Carbene-Mediated Quaternarization of the Anomeric Position of Carbohydrates: Synthesis of Allylic Ketopyranosides, Access to the Missing α-Gluco and β-Manno Stereoisomers, and Preparation of Quaternary 2-Deoxy 2-Acetamido Sugars

Article abstract of DOI:10.1021/acs.joc.7b01493

Following our work on the C-H functionalization of carbohydrates by the 1,5 insertion of metal-carbenes, we report herein the robust and scalable conversion of sugar γ-lactones into highly valuable glycosides having a quaternary anomeric position substituted by an allyl chain ready for further functionalization. A divergent synthetic approach furthermore provided a straightforward access to ketopyranosides with a large chemo- and stereodiversity at position 2.

Full text of DOI:10.1021/acs.joc.7b01493

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Article
Carbene-Mediated Quaternarization of the Anomeric Position
of Carbohydrates: Synthesis of Allylic Ketopyranosides,
Access to the Missing #-Gluco and #-Manno Stereoisomers,
and Preparation of Quaternary 2-Deoxy-2-Acetamido Sugars
Kévin Mébarki, Marine Gavel, Floriane Heis, Antoine Yvan Philippe Joosten, and Thomas Lecourt
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01493 • Publication Date (Web): 09 Aug 2017
Downloaded from http://pubs.acs.org on August 9, 2017
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Carbene-Mediated Quaternarization of the Anomeric Position of
Carbohydrates: Synthesis of Allylic Ketopyranosides, Access to
7
8
9
the Missing
α-Gluco and β-Manno Stereoisomers, and Preparation
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of Quaternary 2-Deoxy-2-Acetamido Sugars
Kévin Mébarki, Marine Gavel, Floriane Heis, Antoine Yvan Philippe Joosten, and Thomas
Lecourt*
Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA UMR 6014, 76000 Rouen,
France.
Graphical Abstract:
OP6
OMe
O
P4O
OH
OP3
OP6
OP6
β-manno
α-gluco
OMe
OMe
O
O
O
O
OP6
P4O
P4O
OH
OMe
O
OP3
OP3
α-manno
β-gluco
α-manno
β-gluco
P4O
NHAc
OP3
2-deoxy 2-acetamido
ketopyranosides
Abstract:
Following our work on the C-H functionalization of carbohydrates by 1,5 insertion of
metal-carbenes, we report herein the robust and scalable conversion of sugar γ-lactones
into highly valuable glycosides having a quaternary anomeric position substituted by an
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allyl chain ready for further functionalization. A divergent synthetic approach
furthermore provided a straightforward access to ketopyranosides with a large chemo-
and stereodiversity at position 2.
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Introduction:
The field of glycobiology has made significant progress in recent years, in particular as a
result of the emergence of new synthetic tools in carbohydrate chemistry. Efficient and
innovative synthetic methods have contributed to a better understanding of the role
played by complex oligosaccharides in numerous biological events, and paved the way
to the new era of chemical glycobiology.1 In this context, we recently reported a new
approach toward ketopyranosides, in which quaternarization of the anomeric position
was performed in a late stage of the synthetic process.2 After glycosylation with
anchimeric assistance of a 2-O-bromoacetyl, functionalization of the anomeric C-H bond
with retention of configuration was promoted by 1,5 insertion of a Rh(II)-carbene.3
Apart from allowing a more efficient access to ketopyranosides having an axial aglycone,
this strategy also opened the way to the unprecedented β-anomers (Scheme 1).
Although critical to ensure a clean C-H functionalization process, anchoring the metal-
carbene at position 2 also had some limitations. First, only ketopyranosides in the
α-
manno, -gluco and -galacto series could be obtained because insertion into the
β
β
anomeric C-H bond took place after formation of a 1,2-trans glycosidic linkage.
Moreover, 2-deoxy-2-amino sugars with a quaternary anomeric position, which are
highly desirable since GlcNAc, GalNAc and ManNAc are major components of
glycoconjugates,4,5 could not be prepared by direct functionalization of the anomeric C-H
bond of 2-deoxy 2-amino sugars. In fact, only complex mixtures were obtained, if an
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amide tether between the metal-carbene and the sugar moiety replaced the ester
linkage.6
3
4
5
6
7
8
9
OP6
O
OP6
O
OP6
O
P4O
P3O
P4O
P3O
Accessible:
P4O
P3O
O
SPh
O
β
β
-gluco
O
O
O
H
H
10
11
12
13
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15
16
17
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O
-galacto
O
cis
Br
N2
α
-manno
1)
OH
Rh2L4
O
Ester
Linker
2) TsNHNHTs
Br
Not Accessible:
O
O
N2
O
P6O
P4O
P3O
P6O
α
α
-galacto
-gluco
P6O
P4O
P3O
O
O
O
P4O
O
O
cis
O
H
H
P3O
β
-manno
SPh
O
O
GlcNAc
ManNAc
Stereoselective
Glycosylation
Stereospecific
C-H Functionalization
Scheme 1. Carbene-Mediated Quaternarization of the Anomeric Position: Scope and
Limitations
The design of new chemical tools for glycobiology with a ketopyranosidic central core
would require a straightforward and robust access toward compounds covering a larger
chemical space than the
α
-manno,
β
-gluco and
β
-galacto series. In this context, we would
-manno and -gluco γ-lactones into
like to report herein transformation of
α
β
ketopyranosides bearing an allyl pending chain, and the efficient chemical and
stereochemical diversification at position 2 following a diversity-oriented approach.
Results and Discussion:
Sugar lactones 1 (Scheme 2) and 2 (Scheme 3) with a tert-butyldimethylsilyl ether
protecting group at position 3 were routinely prepared on gram scale by decomposition
of diazo sugars under Rh2(OAc)4 catalysis in refluxing 1,2 dichloroethane.7 Since partial
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reduction of 1 with DIBAL-H in DCM at -78 °C and Wittig olefination gave a mixture of
C,O-glycosides 3 and 4 by migration of the tert-butyldimethylsilyl group (Scheme 2),
switching toward a robust benzyl ether was thus considered. Although deprotection of
lactone 1 with TBAF resulted in massive degradation, HF/Pyridine gave alcohol 5 in
89% yield after purification by silica gel flash chromatography.
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7
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O
OR2
O
O
O
Ph
O
1) DIBAL-H
Ph
O
O
O
R3O
R3O
OMe
2) Ph3P=CH2
OMe
86%
HF
89%
1
5
R3=TBS
R3=H
3
R2=H, R3=TBS
R2=TBS, R3=H
4
Table 1
O
OH
O
O
Ph
O
O
BnO
1) DIBAL-H
Ph
O
O
O
BnO
OMe
85%
2) Ph3P=CH2
OMe
6
7
Scheme 2. Preparation of ketopyranoside 7 in the α-manno series.
Not surprisingly, benzylation under Williamson’s conditions induced degradation of
lactone 5.8 Benzyl 2,2,2-trichloroacetimidate (BnTCA)9 gave 6 in moderate yield and low
purity because Lewis or Brønsted acid activation induced competitive cleavage of the
4,6-O-benzylidene function (Table 1, entries 1-3). Benzylation of 5 was next attempted
with 2-benzyloxy-1-methylpyridinium triflate (BnPYR) and MgO.10 Even if conversion
remained partial, pure lactone 6 was obtained in 66% yield after prolonged heating in
trifluorotoluene (entries 4 and 5). Under microwave irradiation,11 the reaction time was
reduced to 9 h, and the yield improved to 74%, without affecting the purity of 6 (entry
6). Finally, clean and full conversion of 5 was achieved with benzyl bromide (BnBr) and
silver(I) oxide (Ag2O) in refluxing dichloromethane to give pure 3-O-benzyl lactone 6 in
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88% isolated yield after silica gel flash chromatography (entries 7 and 8).12 Partial
reduction of 6 with DIBAL-H at -78 °C in DCM and Wittig olefination gave α-
ketopyranoside 7 having a complete set of orthogonal protecting groups in 85% yield
over two steps (Scheme 2).
10
11
12
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Table 1. Benzylation at position 3 in the
α
-manno series.
