting group requires harsher
reaction conditions, the selective cleavage of the less stable aceto-
nide allows further transformations of the resulting vicinal diols
like, for example, a glycol cleavage, while the hydroxy groups of
the tetrahydrofuran ring are still protected. Therefore, the four
stereoisomeric C-phenyl furanosides (1S,4R)-4a, (1S,4S)-4b,
(1R,4R)-4c, and (1R,4S)-4d with their two different substituents
in positions 1 and 4 represent versatile building blocks for further
transformations, allowing selective variations at the different
positions of the tetrahydrofuran ring.14,29
Compound 5c was also transformed into a C-glycoside using
Mitsunobu conditions. However, in order to improve the yield of
the cyclization, a higher amount of the reagents was used and
the reaction mixture was heated to reflux. These modifications
gave the (1R,4R)-configured C-glycoside 3c in 75% yield.
3. Conclusion
While in the 1H NMR spectrum of 3a the signal of 1-H appears
as a doublet (J = 3.7 Hz), the corresponding proton of 3c gives a sin-
glet, indicating its trans-orientation relative to 2-H in the tetrahy-
drofuran ring. NOE experiments further confirmed this
assignment: Irradiation with the resonance frequency of 4-H
(3.89 ppm) did not increase the signal of 1-H (5.20 ppm). This
proved the phenyl ring to be in the a-position of the D-mannofur-
anoside 3c. The determined (1R,4R)-configuration of 3c confirmed
the (1S)-configuration of the precursor 5c.
Stereocontrolled syntheses starting from
D-mannono-1,4-lac-
tone 1a yielded the four diastereomeric C-glycosides (1S,4R)-4a,
(1S,4S)-4b, (1R,4R)-4c, and (1R,4S)-4d. These chiral pool syntheses
comprised stereoselective reductions of the diastereomeric hemi-
ketals (4R)-2a and (4S)-2b. The next key steps of the synthetic
pathways were stereospecific cycloetherifications of the resulting
diols (1R,4R)-5a, (1S,4R)-5c, and (1S,4S)-5d. These ring closures
yielding the desired C-glycosides could be achieved by performing
Mitsunobu reactions or by an intramolecular SN2 reaction of the
mesylate 7. The final cleavage of the 5,6-O-isopropylidene protect-
ing group gave access to the diastereomeric diols (1S,4R)-4a,
(1S,4S)-4b, (1R,4R)-4c, and (1R,4S)-4d. With the phenyl ring in
When 5d was subjected to the Mitsunobu reaction, besides the
(1R,4S)-configured C-glycoside 3d bearing the phenyl ring in the
a-
position its (1S,4S)-configured diastereomer 3b was also obtained,

E. Ravarino et al. / Carbohydrate Research 361 (2012) 162–169
165
O
HO
HO
H3C
OH OH
O
O
O
H
H
O
(a)
(c)
(b)
(d)
H3C
H3C
H
H
O
CH3
O
O
O
O
O
O
H3C
CH3
H3C
CH3
H3C
CH3
5a
3a
O
4a
O
O
HO
HO
H3C
OH OH
H
H
O
O
H3C
H3C
H
H
O
CH3
O
O
O
O
O
O
H3C
CH3
H3C
CH3
H3C
CH3
5c
3c
4c
(e)
O
S
O
O
H3C
O
O
O
HO
HO
H3C
H
H
HO
O
O
O
O
O
O
O
H
H
O
(f)
(g)
(h)
(k)
H3C
H3C
H3C
O
CH3
O
O
CH3
O
O
O
H3C
O
O
H3C
O
CH3
CH3
H3C
CH3
H3C
CH3
6
7
3b
O
4b
O
O
HO
HO
H3C
H
H
OH OH
H
H
O
O
(i) or (j)
H3C
H3C
O
CH3
O
O
O
O
O
O
H3C
CH3
H3C
CH3
H3C
CH3
5d
3d
4d
Scheme 3. Reagents and conditions: (a) DIAD, PPh3, THF, rt, 24 h, 25%; (b) pTsOH, MeOH, rt, 4 h, 73%; (c) DIAD, PPh3, THF,
D, 16 h, 75%; (d) pTsOH, MeOH, rt, 4 h, 62%; (e) BzCl,
DIEA, DMAP, CH2Cl2, rt, 16 h, 52%; (f) MsCl, DIEA, CH2Cl2, rt, 16 h, 85%; (g) NaOMe, MeOH, rt, 16 h, 93%; (h) pTsOH, MeOH, rt, 4 h, 61%; (i) DIAD, PPh3, THF,
17% 3b; (j) MsCl, DIEA, CH2Cl2, rt, 16 h, 30% 3d, and 10% 3b; (k) pTsOH, MeOH, rt, 4 h, 36%.
D, 16 h, 63% 3d, and
position 1, the ethylene glycol structure in position 4 and the ace-
tonide protected glycol structure of the tetrahydrofuran ring, these
compounds represent versatile building blocks which allow selec-
tive transformations at the different ring positions.
Where necessary, the assignment of the signals in the 1H NMR and
13C NMR spectra was performed using 1H–1H and 1H–13C COSY
NMR spectra as well as NOE (nuclear Overhauser effect) difference
spectroscopy. IR: IR Prestige-21(Shimadzu). MS: HRMS: MicrOTOF-
QII (Bruker); ESI: LCQ Finnigan MAT mass spectrometer (Thermo
Finnigan), peaks are given in m/z (% of basis peak). HPLC method
for the determination of product purity: Merck Hitachi Equipment;
UV detector: L-7400; autosampler: L-7200; pump: L-7100; degas-
4. Experimental
4.1. Chemistry: General
ser: L-7614; column: LiChrospherÒ 60 RP-select B (5
CARTÒ 250-4 mm cartridge; flow rate: 1.00 mL/min; injection
volume: 5.0 L; detection at k = 210 nm for 30 min; solvents: A:
lm); LiCro-
Unless otherwise mentioned, THF was dried with sodium/ben-
zophenone and was freshly distilled before use. Thin layer chroma-
tography (tlc): Silica Gel 60 F254 plates (Merck). Flash
l
water with 0.05% (V/V) trifluoroacetic acid; B: acetonitrile with
0.05% (V/V) trifluoroacetic acid; gradient elution: (A%): 0–4 min:
90% , 4–29 min: gradient from 90% to 0%, 29–31 min: 0%, 31–
31.5 min: gradient from 0% to 90%, 31.5–40 min: 90%. X-Ray
diffraction: Data sets were collected with a Nonius KappaCCD dif-
fractometer. Programs used: data collection, COLLECT (Nonius B.V.,
1998); data reduction Denzo-SMN;36 absorption correction, Den-
zo;37 structure solution SHELXS-97;38 structure refinement SHEL-
XL-9739 and graphics, XP (BrukerAXS, 2000). Thermals ellipsoids
are shown with 30% probability, R-values are given for observed
reflections, and wR2 values are given for all reflections. Exceptions
and special features: Flack parameter was refined to ꢁ0.4(3).
