Carbohydrate-based aza-macrocycles by Richman-Atkins cyclization of glucopyranose precursors

Article abstract of DOI:10.1016/j.carres.2016.11.016

2, 3-Di-ω-halo- as well as 2, 3-di-ω-toluenesulfonamide-alkylated glucopyranoside derivatives were prepared. Their condensation with α,ω-bis-toluenesulfonamide components under varying Richman-Atkins conditions with alkali carbonate in DMF led to carbohyd

Full text of DOI:10.1016/j.carres.2016.11.016

Accepted Manuscript
Carbohydrate-based aza-macrocycles by Richman-Atkins cyclization of
glucopyranose precursors
Andreas Rathjens, Joachim Thiem
PII:
S0008-6215(16)30504-3
10.1016/j.carres.2016.11.016
CAR 7299
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 27 October 2016
Revised Date: 28 November 2016
Accepted Date: 28 November 2016
Please cite this article as: A. Rathjens, J. Thiem, Carbohydrate-based aza-macrocycles by Richman-
Atkins cyclization of glucopyranose precursors, Carbohydrate Research (2016), doi: 10.1016/
j.carres.2016.11.016.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Carbohydrate-Based Aza-Macrocycles by Richman-Atkins
Cyclization of Glucopyranose Precursors
Andreas Rathjens and Joachim Thiem *
University of Hamburg, Faculty of Science, Department of Chemistry, Martin-
Luther-King-Platz 6, D-20146 Hamburg, Germany
Received
Keywords: Aza-Macrocycles/ Glycophanes/Carbohydrates/Richman-Atkins
Cyclization/ Coronands
A B S T R A C T
2, 3-Di-ω-halo- as well as 2, 3-di-ω-toluenesulfonamide-alkylated
glucopyranoside derivatives were prepared. Their condensation with α,ω-bis-
toluenesulfonamide components under varying Richman-Atkins conditions with
alkali carbonate in DMF led to carbohydrate-linked aza-macrocycles displaying
14-, 17-, 18-, 21-, 24-, and 25-membered ring structures. Isomeric aza-
macrocylic coronands of 20- as well as 30-membered ring size containing two
saccharides could be obtained employing Richman-Atkins condensations of two
functionalized sugar building units.
_______
* Corresponding author. Tel.: +49 40 42838 4241; fax: +49 40 42838 4325.
E-mail address: thiem@chemie.uni-hamburg.de (J. Thiem).
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1. Introduction
Supramolecular chemistry became en vogue with the synthesis of crown
ethers by Pedersen et al., 1-3 which induced a plethora of studies with regard to
synthesis and a large variety of different complexation properties. The
application of crown ether structures in preparative chemistry such as by phase
transfer catalysis and analytical chemistry e.g. in ion chromatography are well
described. Aza-macrocycles 4 were reported as early as 1886 with tetra-aza
quaterene by von Baeyer, 5 and already Curtis 6, 7 described interactions of aza
coronands with Ni(II) salts. It is interesting to recall that transition metals are
decisive in many biological processes, and further are ubiquitously used as
catalysts. For decontamination of toxic metals or their derivatives aza
macrocycles are under survey, 8 and more recently applications in medical
diagnostics employing carbohydrate copper, gold, as well as silver complexes in
tumor treatment were reported. 9,10 As an additional feature in supramolecular
chemistry chirality is of particular relevance, 11-14 and thus the development
and studies of carbohydrate-based crown ethers initiated by Stoddart et al. 15-20
was obvious and very successful in an array of different reactions e.g.
asymmetrical Michael reactions. 21-23 The very advantageous formation of
carbohydrate containing complex macrocycles employing metathesis was
recently reported. 24
Focus of the present study was on the preparation of carbohydrate-based
nitrogen containing macrocycles employing easily obtained activated sugar
precursor structures and a highly efficient ring closing procedure. The general
formation of aza-cycles was first demonstrated by Richman and Atkins using
alkali salts of sulfamide with primary halides, mesylates or tosylates. 25 More
detailed studies confirmed the rather straightforward mechanism of the
Richman-Atkins cyclization and the influence of solvents, temperature, bases
and other reaction parameters. 26-32 Until to date there were only three reports
employing this advantageous approach to obtain saccharide-based aza
macrocycles. 33-35
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2. Results and discussion
2.1. Synthesis of monosaccharide models
Starting with commercially available methyl α-D-glucopyranoside the
benzylidene acetal 1 36 was obtained, which has two hydroxyl functions ready
for etherification with a bifunctional spacer system. Thus treatment of 1
employing phase transfer catalysis (PTC) 37 with bis(2-chloroethyl)ether
according to Gross et al. 38 gave equal amounts of the dialkylated product 3 and
the crown ether 2. This 9-crown-3 system apparently formed by intramolecular
nucleophilic substitution was surprisingly not mentioned in reference38. By
enhancing the concentration of the haloether the relative ratio of products
could be largely shifted towards the desired compound 3. Further straight
forward transformations with sodium azide in DMF gave the diazido derivative
4 in 88 % yield, hydrogenation lead to the diamino compound 5 in 93 % yield,
and a final tosylation resulted in formation of the bis-toluenesulfonamide 6. By
treatment of 3 with toluene sulfonamide in high excess 39 compound 6 was
obtained directly in 47 % yield but accompanied by coronand 7 in 30 % yield.
