Pd-catalyzed coupling reactions of anhydro-aldose tosylhydrazones with aryl bromides to produce substituted exo-glycals

Article abstract of DOI:10.1016/j.carres.2018.02.010

Palladium-catalyzed cross-couplings of O-peracylated and O-permethylated 2,6-anhydro-aldose tosylhydrazones with aryl halides were studied under thermic conditions in the presence of LiOtBu and phosphine ligands. The reactions gave the corresponding aryl substituted exo-glycals as mixtures of diastereomers in 11–75% yields. The transformations represent a new access to these types of glycomimetic compounds. The double bond of some aryl substituted exo-glycals was saturated to give good yields of benzylic C-glycosyl derivatives.

Full text of DOI:10.1016/j.carres.2018.02.010

Accepted Manuscript
Pd-catalyzed coupling reactions of anhydro-aldose tosylhydrazones with aryl
bromides to produce substituted exo-glycals
Tímea Kaszás, Anton Ivanov, Marietta Tóth, Peter Ehlers, Peter Langer, László
Somsák
PII:
S0008-6215(18)30052-1
10.1016/j.carres.2018.02.010
CAR 7526
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 29 January 2018
Revised Date: 16 February 2018
Accepted Date: 16 February 2018
Please cite this article as: Tí. Kaszás, A. Ivanov, M. Tóth, P. Ehlers, P. Langer, Láó. Somsák, Pd-
catalyzed coupling reactions of anhydro-aldose tosylhydrazones with aryl bromides to produce
substituted exo-glycals, Carbohydrate Research (2018), doi: 10.1016/j.carres.2018.02.010.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Pd-catalyzed coupling reactions of anhydro-aldose tosylhydrazones with
aryl bromides to produce substituted exo-glycals
Tímea Kaszás1,2, Anton Ivanov2, Marietta Tóth1, Peter Ehlers2, Peter Langer2, and László
Somsák1*
1Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen,
Hungary
2Department of Chemistry, University of Rostock, Albert-Einstein-Str. 3a, 18059 Rostock,
Germany
Abstract
Palladium-catalyzed cross-couplings of O-peracylated and O-permethylated 2,6-anhydro-
aldose tosylhydrazones with aryl halides were studied under thermic conditions in the
presence of LiOtBu and phosphine ligands. The reactions gave the corresponding aryl
substituted exo-glycals as mixtures of diastereomers in 11-75% yields. The transformations
represent a new access to these types of glycomimetic compounds. The double bond of some
aryl substituted exo-glycals was saturated to give good yields of benzylic C-glycosyl
derivatives.
Keywords: Cross coupling; Pd-catalysis; Anhydro-aldose tosylhydrazones; Carbenes;
Substituted exo-glycals.
*Corresponding author - Tel: +36 52512900 ext. 22348; Fax: +36 52512744; E-mail:
somsak.laszlo@science.unideb.hu.
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1. Introduction
Formation of a carbon-carbon bond at the anomeric position of carbohydrates has received
great attention due to the versatile applicability of such sugar derivatives as chiral synthons in
syntheses of complex natural products as well as to manyfold biological activities of C-
glycosyl compounds [1-3]. As a part of a program targeting the systematic study of
applications of anhydro-aldose tosylhydrazones (compounds H in Scheme 1) as coupling
partners in metal-free [4, 5] and transition metal-catalyzed coupling reactions we have been
interested in the Pd-catalyzed coupling of H with bromobenzenes. According to general
mechanistic considerations, such coupling reactions [6-8] are expected to result in substituted
exo-glycals (compounds E in Scheme 1). Aryl substituted pyranoid exo-glycals represent
valuable starting compounds for the syntheses of benzylic C-glycosyl derivatives [9-11], also
elaborated to porphyrine glycoconjugates [12], C-glycosyl benzyl alcohols used to get
glycosidase inhibitors [13], ketopyranose derivatives [14] including disaccharides [15], and
spiro-oxazolines [16].
In the literature only a few methods have been published for the preparation of aryl
substituted exo-glycals with a pyranoid ring. In the earliest report O-perbenzylated exo-glucal
A was applied as the starting material (Scheme 1) in a Pd(II)-catalyzed reaction with
arylmercury(II) acetate to yield substituted exo-glucal E [17]. (Z)-Configured iodo-exo-
glycals B of the D-gluco-, D-manno- and D-galacto- series underwent Suzuki or B-alkyl
Suzuki cross-coupling reactions with boronic acids or boranes to yield aryl and hetaryl
functionalized exo-glycals E in a stereoselective manner [18]. O-Permethylated (Z)-exo-glucal
E could be conveniently prepared in a convergent way by a Stille cross-coupling of (Z)-iodo-
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exo-glucal B with tetraphenyl stannane [19]. Stereoselective palladium-catalyzed Suzuki
cross-couplings of acetal-protected bromo methoxycarbonyl-exo-mannals C with boronic
acids were carried out to obtain phenyl methoxycarbonyl-exo-glycals E [20]. Wittig reactions
of an anomeric mixture of the O-perbenzylated 2-deoxy-D-galactopyranosyl phosphonium salt
D with arenecarboxaldehydes gave mixtures of E/Z-isomers of E [11, 15, 16]. Ramberg-
Bäcklund rearrangement of protected glycosyl sulfones G yielded the corresponding E/Z-
isomeric mixtures of phenyl- or diphenyl substituted exo-glycals E [12, 21]. A gold-catalyzed
ring-closure reaction of alkyne F was developed for the synthesis of O-perbenzylated (Z)-
phenyl-exo-glucal E [10]. Phosphine-mediated cycloisomerization of alkynyl-substituted
hemiketals I resulted in acetal-protected phenyl-substituted exo-glycals E as single Z-
diasteromers with a 2-keto functionality in the pyranoid ring [22].
In most of the above methods base stable protecting groups had to be applied and/or the
reagents like boronic acids [23] or stannanes [24] needed be prepared from aryl halides. In the
present work we have investigated the formation aryl substituted exo-glycals E in the first Pd-
catalyzed cross coupling reactions of ester or ether protected anhydro-aldose tosylhydrazones
H with easily available aryl bromides.
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Scheme 1. Strategies for the synthesis of aryl-substituted exo-glycals.
2. Results and discussion
Optimal reaction conditions were sought for by applying literature conditions [25] to
tosylhydrazone 1 [26-28] and bromobenzene (1,4-dioxane, 70 oC with 2 mol%
tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) catalyst in the presence of LiOtBu and
XPhos, Table 1). Both short and longer reaction times resulted in moderate yields with the
XPhos ligand (entries 1 and 2). Other ligands such as SPhos, RuPhos and P(4-F-C6H4)3 were
found to be also effective (entries 3-5, respectively), however, the yield did not improve
significantly. On the other hand, P(2-furyl)3 proved ineffective in this reaction (entry 6). It
was observed that 4 mol% of CataCXium A gave the better result both in short and longer
times (entries 7 and 8), however, application of 10 mol% did not affect the yield (entry 9).
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The application of toluene as the solvent was not favourable in this reaction (entry 10).
Reducing the reaction temperature to 60 oC (entry 11) resulted in the formation of exo-
galactal 3 only, while raising the temperature to 100 oC did not improve the the yield as
compared to that of the reaction at 70 oC (entry 12). Reducing the amount of LiOtBu resulted
in a diminished yield (entry 13). Performing the reaction with 1-bromo-chlorobenzene or 4-
bromoanisole gave only low yields of the expected products (entries 14, 15). The target
compounds 2 were always obtained as inseparable mixtures of diastereoisomers and the
formation of the by-product exo-galactal 3 could never be avoided.
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Table 1. Optimization of the reaction conditions and coupling of tosylhydrazone 1 with aryl bromides
Yield (%)a
R-C6H4-Br LiOtBu
Entry
R
Ligand (mol%)
Solvent
T (°C)
t (h)
E:Z for 2
3b
+
equiv.
equiv.
2
1
2
H
H
H
H
H
H
H
H
H
H
H
3
3
3
3
3
3
3
3
3
3
3
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
XPhos (4)
XPhos (4)
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
70
70
70
70
70
70
70
70
70
70
60
2
31
24
40
28
34
-
a
a
a
a
a
a
a
a
a
a
a
18
18
18
18
18
3
1:4
31
+
3
SPhos (4)
4
RuPhos (4)
+
5
P(4-F-C6H4)3 (4)
P(2-furyl)3 (4)
CataCXium A (4)
CataCXium A (4)
CataCXium A (10)
CataCXium A (4)
CataCXium A (4)
+
6
-
+
7
44
44
44
10
-
1:3
1:3
22
19
+
8
18
18
18
18
9
10
11
1:4
18
+
1,4-Dioxane
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12
13
14
15
H
H
3
6
6
3
2.2
1.5
2.2
2.2
CataCXium A (4)
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
100
70
18
20
16
3
42
17
6
1:3
1:6
1:3
1:4
25
3
a
a
b
c
CataCXium A (4)
CataCXium A (4)
CataCXium A (4)
4-Cl
4-CH3O
70
2
70
21
16
a
Yields calculated on the basis of the proton NMR spectra of the worked-up reaction mixture.
b Observation of exo-glycal 3 without determination of its proportion is denoted by +.
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The examinations were extended to the
D
-gluco configured tosylhydrazone 4 [27, 28] (Table
2). The corresponding phenyl substituted exo-glucal 5a was isolated in moderate yields
(entries 1, 2). The coupling was found to be not significantly affected by the substituents on
the aromatic ring; both electron-rich (entries 3, 4) and electron-deficient (entries 5-8)
bromobenzenes gave more or less similar yields of the expected products. The exo-glucal by-
product 6 always formed in significant quantitities.
Table 2. Pd-catalyzed coupling of tosylhydrazone 4 with aryl bromides
Yield (%)
R-C6H4-Br
equiv.
LiOtBu
equiv.
Entry
R
t (h)
E:Z for 5
1:2
6b
36a
20a
19a
27
16a
24
4
5
1
2
3
4
5
6
7
8
H
H
3
6
6
3
6
6
6
6
2.2
1.5
2.2
2.2
2.2
1.5
2.2
1.5
1.5
20
24a
17a
41a
11
a
a
b
c
d
e
f
1:2.5
1:2
4-CH3
4-CH3O
4-F
15
2.5
15
1:2
32a
1:2
4-NO2
4-CN
3-CN
16
33
1:2
15
46
1:2
16.5
20
1:2
+
g
a
Yields calcdulated on the basis of the proton NMR spectra of the worked-up reaction mixture.
b Observation of exo-glycal 6 without determination of its proportion is denoted by +.
To get an insight into the effect of an ether type protecting group on the outcome of the
studied coupling reaction, the known β-
D