O
O
O
O
O
O
Ph
O
Ph
O
O
O
HO
BnO
OMe
OMe
5
6
Entry
Reagent
(equiv.)
Additive
(equiv.)
Temp. Time
Conv.
(%)a
Yield
(%)b
(°C)
0
(h.)
1
1c
2c
BnTCA (3)
BnTCA (3)
BnTCA (3)
BnPYR (2)
BnPYR (2)
BnPYR (2)
BnBr (1.2)
BnBr (3)
TfOH (0.2)
70
100
50
74
80
80
0
57
31
12
66
64
74
-
TMSOTf (0.2)
BF3.OEt2 (0.2)
MgO (2)
0
1.5
1.5
48
48
10
4
3c
0
4d
5d
6d,e
7c
85
100
80
R.T.
40
MgO (2)
MgO (2)
Ag2O (1.2)
Ag2O (2.4)
8c
4
100
88
a: evaluated by 1H NMR analysis of the crude; b: isolated after flash chromatography
c: CH2Cl2 as solvent; d: trifluorotoluene as solvent; e: microwave irradiation.
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3
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7
The same sequence was next performed in the
β
-gluco series. Desilylation of 2 with
8
9
HF/pyridine followed by benzylation either with BnPYR/MgO or BnBr/Ag2O gave
lactone 9 with a 3-O-benzyl ether in 57 and 90% yield respectively over two steps. After
partial reduction with DIBAL-H and olefination, β-ketopyranoside 10 was finally
10
11
12
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obtained in 84% yield (Scheme 3).
BnPYR
MgO
Ph
O
Ph
O
O
O
O
O
Ph
O
O
O
1) DIBAL-H
OMe
O
OMe
O
R3O
BnO
60%
OMe
BnO
HO
or BnBr
Ag2O
2) Ph3P=CH2
O
O
HF
2
8
R3=TBS
R3=OH
95%
9
10 84%
95%
Scheme 3. Preparation of ketopyranoside 10 in the β-gluco series.
Having developed a robust and scalable access to
α-manno and
β
-gluco C,O-glycosides 7
and 10, ketopyranosides 15 and 16 in the -gluco and β-manno series, as well as 2-
α
deoxy 2-acetamido sugars with a quaternary anomeric position 17-20, were next
prepared following a diversity-oriented approach (scheme 4). To our surprise, oxidation
of 7 under Swern conditions gave a complex mixture from which 1,6-anhydro derivative
13, resulting from cleavage of the glycosidic bond, was identified. Methyl 2-ulosides 11
and 12 were finally prepared in 64 and 65% yield respectively by oxidation of 7 and 10
with Dess-Martin Periodinane (DMP). It is worth of note that pyridine should be used as
a cosolvant,13 and the amount of DMP carefully controlled, in order to prevent formation
of 14, presumably obtained by radical hydrogen abstraction at position 3 followed by β-
fragmentation of the benzyl ether.
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O
Ph
O
OBn
O
O
OMe
O
OH
HO
O
OH
6
13
14
7
8
9
Reduction of 11 and 12 into the missing
α-gluco and β-manno ketopyranosides 15 and
10
11
12
13
14
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16 was next investigated with NaBH4, DIBAL-H and L-Selectride.14
Ph
O
Ph
O
O
O
O
O
DMP
64%
BnO
BnO
7
HO
OMe
OMe
OMe
O
Table 2
11
15
OH
O
Ph
O
O
Ph
O
O
O
DMP
OMe
BnO
BnO
10
O
65%
Table 2
12
16
Scheme 4. Preparation and reduction of methyl 2-ulosides 11 and 12.
From methyl α-uloside 11, ketopyranoside 15 in the α-gluco series was obtained as the
major diastereoisomer with NaBH4 or DIBAL-H, (table 2, entries 1 and 2), whereas L-
Selectride mainly gave back the quaternary mannoside 7. Similarly to previous reports
from the literature,15 reduction of 11 by NaBH4 mainly occurred by axial attack of the
hydride, thus showing that the quaternary anomeric centre had little influence on the
stereochemical outcome of the reaction. However, reduction of uloside 12 with NaBH4
did not yield β−mannoside 16 as expected,16 but rather a 1:1 mixture of epimers. The
quaternary anomeric centre, in addition to the cyclic 4,6-O-benzylidene,17 thus had a
dramatic impact on the stereochemical outcome of the reduction in the
β series. The
desired methyl β-ketopyranoside 16 in the manno series was finally obtained with
complete stereocontrol by reduction with L-selectride.18
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Table 2. Reduction of ulosides 11 and 12.
3
4
5
6
7
8
9
Alcohols Yield
Entry 2-uloside
Reagent
NaBH4
10
11
12
13
14
15
16
17
18
19
20
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59
60
(d.r.)a
(%)b
7/15
1
2
3
4
5
6
11
11
11
12
12
12
91
(3:7)
7/15
DIBAL-H
L-Selectride
NaBH4
51
56
60
51
61
(1:3)
7/15
(4:1)
10/16
(1:1)
10/16
DIBAL-H
L-Selectride
(7:1)
10/16
(0:1)
a: evaluated by 1H NMR analysis of the crude; b: isolated after flash chromatography.
With suitable conditions for accessing the missing α-gluco and β-manno series in hands,
we next turned our attention toward the preparation of quaternary 2-deoxy 2-
acetamido sugars from methyl 2-ulosides 11 and 12 (scheme 5). Since classical
approaches relying on substitution of 2-O-sulfonates with azides,19 or on formation of
oximes followed by reductive cleavage of the N-O bond,20 all failed despite extensive
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efforts, direct reductive amination of 11 and 12 with NH4OAc and NaBH3CN was thus
considered.21 Under microwave irradiation,22 amination was performed at 80 °C without
degradation of the starting materials, but competitive reduction of 11 and 12 into
alcohols 7/15 and 10/16 gave a complex mixture. By delaying introduction of the
reducing agent after 10 min heating with NH4OAc alone, the desired 2-deoxy 2-
acetamido sugars 17-20 were finally obtained in good yield after acetylation.
Configuration of 17-20 was determined on the basis of vicinal coupling constants
between H2 and H3 (J = 4.5 Hz for 18 in the manno series, and J = 9.2 Hz for 19 with a
gluco configuration).
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
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1) NH4OAc
NaBH3CN
NHAc
O
Ph
O
Ph
O
O
O
O
+
BnO
BnO
11
AcHN
OMe
2) Ac2O
Pyridine
OMe
17 38 %
18 33 %
NHAc
O
1) NH4OAc
NaBH3CN
12
Ph
O
O
Ph
OMe
O
O
O
OMe
BnO
BnO
+
AcHN
2) Ac2O
Pyridine
19 32 %
20 29 %
Scheme 5. Preparation of 2-deoxy 2-acetamido ketopyranosides 17-20.
Overall, we reported herein the preparation of eight non-natural sugars derivatives with
a quaternary anomeric position substituted by an allyl pending chain. From lactones 1
and 2, a robust and scalable synthetic sequence first gave α-manno and β-gluco
ketopyranosides 7 and 10 in 67 and 76% yield respectively over 4 steps. After oxidation
into key ulosides 11 and 12, a diversity-oriented approach provided a straightforward
access to ketopyranosides 15 and 16 in the missing α-gluco and β-manno series, as well
as to the four stereoisomers 17-20 of unprecedented quaternary 2-deoxy 2-acetamido
sugars. Having in hands a large diversity of non-natural carbohydrate derivatives having
a quaternary anomeric position substituted by an allyl chain ready for further
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functionalization, new chemical tools for glycobiology are currently under preparation
in our laboratory.
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Experimental Section
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11
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General Information and Method. For reactions, solvents were purchased anhydrous
(dichloromethane,
and
pyridine)
or
distilled
(tetrahydrofuran
over
sodium/benzophenone). All reactions were conducted under an argon atmosphere. All
reagents were used as received unless otherwise indicated. Reactions were monitored
by thin-layer chromatography with silica gel 60 F254 pre-coated aluminium plate (0.25
mm). Visualization was performed under UV light and phosphomolybdic acid oxidation.