The latter could be obtained selectively in 74 % yield under stoichiometric
conditions.
Reaction of 1 with 2-bromopropane nitril under PTC conditions gave
both, the mono- and the bis-cyanoethylated compound 8. High pressure 40
hydrogenolysis of the latter employing rhodium on aluminium oxide 41 gave the
bis-3-aminopropyloxy derivative 9 quantitatively, and by final tosylation the
crystalline starting material 10 for a Richman-Atkins cyclization was obtained.
As a third pathway alkylation of 1 was performed employing bromoacetic
acid tert-butyl ester to give compound 11. Reduction with lithium aluminium
hydride resulted in formation of the corresponding diol 12, 42 which was
tosylated to give precursor derivative 13 43 in 73 % yield (Scheme 1).
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2.2. Sugar-based 18- to 25-membered oxa-aza macrocycles by Richman-
Atkins cyclization
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For elaboration of advantageous reaction parameters macrocyclization
reactions of the sugar dihalo precursor 3 with alkyl sulfonamide building units
14 - 16, 44,45 and 17 were studied. Previously used solvents such as DMSO or
HMPA were inferior to freshly prepared anhydrous DMF, both regarding
reaction as well as workup. Potassium or cesium carbonate were much better
bases than sodium carbonate and allowed the reaction to proceed under
essentially milder conditions. Surprisingly the structure of the bis-sulfonamide
reagenthas only little influence, and regardless of the resulting ring size yields
were in the range of 40-70 % without optimization.
Treatment of compounds 3 and 14 in DMF at 80 °C with cesium carbonate
resulted in formation of the 18-membered macrocycle 18 in 62 % yield. Mild
methanolic acid treatment led to selective cleavage of the benzylidene ring in
19, and further acetylation gave compound 20. Interestingly, most of these
macrocycles showed pronounced glass temperatures in the range of 60 – 80 °C.
The corresponding transformations of 3 and 15 gave the 21-membered
component 21, and that of 3 and 16 lead to the 24-membered compound 22.
Finally, condensation of 3 and 17 gave the 25-membered derivative 23 in
around 50% yield with glass temperatures of 60-90 °C (Scheme 2).
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2.3. Alternative Richman-Atkins cyclization for sugar-based oxa-aza
macrocycles
Saccharides with two sulfonamide groups can be condensed under
Richman-Atkins conditions with α, ω-bis-tosyloxy components. Thus, derivative
10 was reacted with 24 in DMF at 80 °C and cesium carbonate as base to give
the 17-membered saccharide macrocycle 25 in 78 % yield. The corresponding
reaction of 13 and the diethylene tris-sulfonamide 15 under similar conditions
gave
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the saccharide coronand 26 in 76 % yield. This 14-membered macrocycle
contains three nitrogen functions and presents a structure en route to sugar-
based cyclams (Scheme 3).
Ph
O
Ph
O
O
O
O
O
a)
O
O
O
O
OMe
OMe
NHTs
NTs
O
NHTs
NTs
10
25
Ph
O
O
O
Ph
O
O
O
O
O
O
O
b)
OMe
OMe
NTs
OTs
NTs
Ts
OTs
13
N
26
Scheme 3. Ring closing reactions of compounds 10 and 13.
Reaction conditions:
O
a)
b)
(24), Cs2CO3, DMF, 80°C;
(15), Cs2CO3, DMF, 80°C.
OTs
TsO
Ts
N
NHTs
TsHN
2.4. Formation of coronands with two saccharide units by Richman-Atkins
cyclization
In line with the above discussed approach the formation of two sugar-based
isomeric crown ethers could be realized. By reaction of the dichloro precursor
3 with the bis-toluene sulfonamide 6 the two isomeric 30-membered
components 28 and 29 were obtained, which only differ in their bridging
positions. Chromatographic separation was not feasible, and in 1H-NMR all
signals were largely on top of each other. However, the 13C-NMR in
combination with the DEPT spectrum confirmed the structure, which was
further substantiated by FAB-MS (Scheme 4).