chromatography (fc): Silica Gel 60, 40–64 lm (Macherey-Nagel);
parentheses include: diameter of the column, length of column,
fraction size, eluent, and Rf value. Melting point (mp): Melting
point apparatus SMP 3 (Stuart Scientific), uncorrected. Optical
rotation
a [deg] was determined with a Polarimeter 341 (Perkin El-
mer); path length 1 dm, wavelength 589 nm (sodium D line); the
unit of the specific rotation ½a D20
ꢂ
[deg mL dmꢁ1 gꢁ1] is omitted;
the concentration of the sample c [mg mLꢁ1] and the solvent used
are given in brackets. 1H NMR (400 MHz), 13C NMR (100 MHz):
Mercury plus 400 spectrometer (Varian); d in ppm related to tetra-
methylsilane; coupling constants are given with 0.5 Hz resolution.

166
E. Ravarino et al. / Carbohydrate Research 361 (2012) 162–169
4.2. Synthetic procedures
dry THF (70 mL) at ꢁ78 °C. The reaction was stirred for 1 h and then
warmed to room temperature. Afterward, a saturated aqueous solu-
tion of NaHCO3 was added to quench the reaction. Extraction with
CH2Cl2 (3ꢃ) was performed; the combined organic layers were
dried over Na2SO4, filtered, and concentrated under diminished
pressure. The residue was purified by flash chromatography
(Ø = 5 cm, h = 15 cm, V = 80 mL, cyclohexane/ethyl acetate = 8/2,
Rf = 0.27) to give 2b as colorless solid (1.51 g, 4.49 mmol, 53%).
4.2.1. 2,3:5,6-Di-O-isopropylidene-1-C-phenyl-D-
mannofuranose (2a)
Under N2 atmosphere a 2.0 M solution of phenyllithium in dibu-
tyl ether (5.5 mL, 11 mmol) was added to a solution of 2,3:5,6-di-
O-isopropylidene-D-mannono-1,4-lactone (1a) (2.6 g, 10 mmol) in
THF (50 mL) at ꢁ78 °C. After stirring at ꢁ78 °C for 1 h, the mixture
was allowed to warm to room temperature. Then a saturated aque-
ous solution of NaHCO3 (15 mL) was added and the mixture was
extracted with CH2Cl2 (3ꢃ). The combined organic layers were
dried (Na2SO4), filtered, and the solvent was removed in vacuo.
The residue was purified by flash column chromatography
(Ø = 8 cm, h = 15 cm, V = 60 mL, n-hexane/ethyl acetate = 8/2,
Rf = 0.24) to give 2a as colorless solid (3.2 g, 9.5 mmol, 95%). Mp:
Mp: 148 °C; ½a 2D0
ꢂ
+44.8 (3.7; CH2Cl2); 1H NMR (DMSO-d6): d 1.17
(s, 3H, CH3), 1.28 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.37 (s, 3H, CH3),
3.69 (dd, J = 8.4/7.0 Hz, 1 H, 6-H), 4.09 (dd, J = 8.2/2.1 Hz, 1H, 4-H),
4.14 (dd, J = 8.4/6.6 Hz, 1H, 6-H), 4.33–4.40 (m, 5-H), 4.49 (d,
J = 5.7 Hz, 1H, 2-H), 4.73 (dd, J = 5.7/2.1 Hz, 1H, 3-H), 6.84 (s, 1H,
OH), 7.25–7.36 (m, 3H, Harom.), 7.46–7.50 (m, 2H, Harom.); 13C NMR
(DMSO-d6): d 25.1 (1C, C(CH3)2), 25.4 (1C, C(CH3)2), 26.7 (1C,
C(CH3)2), 26.8 (1C, C(CH3)2), 65.5 (1C, C-6), 77.4 (1C, C-5), 81.5
(1C, C-3), 86.6 (1C, C-2), 87.8 (1C, C-4), 106.9 (1C, C-1), 108.8 (1C,
C(CH3)2), 112.0 (1C, C(CH3)2), 127.1 (2C, C-20phenyl, C-60phenyl),
127.2 (2C, C-30phenyl, C-50phenyl), 127.7 (1C, C-40phenyl), 140.6 (1C, C-
116 °C; ½a 2D0
ꢂ
+62.1 (5.1; CH2Cl2); 1H NMR (DMSO-d6): d 1.15 (s,
3H, CH3), 1.24 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.36 (s, 3H, CH3),
3.99 (dd, J = 8.3/6.1 Hz, 1 H, 6-H), 4.06 (dd, J = 8.3/6.6 Hz, 1H, 6-
H), 4.22 (dd, J = 5.9/3.9 Hz, 1H, 4-H), 4.39 (q, J = 6.1 Hz, 1H, 5-H),
4.47 (d, J = 5.8 Hz, 1H, 2-H), 4.85 (dd, J = 5.8/3.9 Hz, 1H, 3-H), 6.62
(s, 1H, OH), 7.25–7.35 (m, 3H, Harom.), 7.43–7.47 (m, 2H, Harom.);
13C NMR (DMSO-d6): d 24.0 (1C, C(CH3)2), 25.3 (1C, C(CH3)2), 25.4
(1C, C(CH3)2), 26.6 (1C, C(CH3)2), 65.7 (1C, C-6), 73.2 (1C, C-5),
77.9 (1C, C-4), 79.9 (1C, C-3), 86.2 (1C, C-2), 105.1 (1C, C-1),
107.8 (1C, C(CH3)2), 111.3 (1C, C(CH3)2), 127.0 (2C, C-20phenyl, C-
60phenyl), 127.1 (2C, C-30phenyl, C-50phenyl), 127.7 (1C, C-40phenyl),
10phenyl); IR (neat):
m
[cmꢁ1] = 3528, 2982, 2936, 1376, 1208, 1056,
854, 696; HRMS (m/z): [M+H]+ calcd for C18H25O6, 337.1646; found,
337.1649; HPLC: tR = 17.0 min, purity 99.0%.