1H NMR spectra were recorded at 300 MHz, and 13C NMR spectra at 75 MHz.
Abbreviations used for peak multiplicities are s: singlet, d: doublet, t: triplet, q:
quadruplet and m: multiplet. Coupling constants J are in Hz and chemical shifts are given
in ppm and calibrated with CDCl3 (residual solvent signals). Carbon multiplicities were
assigned by distortionless enhancement by polarization transfer (DEPT) experiments.
1
The H and 13C signals were assigned by COSY and HSQC experiments. Accurate mass
measurements (HRMS) were performed with a Q-TOF analyser. Infrared spectra (IR)
were recorded by application on a Single Reflection Attenuated Total Reflectance (ATR)
Accessories, and data are reported in cm-1. Optical rotations were determined with a
water-jacketed 10 cm cell. Specific rotations are reported in 10-1 deg cm2 g-1 and
concentrations in g per 100 mL. Melting points are uncorrected. Microwave experiments
were conducted in a Biotage Initiator equipped with a monomode cavity with a
microwave power delivery system ranging from 0 to 850 W allowing pressurized
reactions (0 to 30 bars) to be carried out in sealed glass vials (0.5 to 20 mL) equipped
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with a snap cap and a silicon septum. The temperature (0 to 300 °C) was monitored via a
contact-less infrared sensor and was calibrated with a Ruby Thermometer.
3
4
5
6
7
8
9
(2R,4aR,5aS,8aS,9S,9aS)-9-hydroxy-5a-methoxy-2-
10
11
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phenylhexahydrofuro[2',3':5,6]pyrano[3,2-d][1,3]dioxin-7(8aH)-one 5. To
a
solution of lactone 1 (1.456 g, 3.334 mmol) in THF (50 mL), was added a solution of
HF.pyridine (dry THF/dry pyridine/HF.pyridine, 2:2:1, 65.5 mL, 333 mmol) at room
temperature. After 18 h, ethyl acetate (150 mL) and a saturated solution of NaHCO3 (600
mL) were carefully added. After 30 min, the organic layer was separated and the
aqueous layer was extracted with ethyl acetate (3 x 150 mL). The combined organic
layers were dried (MgSO4), filtrated, and concentrated under reduce pressure.
Purification by silica gel chromatography (cyclohexane/ethyl acetate 1.5:1) gave 5 as a
white foam (946 mg, 89%):
1
Rf = 0.22 (Silica, cyclohexane/ethyl acetate 3:1); H NMR (300 MHz, CDCl3): δ (ppm)
7.57-7.26 (m, 5H, HAr), 5.56 (s, 1H, H7), 4.61 (d, J = 4.2 Hz, 1H, H2), 4.28-4.24 (m, 1H, H6),
4.09 (dd, J = 9.3, 4.2 Hz, 1H, H3), 3.86-3.70 (m, 3H, H4, H5, H6), 3.37 (s, 3H, OMe), 2.82
(d, J = 16.3 Hz, 1H, CH2-C=O), 2.61 (d, J = 16.3 Hz, 1H, CH2-C=O), 2.50 (br s, 1H, OH); 13C
NMR (75 MHz, CDCl3): δ (ppm) 171.4 (C=0), 136.9 (CqAr), 129.4 (CAr), 128.4 (CAr), 126.3
(CAr), 103.5 (C1), 102.1 (C7), 81.0 (C2), 77.6 (C4), 68.1 (C6), 67.7 (C3), 64.3 (C5), 51.9
(OMe), 40.4 (CH2-C=O); FT-IR (film): 3467, 2922, 2859, 1778, 1455, 1393, 1300, 1254,
1226, 1165, 1191, 1088, 1025, 999, 954, 917, 774, 702, 670, 568, 535 cm-1; HRMS (ESI):
m/z Calcd for C16H22NO7 [M + NH4]+ 340.1396, found 340.1395; [α]D20 = - 58 (CHCl3, c =
1.85).
(2R,4aR,5aR,8aR,9S,9aS)-9-hydroxy-5a-methoxy-2-
phenylhexahydrofuro[2',3':5,6]pyrano[3,2-d][1,3]dioxin-7(8aH)-one 8. To
a
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solution of lactone 2 (800 mg, 1.83 mmol) in THF (30 mL), was added a solution of
HF.pyridine (dry THF/dry pyridine/HF.pyridine, 2:2:1, 21 mL, 183 mmol) at room
temperature. After 18 h, ethyl acetate (100 mL) and a saturated solution of NaHCO3
(400 mL) were carefully added. After 30 min, the organic layer was separated and the
aqueous layer was extracted with ethyl acetate (3 x 150 mL). The combined organic
layers were dried (MgSO4), filtrated, and concentrated under reduce pressure.
Purification by silica gel chromatography (cyclohexane / ethyl acetate 1.5:1) gave 8 as a
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white foam (560 mg, 95%). Rf = 0.38 (Silica, dichloromethane/ethyl acetate 15:1); H
NMR (300 MHz, CDCl3): δ (ppm) 7.50-7.38 (m, 5H, HAr), 5.57 (s, 1H, H7), 4.43 (d, J = 6.4
Hz, 1H, H2), 4.35 (dd, J = 10.0, 4.9 Hz, 1H, H6), 3.91 (dd, J = 10.2, 6.4 Hz, 1H, H3), 3.78-
3.73 (m, 2H, H6, H4), 3.62 (ddd, J = 10.0, 9.1, 4.9 Hz, 1H, H5), 3.38 (s, 3H, OMe), 2.93 (br
s, 1H, OH), 2.82 (d, J = 17.1 Hz, 1H, CH2-C=O), 2.67 (d, J = 17.1 Hz, 1H, CH2-C=O);13C NMR
(75 MHz, CDCl3): δ (ppm) 172.0 (C=O), 136.7 (CqAr), 129.6 (CAr), 128.6 (CAr), 126.4 (CAr),
103.8 (C1), 102.0 (C7), 83.4 (C2), 78.1 (C4), 72.8 (C3), 68.7 (C6), 66.0 (C5), 50.4 (OMe),
35.9 (CH2-C=O); FT-IR (film): 3454, 2922, 2857, 1788, 1456, 1380, 1212, 1167, 1079,
1007, 918, 835, 754, 699, 542 cm-1; HRMS (ESI): m/z Calcd for C16H22NO7 [M + NH4]+
340.1396, found 340.1396; [α]D20 = + 3 (CHCl3, c = 1.0).
(2R,4aR,5aS,8aS,9S,9aR)-9-(benzyloxy)-5a-methoxy-2-
phenylhexahydrofuro[2',3':5,6]pyrano[3,2-d][1,3]dioxin-7(8aH)-one 6. Procedure
A: A suspension of alcohol 5 (100 mg, 0.310 mmol), MgO (25 mg, 0.620 mmol) and 2-
benzyloxy-methylpyridinium triflate (217 mg, 0.620 mmol) in trifluorotoluene (0.6 mL)
under an argon atmosphere was heated under microwave irradiation at 85 °C. After 10
h, dichloromethane (3 mL) and a saturated solution of NaHCO3 (3 mL) were added, and
the mixture was stirred until it became homogenous. After separation, the aqueous layer
was extracted with dichloromethane, the combined organic phases were dried (MgSO4),
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filtered, and concentrated under reduce pressure. After purification by silica gel
chromatography (cyclohexane/ethyl acetate 3:1), 6 was obtained as a colourless oil (85
mg, 66%). Procedure B: A suspension of 5 (300 mg, 0.93 mmol), Ag2O (646.5 mg, 2.79
mmol) and benzyl bromide (265 ꢀL, 2.23 mmol) in dichloromethane (2.1 mL) under an
argon atmosphere was heated at 40 °C in a sealed tube (dark). After 4h30, the reaction
mixture was diluted with dichloromethane (20 mL), filtered through a Celite pad, and
added with a saturated solution of NaHCO3 (20 mL). After separation of the organic
layer, the aqueous layer was extracted with dichloromethane (2 x 20 mL). The combined
organic layers were dried (MgSO4), filtered and concentrated under reduce pressure.