-galactopyranosyl cyanide [29] (7, Scheme 2) was
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O-permethylated under Hakomori conditions to give 8 [30]. Reduction of 8 in the presence of
tosylhydrazine under literature conditions [26-28] furnished the O-methyl protected anhydro-
aldose tosylhydrazone 9 in medium yield. Coupling of 9 with aryl bromides gave the
substituted exo-galactals 10 in good yields. The corresponding unsubstituted exo-glycal by-
product was not present in the reaction leading to 10a, and a very minor amount of it could be
detected in the 1H NMR spectrum of the crude mixture giving 10b.
Scheme 2. Preparation of an ether protected anhydro-aldose tosylhydrazone and its coupling
with aryl bromides.
In the case of compounds 5f nuclear Overhauser effects were observed between the ortho
protons of the phenyl ring and the olefinic hydrogen as well as H-2 allowed to assign the E-
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configuration of the double bond while only the ortho protons and the olefinic one were in the
vicinity of each other in the Z-isomer (Fig. 1). In addition, a significant difference in the
chemical shift of the olefinic proton was observed for the isomers which proved to be general
and was used as a diagnostic means to determine the configuration of the double bond in these
series of compounds (D-galacto series: 6.54-6.46 ppm for (E)-2, 5.76-5.70 ppm for (Z)-2,
6.34, 6.30 ppm for (E)-10, 5.83, 5.82 ppm for (Z)-10;
5.98-5.85 ppm for (Z)-5).
D-gluco series: 6.68-6.57 ppm for (E)-5,
Figure 1. Characteristic NMR data for the configuration of the double bond in E/Z isomers of
compounds 5f (↔ denotes observed n. O. e.).
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H
H
O
O
O
Ar
C
N
ArBr
+
N
S
(PGO)n
(PGO)n
(PGO)n
Br
Pd2(dba)3
ligand (L)
LiOtBu
O
O
I
II
III
H
C
O
Pd
L
LiOtBu
-tBuOH
-TsLi
Ar
H
VII
Br
Pd
Ar
H
H
O
O
O
C
C
CH
L
N2
-N2
Br
IV
V
VI
Pd
H
L
VIII
Br
X
Pd
Ar
L
Pd
IX
L
ArBr
HBr
Scheme 3. Plausible mechanism of the transformations.
The formation of mixtures of substituted and unsubstituted exo-glycals in the studied
transformations can be explained by considering the mechanistic possibilities outlined in
Scheme 3. Tosylhydrazones I upon deprotonation and loss of a sulfinate ion may lead to the
diazo intermediate IV which can give rise to carbene V by eliminating a nitrogen molecule.
Carbene V may either undergo an intramolecular C‒H insertion to form the exo-glycal II [27,
28] or enter the usual catalytic cycle to produce VI by coordinating to the arylpalladium
species X formed by an oxidative addition of ArBr to IX. Migration of the Ar moiety leads to
VII which, upon β-hydride elimination, furnishes the substituted exo-glycal III and the Pd-
complex VIII which loses HBr to complete the catalytic cycle. Since the intramolecular
carbene insertion (V→II) competes with the intermolecular complexation (V→VI) the
formation of II is practically unavoidable.
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In order to assess the synthetic utility of these exo-glycals, the mixtures 2a + 3 and 5a + 6
were subjected to catalytic hydrogenation over Pd/C (Scheme 4). These reactions gave good
yields of the expected benzylic C-glycosyl derivatives 11 and 13, as well as the by-products
12 and 14, respectively (isolated yields refer to the substituted vs unsubstituted exo-glycal
components of the respective mixtures). The configuration of the „anomeric” carbon in these
compounds was assigned as β on the basis of the vicinal proton-proton coupling constanst
(11: J 9.6 Hz, 12: J 9.0 Hz, 13: J 9.8 Hz, 14: J 9.7 Hz). The very high stereoselectivity of
these reductions is in accord with previous literature results [9-11].
Scheme 4. Hydrogenation of the double bonds of the exo-glycals.
In conclusion, this study on the Pd-catalyzed couplings of O-peracylated 2,6-anhydro-aldose
tosylhydrazones with bromobenzenes revealed that the reactions gave the expected aryl
substituted exo-glycals as mixtures of diastereomers in low to good yields. The method
resulted in very good yields with O-permethylated sugar tosylhydrazones. The sugar
configuration seemed not to have any effect on the outcome of the transformations. Thus,
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such coupling reactions provide a new general method for the preparation of aryl substituted
exo-glycals whose synthetic utility was demonstrated by their reduction to give benzylic C-
glycosyl compounds.
3. Experimental
3.1. General methods
Optical rotations were determined with a Perkin–Elmer 241 polarimeter at room temperature.
1
NMR spectra were recorded with Bruker Avance 250 II (250/63 MHz for H/13C), Bruker
1
1
Avance 300 III (300/75 MHz for H/13C), Bruker 360 AM Avance (360/90 MHz for H/13C)
or Bruker DRX 400 (400/100 MHz for 1H/13C) spectrometers. Chemical shifts are referenced
to TMS as the internal reference (1H), or to the residual solvent signals (1H, 13C). The
1
13
assignments of the H and C NMR signals of compounds 2, 5, 10-13 were performed by
their NOE (5f), COSY (2a, 5a-c, 5e-g, 10a, 10b, 11-13), HSQC (2a, 5a-c, 5e-g, 11-13),
HMBC (2a, 5a-c, 5g) and NOESY (10a) spectra. Mass spectra were obtained by an Agilent
HP GC / MS 5890 / 5973 instrument (EI, 70 eV) by GC inlet or by a MX-1321 and Finnigan
MAT 95 XP (Thermo Electron Corp., San Jose, CA, USA) instruments (EI, 70 eV) by direct
inlet or by an Agilent 1969A Time-of-Flight LC-MS or by a Thermo Scientific LTQ XL
(Thermo Electron Corp., San Jose, CA, USA) LC-MS. LC-MS mass spectrometers operated
in a full scan positive ion ESI mode. TLC was performed on DCAlurolle Kieselgel 60 F254
(Merck). TLC plates were visualized under UV light, and by gentle heating. For column
chromatography Kieselgel 60 (Merck, particle size (0.063–0.200 mm) or Al2O3 neutral
(Across Organics, particle size: (0.050–0.200 mm, 60A) was applied. 1,4-Dioxane and THF
was distilled from sodium benzophenone ketyl and stored over sodium wires.
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3.2. General procedure I for the reaction of anhydro-aldose tosylhydrazones with aryl
bromides
A bromobenzene, LiOtBu, (in a ratio relative to 1 or 4 indicated in Tables 1 and 2,
respectively) CataCxium A (4 mol% toward 2 and 5) or XPhos (4 mol% toward 10) and
Pd2(dba)3 (2 mol%), was added to abs. 1,4-dioxane (3 mL). The suspension was stirred and
heated to 70 °C (bath temp) under an argon atmosphere, and then a solution of a
tosylhydrazone 1 [26-28] (0.1 g, 0.19 mmol), 4 [27, 28] (0.1 g, 0.13 mmol) or 9 (0.1 g, 0.24
mmol) in abs. 1,4-dioxane (2 mL) was added dropwise in 15 minutes. When TLC (1:1
EtOAc–hexane or 1:1 EtOAc–heptane for 1, 1:2 EtOAc–hexane or 1:2 EtOAc–hexane for 4,
1:1 EtOAc–heptane for 9) indicated complete consumption of the starting compound (1 h–1
day), the mixture was cooled and the insoluble material filtered off through a pad of celite and
washed thoroughly with abs. 1,4-dioxane (3 × 3 mL). The solvent was removed under
reduced pressure, and the residue was purified by column chromatography (neutral Al2O3)
with eluents indicated for the particular compounds to give aryl substituted exo-glycals.
3.2.1. 3,4,5,7-Tetra-O-acetyl-2,6-anhydro-1-deoxy-1-phenyl-D-galacto-hept-1-enitol (2a)
Prepared from tosylhydrazone 1 (0.1 g, 0.19 mmol), 4-bromobenzene (3 equiv., 0.06 mL, 0.09
g, 0.57 mmol) and LiOtBu (2.2 equiv., 0.03 g, 0.41 mmol) according to General procedure I.
Purified by column chromatography (1:1 EtOAc–heptane) to yield 49 mg yellow amorphous
product containing 2a (E:Z = 1:3) and 3 in 2 : 1 ratio. Rf: 0.45 (1:1 EtOAc–hexane). NMR: E
1
isomer: H NMR (360 MHz, CDCl3) δ 7.26–7.18 (m, 3H, aromatics), 7.13 (d, 2H, J 7.6 Hz,
aromatics), 6.54 (s, 1H, H-1), 5.84 (dd, 1H, J1,3 0.7, J3,4 7.3 Hz, H-3), 5.55 (pseudo t, 1H, J5,6
3.3 Hz, H-5), 5.22 (dd, 1H, J4,5 3.4 Hz, H-4), 4.39 (dd, 1H, J6,7a 7.5, J7a,7b 11.1 Hz, H-7a),
13
4.36–4.07 (m, 2H, H-6, H-7b), 2.13, 2.11, 2.04, 2.00 (4s, 12H, 4×CH3). C NMR (75 MHz,
CDCl3) δ 170.7, 170.0, 169.6, 169.5 (4×CO), 145.5 (C-2), 134.5–126.6 (aromatics), 118.1 (C-
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1
1), 75.2 (C-6), 70.2 (C-4), 66.7 (C-3, C-5), 61.5 (C-7), 21.1–20.3 (4×CH3). Z isomer: H
NMR (360 MHz, CDCl3) δ 7.62 (d, 2H, J 8.7 Hz, aromatics), 7.35–7.19 (m, 3H, aromatics),
5.81 (dd, 1H, J1,3 1.6, J3,4 10.0 Hz, H-3), 5.76 (d, 1H, H-1), 5.58 (dd, 1H, J5,6 1.6 Hz, H-5),
5.13 (dd, 1H, J4,5 3.3 Hz, H-4), 4.32 (dd, 1H, J7a,7b 11.7 Hz, H-7a), 4.23 (dd, 1H, H-7b), 4.16
13
(ddd, 1H, J6,7a 4.7, J6,7b 7.8 Hz, H-6), 2.20, 2.19, 2.10, 2.03 (4s, 12H, 4×CH3). C NMR (90
MHz, CDCl3) δ 170.5, 170.1, 170.0, 169.5 (4×CO), 146.8 (C-2), 134.5–126.6 (aromatics),
111.2 (C-1), 75.8 (C-6), 71.5 (C-4), 67.7 (C-5), 67.4 (C-3), 62.4 (C-7), 21.0, 20.8, 20.7
(4×CH3). HR-ESI-MS positive mode (m/z): calcd. for [M+Na]+=443.1313, found:
[M+Na]+=443.1316, C21H24O9 (420.14).
3.2.2. 3,4,5,7-Tetra-O-acetyl-2,6-anhydro-1-(4-chlorophenyl)-1-deoxy-D-galacto-hept-1-
enitol (2b)
Prepared from tosylhydrazone 1 (0.5 g, 0.95 mmol), 1-bromo-4-chlorobenzene (6 equiv., 1.09
g, 5.68 mmol) and LiOtBu (2.2 equiv., 0.17 g, 2.08 mmol) according to General procedure I.
Purified by column chromatography (1:8 EtOAc–hexane) to yield 34 mg yellow amorphous
product containing 2b (E:Z = 1:3) and 3 in 3 : 1 ratio. Rf: 0.41 (1:1 EtOAc–hexane). NMR: E
isomer:1H NMR (400 MHz, CDCl3) δ 7.30–7.23 (m, 2H, aromatics), 7.07 (d, 2H, J 8.2 Hz,
aromatics), 6.46 (s, 1H, H-1), 5.80 (strongly coupled, 1H, H-3), 5.55 (pseudo t, 1H, J5,6 3.1
Hz, H-5), 5.21 (dd, 1H, J4,5 3.3 Hz, H-4), 4.39 (dd, 1H, J6,7a 7.6, J7a,7b 12.2 Hz, H-7a), 4.36–
4.11 (m, 2H, H-6, H-7b), 2.13, 2.11, 2.09, 2.02 (4s, 12H, 4×CH3). 13C NMR (90 MHz, CDCl3)
δ 170.7, 170.0, 169.6, 169.5 (4×CO), 146.2 (C-2), 133.4–127.9 (aromatics), 116.9 (C-1), 75.2
1
(C-6), 70.1 (C-4), 66.7, 66.6 (C-3, C-5), 61.4 (C-7), 21.1–20.3 (4×CH3). Z isomer: H NMR
(400 MHz, CDCl3) δ 7.55 (d, 2H, J 8.4 Hz, aromatics), 7.26 (d, 2H, J 8.1 Hz aromatics), 5.80
(dd, 1H, J1,3 1.6, J3,4 9.8 Hz, H-3), 5.71 (d, 1H, H-1), 5.57 (dd, 1H, J5,6 1.5 Hz, H-5), 5.13 (dd,
1H, J4,5 3.1 Hz, H-4), 4.29 (dd, 1H, J7a,7b 11.4 Hz, H-7a), 4.24 (dd, 1H, H-7b), 4.16 (ddd, 1H,
15