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A corresponding transformation could be performed by reaction of the
bis-sulfonamide 10 and the bis-tosyloxy derivative 13, which led to both
isomerically linked 20-membered bis-saccharide macrocycles 29 and 30 in 32
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Cs2CO3
10
13
+
DMF, 70°C
Ph
O
Ph
O
O
O
O
O
O
+
O
O
O
OMe
OMe
NTs
NTs
O
NTs
NTs
OMe
MeO
O
O
O
O
O
O
O
Ph
29
Ph
O
O
30
Scheme 5. Synthesis of 20-membered macrocycles with two saccharide units.
and 35 % yield, respectively. In contrast to the previous example, these
compounds could be nicely separated. All NMR spectra were in keeping with
their structures, however, an unequivocal assignment could not be realized.
Since both samples are non-crystalline with glass temperatures of 89-95 °C and
84-88 °C, respectively, X-ray elucidations for asserting the absolute
configurations could not be performed (Scheme 5).
3. Conclusion
Employing varying Richman-Atkins conditions with alkali carbonate in DMF
proved to be a facile approach for the synthesis of saccharide-based aza-
macrocycles. Thus, 2,3-ω-haloalkylated as well as ω- toluenesulfonamide-
alkylated glucopyranoside derivatives could be successfully condensed with
α,ω-bis-tosylsulfonamide components and gave sugar-based aza-macrocycles
displaying 14-, 17-, 18-, 21-, 24-, and 25-membered rings in convincing yields.
Corresponding condensations of two differently functionalized carbohydrate
units led to isomeric aza-macrocyles of 20- as well as 30-membered rings
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containing two saccharides. Studies regarding host as well as catalytic
properties of representative components are presently under way.
4. Experimental
4.1. General methods
All reactions were monitored by thin layer chromatography on silica gel
foils GF254 (Merck). Detection was by UV or spraying with 20 % ethanolic
sulfuric acid and subsequent heating. Amines were detected with 10 %
ninhydrin in ethanol and further heating to 200° C. Column chromatography
was done on silica gel 60 (230-400 mesh, Merck) by the flash mode with the
solvent mixture recorded. 1H NMR (400 MHz) and 13C NMR spectra (100 and 62
MHz) were done on Bruker AMX-400 and AC-250. Signal assignment was by
1H,1H- and 1H,13C-COSY measurements. CDCl3 (δ 77.0 for 13C) and TMS (δ 0.0 for
1H) were used as internal standards. FAB mass spectra were recorded on
double focussing mass spectrometer VG 70-250 S (VG Analytical) with m-
nitrobenzyl alcohol as matrix material and xenon as ionisation gas. MALDI-TOF
mass spectra were done on Bruker Biflex with nitrogen laser 337 nm, pulse
width 5 ms and α-cyano-4-hydroxy- cinnamic acid as matrix. Melting points and
glass temperatures are uncorrected and were taken with a Leitz heating
microscope or with an Olympus BH polarising microscope and Mettler FP82
heating table. Optical rotations were measured with Perkin-Elmer polarimeters
241 and 243 using sodium D line (589 nm), cuvette length 10 cm, and
temperature 20 °C. Elemental analysis was performed by the Microanalytical
Section of the Department of Chemistry.
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4.2. General procedures
4.2.1. Alkylation by Phase Transfer Catalysis (GP1)
The saccharide derivative was dissolved in the given solvent and
alkylation reagent (0.55 eq) and phase transfer catalyst (1.5 eq) were added.
Under vigorous stirring 20-50 % aqueous sodium hydroxide was added and the
reaction performed as recorded. For workup the aqueous phase was
thoroughly extracted by an organic solvent, combined with the organic phase,
dried over sodium sulfate, and after evaporation the residue purified or
separated by chromatography.
4.2.2. Tosylation of Amines and Alcohols (GP2)
The starting material was dissolved in anhydrous pyridine (5-15 mL per
hydroxyl or amino group) and cooled to -20 °C. Under stirring tosyl chloride
(1.15 eq per hydroxyl or amino group) added. After termination of the reaction
(1-5 d) the solvent was evaporated in vacuo (temperature below 50 °C) and
several times co-evaporated with toluene. The raw material was purified by
chromatography.
4.2.3. Richman-Atkins Cyclization (GP3)
The ditosylate or dichloride (0.5-1.0 mmol) and the nucleophilic component
(0.5-1.0 mmol) were dissolved in anhydrous dimethylformamide (10 mL). After
addition of base (3-5 eq of Na2CO3, K2CO3 or Cs2CO3) the reaction was kept as
60-80 °C for several days. Workup was by filtration over silica gel and
evaporation. The remainder was dissolved in toluene/ethyl acetate and treated
by ultra sonification for 5 min followed by filtration over silica gel, evaporation
and purification of the raw material by chromatography.