4.2.4. (1R)-2,3:5,6-Di-O-isopropylidene-1-C-phenyl-D-mannitol
(5a)
L-Selectride (1 M in THF, 12.18 mL, 12.18 mmol) was added
dropwise to a solution of 2a (1.2 g, 3.58 mmol) in dry THF
(70 mL) at ꢁ78 °C over a period of 30 min. The reaction is then
slowly brought to room temperature and stirred overnight. The
mixture was concentrated in vacuo, the residue was dissolved in
CH2Cl2 (40 mL) and quenched with EtOH (1.1 mL), H2O (0.24 mL),
NaOH 6 M (0.9 mL), and H2O2 30% (0.9 mL). Stirring was continued
for 1 h. Then the mixture was extracted with EtOAc, the organic
phase dried over sodium sulfate and concentrated. The residue
was purified by flash column chromatography (Ø = 5 cm,
h = 15 cm, V = 60 mL, cyclohexane/EtOAc = 2:1, Rf = 0.35) to give
140.3 (1C, C-10phenyl); IR (neat):
m
[cmꢁ1] = 3358, 2975, 2937,
1450, 1371, 1209, 1062, 1033, 1011, 849, 699; HRMS (m/z):
[M+Na]+ calcd for C18H24O6Na, 359.1465; found, 359.1465; HPLC:
tR = 17.9 min, purity 97.5%.
4.2.2. 2,3:5,6-Di-O-isopropylidene-D-talono-1,4-lactone (1b)
2,3:5,6-Di-O-isopropylidene- -mannono-1,4-lactone (1a) (4.0 g
D
15.4 mmol) was dissolved in anhydrous EtOAc (40 mL) and piper-
idine (3.07 mL, 31 mmol) was added dropwise at 0 °C. The mixture
was stirred at room temperature for 5 h. After TLC had revealed
that the reaction was complete, the excess of piperidine and the
solvent was removed in vacuo to give a white solid. The residue
was dissolved in EtOAc (50 mL). Then triethylamine (3.45 mL,
24.5 mmol) and dimethylaminopyridine (25 mg, 0.2 mmol) were
added. Subsequently, the reaction was cooled to 0 °C and methane-
sulfonyl chloride (1.8 mL) was added dropwise. The mixture was
warmed to room temperature and stirred overnight. The reaction
was then quenched with water and extracted with CH2Cl2 (4ꢃ).
The organic layer was washed with 1% HCl solution, water, and
brine. After treatment with sodium sulfate the organic phase was
filtrated and concentrated under reduced pressure. The residue
was purified by flash column chromatography (Ø = 5 cm,
h = 15 cm, V = 60 mL, cyclohexane/ethyl acetate = 8/2, Rf = 0.19) to
give 1b as a colorless solid (2.66 g, 10.3 mmol, 66%). Mp: 129 °C;
5a as colorless oil (1.0 g, 2.95 mmol, 82%). ½a D20
ꢁ16.5 (1.2; CH2Cl2);
ꢂ
1H NMR (CDCl3): d 1.29 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.35 (s, 1H,
CH3), 1.50 (s, 1H, CH3), 3.01–3.04 (m, 1H, OH), 3.13–3.16 (m, 1H,
OH), 3.85–3.90 (m, 1H, 4-H), 4.02–4.09 (m, 3H, 5-H, 6-H), 4.39
(dd, J = 6.8/1.0 Hz, 1H, 3-H), 4.42–4.46 (m, 1H, 2-H), 5.11 (dd,
J = 7.4/4.1 Hz, 1H, 1-H), 7.27–7.32 (m, 1H, Harom.), 7.34–7.39 (m,
2H, Harom.), 7.41–7.45 (m, 2H, Harom.); 13C NMR (CDCl3): d 25.0
(1C, C(CH3)2), 25.57 (1C, C(CH3)2),26.9 (1C, C(CH3)2), 27.1 (1C,
C(CH3)2), 67.2 (1C, OCHCH2O C-6), 69.7 (1C, C-4), 72.0 (1C, C-1),
75.9 (1C, C-3), 76.4 (1C, OCHCH2O C-5), 79.9 (1C, C-2), 108.5 (1C,
C(CH3)2), 109.5 (1C, C(CH3)2), 126.6 (2C, C-20phenyl, C-60phenyl),
128.1 (1C, C-40phenyl), 128.7 (2C, C-30phenyl, C-50phenyl), 141.1 (1C,
C-10phenyl); IR (neat):
1215, 1065, 1038, 841, 702; HRMS (m/z): [M+H]+ calcd for
18H27O6, 399.1802; found, 399.1775; HPLC: tR = 16.2 min, purity
m
[cmꢁ1] = 3321, 2986, 2936, 2361, 1369,
½
a 2D0
ꢂ
+35.9 (4.1; CH2Cl2); 1H NMR (CDCl3): d 1.33 (s, 3H, CH3),
C
1.34 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.47 (s, 3H, CH3), 3.99 (dd,
J = 8.3/7.5 Hz, 1 H, 6-H), 4.12 (dd, J = 8.3/6.9 Hz, 1H, 6-H), 4.25–
4.29 (m, 1H, 5-H), 4.54 (d, J = 1.1 Hz, 1H, 4-H), 4.76 (d, J = 5.5 Hz,
1H, 3-H), 4.78 (d, J = 5.5 Hz, 1H, 2-H); 13C NMR (CDCl3): d 25.5
(1C, C(CH3)2), 25.6 (1C, C(CH3)2), 25.7 (1C, C(CH3)2), 26.9 (1C,
C(CH3)2), 65.2 (1C, C-6), 75.1 (1C, C-2), 75.2 (1C, C-5), 78.6 (1C, C-
3), 79.7 (1C, C-4), 110.7 (1C, C(CH3)2), 113.4 (1C, C(CH3)2), 174.3
98.4%.
4.2.5. (1S)-2,3:5,6-Di-O-isopropylidene-1-C-phenyl-D-mannitol
(5c)
ZnCl2 (1 M solution in diethyl ether, 3.55 mL, 3.55 mmol) was
added to a solution of 2a (884 mg, 2.63 mmol) in dry CH2Cl2
(80 mL) at ꢁ78 °C and the mixture was stirred for 40 min. After-
ward, L-selectride (1 M in THF, 8.9 mL, 8.9 mmol) was added drop-
wise over a period of 30 min at ꢁ78 °C. The reaction was then
slowly brought to room temperature and stirred overnight. To
quench the reaction EtOH (1.1 mL), H2O (0.24 mL), NaOH 6 M
(0.9 mL), and H2O2 30% (0.9 mL) were added and stirring was con-
tinued for 1 h. Then the mixture was extracted with EtOAc, the or-
ganic layer dried over sodium sulfate, and concentrated. The
residue was purified by flash column chromatography (Ø = 5 cm,
(1C, C-1); IR (neat):
1085, 1067, 975, 859, 796; HRMS (m/z): [M+H]+ calcd for
12H19O6, 259.1176; found, 259.1188.
m
[cmꢁ1] = 2990, 1787, 1372, 1218, 1151,
C
4.2.3. 2,3:5,6-Di-O-isopropylidene-1-C-phenyl-D-talofuranose
(2b)
A 2.0 M solution of phenyllithium in dibutylether (4.64 mL,
9.27 mmol) was added to a solution of 1b (2.19 g, 8.43 mmol) in

E. Ravarino et al. / Carbohydrate Research 361 (2012) 162–169
167
h = 15 cm, V = 60 mL, cyclohexane/EtOAc = 2/1, Rf = 0.30) to give 5c
(0.38 mL, 425.8 mg, 3.0 mmol) in acetonitrile (30 mL) at ꢁ40 °C.