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13
J6,7a 4.5, J6,7b 8.3 Hz, H-6), 2.20, 2.19, 2.10, 2.03 (4s, 12H, 4×CH3). C NMR (100 MHz,
CDCl3) δ 170.5, 170.2, 170.0, 169.5 (4×CO), 147.4 (C-2), 133.2–128.1 (aromatics), 110.0 (C-
1), 75.9 (C-6), 71.3 (C-4), 67.6 (C-5), 67.3 (C-3), 62.4 (C-7), 21.0, 20.9, 20.8 (4×CH3). ESI-
MS positive mode (m/z): calcd. for [M+Na]+=477.09, found: [M+Na]+=477.25, C21H23ClO9
(454.10).
3.2.3. 3,4,5,7-Tetra-O-acetyl-2,6-anhydro-1-deoxy-1-(4-methoxyphenyl)-D-galacto-hept-
1-enitol (2c)
Prepared from tosylhydrazone 1 (0.1 g, 0.19 mmol), 1-bromo-4-methoxybenzene (3 equiv.,
0.07 mL, 0.11 g, 0.57 mmol) and LiOtBu (2.2 equiv., 0.03 g, 0.41 mmol) according to
General procedure I. Purified by column chromatography (1:1 EtOAc–heptane) to yield 15
mg (18%) of 5c (E:Z = 1:4) as a grey amorphous product. Rf: 0.39 (1:1 EtOAc–hexane).
1
NMR: E isomer: H NMR (250 MHz, CDCl3) δ 7.06 (d, 2H, J 8.2 Hz, aromatics), 6.90–6.79
(m, 2H, aromatics), 6.48 (s, 1H, H-1), 5.82 (dd, 1H, J1,3 0.8, J3,4 6.6, Hz, H-3), 5.55 (pseudo t,
1H, J5,6 3.5 Hz, H-5), 5.24 (dd, 1H, J4,5 3.5 Hz, H-4), 4.47–4.08 (m, 3H, H-6, H-7a, H-7b),
3.79 (1s, 3H, O–CH3), 2.11, 2.04, 2.01, 1.99 (4s, 12H, 4×CH3). 13C NMR (75 MHz, CDCl3) δ
170.7, 170.0, 169.6, 169.5 (4×CO), 144.3 (C-2), 158.9–113.4 (aromatics), 118.7 (C-1), 75.1
(C-6), 69.8 (C-4), 66.8, 66.5 (C-3, C-5), 61.4 (C-7), 55.4 (O–CH3), 21.1, 20.9, 20.8 (4×CH3).
Z isomer: 1H NMR (250 MHz, CDCl3) δ 7.57 (d, 2H, J 8.9 Hz, aromatics), 6.83 (d, 2H, J 8.9
Hz, aromatics), 5.79 (dd, 1H, J1,3 1.5, J3,4 9.7 Hz, H-3), 5.70 (d, 1H, H-1), 5.57 (dd, 1H, J5,6
1.6 Hz, H-5), 5.11 (dd, 1H, J4,5 3.4 Hz, H-4), 4.31 (dd, 1H, J7a,7b 11.6 Hz, H-7a), 4.23 (dd, 1H,
H-7b), 4.14 (ddd, 1H, J6,7a 4.6, J6,7b 8.0 Hz, H-6), 3.81 (1s, 3H, O–CH3), 2.19, 2.18, 2.10, 2.02,
13
(4s, 12H, 4×CH3). C NMR (75 MHz, CDCl3) δ 170.6, 170.3, 170.1, 169.6 (4×CO), 145.0
(C-2), 158.9–113.4 (aromatics), 110.9 (C-1), 75.7 (C-6), 71.5 (C-4), 67.8 (C-5), 67.5 (C-3),
16