4.3. Syntheses
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4.3.1. Methyl 4, 6-O-benzylidene-2, 3-O-(3-oxapentylene)-α-D-
glucopyranoside (2) and Methyl 4, 6-O-benzylidene-2, 3-di-O-(5-chloro-
oxapentyl)-α- -glucopyranoside (3)
D
Reaction of compound 1 (15.0 g, 53 mmol), bis(2-chloroethyl)-ether (37.8
g, 31 mL, 264 mmol), tetrabutylammonium bromide (5.0 g, 15.5 mmol) in
toluene (400 mL) and sodium hydroxide (50 % aqueous solution, 200 mL)
according to GP1 was done for 3 days at 60°C. Workup gave a mixture which
was separated by column chromatography (dichloromethane/acetone 30 : 1 to
15 : 1).
Compound 2: yield 3.6 g (19 %), mp 116 °C (from isopropanol), [α]D20 = +
94.2 (c =1.0, CHCl3); 1H-NMR (400 MHz,CDCl3): δ=7.51-7.33 (m, 5H, Ph), 5.54 (s,
1H, PhCH), 4.80 (d, 1H, J1,2 3.5 Hz, H-1), 3.49 (dd, 1H, J1,2 3.5, J2,3 9.5 Hz, H-2),
3.87 (dd, 1H, J2,3 = J3,4 9.5 Hz, H-3), 3.51 (dd, 1H, J3,4 = J4,5 9.5 Hz, H-4), 3.73 (dd,
1H, J5,6ax 10.0, J6ax,6eq 10.5 Hz, H-6ax), 4.28 (dd, 1H, J5,6eq 4.5, J6ax,6eq 10.5 Hz, H-
6eq), 3.44 (s, 3H, OCH3), 4.14-4.02 (m, 2H, OCH2), 3.84-3.74 (m, 7H, OCH2). 13C-
NMR (100 MHz, CDCl3): δ= 99.53 (C-1), 82.40 (C-2), 79.59 (C-3), 80.70 (C-4),
62.41 (C-5), 69.07 (C-6), 55.22 (OCH3), 74.95, 73.56, 71.10 (4C, OCH2), 101.60
(PhCH), 137.38, 129.26, 128.20, 126.24 (6C, Ph). Calcd. for C18H24O7 (352.4): C,
61.35; H, 6.86. Found: C, 61.27; H, 6.85. FAB-MS found [M+H+] 353 (100%); [M+-
OCH3] 321 (40%).
Compound 3: yield 5.3 g (20 %), colorless syrup, [α]D20 = + 43.1 (c =1.0,
1
CHCl3); ref.37: mp 62-63 °C, [α]D = + 42.2 (c =1.4, CHCl3); H-NMR (400
MHz,CDCl3): δ=7.49-7.35 (m, 5H, Ph), 5.53 (s1H, PhCH), 4.86 (d, 1H, J1,2 4.0 Hz,
H-1), 4.27 (dd, 1H, J5,6eq 4.5, J6ax,6eq 10.0 Hz, H-6eq), 3.43 (s, 3H, OCH3), 3.96-3.63
and 3.54-3.49 (m, 21H, H-2, -3, -4, -5, -6ax, OCH2, CH2Cl). 13C-NMR (100 MHz,
CDCl3): δ= 99.64 (C-1), 82.27, 81.23, 79.60 (C-2, C-3, C-4), 62.87 (C-5), 55.81
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(OCH3), 72.76, 71.74, 71.56, 71.24, 69.62 (7C, C-6, OCH2), 43.37, 43.21 (2C,
CH2Cl), 101.99 (PhCH), 137.93, 129.50, 128.74, 126.61 (6C, Ph).
4.3.2. Methyl 4, 6-O-benzylidene-2, 3-di-O-(5-azido-3-oxapentyl)-α-D-
glucopyranoside (4)
Compound 3 (2.5 g, 5.0 mmol) and sodium azide ( 1.95 g, 30 mmol) were
dissolved in DMF ( 50 mL), tetramethylenediamine (TMEDA, 1 mL) added and
heated to 80 °C for 24 hours. The cooled suspension was filtered over silica, the
solvent removed by distillation and the raw material purified by flash
chromatography with dichloromethane/acetone 30 : 1 to give 2.23 g (88 %) of 4
1
as slightly yellow syrup; [α]D20 = + 44.7 (c =1.0, CHCl3); H-NMR (400
MHz,CDCl3): δ = 7.49-7.35 (m, 5H, Ph), 5.52 (s, 1H, PhCH), 4.85 (d, 1H, J1,2 3.5
Hz, H-1), 3.51 (dd, 1H, J1,2 3.5, J2,3 9.0 Hz, H-2), 3.79 (dd, 1H, J2,3 = J3,4 9.0 Hz, H-
3), 3.57 (dd, 1H, J3,4 9.0, J4,5 9.5 Hz, H-4), 3.72 (dd, 1H, J5,6ax = J6ax,6eq 10.0 Hz, H-
6ax), 4.27 (dd, 1H, J5,6eq 4.5, J6ax,6eq 10.0 Hz, H-6eq), 3.44 (s, 3H, OCH3), 4.00-3.55
(m, 13H, H-5, OCH2), 3.40-3.21 (m, 4H, CH2N3). 13C-NMR (100 MHz, CDCl3): δ =
99.15 (C-1), 81.74, 80.73, 79.10 (C-2, C-3, C-4), 62.39 (C-5), 55.29 (OCH3), 72.23,
71.49, 70.75, 70.04, 69.66, 69.12 (7C, C-6, OCH2), 50.83, 50.67 (2C, CH2N3),
101.48 (PhCH), 137.47, 128.99, 128.22, 126.13 (6C, Ph).