The mixture was stirred at ꢁ40 °C for 1 h, then a saturated aqueous
solution of K2CO3 (3 mL) was added and the mixture was stirred for
1 h at ambient temperature. Then water was added and the mix-
ture was extracted with ethyl acetate (3ꢃ). The combined organic
layers were dried (Na2SO4), filtered, and the solvent was removed
in vacuo. The residue was purified by flash column chromatogra-
phy (Ø = 4 cm, h = 15 cm, V = 30 mL, n-hexane/ethyl acetate = 8/2
? 1/2) to give 3a (n-hexane/ethyl acetate = 8/2, Rf = 0.29) as color-
less oil (233 mg, 0.73 mmol, 24%) and 4a (n-hexane/ethyl ace-
tate = 1/2, Rf = 0.14) as colorless solid (389 mg, 1.39 mmol, 46%).
(b) Under N2 atmosphere, triphenylphosphine (262.3 mg, 1 mmol)
was added to a solution of 5a (170 mg, 0.5 mmol) in dry THF
(45 mL). Then diisopropyl azodicarboxylate (0.19 mL, 1 mmol)
was added at 0 °C and the reaction was stirred for 24 h at room
temperature. Afterward, the mixture was concentrated in vacuo
and the residue was purified by flash column chromatography
(Ø = 2.5 cm, h = 15 cm, V = 15 mL, cyclohexane/EtOAc = 9:1,
Rf = 0.29) to give 3a as a colorless oil (40 mg, 0.13 mmol, 25% yield).
as colorless oil (587 mg, 1.73 mmol, 66%). ½a D20
ꢂ
+56.3 (1.5; CH2Cl2);
1H NMR (CDCl3): d 1.27 (s, 3H, CH3), 1.32 (s, 3H, CH3), 1.40 (s, 1H,
CH3), 1.60 (s, 1H, CH3), 3.24 (s br, 2H, OH), 3.60 (d, J = 7.0 Hz, 1H,
4-H), 4.00–4.11 (m, 3H, 5-H, 6-H), 4.38 (dd, J = 7.5/1.0 Hz, 1H, 3-
H), 4.52 (dd, J = 7.5/4.0 Hz, 1H, 2-H), 4.97 (d, J = 4.0 Hz, 1H, 1-H),
7.29–7.34 (m, 1H, Harom.), 7.35–7.40 (m, 2H, Harom.), 7.42–7.46
(m, 2H, Harom.); 13C NMR (CDCl3): d 24.8 (1C, C(CH3)2), 25.5 (1C,
C(CH3)2),26.6 (1C, C(CH3)2), 26.9 (1C, C(CH3)2), 67.3 (1C, C-6),
70.3 (1C, C-4), 72.1 (1C, C-1), 75.9 (1C, C-3), 76.2 (1C, C-5), 80.3
(1C, C-2), 108.7 (1C, C(CH3)2), 109.4 (1C, C(CH3)2), 127.2 (2C, C-
20phenyl, C-60phenyl), 128.4 (1C, C-40phenyl), 128.8 (2C, C-30phenyl, C-
50phenyl), 140.6 (1C, C-10phenyl); IR (neat):
m
[cmꢁ1] = 3402, 3379,
2986, 2928, 2851, 1454, 1373, 1246, 1211, 1061, 845, 698; HRMS
(m/z): [M+H]+ calcd for C18H27O6, 399.1802; found, 399.1776;
HPLC: tR = 15.5 min, purity 98.6%.
4.2.6. (1S)-2,3:5,6-Di-O-isopropylidene-1-C-phenyl-D-talitol (5d)
L-Selectride (1 M in THF, 12.18 mL, 12.18 mmol) was added
dropwise to a solution of 2b (1.2 g, 3.58 mmol) in dry THF
(70 mL) at ꢁ78 °C over a period of 30 min. The reaction was then
slowly brought to room temperature and stirred overnight. The
mixture was concentrated in vacuo, the residue was dissolved in
CH2Cl2 (40 mL) and quenched with EtOH (1.1 mL), H2O (0.24 mL),
NaOH 6 M (0.9 mL), and H2O2 30% (0.9 mL). After stirring for 1 h,
the mixture was extracted with EtOAc, the organic phase dried
over sodium sulfate, and concentrated in vacuo. The residue was
purified by flash column chromatography (Ø = 5 cm, h = 15 cm,
V = 60 mL, cyclohexane/EtOAc = 2/1, Rf = 0.42) to give 5d as color-
Analytical data of 3a: ½a D20
ꢂ
+75.3 (5.4; CH2Cl2); 1H NMR (CDCl3): d
1.29 (s, 3H, CH3), 1.41 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.48 (s, 3H,
CH3), 3.70 (dd, J = 7.3/3.7 Hz, 1H, 4-H), 4.17 (d, J = 5.6 Hz, 2H, 6-
H), 4.53 (dt, J = 7.3/5.6 Hz, 1H, 5-H), 4.61 (d, J = 3.7 Hz, 1H, 1-H),
4.81 (dd, J = 6.0/3.7 Hz, 1H, 2-H), 4.87 (dd, J = 6.0/3.7 Hz, 1H, 3-H),
7.26–7.39 (m, 5H, Harom.); 13C NMR (CDCl3): d 24.4 (1C, C(CH3)2),
25.5 (1C, C(CH3)2), 25.7 (1C, C(CH3)2), 27.1 (1C, C(CH3)2), 67.2 (1C,
C-6), 73.4 (1C, C-5), 80.9 (1C, C-3), 81.7 (1C, C-4), 82.4 (1C, C-2),
83.8 (1C, C-1), 109.2 (1C, C(CH3)2), 112.7 (1C, C(CH3)2), 127.6 (2C,
C-20phenyl, C-60phenyl), 128.0 (1C, C-40phenyl), 128.1 (2C, C-30phenyl, C-
less solid (909 mg, 2.69 mmol, 75%). Mp: 84 °C; ½a D20
ꢂ
+47.4 (1.6;
50phenyl), 135.6 (1C, C-10phenyl); IR (neat):
1455, 1206, 1065, 843, 698; HRMS (m/z): [M+Na]+ calcd for
18H24O5Na, 343.1516; found, 343.1528; HPLC: tR = 19.6 min, pur-
m
[cmꢁ1] = 2986, 2935,
CH2Cl2); 1H NMR (CDCl3): d 1.34 (s, 3H, CH3), 1.40 (s, 3H, CH3),
1.46 (s, 1H, CH3), 1.54 (s, 1H, CH3), 2.58 (s br, 1H, OH), 2.86 (s br,
1H, OH), 3.94 (dd, J = 8.5/6.8 Hz, 1H, 6-H), 4.07 (dd, J = 9.4/3.9 Hz,
1H, 4-H), 4.10 (dd, J = 8.5/6.8 Hz, 1H, 6-H), 4.17 (dd, J = 9.3/6.6 Hz,
1H, 3-H), 4.33 (td, J = 6.7/4.0 Hz, 1H, 5-H), 4.45 (dd, J = 6.6/1.8 Hz,
1H, 2-H), 5.18–5.22 (m, 1H, 1-H), 7.25–7.30 (m, 1H, Harom.), 7.33–
7.38 (m, 2H, Harom.), 7.39–7.43 (m, 2H, Harom.); 13C NMR (CDCl3):
d 24.7 (1C, C(CH3)2), 25.3 (1C, C(CH3)2), 26.6 (1C, C(CH3)2), 27.02
(1C, C(CH3)2), 66.4 (1C, 6-C), 69.7 (1C, C-4), 70.6 (1C, C-1), 76.5
(1C, C-5), 77.49 (1C, C-3), 80.4 (1C, C-2), 108.9 (1C, C(CH3)2),
109.4 C(CH3)2), 126.5 (2C, C-20phenyl, C-60phenyl), 127.7 (1C, C-
40phenyl), 128.5 (2C, C-30phenyl, C-50phenyl), 142.5 (1C, C-10phenyl); IR
C
ity 97.3%.