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62.4 (C-7), 55.4 (O–CH3), 21.1, 20.9, 20.8 (4×CH3). HR-ESI-MS positive mode (m/z): calcd.
for [M+Na]+=473.1418, found: [M+Na]+=473.1414, C22H26O10 (450.15).
3.2.4. 2,6-Anhydro-3,4,5,7-tetra-O-benzoyl-1-deoxy-1-phenyl-D-gluco-hept-1-enitol (5a)
Prepared from tosylhydrazone 4 (0.1 g, 0.13 mmol), bromobenzene (3 equiv., 0.04 mL, 0.06
g, 0.39 mmol) and LiOtBu (2.2 equiv., 0.02 g, 0.28 mmol) according to General procedure I.
Purified by column chromatography (1:5 EtOAc–heptane) to yield 48 mg yellow amorphous
product containing 5a (E:Z = 1:2) and 6 in 1 : 1.5 ratio. Rf: 0.42 (1:2 EtOAc–hexane). NMR:
1
E isomer: H NMR (400 MHz, CDCl3) δ 8.19–7.03 (m, 25H, aromatics), 6.67 (s, 1H, H-1),
6.16 (dd, 1H, J1,3 0.4, J3,4 3.6 Hz, H-3), 5.94–5.74 (m, 1H, H-4), 5.72 (dd, 1H, J4,5 7.8, J5,6 3.0
13
Hz, H-5), 4.86–4.82 (m, 1H, H-6), 4.81–4.55 (m, 2H, H-7a, H-7b). C NMR (100 MHz,
CDCl3) δ 166.4, 165.0, 164.7 (4×CO), 146.4 (C-2), 134.5–125.2 (aromatics), 116.6 (C-1),
1
74.8 (C-6), 70.1 (C-4), 69.1 (C-5), 67.6 (C-3), 63.4 (C-7). Z isomer: H NMR (400 MHz,
CDCl3) δ 8.19–7.03 (m, 25H, aromatics), 6.06 (dd, 1H, J1,3 0.8, J3,4 7.5 Hz, H-3), 5.92 (d, 1H,
H-1), 5.87 (pseudo t, 1H, J4,5 7.3 Hz, H-4), 5.94–5.74 (m, 1H, H-5), 4.80 (dd, 1H, J6,7a 2.5,
13
J7a,7b 12.2 Hz, H-7a), 4.77–4.55 (m, 2H, H-6, H-7b). C NMR (100 MHz, CDCl3) δ 166.3,
165.6, 165.3, 165.0 (4×CO), 145.9 (C-2), 134.5–125.2 (aromatics), 112.2 (C-1), 76.3 (C-6),
73.1 (C-4), 70.5 (C-3), 69.4 (C-5), 63.7 (C-7). HR-ESI-MS positive mode (m/z): calcd. for
[M+Na]+=691.1939, found: [M+Na]+=691.1935, C41H32O9 (668.21).
3.2.5. 2,6-Anhydro-3,4,5,7-tetra-O-benzoyl-1-deoxy-1-(4-methylphenyl)-D-gluco-hept-1-
enitol (5b)
Prepared from tosylhydrazone 4 (0.3 g, 0.39 mmol), 1-bromo-4-methylbenzene (6 equiv.,
0.29 mL, 0.40 g, 2.32 mmol) and LiOtBu (2.2 equiv., 0.07 g, 0.85 mmol) according to
General procedure I. Purified by column chromatography (1:8 EtOAc–heptane) to yield 152
mg yellow amorphous product containing 5b (E:Z = 1:2) and 6 in 2 : 1 ratio. Rf: 0.42 (1:2
17

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1
EtOAc–hexane). NMR: E isomer: H NMR (400 MHz, CDCl3) δ 8.18–6.89 (m, 24H,
aromatics), 6.65 (s, 1H, H-1), 6.16 (dd, 1H, J1,3 0.4, J3,4 3.9 Hz, H-3), 5.85–5.75 (m, 1H, H-4),
5.71 (dd, 1H, J4,5 7.7, J5,6 2.6 Hz, H-5), 4.85–4.82 (m, 1H, H-6), 4.81–4.49 (m, 2H, H-7a, H-
13
7b), 2.21 (s, 3H, CH3). C NMR (90 MHz, CDCl3) δ 166.2, 165.0, 164.7 (4×CO), 145.9 (C-
2), 143.5–125.4 (aromatics), 116.6 (C-1), 74.8 (C-6), 70.5 (C-4), 69.1 (C-5), 67.3 (C-3), 63.6
1
(C-7), 21.1 (CH3). Z isomer: H NMR (400 MHz, CDCl3) δ 8.18–6.89 (m, 24H, aromatics),
6.05 (dd, 1H, J1,3 0.8, J3,4 7.6 Hz, H-3), 5.90 (s, 1H, H-1), 5.87 (pseudo t, 1H, J4,5 7.3 Hz, H-
4), 5.85–5.75 (m, 1H, H-5), 4.78 (dd, 1H, J6,7a 2.5, J7a,7b 12.2 Hz, H-7a), 4.75–4.61 (m, 1H, H-
13
7b), 4.60–4.49 (m, 1H, H-6), 2.26 (s, 3H, CH3). C NMR (90 MHz, CDCl3) δ 166.2, 165.5,
165.3, 165.0 (4×CO), 145.2 (C-2), 143.5–125.4 (aromatics), 112.2 (C-1), 76.3 (C-6), 73.2 (C-
4), 70.5 (C-3), 69.5 (C-5), 63.7 (C-7), 21.3 (CH3). HR-ESI-MS positive mode (m/z): calcd.
for [M+Na]+=705.2095, found: [M+Na]+=705.2089, C42H34O9 (682.22).
3.2.6. 2,6-Anhydro-3,4,5,7-tetra-O-benzoyl-1-deoxy-1-(4-methoxyphenyl)-D-gluco-hept-
1-enitol (5c)
Prepared from tosylhydrazone 4 (0.1 g, 0.13 mmol), 1-bromo-4-methoxybenzene (3 equiv.,
0.05 mL, 0.07 g, 0.39 mmol) and LiOtBu (2.2 equiv., 0.02 g, 0.28 mmol) according to
General procedure I. Purified by column chromatography (1:8 EtOAc–heptane) to yield 10
mg (11%) of 5c (E:Z = 1:2) as a brown amorphous product. Rf: 0.41 (1:2 EtOAc–heptane).
NMR: E isomer: 1H NMR (300 MHz, CDCl3) δ 8.22–6.86 (m, 22H, aromatics), 6.73 (d, 2H, J
8.8 Hz, aromatics), 6.62 (s, 1H, H-1), 6.14 (d, 1H, J1,2 0.4, J3,4 4.0 Hz, H-3), 5.90–5.64 (m,
13
2H, H-4, H-5), 4.83–4.42 (m, 3H, H-6, H-7a, H-7b), 3.69 (1s, 3H, O–CH3). C NMR (75
MHz, CDCl3) δ 166.2, 165.0, 164.7, 164.5 (4×CO), 143.5 (C-2), 161.0–110.3 (aromatics),
114.2 (C-1), 75.6 (C-6), 71.7 (C-4), 69.5 (C-5), 68.4 (C-3), 62.7 (C-7), 55.3 (O–CH3). Z
1
isomer: H NMR (300 MHz, CDCl3) δ 8.22–6.86 (m, 22H, aromatics), 6.65 (d, 2H, J 8.9 Hz
18