4.3.3. Methyl 4, 6-O-benzylidene-2, 3-di-O-(5-amino-3-oxapentyl)-α-D-
glucopyranoside (5)
Compound 4 (2.16 g, 4.25 mmol) was dissolved in methanol (50 mL) and
triethylamine (2 mL) as well as palladium/charcoal (5 %, 500 mg) added. The
mixture was hydrogenated at normal pressure and room temperature for 24
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hours. Filtration over Celite and evaporation gave 1.8 g (93 %) of 5 as colorless
1
syrup; [α]D20 = + 43.4 (c =1.0, CHCl3); H-NMR (400 MHz,CDCl3): δ = 7.49-7.34
(m, 5H, Ph), 5.52 (s, 1H, PhCH), 4.84 (d, 1H, J1,2 3.5 Hz, H-1), 4.00-3.23 (m, 19 H,
H-2, -3, -4, -5, -6ax, OCH2, CH2NH2), 4.27 (dd, 1H, J5,6eq 4.0, J6ax,6eq 10.0 Hz, H-
6eq), 3.43 (s, 3H, OCH3), 2.88-2.73 (m, 2H, CH2NH2), 1.60 (m, 4H, NH2). 13C-NMR
(100 MHz, CDCl3): δ = 99.16 (C-1), 81.82, 80.69, 78.94 (C-2, C-3, C-4), 62.39 (C-
5), 55.32 (OCH3), 73.03, 72.20, 71.09, 70.62, 70.03, 69.11 (7C, C-6, OCH2), 41.90,
41.83 (2C, CH2NH2), 101.46 (PhCH), 137.47, 128.98, 128.22, 126.13 (6C, Ph).
4.3.4. Methyl 4, 6-O-benzylidene-2, 3-di-O-(5-tosylamino-3-oxapentyl)-α-D-
glucopyranoside (6)
a) Compound 3 (424 mg, 0.86 mmol), p-toluenesulfonamide (3.46 g, 20.2
mmol), and potassium carbonate (2.8 g, 20.2 mmol) in DMF (20 mL) were
treated according to GP3 for 24 h at 80°C. Workup as in GP 3 and separation by
flash chromatography (toluene/ethyl acetate 1 : 1) gave 330 mg (47 %) of
compound 6 and 154 mg (30 %) of compound 7.
b) Compound 5 (1.76 g, 3.86 mmol), p-toluenesulfonyl chloride (1.62 g,
8.5 mmol) dissolved in anhydrous pyridine (50 mL) were treated according to
GP2 for 48 h at -20°C. Workup as in GP 2 and separation by flash
chromatography (dichloromethane/acetone 10 : 1) gave 1.61 g (54 %) of
1
compound 6. Glass temperature 51-53 °C; [α]D20 = + 33.9 (c =1.0, CHCl3); H-
NMR (400 MHz,CDCl3): δ = 7.75-7.24 (m, 13H, Ph), 5.56 (s, 1H, PhCH), 4.83 (d,
1H, J1,2 3.5 Hz, H-1), 3.55 (dd, 1H, J1,2 3.5, J2,3 9.0 Hz, H-2), 3.81 (dd, 1H, J2,3 = J3,4
9.0 Hz, H-3), 3.62 (dd, 1H, J3,4 = 9.0 J4,5 9.5 Hz, H-4), 3.80 (ddd, 1H, J4,5 9.5, J5,6ax
10.0 J5,6eq 4.5 Hz, H-5), 3.74 (dd, 1H, J5,6ax = J6ax,6eq 10.0 Hz, H-6ax), 4.27 (dd, 1H,
J5,6eq 4.5, J6ax,6eq 10.0 Hz, H-6eq), 3.43 (s, 3H, OCH3), 5.75, 5.71 (d, 2H, JCH,NH 6.0
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Hz, NHTs), 3.90-3.36 (m, 12H, OCH2), 3.13-2.99 (m, 4H, CH2NTs), 2.39 (s, 6H,
CH3Ts). 13C-NMR (100 MHz, CDCl3): δ= 98.66 (C-1), 80.21 (C-2), 81.65 (C-3),
78.67 (C-4), 62.47 (C-5), 69.05 (C-6), 55.31 (OCH3), 72.17, 70.99, 70.69, 70.47,
69.71, 69.30 (6C, OCH2), 43.00 (2C, CH2NHTs), 21.48 (2C, CH3Ts), 101.44 (PhCH),
143.17-137.32 and 129.65-126.17 (18C, Ph). Calcd. for C36H48O12S2 (764.9): C,
56.53; H, 6.33; N, 3.66; S, 8.38. Found: C, 56.53; H, 6.43; N, 3.73; S, 8.37.