4.2.8. C-Phenyl 2,3-O-isopropylidene-b-D-mannofuranoside (4a)
p-Toluenesulfonic acid monohydrate (36 mg, 0.19 mmol) was
added to solution of 3a (676 mg, 2.1 mmol) in methanol
a
(20 mL). The mixture was stirred at ambient temperature for 4 h.
Then a saturated aqueous solution of NaHCO3 was added and the
mixture was extracted with ethyl acetate (3ꢃ). The combined or-
ganic layers were dried (Na2SO4), filtered, and the solvent was re-
moved in vacuo. The residue was purified by flash column
chromatography (Ø = 3 cm, h = 15 cm, V = 20 mL, n-hexane/ethyl
acetate = 1/2, Rf = 0.14) to give 4a as colorless solid (430 mg,
(neat):
m
[cmꢁ1] = 3468, 2986, 2928, 2301, 1740, 1454, 1373,
1250, 1211, 1061, 876, 849, 698; MS (ESI): m/z = 698 (2 M+Na+,
19), 361 (M+Na+); HPLC: tR = 15.6 min, purity 95.3%.
1.5 mmol, 73%). Mp: 114 °C; ½a D20
ꢂ
+72.2 (5.3; CH2Cl2); 1H NMR
Further recrystallization from diisopropyl ether gave colorless
crystals that were suitable for X-ray crystal structure analysis. X-
(CDCl3): d 1.29 (s, 3H, CH3), 1.47 (s, 3H, CH3), 3.71 (dd, J = 7.9/
4.1 Hz, 1H, 4-H), 3.81 (dd, J = 11.5/5.8 Hz, 1H, 6-H), 3.93 (dd,
J = 11.5/3.6 Hz, 1H, 6-H), 4.18 (ddd, J = 7.9/5.8/3.6 Hz, 1H, 5-H),
4.62 (d, J = 3.7 Hz, 1H, 1-H), 4.82 (dd, J = 6.1/3.7 Hz, 1H, 2-H), 4.94
(dd, J = 6.1/4.1 Hz, 1H, 3-H), 7.27–7.40 (m, 5H, Harom.); 13C NMR
(CDCl3): d 24.6 (1C, C(CH3)2), 25.8 (1C, C(CH3)2), 64.9 (1C, C-6),
70.5 (1C, C-5), 81.1 (1C, C-4), 81.5 (1C, C-3), 82.3 (1C, C-2), 83.7
(1C, C-1), 112.8 (1C, C(CH3)2), 127.6 (2C, C-20phenyl, C-60phenyl),
128.1 (2C, C-30phenyl, C-50phenyl), 128.2 (1C, C-40phenyl), 135.4 (1C,
ray crystal structure analysis of 5d: formula
M = 338.39, colorless crystal,
0.15 ꢃ 0.05 ꢃ 0.03 mm,
a = 9.8969(7), b = 10.7879(7), c = 17.3024(9) Å, V = 1847.3(2) Å3,
calc = 1.217 g cmꢁ3 = 0.749 mmꢁ1, empirical absorption correc-
tion (0.895 6 T 6 0.977), Z = 4, orthorhombic, space group
C18H26O6,
q
, l
P212121 (No. 19), k = 1.54178 Å, T = 223(2) K,
x and u scans,
12,125 reflections collected ( h, k, l), [(sinh)/k] = 0.59 Åꢁ1, 2836
independent (Rint = 0.073) and 2257 observed reflections
C-10phenyl); IR (neat):
1208, 1096, 1011, 858, 734; HRMS (m/z): [M+Na]+ calcd for
15H20O5Na, 303.1203; found, 303.1206; HPLC: tR = 13.9 min, pur-
m
[cmꢁ1] = 3473, 2984, 2925, 2872, 1384,
[I >2r
(I)], 223 refined parameters, R = 0.048, wR2 = 0.111, max.
(min.) residual electron density 0.18 (ꢁ0.21) e.Åꢁ3
,
hydrogen
C
atoms calculated and refined as riding atoms. CCDC-872980 con-
tains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
ity 98.4%.
4.2.9. C-Phenyl 2,3:5,6-di-O-isopropylidene-a-D-
mannofuranoside (3c)
Triphenylphosphine (525 mg, 2.0 mmol) was added to a solution
of 5c (340 mg, 1.0 mmol) in dry THF (40 mL), under N2 atmosphere.