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aromatics), 6.03 (dd, 1H, J1,3 1.2, J3,4 7.5 Hz, H-3), 5.85 (d, 1H, H-1), 5.90–5.64 (m, 2H, H-4,
H-5), 4.83–4.42 (m, 3H, H-6, H-7a, H-7b), 3.71 (1s, 3H, O–CH3). 13C NMR (75 MHz, CDCl3)
δ 166.2, 165.4, 165.2, 164.9 (4×CO), 144.1 (C-2), 161.0–110.3 (aromatics), 113.9 (C-1), 76.3
(C-6), 73.3 (C-4), 70.5 (C-3), 69.5 (C-5), 62.7 (C-7), 55.3 (O–CH3). HR-ESI-MS positive
mode (m/z): calcd. for [M+Na]+=721.2044, found: [M+Na]+=721.2041, C42H34O10 (698.22).
3.2.7. 2,6-Anhydro-3,4,5,7-tetra-O-benzoyl-1-deoxy-1-(4-fluorophenyl)-D-gluco-hept-1-
enitol (5d)
Prepared from tosylhydrazone 4 (0.3 g, 0.39 mmol), 1-bromo-4-fluorobenzene (6 equiv., 0.25
mL, 0.41 g, 2.32 mmol) and LiOtBu (2.2 equiv., 0.07 g, 0.85 mmol) according to General
procedure I. Purified by column chromatography (1:4 EtOAc–heptane) to 122 mg yellow
amorphous product containing 5d (E:Z = 1:2) and 6 in 2 : 1 ratio. Rf: 0.39 (1:2 EtOAc–
hexane). NMR: E isomer: 1H NMR (400 MHz, CDCl3) δ 8.25–7.01 (m, 24H, aromatics), 6.68
(s, 1H, H-1), 6.17 (dd, 1H, J1,3 0.4 Hz, J3,4 3.6 Hz, H-3), 5.87–5.74 (m, 1H, H-4), 5.73 (dd,
1H, J4,5 7.8, J5,6 2.5 Hz, H-5), 4.87–4.81 (m, 1H, H-6), 4.74 (dd, 1H, J6,7a 3.1, J7a,7b 7.9 Hz, H-
13
7a), 4.87–4.49 (m, 1H, H-7b). C NMR (90 MHz, CDCl3) δ 166.2, 165.0, 164.7 (4×CO),
146.4 (C-2), 143.7–123.2 (aromatics), 116.5 (C-1), 74.8 (C-6), 70.5 (C-4), 69.2 (C-5), 67.2
1
(C-3), 63.6 (C-7). Z isomer: H NMR (400 MHz, CDCl3) δ 8.25–7.01 (m, 24H, aromatics),
6.07 (dd, 1H, J1,3 1.0, J3,4 7.5 Hz, H-3), 5.93 (d, 1H, H-1), 5.88 (pseudo t, 1H, J4,5 7.4 Hz, H-
4), 5.87–5.74 (m, 1H, H-5), 4.80 (dd, 1H, J7a,7b 12.2 Hz, H-7a), 4.76 (dd, 1H, H-7b), 4.49 (dd,
13
1H, J5,6 9.1 J6,7a 2.3, J6,7a 6.6 Hz, H-6). C NMR (90 MHz, CDCl3) δ 166.2, 165.5, 165.3,
165.0 (4×CO), 145.9 (C-2), 143.7–123.2 (aromatics), 112.3 (C-1), 76.3 (C-6), 73.2 (C-4),
70.5 (C-3), 69.5 (C-5), 63.7 (C-7). ESI-MS positive mode (m/z): calcd. for [M+H]+=687.20,
found: [M+H]+=686.25, C41H31FO9 (686.20).
19

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3.2.8.
2,6-Anhydro-3,4,5,7-tetra-O-benzoyl-1-deoxy-1-(4-nitrophenyl)-D-gluco-hept-1-
enitol (5e)
Prepared from tosylhydrazone 4 (0.3 g, 0.39 mmol), 1-bromo-4-nitrobenzene (6 equiv., 0.47
g, 2.32 mmol) and LiOtBu (1.5 equiv., 0.05 g, 0.58 mmol) according to General procedure I.
Purified by column chromatography (1:8 EtOAc–heptane) to yield 90 mg (33%) of 5e (E:Z =
1:2) as a yellow amorphous product. Rf: 0.39 (1:2 EtOAc–hexane). NMR: E isomer: 1H NMR
(400 MHz, CDCl3) δ 8.19–7.14 (m, 24H, aromatics), 6.63 (s, 1H, H-1), 6.18 (strongly
coupled, 1H, H-3), 5.84–5.76 (m, 2H, H-4, H-5), 4.89–4.77 (m, 1H, H-6), 4.75–4.60 (m, 2H,
H-7a, H-7b). 13C NMR (100 MHz, CDCl3) δ 166.2, 165.0, 164.8, 164.5 (4×CO), 149.1 (C-2),
147.0–123.2 (aromatics), 114.0 (C-1), 75.2 (C-6), 71.0, 69.1 (C-4, C-5), 67.1 (C-3), 60.4 (C-
7). Z isomer: 1H NMR (400 MHz, CDCl3) δ 8.19–7.14 (m, 24H, aromatics), 6.07 (dd, 1H, J1,3
0.7, J3,4 7.0 Hz, H-3), 5.98 (d, 1H, H-1), 5.88 (pseudo t, 1H, J4,5 6.7 Hz, H-4), 5.84–5.76 (m,
13
1H, H-5), 4.88–4.77 (m, 1H, H-7a), 4.75–4.60 (m, 2H, H-6, H-7b). C NMR (100 MHz,
CDCl3) δ 166.1, 165.4, 165.3, 164.9 (4×CO), 149.5 (C-2), 147.0–123.2 (aromatics), 110.3 (C-
1), 76.5 (C-6), 72.6 (C-4), 70.3 (C-3), 69.2 (C-5), 63.4 (C-7). HR-ESI-MS positive mode
(m/z): calcd. for [M+Na]+=736.1789, found: [M+Na]+=736.1781, C41H31NO11 (713.19).
3.2.9. 2,6-Anhydro-3,4,5,7-tetra-O-benzoyl-1-(4-cyanophenyl)-1-deoxy-D-gluco-hept-1-
enitol (5f)
Prepared from tosylhydrazone 4 (0.3 g, 0.39 mmol), 4-bromobenzonitrile (6 equiv., 0.42 g,
2.32 mmol) and LiOtBu (2.2 equiv., 0.07 g, 0.85 mmol) according to General procedure I.
Purified by column chromatography (1:4 EtOAc–heptane) to yield 122 mg (46%) of 5f (E:Z =
1
1:2) as a pale yellow amorphous product. Rf: 0.33 (1:2 EtOAc–hexane). NMR: E isomer: H
NMR (400 MHz, CDCl3) δ 8.16–7.16 (m, 24H, aromatics), 6.60 (s, 1H, H-1), 6.14 (strongly
coupled, 1H, H-3), 5.82–5.71 (m, 2H, H-4, H-5), 4.86–4.75 (m, 1H, H-6), 4.74–4.60 (m, 2H,
20