After purification by silica gel chromatography (cyclohexane/ethyl acetate 2:1) 6 was
obtained as a colourless oil (340 mg, 88%).
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Rf = 0.28 (Silica, cyclohexane/ethyl acetate 3:1); H NMR (300 MHz, CDCl3): δ (ppm)
7.53-7.25 (m, 10H, HAr), 5.61 (s, 1H, H7), 4.88 (d, J = 12.3 Hz, 1H, O-CH2-Ph), 4.78 (d, J =
12.3 Hz, 1H, O-CH2-Ph), 4.58 (d, J = 3.6 Hz, 1H, H2), 4.28 (dd, J = 9.8, 3.6 Hz, 1H, H6), 4.06
(t, J = 9.5 Hz, 1H, H4), 3.99 (dd, J = 9.5, 3.6 Hz, 1H, H3), 3.77 (t, J = 9.8 Hz, 1H, H6), 3.76-
3.74 (m, 1H, H5), 3.30 (s, 3H, OMe), 2.80 (d, J = 16.5 Hz, 1H, CH2-C=O), 2.66 (d, J = 16.5
Hz, 1H, CH2-C=O); 13C NMR (75 MHz, CDCl3): δ (ppm) 171.6 (C=O), 137.8 (CqAr), 137.2
(CqAr), 129.2 (CAr), 128.5 (CAr), 128.4 (CAr), 127.9 (CAr), 126.1 (CAr), 103.7 (C1), 101.6
(C7), 80.1 (C2), 77.6 (C4), 73.2 (C3), 73.1 (O-CH2-Ph), 68.3 (C6), 64.6 (C5), 51.9 (OMe),
40.3 (CH2-C=O); FT-IR (film): 2933, 2871, 1797, 1493, 1454, 1377, 1302, 1282, 1217,
1177, 1155, 1096, 1077, 1004, 962, 750, 698 cm-1; HRMS (ESI): m/z Calcd for C23H25O7
[M + H]+ 413.1600, found 413.1613; [α]D20 = - 40 (CHCl3, c = 1.0).
(2R,4aR,5aR,8aR,9S,9aR)-9-(benzyloxy)-5a-methoxy-2-
phenylhexahydrofuro[2',3':5,6]pyrano[3,2-d][1,3]dioxin-7(8aH)-one 9. Procedure
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A: A suspension of alcohol 8 (100 mg, 0.310 mmol), MgO (25 mg, 0.620 mmol) and 2-
benzyloxy-methylpyridinium triflate (217 mg, 0.620 mmol) in trifluorotoluene (0.6 mL)
under an argon atmosphere was heated under microwave irradiation at 85 °C. After 10
h, dichloromethane (3 mL) and a saturated solution of NaHCO3 (3 mL) were added, and
the mixture was stirred until it became homogenous. After separation, the aqueous layer
was extracted with dichloromethane, the combined organic phases were dried (MgSO4),
filtered, and concentrated under reduce pressure. After purification by silica gel
chromatography (cyclohexane/ethyl acetate 3:1), 9 was obtained as a colourless oil (77
mg, 60%). Procedure B: A suspension of 8 (300 mg, 0.93 mmol), Ag2O (646.5 mg, 2.79
mmol) and benzyl bromide (265 ꢀL, 2.23 mmol) in dichloromethane (2.1 mL) under an
argon atmosphere was heated at 40 °C in a sealed tube (dark). After 3h30, the reaction
mixture was diluted with dichloromethane (20 mL), filtered through a Celite pad, and
added with a saturated solution of NaHCO3 (20 mL). After separation, the aqueous layer
was extracted with dichloromethane (2 x 20 mL), and the combined organic layers were
dried (MgSO4), filtered and concentrated under reduce pressure. After purification by
silica gel chromatography (cyclohexane/ethyl acetate 2:1) 9 was obtained as a
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colourless oil (365 mg, 95%). Rf = 0.34 (Silica, cyclohexane/ethyl acetate 3:1); H NMR
(300 MHz, CDCl3): δ (ppm) 7.52-7.31 (m, 10H, HAr), 5.63 (s, 1H, H7), 4.85 (s, 2H, O-CH2-
Ph), 4.54 (d, J = 5.6 Hz, 1H, H2), 4.34 (dd, J = 10.3, 4.8 Hz, 1H, H6), 3.99 (t, J = 9.7 Hz, 1H,
H4), 3.87-3.74 (m, 2H, H3, H6), 3.67 (dt, J = 9.7, 4.8 Hz, 1H, H5), 3.40 (s, 3H, OMe), 2.86
(d, J = 17.2 Hz, 1H, CH2-C=O), 2.69 (d, J = 17.2 Hz, 1H, CH2-C=O); 13C NMR (75 MHz,
CDCl3): δ (ppm) 171.6 (C=O), 137.4 (CqAr), 136.9 (CqAr), 129.2 (CAr), 128.5 (CAr), 128.4
(CAr), 128.0 (CAr), 126.1 (CAr), 103.9 (C1), 101.6 (C7), 83.9 (C2), 78.8 (C3), 78.2 (C4), 73.7
(O-CH2-Ph), 68.9 (C6), 66.4 (C5), 50.7 (OMe), 36.8 (CH2-C=O); FT-IR (film): 2933, 1793,
1605, 1497, 1454, 1372, 1331, 1268, 1245, 1213, 1170, 1091, 1028, 916, 890, 752, 698,
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601 cm-1; HRMS (ESI): m/z Calcd for C23H24O7Na [M + Na]+ 435.1420, found 435.1415;
[α]D20 = + 5 (CHCl3, c = 1.0).
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(2R,4aR,6S,7S,8R,8aR)-6-allyl-8-(benzyloxy)-6-methoxy-2-
9
phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol 7. To a solution of 6 (520 mg, 1.26
mmol) in CH2Cl2 (10 mL) at -78 °C was added drop-wise a 1 M solution of DIBAL-H in
hexanes (1.388 mL, 1.388 mmol). After 15 min at -78 °C, the mixture was quenched with
methanol, and added with CH2Cl2 (20 mL) and Rochelle salts (1 M, 20 mL). After 12 h of
vigorous stirring at room temperature, the organic layer was separated, and the aqueous
layer was extracted with dichloromethane (3 x 15 mL). The combined organic layers
were dried (MgSO4), filtered and concentrated under reduce pressure. Filtration over a
silica plug delivered the lactol as a mixture of diastereoisomers. A suspension of
methyltriphenylphosphonium bromide (678 mg, 1.89 mmol) in THF (8 mL) at 0 °C was
added with potassium tert-butoxide (213 mg, 1.89 mmol) and a solution of lactol in THF
(2 mL). After 15 min stirring at room temperature, CH2Cl2 (25 mL) and water (15 mL)
were added. After separation, the aqueous layer was extracted with dichloromethane (3
x 25 mL), and the combined organic layers were dried (MgSO4), filtered and
concentrated under reduce pressure. Purification by silica gel chromatography
(dichloromethane/ethyl acetate from 100:0 to 90:10) gave 7 as a colorless oil (442 mg,
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85% over 2 steps). Rf = 0.53 (silica, cyclohexane / ethyl acetate 2.5:1); H NMR (300
MHz, CDCl3): δ (ppm) 7.54-7.29 (m, 10H, HAr), 5.77 (dddd, J = 17.1, 10.3, 7.3, 6.7 Hz, 1H,
CH2-CH=CH2), 5.63 (s, 1H, H7), 5.28-5.18 (m, 2H, CH2-CH=CH2), 4.86 (d, J = 11.9 Hz, 1H,
O-CH2-Ph), 4.74 (d, J = 11.9 Hz, 1H, O-CH2-Ph), 4.30 (dd, J = 10.4, 4.8 Hz, 1H, H6), 4.11 (t, J
= 9.1 Hz, 1H, H4), 4.04-3.99 (m, 2H, H2, H3), 3.88 (t, J = 10.4 Hz, 1H, H6), 3.70 (ddd, J =
10.4, 9.1, 4.8 Hz, 1H, H5), 3.27 (s, 3H, OMe), 2.73 (m, 2H, CH2-CH=CH2, OH), 2.54 (dd, J =
14.7, 6.7 Hz, 1H, CH2-CH=CH2); 13C NMR (75 MHz, CDCl3): δ (ppm) 138.1 (CqAr), 137.6
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(CqAr), 131.6 (CH2-CH=CH2), 128.9 (CAr), 128.5 (CAr) , 128.2 (CAr), 127.85 (CAr), 127.83
(CAr), 126.1 (CAr), 119.1 (CH2-CH=CH2), 102.6 (C1), 101.5 (C7), 78.6 (C4), 76.1 (C3), 72.8
(O-CH2-Ph), 69.5 (C2), 68.9 (C6), 64.1 (C5), 47.4 (OMe), 35.2 (CH2-CH=CH2); FT-IR (film):
3482, 3033, 2912, 1643, 1497, 1454, 1374, 1211, 1094, 1059, 1026, 1004, 915, 848, 817,
745, 695, 649 cm-1; HRMS (ESI): m/z Calcd for C24H29O6 [M + H]+ 413.1964, found
413.1963; [α]D20 = - 26 (CHCl3, c = 1.0).