4.3.5Methyl 4, 6-O-benzylidene-2, 3-O-(6-tosyl-3,9-dioxa-6-aza-undecylene)-
α-
D
-glucopyranoside (7)
Compound 3 (755 mg, 1.52 mmol), p-toluenesulfonamide (287 g, 1.67
mmol), and cesium carbonate (2.48 g, 7.6 mmol) in DMF (10 mL) were treated
according to GP3 for 24 h at 80°C. Workup as in GP 3 and separation by flash
chromatography (toluene/ethyl acetate 2 : 1) gave 671 mg (74 %) of compound
1
7. Mp 107 °C; [α]D20 = + 18.3 (c =1.0, CHCl3); H-NMR (400 MHz,CDCl3): δ = 7.70-
7.27 (m, 9H, Ph), 5.52 (s, 1H, PhCH), 4.83 (d, 1H, J1,2 3.5 Hz, H-1), 3.48 (dd, 1H,
J1,2 3.5, J2,3 9.0 Hz, H-2), 3.56 (dd, 1H, J2,3 = J3,4 9.0 Hz, H-3), 4.00-3.60 (m, 15H, H-
4, -5, -6ax, OCH2), 4.27 (dd, 1H, J5,6eq 4.5, J6ax,6eq 10.0 Hz, H-6eq), 3.43 (s, 3H,
OCH3), 3.45-3.35 and 3.29-3.16 (m, 2H, JCH,NH 6.0 Hz, CH2NTs), 2.42 (s, 4H,
CH3Ts). 13C-NMR (100 MHz, CDCl3): δ= 98.14 (C-1), 79.70 (C-2), 82.21 (C-3),
77.73 (C-4), 62.29 (C-5), 69.07 (C-6), 55.23 (OCH3), 72.26, 70.90, 70.45, 70.36,
70.28 (6C, OCH2), 50.38 (2C, CH2NTs), 21.49 (2C, CH3Ts), 101.37 (PhCH), 143.26-
136.25 and 129.70-126.05 (12C, Ph). Calcd. for C29H39NO10S (593.7): C, 58.67; H,
6.62; N, 2.36; S, 5.40. Found: C, 58.72; H, 6.70; N, 2.33; S, 5.25. FAB-MS found
[M+Cs+] 726 (40%), M+Rb+] 678 (35%), [M + Na+] 616 (25%), [M + H+] 594 (70%).
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4.3.6Methyl 4, 6-O-benzylidene-2, 3-di-O-(2-cyanoethyl)-α-
glucopyrano-side (8)
D
-
Reaction of compound 1 (1.0 g, 3.5 mmol), 2-bromopropane nitril (950
mg, 0.6 mL, 7.1 mmol), tetrabutylammonium hydrogensulfate (600 mg, 1.8
mmol) in DMF (15 mL) and sodium hydroxide (20 % aqueous solution, 10 mL)
according to GP1 was done for 24 hour at 20°C. Workup gave a mixture of 567
mg (42 %) compound 8 and 536 mg (46 %) of methyl 4, 6-O-benzylidene-2-O-(2-
cyanoethyl)-α-D-glucopyranoside which were separated by column
chromatography (dichloromethane/acetone 10 : 1).
Compound 8: mp 125 °C, ref.40 126-127 °C; [α]D20 = + 53.9 (c =1.0, CHCl3),
ref.39 + 58.0 (c=1.2 in CHCl3); 1H-NMR (400 MHz,CDCl3): δ=7.48-7.36 (m, 5H, Ph),
5.54 (s, 1H, PhCH), 4.86 (d, 1H, J1,2 3.5 Hz, H-1), 3.45 (dd, 1H, J1,2 3.5, J2,3 9.5 Hz,
H-2), 3.80 (dd, 1H, J2,3 = J3,4 9.5 Hz, H-3), 3.57 (dd, 1H, J3,4 = 9.5, J4,5 10.0 Hz, H-4),
3.86 (ddd, 1H, J4,5 10.0, J5,6ax 10.0, J5,6eq 4.5 Hz, H-5), 3.73 (dd, 1H, J5,6ax = J6ax,6eq
10.0 Hz, H-6ax), 4.29 (dd, 1H, J5,6eq 4.5, J6ax,6eq 10.0 Hz, H-6eq), 3.46 (s, 3H,
OCH3), 4.04-4.01 (m, 2H, OCH2), 3.93-3.79 (m, 2H, OCH2), 2.65 and 2.58 (each
dd, 2H, JCH,CH 6.1 Hz, CH2CN).