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13
H-7a, H-7b). C NMR (90 MHz, CDCl3) δ 166.2, 165.0, 164.8, 164.6 (4×CO), 148.7 (C-2),
139.4–118.5 (aromatics), 114.4 (C-1), 110.7 (CN), 75.2 (C-6), 71.0 (C-4), 69.1 (C-5), 67.1
1
(C-3), 63.4 (C-7). Z isomer: H NMR (400 MHz, CDCl3) δ 8.16–7.16 (m, 24H, aromatics),
6.05 (dd, 1H, J1,3 0.5, J3,4 7.00 Hz, H-3), 5.91 (d, 1H, H-1), 5.86 (pseudo t, 1H, J4,5 6.9 Hz, H-
4), 5.82–5.71 (m, 1H, H-5), 4.85–4.77 (m, 1H, H-7a), 4.74–4.60 (m, 2H, H-6, H-7b). 13C NMR
(90 MHz, CDCl3) δ 166.1, 165.4, 165.2, 164.9 (4×CO), 149.0 (C-2), 139.4–118.5 (aromatics),
110.7 (C-1), 110.4 (CN), 76.4 (C-6), 72.7 (C-4), 70.4 (C-3), 69.2 (C-5), 63.4 (C-7). HR-ESI-
MS positive mode (m/z): calcd. for [M+Na]+=716.1891, found: [M+Na]+=716.1887,
C42H31NO9 (693.20).
3.2.10. 2,6-Anhydro-3,4,5,7-tetra-O-benzoyl-1-(3-cyanophenyl)-1-deoxy-D-gluco-hept-1-
enitol (5g)
Prepared from tosylhydrazone 4 (0.2 g, 0.26 mmol), 3-bromobenzonitrile (6 eqiuv., 0.28 g,
1.54 mmol) and LiOtBu (1.5 equiv., 0.03 g, 0.39 mmol) according to General procedure I.
Purified by column chromatography (1:7 EtOAc–hexane) to yield 36 mg (20%) of 5g (E:Z =
1:2) as a yellow amorphous product. Rf: 0.33 (1:2 EtOAc–hexane). NMR: E isomer: 1H NMR
(400 MHz, CDCl3) δ 8.18–7.08 (m, 24H, aromatics), 6.57 (s, 1H, H-1), 6.09 (strongly
coupled, 1H, H-3), 5.82–5.73 (m, 2H, H-4, H-5), 4.82–4.75 (m, 1H, H-6), 4.72–4.61 (m, 2H,
H-7a, H-7b). 13C NMR (100 MHz, CDCl3) δ 166.2, 165.0, 164.6, 164.5 (4×CO), 148.5 (C-2),
135.5–118.3 (aromatics), 113.8 (C-1), 112.8 (CN), 75.2 (C-6), 71.1 (C-4), 69.1 (C-5), 67.1
1
(C-3), 63.4 (C-7). Z isomer: H NMR (400 MHz, CDCl3) δ 8.18–7.08 (m, 24H, aromatics),
6.04 (dd, 1H, J1,3 0.8, J3,4 6.6 Hz, H-3), 5.89 (d, 1H, H-1), 5.84 (pseudo t, 1H, J4,5 6.5 Hz, H-
4), 5.82–5.73 (m, 1H, H-5), 4.93–4.83 (m, 1H, H-7a), 4.78 (d, 1H, H-7b), 4.72–4.61 (m, 1H,
H-6). 13C NMR (100 MHz, CDCl3) δ 166.1, 165.4, 165.2, 164.9 (4×CO), 148.1 (C-2), 135.5–
118.3 (aromatics), 112.6 (CN), 110.3 (C-1), 76.3 (C-6), 72.6 (C-4), 70.4 (C-3), 69.2 (C-5),
21

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63.3 (C-7). ESI-MS positive mode (m/z): calcd. for [M+Na]+=716.19, found:
[M+Na]+=716.67, C42H31NO9 (693.20).
3.3. 2,6-anhydro-3,4,5,7-tetra-O-methyl-D-glycero-L-manno-heptononitrile (8)
2,6-anhydro- -glycero- -manno-heptononitrile 7 (0.1 g, 0.53 mmol) and sodium hydride (3
D
L
equiv. / OH, 0.15 g, 6.34 mmol) were added to abs. dimethyl sulfoxide (1.4 mL). The
suspension was stirred and cooled to 0 °C, iodomethane (3 equiv. / OH, 0.39 mL, 0.90 g, 6.34
mmol) was added dropwise, then the reaction mixture was allowed to warm up to rt. When
TLC (1:1 EtOAc–hexane) indicated complete consumption of the starting compound (1 day),
a few drops methanol was added to the suspension. The reaction mixture was diluted with
diethyl ether, washed with water (3 × 3 mL) and dried on anhydrous magnesium sulfate. The
solution was concentrated under reduced pressure. The residue was purified by silica gel
column chromatography (eluent: 1:2 EtOAc–hexane) to give 60 mg (46%) of 8 as a yellow
1
amorphous product. Rf: 0.53 (1:1 EtOAc–hexane); [α]D +21 (c 0.55, CHCl3). H NMR (400
MHz, CDCl3) δ 3.90 (d, J2,3 9.9 Hz, H-2), 3.74–3.64 (m, 2H, H-3, H-6), 3.59–3.46 (m, 3H, H-
5, H-7a, H-7b), 3.67, 3.57, 3.53, 3.39 (4s, 12H, 4×CH3), 3.13 (dd, 1H, J3,4 9.3, J4,5 2.7 Hz, H-
13
4). C NMR (90 MHz, CDCl3) δ 116.8 (C-1), 84.9 (C-4), 78.0 (C-3, C-5), 74.8 (C-6), 70.5
(C-7), 67.8 (C-2), 61.6, 59.4, 58.3 (4×CH3). C11H19NO5 (245.13). Spectral data correspond to
the published values.[30]
3.4. 2,6-Anhydro-3,4,5,7-tetra-O-methyl-D-glycero-L-manno-heptose tosylhydrazone (9)
Raney-nickel (6.0 g, an aqueous suspension, Merck) was added at room temperature to a
vigorously stirred solution of pyridine (23 mL), acetic acid (14 mL), and water (14 mL). Then
sodium hypophosphite (2.96 g, 33.6 mmol), tosylhydrazine (1.49 g, 8.00 mmol), and nitrile 8
(0.98 g, 4.00 mmol) were added to the mixture. When TLC (1:1 EtOAc–hexane) indicated
22