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(2R,4aR,6R,7R,8R,8aR)-6-allyl-8-(benzyloxy)-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol 10. To a solution of 9 (450 mg, 1.08
mmol) in CH2Cl2 (3 mL) at -78 °C was added drop wise a 1 M solution of DIBAL-H in
hexanes (1.42 mL, 1.42 mmol). After 15 min at -78 °C, the mixture was quenched with
methanol, and added with CH2Cl2 (5 mL) and Rochelle salts (1 M, 5 mL). After 12 h of
vigorous stirring at room temperature, the organic layer was separated, and the aqueous
layer was extracted with dichloromethane (3 x 15 mL). The combined organic layers
were dried (MgSO4), filtered and concentrated under reduce pressure. Filtration over a
silica plug delivered the lactol as a mixture of diastereoisomers. A suspension of
methyltriphenylphosphonium bromide (1.02 g, 2.86 mmol) in THF (2.5 mL) at 0 °C was
added with potassium tert-butoxide (321 mg, 2.86 mmol) and a solution of lactol in THF
(2.5 mL). After 15 min stirring at room temperature, CH2Cl2 (10 mL) and water (10 mL)
were added. After separation, the aqueous layer was extracted with dichloromethane (3
x 15 mL), and the combined organic layers were dried (MgSO4), filtered and
concentrated under reduce pressure. Purification by silica gel chromatography
(cyclohexane/ethyl acetate from 3:1) gave 10 as a colorless oil (374 mg, 84% over 2
1
steps). Rf = 0.28 (silica, cyclohexane/ethyl acetate 3:1); H NMR (300 MHz, CDCl3): δ
(ppm) 7.51-7.29 (m, 10H, HAr), 5.91 (dddd, J = 18.0, 11.8, 7.8, 6.3 Hz, 1H, CH2-CH=CH2),
5.59 (s, 1H, H7), 5.19-5.14 (m, 2H, CH2-CH=CH2), 5.02 (d, J = 11.4 Hz, 1H, O-CH2-Ph), 4.76
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(d, J = 11.4 Hz, 1H, O-CH2-Ph), 4.31 (dd, J = 10.4, 4.5 Hz, 1H, H6), 3.93-3.90 (m, 1H, H3),
3.80-3.72 (m, 3H, H2, H4, H6), 3.60 (td, J = 9.4, 4.5 Hz, 1H, H5), 3.37 (s, 3H, OMe), 2.72
(dd, J = 15.2, 6.3 Hz, 1H, CH2-CH=CH2), 2.59 (dd, J = 15.2, 7.8, Hz, 1H, CH2-CH=CH2), 2.37
(d, 1H, OH, J = 2.4 Hz); 13C NMR (75 MHz, CDCl3): δ (ppm) 138.2 (CqAr), 137.3 (CqAr),
131.6 (CH2-CH=CH2), 129.0 (CAr), 128.5 (CAr), 128.3 (CAr), 128.1 (CAr), 127.9 (CAr), 125.9
(CAr), 118.2 (CH2-CH=CH2), 102.4 (C1), 101.2 (C7), 82.2 (C2), 80.1 (C4), 74.6 (O-CH2-Ph),
71.6 (C3), 69.2 (C6), 64.7 (C5), 48.9 (OMe), 35.3 (CH2-CH=CH2); FT-IR (film): 3479, 3362,
2922, 2854, 1454, 1375, 1212, 1177, 1076, 1059, 1026, 1006, 962, 915, 865, 762, 745,
697, 660, 488 cm-1; HRMS (ESI): m/z Calcd for C24H32NO6 [M + NH4]+ 430.2230, found
430.2228; [α]D20 = + 10 (CHCl3, c = 1.0).
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(2R,4aR,6S,8R,8aR)-6-allyl-8-(benzyloxy)-6-methoxy-2-
phenyltetrahydropyrano[3,2-d][1,3]dioxin-7(6H)-one 11. A solution of Dess-Martin
periodinane (144 mg, 0.338 mmol) in pyridine (1 mL) was stirred at room temperature
for 30 min, and added with a solution of alcohol 7 (140 mg, 0.338 mmol) in
dichloromethane (1 mL). After 10 h at room temperature, additional Dess-Martin
periodinane (144 mg, 0.338 mmol) was added to the reaction mixture. After 10 h, TLC
revealed complete consumption of the starting material, and dichloromethane (8 mL), a
saturated solution of NaHCO3 (4 mL) and a saturated solution of Na2S2O3 (4 mL) were
added. After 4 h, the organic layer was separated and the aqueous layer was extracted
with dichloromethane (3 x 10 mL). The combined organic layers were dried (MgSO4),
filtered and concentrated under reduce pressure. After purification by silica gel
chromatography (cyclohexane/ethyl acetate 5:1), ketone 11 was obtained as a colorless
1
film (90 mg, 64%). Rf = 0.85 (silica, cyclohexane / ethyl acetate 3:1); H NMR (300 MHz,
CDCl3): δ (ppm) 7.53-7.27 (m, 10H, HAr), 5.81 (dddd, J = 17.6, 10.4, 7.4, 6.2 Hz, 1H, CH2-
CH=CH2), 5.56 (s, 1H, H7), 5.21-5.12 (m, 2H, CH2-CH=CH2), 4.93 (d, J = 12.0 Hz, 1H, O-
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CH2-Ph), 4.69 (d, J = 12.0 Hz, 1H, O-CH2-Ph), 4.61 (d, J = 10.4 Hz, 1H, H3), 4.39 (dd, J =
10.3, 5.3 Hz, 1H, H6), 4.09 (td, J = 10.3, 5.3 Hz, 1H, H5), 3.86-3.78 (m, 2H, H4, H6), 3.31 (s,
3H, OMe), 2.70-2.56 (m, 2H, CH2-CH=CH2); 13C NMR (75 MHz, CDCl3): δ (ppm) 198.2
(C2), 137.7 (CqAr), 137.0 (CqAr), 131.5 (CH2-CH=CH2), 129.2 (CAr), 128.4 (CAr), 128.3
(CAr), 127.9 (CAr), 127.8 (CAr), 126.2 (CAr), 118.9 (CH2-CH=CH2), 102.2 (C1), 101.1 (C7),
82.4 (C4), 80.5 (C3), 73.4 (O-CH2-Ph), 68.8 (C6), 63.9 (C5), 48.6 (OMe), 35.4 (CH2-
CH=CH2); FT-IR (film): 3063, 3030, 2924, 2854, 1720, 1602, 1495, 1454, 1361, 1313,
1270, 1207, 1176, 1095, 1069, 1027, 910, 733, 712, 695, 604, 461 cm-1; HRMS (ESI): m/z
Calcd for C24H30NO6 [M + NH4]+ 428.2073, found 428.2071; [α]D20 = - 7 (CHCl3, c = 2.5).