Then diisopropyl azodicarboxylate (0.4 mL, 2.0 mmol) was added at
0 °C and the reaction was heated to reflux. After 2 h a solution of
triphenylphosphine (787 mg, 3.0 mmol) and diisopropyl
4.2.7. C-Phenyl 2,3:5,6-di-O-isopropylidene-b-D-
mannofuranoside (3a)
(a) Under N2 atmosphere Et3SiH (0.58 mL, 419 mg, 3.6 mmol)
was added to a solution of 2a (1.01 g, 3.0 mmol) and BF3ꢀEt2O

168
E. Ravarino et al. / Carbohydrate Research 361 (2012) 162–169
azodicarboxylate (0.6 mL, 3.0 mmol) in THF (30 mL) was added
dropwise. The mixture was heated to reflux for 16 h, then it was
concentrated in vacuo and the residue was purified by flash column
chromatography (Ø = 5 cm, h = 15 cm, V = 60 mL, cyclohexane/
EtOAc = 9:1, Rf = 0.28) to give 3c as colorless oil (240 mg,
column chromatography (Ø = 2 cm, h = 15 cm, V = 10 mL, cyclohex-
ane/EtOAc = 9:1) to give 3d (Rf = 0.31) as a colorless oil (54 mg,
0.17 mmol, 30%) and 3b (Rf = 0.18) as a colorless oil (18 mg,
0.06 mmol, 10%). Analytical data of 3d: ½a D20
ꢂ
+16.5 (2.0; CH2Cl2);
1H NMR (CDCl3): d 1.34 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.46 (s, 3H,
CH3), 1.62 (s, 3H, CH3), 3.95 (dd, 8.3/7.1 Hz, 1H, 6-H), 4.06 (t,
J = 5.1 Hz, 1H, 4-H), 4.12 (dd, J = 8.3/6.8 Hz, 1H, 6-H), 4.34 (td,
J = 6.8/5.3 Hz, 1H, 5-H), 4.52 (dd, J = 7.0/5.1 Hz, 1H, 2-H), 4.63 (dd,
J = 7.0/5.0 Hz, 1H, 3-H), 4.88 (d, J = 5.0 Hz, 1H, 1-H), 7.28–7.41 (m,
5H, Harom.); 13C NMR (CDCl3): d 25.5 (1C, C(CH3)2), 25.6 (1C,
C(CH3)2), 26.6 (1C, C(CH3)2), 27.7 (1C, C(CH3)2), 65.5 (1C, C-6),
67.1 (1C, C-5), 81.7 (1C, C-3), 84.1 (1C, C-4), 85.8 (1C, C-1), 87.1
(1C, C-2), 110.0 (1C, C(CH3)2), 115.4 (1C, C(CH3)2), 126.0 (2C, C-
20phenyl, C-60phenyl), 128.0 (1C, C-40phenyl), 128.5 (2C, C-30phenyl, C-
0.75 mmol, 75%). ½a D20
ꢂ
+3.9 (1.4; CH2Cl2); 1H NMR (CDCl3): d 1.38
(s, 3H, CH3), 1.39 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.59 (s, 3H, CH3),
3.89 (dd, 7.6/3.7 Hz, 1H, 4-H), 4.17–4.24 (m, 2H, 6-H), 4.50 (ddd,
J = 10.8/6.1/4.7 Hz, 1H, 5-H), 4.76 (dd, J = 6.0/3.7 Hz, 1H, 3-H), 4.97
(dd, J = 6.0/1.0 Hz, 1H, 2-H), 5.20 (s, 1H, 1-H), 7.28-7.40 (m, 5H,
H
arom.); 13C NMR (CDCl3): d 24.9 (1C, C(CH3)2), 25.3 (1C, C(CH3)2),
26.3 (1C, C(CH3)2), 26.9 (1C, C(CH3)2), 67.0 (1C, C-6), 73.5 (1C, C-
5), 81.1 (1C, C-3), 81.4 (1C, C-4), 85.0 (1C, C-1), 87.5 (1C, C-2),
109.2 (1C, C(CH3)2), 112.8 (1C, C(CH3)2), 125.4 (2C, C-30phenyl
,
C-50phenyl), 127.5 (1C, C-40phenyl), 128.7 (2C, C-20phenyl, C-60phenyl),
50phenyl), 139.5 (1C, C-10phenyl); IR (neat): [cmꢁ1] = 2986, 2928,
m
1454, 1373, 1254, 1211, 1157, 1072, 853, 698; HRMS (m/z):
[M+H]+ calcd for C18H25O5, 321.1697; found, 321.1741; HPLC:
tR = 20.2 min, purity 95.2%.
138.4 (1C, C-10phenyl); IR (neat):
m
[cmꢁ1] = 2986, 2936, 2874,
1450, 1369, 1207, 1161, 1065, 845, 733, 698; HRMS (m/z): [M+H]+
calcd for C18H25O5, 321.1697; found, 321.1706; HPLC: tR = 20.5 min,
purity 98.1%.
4.2.12. C-Phenyl 2,3-O-isopropylidene-a-D-talofuranoside (4d)
4.2.10. C-Phenyl 2,3-O-isopropylidene-
(4c)
a
-
D
-mannofuranoside
p-Toluenesulfonic acid monohydrate (4 mg, 0.02 mmol) was
added to a solution of 3d (54 mg, 0.17 mmol) in methanol
(10 mL). The mixture was stirred at ambient temperature for 4 h.
Then a saturated aqueous solution of sodium bicarbonate was
added and the mixture was extracted with ethyl acetate (3ꢃ).
The combined organic layers were dried (Na2SO4), filtered, and
the solvent was removed in vacuo. The residue was purified by
flash column chromatography (Ø = 1 cm, h = 15 cm, V = 5 mL,
cyclohexane/ethyl acetate = 1/1, Rf = 0.22) to give 4d as colorless
p-Toluenesulfonic acid monohydrate (15 mg, 0.08 mmol) was
added to a solution of 3c (240 mg, 0.75 mmol) in methanol
(40 mL). The mixture was stirred at ambient temperature for 4 h.
Then a saturated aqueous solution of sodium bicarbonate was
added and the mixture was extracted with ethyl acetate (3ꢃ).