4.3.7 Methyl 4, 6-O-benzylidene-2, 3-di-O-(3-aminopropyl)-α-D-
glucopyranoside (9)
Compound 8 (4.1 g, 10.5 mmol) was dissolved in ammonia-saturated
methanol (50 mL). Rhodium on Al2O3 (5 %, 500 mg) were added, and the
mixture was hydrogenated in an autoclave at 50 bar and 20 °C for 3 days.
16

ACCEPTED MANUSCRIPT
Filtration over Celite and evaporation gave 3.9 g (93 %) of 9 as a colorless
syrup; [α]D20 = + 90.4 (c =1.0, CHCl3); 1H-NMR (400 MHz,CDCl3 + D2O): δ=7.49-
7.32 (m, 5H, Ph), 5.54 (s, 1H, PhCH), 4.83 (d, 1H, J1,2 3.5 Hz, H-1), 3.54 (dd, 1H,
J1,2 3.5, J2,3 9.5 Hz, H-2), 3.98-3.60 (m, 7H, H-3, -5, -6ax, OCH2), 3.52 (dd, 1H, J3,4 =
J4,5 9.5 Hz, H-4), 4.28 (dd, 1H, J5,6eq 4.5, J6ax,6eq 10.0 Hz, H-6eq), 3.44 (s, 3H, OCH3),
2.84-2.69 (m, 4H, CH2NH2), 1.81-1.67 (m, 4H, CH2). 13C-NMR (100 MHz, CDCl3):
δ= 98.77 (C-1), 82.11, 80.35, 78.23 (C-2, C-3, C-4), 62.34 (C-5), 69.03 (C-6), 55.31
(OCH3), 71.19, 69.51 (2C, OCH2), 39.69, 39.39 (2C, CH2NH2), 33.98, 33.56 (2C,
CH2), 101.42 (PhCH), 137.41, 128.98, 128.25, 126.06 (6C, Ph).
4.3.8 Methyl 4, 6-O-benzylidene-2, 3-di-O-[3-N-tosylaminopropyl]-α-
D-glucopyranoside (10)
Compound 9 (3.9 g, 9.8 mmol), p-toluenesulfonyl chloride (4.4 g, 23.3
mmol) dissolved in anhydrous pyridine (150 mL) were treated according to GP2
for 48 h at -20°C. Workup as in GP2 and separation by chromatography
(dichloromethane/acetone 17 : 1) gave 2.8 g (41 %) of compound 10. Mp 126
°C; [α]D20 = + 29.5 (c =1.0, CHCl3); 1H-NMR (400 MHz,CDCl3): δ=7.76-7.20 (m,
13H, Ph), 5.52 (s, 1H, PhCH), 4.85 (d, 1H, J1,2 3.5 Hz, H-1), 3.35 (dd, 1H, J1,2 3.5,
J2,3 9.0 Hz, H-2), 3.66 (dd, 1H, J2,3 = 9.0, J3,4 9.5 Hz, H-3), 3.49 (dd, 1H, J3,4 = J4,5 9.5
Hz, H-4), 3.86-3.65 (m, 6H, H-5, -6ax, OCH2), 4.27 (dd, 1H, J5,6eq 4.0, J6ax,6eq 10.0
Hz, H-6eq), 3.45 (s, 3H, OCH3), 5.51, 5.25 (dd, 2H, JCH,NH 5.5 and 6.0 Hz, NHTs),
3.10-2.99 (m, 4H, CH2NHTs), 1.80-1.62 (m, 4H, CH2), 2.40, 2.38 (s, 6H, CH3Ts).
13C-NMR (100 MHz, CDCl3): δ= 98.05 (C-1), 79.63 (C-2), 78.21 (C-3), 81.95 (C-4),
62.27 (C-5), 69.13 (C-6), 55.29 (OCH3), 71.80, 68.98 (2C, OCH2), 41.80, 41.45
(2C, CH2NHTs), 29.28, 28.93 (2C, CH2), 21.49 (2C, CH3Ts), 101.47 (PhCH),
143.15-137.24 and 129.72-126.09 (18C, Ph).