(2R,4aR,6R,8R,8aR)-6-allyl-8-(benzyloxy)-6-methoxy-2-
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phenyltetrahydropyrano[3,2-d][1,3]dioxin-7(6H)-one 12. A solution of Dess-Martin
periodinane (236 mg, 0.557 mmol) in pyridine (2 mL) was stirred at room temperature
for 30 min, and added with a solution of alcohol 10 (230 mg, 0.557 mmol) in
dichloromethane (2 mL). After 10 h at room temperature, additional Dess-Martin
periodinane (236 mg, 0.557 mmol) was added to the reaction mixture. After 10 h, TLC
revealed complete consumption of the starting material, and dichloromethane (20 mL),
a saturated solution of NaHCO3 (10 mL) and a saturated solution of Na2S2O3 (10 mL)
were added. After 4 h, the organic layer was separated and the aqueous layer was
extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried
(MgSO4), filtered and concentrated under reduce pressure. After purification by silica gel
chromatography (cyclohexane/ethyl acetate 5:1), ketone 12 was obtained as a colorless
film (150 mg, 65%). Rf = 0.82 (silica, cyclohexane / ethyl acetate 3:1); 1H NMR (300 MHz,
CDCl3): δ (ppm) 7.53-7.29 (m, 10H, HAr), 5.76 (ddt, J = 17.3, 10.2, 7.0 Hz, 1H, CH2-
CH=CH2), 5.60 (s, 1H, H7), 5.17-5.02 (m, 2H, CH2-CH=CH2), 4.98 (d, J = 12.2 Hz, 1H, O-
CH2-Ph), 4.78 (d, J = 12.2 Hz, 1H, O-CH2-Ph), 4.43-4.40 (m, 1H, H6), 4.22 (d, J = 10.2 Hz,
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1H, H3), 3.98-3.76 (m, 3H, H4, H5, H6), 3.33 (s, 3H, OMe), 2.55-2.53 (m, 2H, CH2-
CH=CH2); 13C NMR (75 MHz, CDCl3): δ (ppm) 201.4 (C2), 137.3 (CqAr), 136.9 (CqAr), 129.8
(CH2-CH=CH2), 129.3 (CAr), 128.6 (CAr), 128.4 (CAr), 128.20 (CAr), 128.17 (CAr), 126.2
(CAr), 119.8 (CH2-CH=CH2), 104.9 (C1), 101.1 (C7), 81.4 (C4), 81.3 (C3), 74.0 (O-CH2-Ph),
69.1 (C6), 65.1 (C5), 51.9 (OMe), 38.9 (CH2-CH=CH2); FT-IR (film): 3040, 2921, 2857,
1735, 1640, 1497, 1455, 1441, 1370, 1243, 1214, 1132, 1076, 999, 876, 741, 699, 459
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cm-1; HRMS (ESI): m/z Calcd for C24H30NO6 [M + NH4]+ 428.2073, found 428.2066; [α]D
= - 10 (CHCl3, c = 2.1).
(2R,4aR,6S,7R,8R,8aR)-6-allyl-8-(benzyloxy)-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol 15.
A solution of 11 (53mg,
0.129mmol) in dichloromethane/methanol 1:1 (1.3 mL) was cooled to 0 °C and added
with NaBH4 (20 mg, 0.516 mmol). After 15 min, dichloromethane (2.5 mL) and a 2%
aqueous solution of AcOH (2.5 mL) were added, and the mixture was stirred at room
temperature for 30 min. After separation, the aqueous layer was extracted with
dichloromethane (3 x 10 mL), and the combined organic phases were dried (MgSO4),
filtered and concentrated under reduce pressure. Purification by silica gel
chromatography (cyclohexane/ethyl acetate 4:1) gave alcohols 7 (18 mg, 34%) and 15
(30 mg, 57%) as colorless films. Rf = 0.44 (silica, cyclohexane/ethyl acetate 3:1); 1H NMR
(300 MHz, CDCl3): δ (ppm) 7.52-7.29 (m, 10H, HAr), 5.79 (dddd, J = 16.8, 10.4, 8.2, 6.3 Hz,
1H, CH2-CH=CH2), 5.57 (s, 1H, H7), 5.19-5.11 (m, 2H, CH2-CH=CH2), 4.96 (d, J = 11.4 Hz,
1H, O-CH2-Ph), 4.78 (d, J = 11.4 Hz, 1H, O-CH2-Ph), 4.33-4.28 (m, 1H, H6), 3.85 (t, J = 9.1
Hz, 1H, H3), 3.80-3.64 (m, 3H, H6, H5, H2), 3.59 (t, J = 9.1 Hz, 1H, H4), 3.30 (s, 3H, OMe),
2.63-2.49 (m, 2H, CH2-CH=CH2), 2.26 (d, 1H, OH, J = 6.9Hz); 13C NMR (75 MHz, CDCl3): δ
(ppm) 138.6 (CqAr), 137.5 (CqAr), 132.5 (CH2-CH=CH2), 129.1 (CAr), 128.5 (CAr), 128.4
(CAr), 128.2 (CAr), 127.9 (CAr), 126.1 (CAr), 119.2 (CH2-CH=CH2), 101.8 (C1), 101.3 (C7),
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82.1 (C4), 79.5 (C3), 75.1 (O-CH2-Ph), 73.6 (C2), 69.1 (C6), 63.6 (C5), 47.9 (OMe), 37.2
(CH2-CH=CH2); FT-IR (film): 3556, 2921, 2853, 1643, 1495, 1454, 1373, 1200, 1179,
1084, 986, 919, 763, 736, 697, 463 cm-1; HRMS (ESI): m/z Calcd for C24H32NO6 [M +
NH4]+ 430.2230, found 430.2213; [α]D20 = +56 (CHCl3, c = 1.0);
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(2R,4aR,6R,7S,8R,8aR)-6-allyl-8-(benzyloxy)-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol 16. A solution of 12 (26 mg, 0.06
mmol) in THF (0.6 mL) was cooled to -78 °C and added drop-wise with a 1M solution of
L-selectride in THF (0.3 mL, 0.30 mmol). After 20 min at -78 °C the mixture was
quenched with methanol. Dichloromethane (5 mL) and Rochelle salts (1 M, 5 mL) were
added, and after 18 h stirring at room temperature, the organic layer was separated and
the aqueous layer was extracted with dichloromethane (3 x 10 mL). The combined
organic phases were dried (MgSO4), filtered, and concentrated under reduce pressure.
After purification by silica gel chromatography (dichloromethane/acetonitrile 97:3),
alcohol 16 was obtained as a colorless film (16 mg, 61%). Rf = 0.39 (silica, cyclohexane /
ethyl acetate 3:1); 1H NMR (300 MHz, CDCl3): δ (ppm) 7.52-7.28 (m, 10H, HAr), 5.70 (ddt,
J = 17.1, 10.2, 7.1 Hz, 1H, CH2-CH=CH2), 5.59 (s, 1H, H7), 5.09-4.93 (m, 2H, CH2-CH=CH2),
4.86 (d, J = 12.3 Hz, 1H, O-CH2-Ph), 4.77 (d, J = 12.3 Hz, 1H, O-CH2-Ph), 4.32-4.23 (m, 2H,
H6, H4), 4.03-4.01 (m, 1H, H2), 3.85-3.76 (m, 2H, H3, H6), 3.52 (ddd, J = 10.5, 9.3, 4.7 Hz,
1H, H5), 3.41 (s, 3H, OMe), 2.90 (d, J = 2.7Hz, 1H, OH), 2.56-2.54 (m, 2H, CH2-CH=CH2);
13C NMR (75 MHz, CDCl3): δ (ppm) 138.1 (CqAr), 137.6 (CqAr), 131.8 (CH2-CH=CH2),
129.1 (CAr), 128.6 (CAr), 128.4 (CAr), 128.2 (CAr), 127.9 (CAr), 126.2 (CAr), 119.2 (CH2-
CH=CH2), 101.7 (C7), 101.0 (C1), 79.4 (C4), 74.9 (C3), 73.1 (O-CH2-Ph), 69.69 (C6), 69.67
(C2), 65.6 (C5), 49.4 (OMe), 35.2 (CH2-CH=CH2); FT-IR (film): 3527, 3070, 3031, 2922,
2853, 1728, 1640, 1496, 1454, 1373, 1314, 1274, 1210, 1176, 1093, 1028, 999, 918, 743,
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696 cm-1; HRMS (ESI): m/z Calcd for C24H32NO6 [M + NH4]+ 430.2230, found 430.2240;
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[α]D20 = + 15 (CHCl3, c = 3.6).