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complete consumption of the starting compound (5 h), the insoluble material was filtered off
through a pad of celite and washed with dichloromethane (3 × 40 mL). The organic layer of
the filtrate was separated, washed with water (12 mL), 10% aqueous hydrogen chloride
solution (2 × 12 mL), cold, saturated sodium hydrogencarbonate solution (2 × 12 mL), water
(12 mL), and then dried on anhydrous magnesium sulfate. The solution was concentrated
under reduced pressure, and traces of pyridine were removed by repeated co-evaporations
with toluene. The residue was purified by silica gel column chromatography (eluent: 2:1
EtOAc–hexane) to give two unidentified isomers 9a and 9b.
9a 526 mg (32%); Rf: 0.33 (2:1 EtOAc–hexane).1H NMR (400 MHz, CDCl3) δ 8.55 (bs, 1H,
NH), 7.79 (d, 2H, J 8.3 Hz, aromatics), 7.29 (d, 2H, J 8.1 Hz, aromatics), 7.10 (d, 1H, J1,2 6.2
Hz, H-1), 3.69 (dd, 1H, J2,3 9.6 Hz, H-2), 3.66 (dd, 1H, J5,6 0.8 Hz, H-5), 3.58–3.42 (m, 3H,
H-6, H-7a, H-7b), 3.36 (pseudo t, 1H, J3,4 9.4 Hz, H-3), 3.21 (dd, 1H, J4,5 3.0 Hz, H-4), 3.53,
13
3.51, 3.35, 3.18 (4s, 12H, 4×CH3), 2.40 (s, 3H, CH3). C NMR (100 MHz, CDCl3) δ 146.4
(C-1), 144.4–126.6 (aromatics), 85.1, 78.5, 77.8, 76.7, 75.5 (C-2–C-6), 71.1 (C-7), 61.4, 60.2,
59.1, 58.1 (4×CH3), 21.6 (CH3). ESI-MS positive mode (m/z): calcd. for [M+H]+=417.17,
found: [M+H]+=417.58, C18H28N2O7S (416.16).
9b 202 mg (12%); Rf: 0.74 (2:1 EtOAc–hexane).1H NMR (400 MHz, CDCl3) δ 9.38 (bs, 1H,
NH), 7.81 (d, 2H, J 8.2 Hz, aromatics), 7.31 (d, 2H, J 8.0 Hz, aromatics), 6.81 (d, 1H, J1,2 4.6
Hz, H-1), 3.99 (dd, 1H, J2,3 10.1 Hz, H-2), 3.69 (dd, 1H, J5,6 0.7 Hz, H-5), 3.63–3.34 (m, 4H,
H-3 H-6, H-7a, H-7b), 3.55, 3.51, 3.39, 3.31 (4s, 12H, 4×CH3), 3.26 (dd, 1H, J4,5 2.7 Hz, H-4),
2.42 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ 146.7 (C-1), 144.5–127.5 (aromatics), 85.9,
79.1, 77.1, 74.9, 74.1 (C-2–C-6), 70.8 (C-7), 61.4, 61.0, 59.2, 57.8 (4×CH3), 21.6 (CH3). ESI-
MS positive mode (m/z): calcd. for [M+H]+=417.17, found: [M+H]+=417.58, C18H28N2O7S
(416.16)
23

ACCEPTED MANUSCRIPT
3.5 2,6-Anhydro-1-deoxy-3,4,5,7-tetra-O-methyl-1-phenyl-D-galacto-hept-1-enitol (10a)
Prepared from tosylhydrazone 9 (0.1 g, 0.24 mmol), bromobenzene (3 equiv., 0.08 mL, 0.11
g, 0.72 mmol) and LiOtBu (2.2 equiv., 0.04 g, 0.53 mmol) according to General procedure I.
Purified by column chromatography (1:1 EtOAc–heptane) to yield 45 mg (61%) of 10a (E:Z
1
= 1:3) as a white amorphous product. E isomer: 11 mg (15%); H NMR (300 MHz, DMSO-
d6) δ 7.41–7.30 (m, 2H, aromatics), 7.28–7.19 (m, 3H, aromatics), 6.34 (s, 1H, H-1), 4.29
(ddd, 1H, J5,6 5.3, J6,7a 8.1, J6,7b 2.4 Hz, H-6), 4.22 (dd, 1H, J1,3 0.4, J3,4 3.9 Hz, H-3), 3.85
(dd, 1H, J4,5 3.1 Hz, H-5), 3.75 (pseudo t, 1H, H-4), 3.69 (dd, 1H, J7a,7b 11.3 Hz, H-7a), 3.45
13
(dd, 1H, H-7b), 3.37, 3.36, 3.29, 3.12 (4s, 12H, 4×CH3). C NMR (75 MHz, DMSO-d6) δ
147.5 (C-2), 135.5–126.2 (aromatics), 117.6 (C-1), 76.8, 76.7, 74.0, 73.3 (C-3–C-6), 69.5 (C-
7), 58.3, 58.1, 57.5, 55.2 (4×CH3). HR-EI-MS positive mode (m/z): calcd. for
[M]+=308.1618, found: [M]+=308.1620, C17H24O5 (308.16). Z isomer: 34 mg (46%); 1H NMR
(300 MHz, DMSO-d6) δ 7.66 (d, 2H, J 8.6 Hz, aromatics), 7.33–7.22 (m, 2H, aromatics),
7.19–7.10 (m, 1H, aromatic), 5.83 (s, 1H, H-1), 4.04 (ddd, 1H, J5,6 2.9, J6,7a 2.7, J6,7b 5.3 Hz
H-6), 3.89 (dd, 1H, J1,3 0.9, J3,4 7.8 Hz, H-3), 3.85 (pseudo t, 1H, J4,5 2.9 Hz, H-5), 3.62 (dd,
1H, J7a,7b 12.0 Hz, H-7a), 3.57 (dd, 1H, H-7b), 3.50 (dd, 1H, H-4), 3.43, 3.42, 3.41, 3.27 (4s,
12H, 4×CH3). 13C NMR (75 MHz, DMSO-d6) δ 149.9 (C-2), 135.3–126.0 (aromatics), 109.8
(C-1), 81.3, 78.3, 77.3, 74.7 (C-3–C-6), 71.0 (C-7), 59.4, 58.3, 58.0, 57.5 (4×CH3). HR-EI-
MS positive mode (m/z): calcd. for [M]+=308.1618, found: [M]+=308.1617, C17H24O5
(308.16).
3.6. 2,6-Anhydro-1-deoxy-3,4,5,7-tetra-O-methyl-1-(4-methylphenyl)-D-galacto-hept-1-
enitol (10b)
Prepared from tosylhydrazone 9 (0.1 g, 0.24 mmol), 1-bromo-4-methylbenzene (3 equiv.,
0.09 mL, 0.12 g, 0.72 mmol) and LiOtBu (2.2 equiv., 0.04 g, 0.53 mmol) according to
24

ACCEPTED MANUSCRIPT
General procedure I. Purified by column chromatography (1:1 EtOAc–heptane) to yield 58
mg (75%) of 10b (E:Z = 1:3) as white amorphous products. E isomer: 15 mg (19%); 1H NMR
(300 MHz, DMSO-d6) δ 7.30–7.10 (m, 4H, aromatics), 6.30 (s, 1H, H-1), 4.25 (ddd, 1H, J5,6
5.3, J6,7a 8.1, J6,7b 2.4 Hz, H-6), 4.22 (dd, 1H, J1,3 0.4, J3,4 3.9 Hz, H-3), 3.85 (dd, 1H, J4,5 3.1
Hz, H-5), 3.73 (pseudo t, 1H, H-4), 3.68 (dd, 1H, J7a,7b 12.0 Hz, H-7a), 3.45 (dd, 1H, H-7b),
3.38, 3.36, 3.28, 3.10 (4s, 12H, 4×CH3), 2.31 (s, 3H, CH3). 13C NMR (63 MHz, DMSO-d6) δ
146.8 (C-2), 135.8–128.0 (aromatics), 117.7 (C-1), 76.7, 76.6, 73.9, 73.2 (C-3–C-6), 69.4 (C-
7), 58.2, 58.1, 57.4, 55.1 (4×CH3), 20.7 (CH3). HR-EI-MS positive mode (m/z): calcd. for
[M]+=322.1775, found: [M]+=322.1770, C18H26O5 (322.18). Z isomer: 43 mg (56%); 1H NMR
(300 MHz, DMSO-d6) δ 7.58–7.48 (m, 2H, aromatics), 7.15–7.08 (m, 2H, aromatics), 5.82 (s,
1H, H-1), 4.02 (ddd, 1H, J5,6 2.9, J6,7a 2.7, J6,7b 5.3 Hz H-6), 3.90 (dd, 1H, J1,3 0.9, J3,4 7.8 Hz,
H-3), 3.84 (pseudo t, 1H, J4,5 2.9 Hz, H-5), 3.60 (dd, 1H, J7a,7b 12.0 Hz, H-7a), 3.54 (dd, 1H,
13
H-7b), 3.50 (dd, 1H, H-4), 3.43, 3.42, 3.41, 3.27 (4s, 12H, 4×CH3), 2.30 (s, 3H, CH3). C
NMR (63 MHz, DMSO-d6) δ 149.0 (C-2), 135.5–128.1 (aromatics), 109.8 (C-1), 81.2, 78.3,
77.2, 74.7 (C-3–C-6), 71.0 (C-7), 59.3, 58.3, 57.9, 57.4 (4×CH3), 20.7 (CH3). HR-EI-MS
positive mode (m/z): calcd. for [M]+=322.1775, found: [M]+=322.1772, C18H26O5 (322.18).
3.7. General procedure II for catalytic hydrogenation
A degassed, vigorously stirred suspension of 10 % Pd/C (75 weight % of 2a and 3; 50 weight
% of 5a and 6) in abs. EtOAc (3 mL) was saturated with H2 (3 ×), and a solution of 2a and 3
(0.17 mmol + 0.02 mmol) or 5a and 6 (0.12 mmol + 0.15 mmol) in abs. EtOAc (3 mL) was
added. The reaction mixture was stirred overnight under H2 atmosphere at rt. The insoluble
materials were filtered off through a pad of celite and washed thoroughly with EtOAc (3 × 3
mL). The solvent was removed under reduced pressure, and the residue was purified by silica
gel column chromatography with eluents indicated for the particular compounds.
25