The combined organic layers were dried (Na2SO4), filtered, and
the solvent was removed in vacuo. The residue was purified by
flash column chromatography (Ø = 2 cm, h = 15 cm, V = 10 mL,
cyclohexane/ethyl acetate = 1/1, Rf = 0.20) to give 4c as colorless
oil (17 mg, 0.06 mmol, 36%). ½a D20
ꢂ
+9.8 (1.0; CH2Cl2); 1H NMR
(CDCl3): d 1.35 (s, 3H, CH3), 1.61 (s, 3H, CH3), 3.77–3.92 (m, 3H,
6-H, 5-H), 4.12 (dd, J = 4.6/3.5 Hz, 1H, 4-H), 4.55 (dd, J = 7.0/
5.3 Hz, 1H, 2-H), 4.83 (dd, J = 7.0/4.6 Hz, 1H, 3-H), 4.88 (d,
J = 5.3 Hz, 1H, 1-H), 7.28–7.41 (m, 5H, Harom.); 13C NMR (CDCl3): d
25.6 (1C, C(CH3)2), 27.7 (1C, C(CH3)2), 64.7 (1C, C-6), 71.4 (1C, C-
5), 81.9 (1C, C-3), 85.9 (1C, C-4), 86.2 (1C, C-1), 86.7 (1C, C-2),
115.4 (1C, C(CH3)2), 126.0 (2C, C-20phenyl, C-60phenyl), 128.3 (1C, C-
40phenyl), 128.8 (2C, C-30phenyl, C-50phenyl), 139.7 (1C, C-10phenyl); IR
oil (130 mg, 0.46 mmol, 62%). ½a D20
ꢂ
+20.1 (1.7; CH2Cl2); 1H NMR
(CDCl3): d 1.39 (s, 3H, CH3), 1.59 (s, 3H, CH3), 2.18–2.60 (s br, 2H,
OH), 3.86 (dd, J = 11.3/5.6 Hz, 1H, 6-H), 3.95 (dd, J = 11.3/3.5 Hz,
1H, 6-H), 3.98 (dd, J = 8.1/4.2 Hz, 1H, 4-H), 4.13 (ddd, J = 8.2/5.6/
3.5 Hz, 1H, 5-H), 4.84 (dd, J = 6.1/4.2 Hz, 1H, 3-H), 4.95 (dd,
J = 6.1/1.2 Hz, 1H, 2-H), 5.21 (s, 1H, 1-H), 7.27-7.39 (m, 5H, Harom.);
13C NMR (CDCl3): d 25.0 (1C, C(CH3)2), 26.4 (1C, C(CH3)2), 64.7 (1C,
C-6), 70.7 (1C, C-5), 80.5 (1C, C-4), 81.7 (1C, C-3), 84.9(1C, C-1),
87.4 (1C, C-2), 113.2 (1C, C(CH3)2), 125.6 (2C, C-20phenyl, C-60phenyl),
127.7 (1C, C-40phenyl), 128.8 (2C, C-30phenyl, C-50phenyl), 138.3 (1C, C-
(neat):
m
[cmꢁ1] = 3325, 2928, 1450, 1369, 1204, 1069, 1034, 856,
752, 698; HRMS (m/z): [M+H]+ calcd for C15H21O5, 281.1384;
found, 281.1395; HPLC: tR = 14.4 min, purity 95.1%.
10phenyl); IR (neat):
m
[cmꢁ1] = 3410, 2937, 1373, 1207, 1084, 1065,
887, 856, 733, 702; HRMS (m/z): [M+H]+ calcd for C15H21O5,
281.1384; found, 281.1428; HPLC: tR = 13.9 min, purity 96.2%.
4.2.13. (1S)-1-O-benzoyl-2,3:5,6-di-O-isopropylidene-1-C-
phenyl-D-mannitol (6)
Compound 5c (677 mg, 2.0 mmol) was dissolved in CH2Cl2
(50 mL) and the solution was cooled to 0 °C. Then N,N-diisopropyl-
ethylamine (0.4 mL, 310 mg, 2.4 mmol), 4-dimethylaminopyridine
(24 mg, 0.2 mmol), and benzoyl chloride (0.26 mL, 310 mg,
2.2 mmol) were added and the mixture was stirred at ambient tem-
perature for 16 h. Then a saturated aqueous solution of NaHCO3 was
added and the mixture was extracted with CH2Cl2 (3ꢃ). The com-
bined organic layers were dried (Na2SO4), filtered, and evaporated
in vacuo. The residue was purified by flash column chromatography
(Ø = 4 cm, h = 15 cm, V = 30 mL, cyclohexane/EtOAc = 8/2, Rf = 0.30)
to give 6 as a colorless solid (460 mg, 1.04 mmol, 52%). Mp: 156 °C;
4.2.11. C-Phenyl 2,3:5,6-di-O-isopropylidene-a-D-talofuranoside
(3d)
(a) Triphenylphosphine (160 mg, 0.6 mmol) was added to a
solution of 5d (100 mg, 0.3 mmol) in dry THF (40 mL), under N2
atmosphere. Then diisopropyl azodicarboxylate (0.12 mL,
0.6 mmol) was added at 0 °C and the reaction was heated to reflux.
After 2 h a solution of triphenylphosphine (240 mg, 0.9 mmol) and
diisopropyl azodicarboxylate (0.18 mL, 0.9 mmol) in THF (20 mL)
was added dropwise. The mixture was heated to reflux for 16 h,
then it was concentrated in vacuo and the residue was purified
by flash column chromatography (Ø = 3 cm, h = 15 cm, V = 20 mL,
cyclohexane/EtOAc = 9:1) to give 3d (Rf = 0.31) as colorless oil
(60 mg, 0.19 mmol, 63%) and 3b (Rf = 0.18) as a colorless oil
(17 mg, 0.05 mmol, 17%). (b) 5d (190 mg, 0.56 mmol) was dis-
solved in CH2Cl2 (30 mL) and the solution was cooled to 0 °C. Then
DIEA (0.46 mL, 2.8 mmol) and methanesulfonyl chloride (0.05 mL,
0.67 mmol) were added. The mixture was stirred at ambient tem-
perature for 16 h. Then a saturated aqueous solution of NaHCO3
was added and the mixture was extracted with CH2Cl2 (3ꢃ). The
combined organic phases were dried (Na2SO4), filtered, and the sol-
vent was removed in vacuo. The residue was purified by flash
½
a 2D0 +5.4 (1.8; CH2Cl2); 1H NMR (CDCl3): d 1.10 (s, 3H, CH3), 1.28 (s,
ꢂ
3H, CH3), 1.45 (s, 1H, CH3), 1.59 (s, 1H, CH3), 2.26 (d br, J = 7.6 Hz, 1H,
OH), 3.24–3.30 (m, 1H, 4-H), 3.88–3.95 (m, 2H, 5-H, 6-H (1H)),
3.99–4.04 (m, 1H, 6-H), 4.28 (dd, J = 7.1/2.0 Hz, 1H, 3-H), 4.90 (t,
J = 7.4 Hz, 1H, 2-H), 6.46 (d, J = 7.8 Hz, 1H, 1-H), 7.30–7.44 (m, 5H,
H
arom.), 7.51–7.58 (m, 3H, Harom.), 8.04–8.07 (m, 2H, Harom.); 13C
NMR (CDCl3): d 25.0 (1C, C(CH3)2), 25.6 (1C, C(CH3)2),26.7 (1C,
C(CH3)2), 26.8 (1C, C(CH3)2), 67.2 (1C, C-6), 70.1 (1C, C-4), 74.9
(1C, C-1), 75.9 (1C, C-3), 76.3 (1C, C-5), 78.5 (1C, C-2), 108.9 (1C,
C(CH3)2), 109.4 (1C, C(CH3)2), 128.4 (4C, Carom.), 128.9 (2C, Carom.),
129.1 (1C, Carom.), 129.9 (2C, Carom.), 130.6 (1C, Carom.), 133.0 (1C,

E. Ravarino et al. / Carbohydrate Research 361 (2012) 162–169
169
Carom.), 137.1 (1C, Carom.), 165.6 (1C, C=O); IR (neat):
m
(15 mL). The mixture was stirred at ambient temperature for 4 h.