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Preparation of quaternary methyl-α-D GlcNAc and ManNAc derivatives 17 and 18. A
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solution of 11 (48 mg, 0.116 mmol) and ammonium acetate (360 mg, 4.665 mmol) in
THF / methanol (0.2 mL / 0.9 mL) was heated at 80 °C under microwave irradiation.
After 10 min, NaBH3CN (74 mg, 1.165 mmol) was added and the solution was heated at
80 °C under microwave irradiation for 5 mn. After cooling to room temperature,
dichloromethane (5 mL) and NaHCO3 (5 mL) were added. After separation, the aqueous
phase was extracted with dichloromethane (3 x 10 mL), and the combined organic
layers were dried (MgSO4), filtered, and concentrated under reduce pressure. The
residue was dissolved in dichloromethane (3 mL) and added with pyridine (190 µL, 2.33
mmol) and acetic anhydride (110 µL, 1.16 mmol). After 1 h, methanol (0.1 mL),
dichloromethane (5 mL) and NaHCO3 (5 mL) were added, and the phases were
separated. The aqueous phase was extracted with dichloromethane (3 x 10 mL), and the
combined organic layers were dried (MgSO4), filtered, and concentrated under reduce
pressure. Purification by silica gel chromatography (chloroforme/methanol 99.5:0.5)
gave 17 (20 mg, 38% over two steps) and 18 (17 mg, 33% over two steps) as colorless
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films.
N-((2R,4aR,6S,7R,8R,8aS)-6-allyl-8-(benzyloxy)-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)acetamide 17: Rf = 0.33 (silica,
1
chloroforme/methanol 99.5:0.5); H NMR (300 MHz, CDCl3): δ (ppm) 7.50-7.23 (m, 10H,
HAr), 5.72 (ddt, J = 17.6, 9.6, 7.3 Hz, 1H, CH2-CH=CH2), 5.55 (s, 1H, H7), 5.41 (d, J = 10.2
Hz, 1H, NH), 5.19-5.04 (m, 2H, CH2-CH=CH2), 4.86 (d, J = 12.3 Hz, 1H, O-CH2-Ph), 4.61 (d,
J = 12.3 Hz, 1H, O-CH2-Ph), 4.28-4.22 (m, 2H, H2, H6), 3.78-3.57 (m, 4H, H6, H4, H3, H5),
3.20 (s, 3H, OMe), 2.45 (dd, J = 14.1, 7.3 Hz, 1H, CH2-CH=CH2), 2.25 (dd, J = 14.1, 7.3 Hz,
1H, CH2-CH=CH2), 1.86 (s, 3H, CH3-C=O); 13C NMR (75 MHz, CDCl3): δ (ppm) 169.4 (C=O),
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138.8 (CqAr), 137.5 (CqAr), 131.4 (CH2-CH=CH2), 129.1 (CAr), 128.38 (CAr), 128.36 (CAr),
128.1 (CAr), 127.6 (CAr), 126.1 (CAr), 119.3 (CH2-CH=CH2), 102.2 (C1), 101.2 (C7), 82.5
(C4), 77.5 (C3), 74.1 (O-CH2-Ph), 69.0 (C6), 63.6 (C5), 54.1 (C2), 47.9 (OMe), 37.6 (CH2-
CH=CH2), 23.7 (CH3-C=O); FT-IR (film): 3286, 3065, 3033, 2923, 2856, 1656, 1515, 1498,
1371, 1313, 1213, 1172, 1087, 997, 915, 748, 696, 598, 478 cm-1; HRMS (ESI): m/z Calcd
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for C24H32NO6 [M + H]+ 454.2230, found 454.2216; [α]D = + 47 (CHCl3, c =12.5). N-
20
((2R,4aR,6S,7S,8R,8aS)-6-allyl-8-(benzyloxy)-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)acetamide 18: Rf = 0.28 (silica,
1
chloroforme/methanol 99.5:0.5); H NMR (300 MHz, CDCl3): δ (ppm) 7.44-7.15 (m, 10H,
HAr), 5.68 (dddd, J = 17.0, 10.2, 7.6, 6.6 Hz, 1H, CH2-CH=CH2), 5.51 (s, 1H, H7), 5.47 (d, J =
10.8 Hz, 1H, NH), 5.10-4.99 (m, 2H, CH2-CH=CH2), 4.75 (dd, J = 10.8, 4.5 Hz, 1H, H2), 4.69
(d, J = 12.0 Hz, 1H, O-CH2-Ph), 4.47 (d, J = 12.0 Hz, 1H, O-CH2-Ph), 4.19 (dd, J = 9.0, 2.7 Hz,
1H, H6), 4.07 (dd, J = 9.6, 4.5 Hz, 1H, H3), 3.74-3.54 (m, 3H, H6, H4, H5), 3.15 (s, 3H,
OMe), 2.46 (dd, J = 15.1, 7.6 Hz, 1H, CH2-CH=CH2), 2.30 (dd, J = 15.1, 6.6 Hz, 1H, CH2-
CH=CH2), 1.98 (s, 3H, CH3-C=O); 13C NMR (75 MHz, CDCl3): δ (ppm) 169.7 (C=O), 138.3
(CqAr), 137.3 (CqAr), 130.7 (CH2-CH=CH2) 128.9 (CAr), 128.3 (CAr), 128.2 (CAr), 127.9 (CAr),
127.5 (CAr), 126.1 (CAr), 119.4 (CH2-CH=CH2), 103.4 (C1), 101.7 (C7), 78.5 (C4), 74.1
(C3), 71.4 (O-CH2-Ph), 68.9 (C6), 64.5 (C5), 50.6 (C2), 48.0 (OMe), 36.6 (CH2-CH=CH2),
23.7 (CH3-C=O); FT-IR (film): 3358, 2960, 2922, 2852, 1654, 1538, 1455, 1374, 1260,
1091, 1016, 798, 696, 498 cm-1; HRMS (ESI): m/z Calcd for C24H32NO6 [M + H]+
454.2230, found 454.2243; [α]D20 = 16 (CHCl3, c = 2.3).
Preparation of quaternary methyl-β-D GlcNAc and ManNAc derivatives 19 and 20.
A solution of 12 (65 mg, 0.158 mmol) and ammonium acetate (488 mg, 6.331 mmol) in
THF / methanol (0.3 mL / 1.4 mL) was heated at 80 °C under microwave irradiation.