ACCEPTED MANUSCRIPT
3.7.1. 3,4,5,7-Tetra-O-acetyl-2,6-anhydro-1-deoxy-1-phenyl-D-glycero-L-manno-heptitol
(11)
Prepared from 2a (0.07 g, 0.17 mmol), according to the General procedure II. Purified by
column chromatography (1:9 EtOAc–toluene) to yield 60 mg (83%) of 11 as a white
1
amorphous product. Rf: 0.38 (1:1 EtOAc–hexane); [α]D +11 (c 0.78, CHCl3). H NMR (400
MHz, CDCl3) δ 7.34–7.15 (m, 5H, aromatic), 5.41 (dd, 1H, J5,6 0.8 Hz, H-5), 5.19 (pseudo t,
1H, J3,4 10.0 Hz, H-3), 5.02 (dd, 1H, J4,5 3.4 Hz, H-4), 4.14 (dd, 1H, J7a,7b 11.2 Hz, H-7a), 4.01
(dd, 1H, H-7b), 3.80 (ddd, 1H, J6,7a 6.4, J6,7b 7.0 Hz, H-6), 3.63 (ddd, 1H, J1a,2 3.7, J1b,2 8.4,
J2,3 9.6 Hz, H-2), 2.86 (dd, 1H, J1a,1b 14.5 Hz, H-1a), 2.79 (dd, 1H, H-1b), 2.16, 1.98, 1.97 (4s,
13
12H, 4×CH3). C NMR (100 MHz, CDCl3) δ 170.5, 170.4, 170.3, 170.0 (4×CO), 138.1–
126.2 (aromatics), 79.1 (C-2), 74.2 (C-6), 72.4 (C-4), 69.7 (C-3), 67.9 (C-5), 61.7 (C-7), 38.2
(C-1), 20.8, 20.7 (4×CH3). ESI-MS positive mode (m/z): calcd. for [M+Na]+=445.15, found:
[M+Na]+=445.33, C21H26O9 (422.16).
3.7.2. 3,4,5,7-Tetra-O-acetyl-2,6-anhydro-1-deoxy-D-glycero-L-manno-heptitol (12)
Prepared from 3 (0.008 g, 0.02 mmol), according to the General procedure II. Purified by
column chromatography (1:9 EtOAc–toluene) to yield 7 mg (83%) of 12 as a white
1
amorphous product. Rf: 0.33 (1:1 EtOAc–hexane); [α]D +9 (c 0.26, CHCl3). H NMR (400
MHz, CDCl3) δ 5.42 (dd, 1H, J5,6 1.0 Hz, H-5), 5.06 (pseudo t, 1H, J3,4 10.1 Hz, H-3), 5.00
(dd, 1H, J4,5 3.2 Hz, H-4), 4.11 (dd, 1H, J7a,7b 11.7 Hz, H-7a), 4.07 (dd, 1H, H-7b), 3.87 (ddd,
1H, J6,7a 6.6, J6,7b 6.8 Hz, H-6), 3.53 (dq, 1H, J1,2 6.2, J2,3 9.0 Hz, H-2), 2.16, 2.06, 2.05, 1.98
13
(4s, 12H, 4×CH3), 1.24 (d, 3H, H-1). C NMR (100 MHz, CDCl3) δ 170.6, 170.5, 170.4,
170.0 (4×CO), 74.8, 74.2 (C-2, C-6), 72.2 (C-4), 70.9 (C-3), 68.0 (C-5), 62.0 (C-1), 21.0,
26

ACCEPTED MANUSCRIPT
20.9, 20.8 (4×CH3), 17.8 (C-1). ESI-MS positive mode (m/z): calcd. for [M+Na]+=369.12,
found: [M+Na]+=369.33, C15H22O9 (346.13).
3.7.3. 2,6-Anhydro-3,4,5,7-tetra-O-benzoyl-1-deoxy-1-phenyl-D-glycero-D-gulo-heptitol
(13)
Prepared from 5a (0.08 g, 0.12 mmol), according to the General procedure II. Purified by
column chromatography (1:99 EtOAc–toluene) to yield 34 mg (42%) of 13 as a white
1
amorphous product. Rf: 0.36 (1:2 EtOAc–hexane); [α]D +18 (c 0.57, CHCl3). H NMR (400
MHz, CDCl3) δ 8.06–7.75 (m, 8H, aromatics), 7.64–7.08 (m, 17H, aromatics), 5.89 (pseudo t,
1H, J4,5 9.7 Hz, H-4), 5.61 (pseudo t, 1H, J5,6 9.6 Hz, H-5), 5.47 (pseudo t, 1H, J3,4 9.5 Hz, H-
3), 4.59 (dd, 1H, J7a,7b 12.1 Hz, H-7a), 4.42 (dd, 1H, H-7b), 4.04 (ddd, 1H, J6,7a 2.8, J6,7b 6.3
Hz, H-6), 4.00 (ddd, 1H, J1a,2 4.8, J1b,2 6.8, J2,3 9.8 Hz, H-2), 2.96 (dd, 1H, J1a,1b 12.3 Hz, H-
13
1a), 2.92 (dd, 1H, H-1b). C NMR (100 MHz, CDCl3) δ 166.3, 166.1, 165.6, 165.4 (4×CO),
138.3–126.0 (aromatics), 79.2 (C-2), 76.2 (C-6), 74.7 (C-4), 72.6 (C-3), 70.2 (C-5), 63.6 (C-
7), 38.0 (C-1). ESI-MS positive mode (m/z): calcd. for [M+Na]+=693.21, found:
[M+Na]+=693.50, C41H34O9 (670.22).
3.7.4. 2,6-Anhydro-3,4,5,7-tetra-O-benzoyl-1-deoxy-D-glycero-D-gulo-heptitol (14)
Prepared from 6 (0.09 g, 0.15 mmol), according to the General procedure II. Purified by
column chromatography (1:99 EtOAc–toluene) to yield 38 mg (43%) of 14 as a white
1
amorphous product. Rf: 0.41 (1:2 EtOAc–hexane); [α]D +43 (c 0.59, CHCl3). H NMR (400
MHz, CDCl3) δ 8.10–7.76 (m, 8H, aromatics), 7.61–7.06 (m, 12H, aromatics), 5.87 (pseudo t,
1H, J4,5 9.7 Hz, H-4), 5.67 (pseudo t, 1H, J5,6 9.8 Hz, H-5), 5.36 (pseudo t, 1H, J3,4 9.5 Hz, H-
3), 4.61 (dd, 1H, J7a,7b 12.2 Hz, H-7a), 4.45 (dd, 1H, H-7b), 4.11 (ddd, 1H, J6,7a 3.0, J6,7b 5.1
13
Hz, H-6), 3.90 (dq, 1H, J1,2 6.1, J2,3 9.7 Hz, H-2), 1.36 (d, 3H, H-1). C NMR (100 MHz,
27

ACCEPTED MANUSCRIPT
CDCl3) δ 166.4, 166.1, 165.6, 165.4 (4×CO), 133.6–127.2 (aromatics), 76.2 (C-6), 75.0 (C-2),
74.5 (C-4), 74.1 (C-3), 70.1 (C-5), 63.6 (C-7), 18.0 (C-1). ESI-MS positive mode (m/z): calcd.
for [M+Na]+=617.18, found: [M+Na]+=617.42, C35H30O9 (594.19).
28