Then water was added and the mixture was extracted with ethyl
acetate (3ꢃ). The combined organic layers were dried (Na2SO4), fil-
tered, and the solvent was removed in vacuo. The residue was puri-
fied by flash column chromatography (Ø = 1 cm, h = 15 cm,
V = 5 mL, cyclohexane/ethyl acetate = 1/1, Rf = 0.19) to give 4b as
[cmꢁ1] = 3568, 2986, 2936, 1705, 1450, 1373, 1273, 1211, 1111,
1069, 1053, 1026, 841, 706; MS (ESI): m/z = 465 (M+Na+, 100);
HPLC: tR = 21.3 min, purity 95.2%.
4.2.14. (1S)-1-O-benzoyl-2,3:5,6-di-O-isopropylidene-4-O-
methylsulfonyl-1-C-phenyl-D-mannitol (7)
colorless solid (35 mg, 0.12 mmol, 61%). Mp: 97 °C; ½a D20
ꢂ
+68.8
Compound 6 (330 mg, 0.75 mmol) and N,N-diisopropylethyl-
amine (0.25 mL, 194 mg, 1.5 mmol) were dissolved in CH2Cl2
(30 mL) and the solution was cooled to 0 °C. Then, methanesulfonyl
chloride (0.09 mL, 127 mg, 1.1 mmol) was added and the mixture
was stirred at ambient temperature for 16 h. Then a saturated
aqueous solution of NaHCO3 was added and the mixture was ex-
tracted with CH2Cl2 (3ꢃ). The combined organic layers were dried
(Na2SO4), filtered, and evaporated in vacuo. The residue was puri-
fied by flash column chromatography (Ø = 3 cm, h = 15 cm,
V = 20 mL, cyclohexane/EtOAc = 8/2, Rf = 0.32) to give 7 as colorless
(1.1; CH2Cl2); 1H NMR (CDCl3): d 1.29 (s, 3H, CH3), 1.45 (s, 3H,
CH3), 2.45 (s br, 1H, OH), 2.81 (s br, 1H, OH), 3.80–3.84 (m, 3H,
6-H, 5-H), 4.25–4.27 (m, 1H, 4-H), 4.87 (dd, J = 6.0/4.0 Hz, 1H, 2-
H), 4.94 (dd, J = 6.0/1.3 Hz, 1H, 3-H), 5.17 (d, J = 4.0 Hz, 1H, 1-H),
7.28–7.40 (m, 5H, Harom.); 13C NMR (CDCl3): d 24.8 (1C, C(CH3)2),
26.3 (1C, C(CH3)2), 64.2 (1C, C-6), 71.8 (1C, C-5), 82.9 (1C, C-2),
83.5 (1C, C-3), 84.4 (1C, C-1), 85.3 (1C, C-4), 112.9 (1C, C(CH3)2),
127.6 (2C, C-20phenyl, C-60phenyl), 128.0 (2C, C-30phenyl, C-50phenyl),
128.1 (1C, C-40phenyl), 136.3 (1C, C-10phenyl); IR (neat):
m
[cmꢁ1] = 3283, 2936, 1454, 1373, 1207, 1069, 868, 698; HRMS
(m/z): [M+H]+ calcd for C15H21O5, 281.1384; found, 281.1387;
HPLC: tR = 12.7 min, purity 97.0%.
solid (330 mg, 0.63 mmol, 85%). Mp: 69 °C; ½a D20
ꢁ22.1 (0.7;
ꢂ
CH2Cl2); 1H NMR (CDCl3): d 1.15 (s, 3H, CH3), 1.30 (s, 3H, CH3),
1.55 (s, 1H, CH3), 1.61 (s, 1H, CH3), 3.24 (s, 3H, OSO2CH3), 4.04–
4.17 (m, 3H, 5-H, 6-H), 4.28 (dd, J = 6.1/3.8 Hz, 1H, 3-H), 4.71 (dd,
J = 6.5/3.8 Hz, 1H, 4-H), 4.85 (dd, J = 7.5/6.1 Hz, 1H, 2-H), 6.57 (d,
J = 7.5 Hz, 1H, 1-H), 7.33–7.46 (m, 5H, Harom.), 7.53–7.58 (m, 1H,
References
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C
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m
[cmꢁ1] =2986, 2936, 1717, 1454,
1335, 1265, 1215, 1172, 1064, 949, 891, 710; MS (ESI): m/z = 543
(M+Na+, 100); HPLC: tR = 22.4 min, purity 96.1%.
4.2.15. C-Phenyl 2,3:5,6-di-O-isopropylidene-b-D-talofuranoside
(3b)
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+45.3
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CH3), 1.44 (s, 3H, CH3), 1.45 (s, 3H, CH3), 3.98 (t, J = 8.2 Hz, 1H,
6-H), 4.06 (dd, J = 8.0/6.5 Hz, 1H, 6-H), 4.21 (dd, J = 3.0/1.2 Hz, 1H,
H-4), 4.27 (ddd, J = 9.4/6.4/3.1 Hz, 1H, 5-H), 4.88 (dd, J = 6.0/
4.1 Hz, 1H, 2-H), 4.94 (dd, J = 5.9/1.2 Hz, 1H, 3-H), 5.28 (d,
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24.8 (1C, C(CH3)2), 25.7 (1C, C(CH3)2), 26.3 (1C, C(CH3)2), 26.3 (1C,
C(CH3)2), 65.9 (1C, C-6), 77.6 (1C, C-5), 82.7 (1C, C-4), 83.0 (1C, C-
2), 84.0 (1C, C-3a C-3), 85.0 (1C, C-6 C-1), 109.8 (1C, C(CH3)2),
112.9 (1C, C(CH3)2), 127.7 (2C, C-30phenyl, C-50phenyl), 127.9 (1C, C-
40phenyl), 128.0 (2C, C-20phenyl, C-60phenyl), 136.8 (1C, C-10phenyl); IR
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(neat):
1076, 1053, 968, 895, 856,702; HRMS (m/z): [M+H]+ calcd for
18H25O5, 321.1697; found, 321.1675; HPLC: tR = 19.3 min, purity
m
[cmꢁ1] = 2986, 2916, 1748, 1454, 1377, 1204, 1157,
C
98.2%.
4.2.16. C-Phenyl 2,3-O-isopropylidene-b-D-talofuranoside (4b)
p-Toluenesulfonic acid monohydrate (4 mg, 0.02 mmol) was
added to a solution of 3b (66 mg, 0.21 mmol) in methanol
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