After 10 min, NaBH3CN (98 mg, 1.58 mmol) was added and the solution was heated at
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80 °C under microwave irradiation for 5 mn. After cooling to room temperature,
dichloromethane (5 mL) and NaHCO3 (5 mL) were added. After separation, the aqueous
phase was extracted with dichloromethane (3 x 10 mL), and the combined organic
layers were dried (MgSO4), filtered, and concentrated under reduce pressure. The
residue was dissolved in dichloromethane (3 mL) and added with pyridine (256 µL,
3.166 mmol) and acetic anhydride (150 µL, 1.58 mmol). After 1 h, methanol (0.2 mL),
dichloromethane (5 mL) and NaHCO3 (5 mL) were added, and the phases were
separated. The aqueous phase was extracted with dichloromethane (3 x 10 mL), and
the combined organic layers were dried (MgSO4), filtered, and concentrated under
reduce pressure. Purification by silica gel chromatography (dichloromethane/methanol
from 96:4 to 93:7) gave 19 (23 mg, 32% over two steps) and 20 (21 mg, 29% over two
steps) as colorless films. N-((2R,4aR,6R,7R,8R,8aS)-6-allyl-8-(benzyloxy)-6-
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methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)acetamide 19: Rf
=
0.33 (silica, dichloromethane/methanol 95:5); 1H NMR (300 MHz, CDCl3): δ (ppm) 7.45-
7.19 (m, 10H, HAr), 5.76 (ddt, J = 17.1, 10.1, 7.2 Hz, 1H, CH2-CH=CH2), 5.53 (s, 1H, H7),
5.08-4.99 (m, 3H, CH2-CH=CH2, NH), 4.86 (d, J = 12.4 Hz, 1H, O-CH2-Ph), 4.66 (d, J = 12.4
Hz, 1H, O-CH2-Ph), 4.41 (t, J = 9.2 Hz, 1H, H2), 4.23 (dd, J = 10.2, 4.8 Hz, 1H, H6), 3.85 (t, J
= 9.3 Hz, 1H, H4), 3.69 (t, J = 10.2 Hz, 1H, H6), 3.57-3.44 (m, 2H, H3, H5), 3.34 (s, 3H,
OMe), 2.44 (dd, J = 14.7, 7.2 Hz, 1H, CH2-CH=CH2), 2.35 (dd, J = 14.7, 7.2 Hz, 1H, CH2-
CH=CH2), 1.87 (s, 3H, CH3-C=O); 13C NMR (75 MHz, CDCl3): δ (ppm) 169.6 (C=O), 138.4
(CqAr), 137.3 (CqAr), 131.3 (CH2-CH=CH2), 129.1 (CAr), 128.5 (CAr), 128.4 (CAr), 128.3
(CAr), 127.9 (CAr), 126.1 (CAr), 118.6 (CH2-CH=CH2), 102.1 (C1), 101.3 (C7), 82.6 (C4),
77.9 (C3), 73.4 (O-CH2-Ph), 69.4 (C6), 64.9 (C5), 52.5 (C2), 49.2 (OMe), 36.9 (CH2-
CH=CH2), 23.7 (CH3-C=O); FT-IR (film): 3285, 2961, 2924, 2853, 1651, 1514, 1454,
1371, 1312, 1260, 1216, 1092, 1053, 1016, 920, 800, 735, 696, 497 cm-1;
HRMS (ESI): m/z Calcd for C24H32NO6 [M + H]+ 454.2230, found 454.2227; [α]D20 = + 15
(CHCl3,
c
=3.7). N-((2R,4aR,6R,7S,8R,8aS)-6-allyl-8-(benzyloxy)-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)acetamide 20: Rf = 0.30 (silica,
1
dichloromethane/methanol 95:5); H NMR (300 MHz, CDCl3): δ (ppm) 7.45-7.28 (m,
10H, HAr), 5.98 (d, J = 9.9 Hz, 1H, NH), 5.75 (ddt, J = 17.2, 10.2, 7.5 Hz, 1H, CH2-CH=CH2),
5.54 (s, 1H, H7), 5.10-5.03 (m, 2H, CH2-CH=CH2), 4.75 (d, J = 12.0 Hz, 1H, O-CH2-Ph),
4.69-4.62 (m, 2H, O-CH2-Ph, H2), 4.39-4.30 (m, 1H, H6), 4.20-4.14 (m, 1H, H4), 3.95 (t, J =
6.9 Hz, 1H, H3), 3.69-3.66 (m, 2H, H6, H5), 3.32 (s, 3H, OMe), 2.57 (dd, J = 14.5, 7.5 Hz,
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1H, CH2-CH=CH2), 2.39 (dd, J = 14.5, 7.5 Hz, 1H, CH2-CH=CH2), 1.95 (s, 3H, CH3-C=O); 13C
NMR (75 MHz, CDCl3): δ (ppm) 168.8 (C=O), 137.1 (CqAr), 136.4 (CqAr), 130.9 (CH2-
CH=CH2), 128.1 (CAr), 127.5 (CAr), 127.4 (CAr), 127.1 (CAr), 126.9 (CAr), 125.2 (CAr), 117.6
(CH2-CH=CH), 100.7 (C1), 100.3 (C7), 80.2 (C4), 74.1 (C3), 72.9 (O-CH2-Ph), 69.0 (C6),
63.6 (C5), 49.3 (C2), 47.2 (OMe), 36.9 (CH2-CH=CH2), 22.4 (CH3-C=O); FT-IR (film): 2962,
2922, 2852, 1632, 1464, 1260, 1093, 1018, 798, 695, 458 cm-1; HRMS (ESI): m/z Calcd
for C24H32NO6 [M + H]+ 454.2230, found 454.2228; [α]D20 = + 11 (CHCl3, c = 4.5);
(1R,2R,3S,4S,5R)-5-allyl-3-(benzyloxy)-6,8-dioxabicyclo[3.2.1]octane-2,4-diol 13.
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Rf = 0.17 (silica, cyclohexane/ethyl acetate 5:1); H NMR (300 MHz, CDCl3): δ (ppm)
7.39-7.31 (m, 5H, HAr), 5.87 (ddt, J = 17.2, 10.1, 7.3 Hz, 1H, CH2-CH=CH2), 5.21-5.13 (m,
2H, CH2-CH=CH2), 4.71 (d, J = 11.4 Hz, 1H, O-CH2-Ph), 4.59 (d, J = 11.4 Hz, 1H, O-CH2-Ph),
4.45 (d, J = 5.7 Hz, 1H, H2), 4.19 (d, J = 7.5 Hz, 1H, H6), 3.86-3.77 (m, 3H, H5, H6, H3),
3.67 (dd, J = 11.4, 6.0 Hz, 1H, H4), 3.04 (d, J = 11.4 Hz, 1H, OH), 2.73-2.59 (m, 2H, CH2-
CH=CH2), 2.36 (br d, 9.9 Hz, 1H, OH); 13C NMR (75 MHz, CDCl3): δ (ppm) 137.3 (CqAr),
131.9 (CH2-CH=CH2), 128.8 (CAr), 128.3 (CAr), 127.9 (CAr), 118.8 (CH2-CH=CH2), 108.8
(C1), 78.8 (C3), 77.1 (C2), 74.1 (O-CH2-Ph), 69.6 (C5), 67.5 (C4), 65.9 (C6), 37.7 (CH2-
CH=CH2); FT-IR (film): 3427, 3073, 3034, 2897, 1718, 1642, 1454, 1400, 1207, 1063,
918, 796, 736, 696, 608, 460 cm-1; [α]D20 = - 10 (CHCl3, c = 4.9).
(2R,4aR,6R)-6-allyl-8-hydroxy-6-methoxy-2-phenyl-4,4a-dihydropyrano[3,2-
1
d][1,3]dioxin-7(6H)-one 14. Rf = 0.11 (silica, cyclohexane/ethyl acetate 5:1); H NMR
(300 MHz, CDCl3): δ (ppm) 7.57-7.29 (m, 5H, HAr), 5.97-5.83 (m, 2H, H7, CH2-CH=CH2),
5.63 (br s, 1H, OH), 5.22-5.16 (m, 2H, CH2-CH=CH2), 4.82 (dd, J = 10.1, 6.8 Hz, 1H, H5),
4.51 (dd, J = 10.1, 6.8 Hz, 1H, H6), 3.96 (t, J = 10.1 Hz, 1H, H6), 3.34 (s, 3H, OMe), 2.71-
2.55 (m, 2H, CH2-CH=CH2); 13C NMR (75 MHz, CDCl3): δ (ppm) 190.2 (C2), 148.0 (C3),
135.2 (CqAr), 131.7 (C4), 130.4 (CH2-CH=CH2), 130.2 (CAr), 128.7 (CAr), 126.5 (CAr), 119.7
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(CH2-CH=CH2), 103.3 (C7), 102.7 (C1), 69.0 (C6), 62.3 (C5), 51.9 (OMe), 38.3 (CH2-
CH=CH2).
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The supporting Information is available free of charge on the ACS publications website.
They include copy of the NMR spectra (1H and 13C) of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20.
Author Informations
Corresponding Author: *E-mail: Thomas.Lecourt@insa-rouen.fr
The authors declare no competing financial interest.
Acknowledgments
The authors would like to thank LABEX SynOrg (ANR-11-LABX-0029) and ANR (JCJC-
2013-QuatGlcNAc) for their financial support, and Véronique Chassagne (Engineering
and Innovation Center – COBRA Laboratory) for the large-scale preparation of starting
diazo sugars.
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