17

ACCEPTED MANUSCRIPT
4.3.9. Methyl 4, 6-O-benzylidene-2, 3-di-O-(tert-butyloxycarbonylmethyl)-α-D-
glucopyranoside (11)
Reaction of compound 1 (1.5 g, 5.3 mmol), tert-butyl bromoacetate (2.27
g, 1.7 mL, 11.7 mmol), tetrabutylammonium bromide (1.7 g, 5.3 mmol) in
dichloromethane (30 mL) and sodium hydroxide (50 % aqueous solution, 10
mL) according to GP1 was done for 1 hour at 20°C. Workup and column
chromatography (dichloromethane/acetone 40 : 1) gave 1.47 g (54%) of
compound 11 as colorless syrup; [α]D20 = - 4.0 (c =1.0, CHCl3); 1H-NMR (400
MHz,CDCl3): δ=7.47-7.35 (m, 5H, Ph), 5.50 (s, 1H, PhCH), 5.08 (d, 1H, J1,2 3.5 Hz,
H-1), 3.58 (dd, 1H, J1,2 3.5, J2,3 9.0 Hz, H-2), 3.93 (dd, 1H, J2,3 9.0, J3,4 9.5 Hz, H-3),
3.64 (dd, 1H, J3,4 = J4,5 9.5 Hz, H-4), 3.81 (ddd, 1H, J4,5 9.5, J5,6ax 10.0, J5,6eq 4.5 Hz,
H-5), 3.74 (dd, 1H, J5,6ax = J6ax,6eq 10.0 Hz, H-6ax), 4.27 (dd, 1H, J5,6eq 4.5, J6ax,6eq
10.0 Hz, H-6eq), 3.46 (s, 3H, OCH3), 4.49 and 4.30 (each d, each 1H, J 17.5 Hz,
OCHa), 4.35 and 4.18 (each d, each 1H, J 16.0 Hz, OCHb), 1.47, 1.39 (s, 18H, t-
Bu). 13C-NMR (100 MHz, CDCl3): δ= 99.73 (C-1), 82.20, 80.25, 79.21 (C-2, C-3, C-
4), 61.98 (C-5), 70.63 (C-6), 55.36 (OCH3), 170.30, 169.33 (2C, CO), 81.84, 81.51
(2C, q, t-Bu),70.07, 69.12 (2C, OCH2), 28.16, 28.11 (6C, CH3-tBu), 101.29 (PhCH),
137.31, 128.98, 128.23, 126.12 (6C, Ph). Calcd. for C18H26O8 (370.4): C, 58.37; H,
7.08. Found: C, 58.09; H, 7.18.
4.3.10. Methyl 4, 6-O-benzylidene-2, 3-di-O-(2-hydroxyethyl)-α-D-
glucopyranoside (12)
Compound 11 (4.4 g, 8.6 mmol) dissolved in anhydrous tetrahydrofuran
(100 mL) was treated with lithium aluminium hydride (1.64 g, 43.1 mmol) and
18

ACCEPTED MANUSCRIPT
refluxed for 24 h. Following addition of methanol filtration over Celite and
evaporation of solvents gave the raw material which was purified by
chromatography (ethyl acetate/ ethanol 12: 1). Yield: 2.54 g (80 %) of
compound 12. Mp 107 °C, ref.42 114 °C; [α]D20 = + 73.4 (c =1.0, CHCl3), ref.42
[α]D20 = + 12.1 (c =0.13, CHCl3); 1H-NMR (400 MHz,CDCl3): δ=7.48-7.35 (m, 5H,
Ph), 5.55 (s, 1H, PhCH), 4.86 (d, 1H, J1,2 3.5 Hz, H-1), 3.53 (dd, 1H, J1,2 3.5, J2,3 9.5
Hz, H-2), 3.88 (dd, 1H, J2,3 = J3,4 9.5 Hz, H-3), 3.57 (dd, 1H, J3,4 = J4,5 9.5 Hz, H-4),
3.73 (ddd, 1H, J4,5 9.5, J5,6ax 10.0, J5,6eq 4.5 Hz, H-5), 3.97-3.66 (m, 9H, H-6ax,
OCH2), 4.28 (dd, 1H, J5,6eq 4.5, J6ax,6eq 10.0 Hz, H-6eq), 3.45 (s, 3H, OCH3), 4.20-
4.12 (m, 4H, CH2OTs), 4.07-3.98 and 3.90-3.79 (each m, each 2C, OCH2), 3.17
and 3.05 (b, each 1H, OH), . 13C-NMR (100 MHz, CDCl3): δ= 98.41 (C-1), 81.92,
80.57, 78.10 (C-2, C-3, C-4), 62.41 (C-5), 69.02 (C-6), 55.31 (OCH3), 74.56, 72.92
(2C, OCH2), 62.07, 61.86 (2C, CH2OH), 101.61 (PhCH), 137.05-126.04 (6C, Ph).
4.3.11. Methyl 4, 6-O-benzylidene-2, 3-di-O-(p-toluenesulfonyloxyethyl)-α-D-
glucopyranoside (13)
Compound 12 (2.2 g, 6.0 mmol) and p-toluenesulfonyl chloride (2.9 g,
15.1 mmol) dissolved in anhydrous pyridine (50 mL) were treated according to
GP2 for 24 h at -20°C. Workup as in GP2 and purification by chromatography
(dichloromethane) gave 2.0 g (73 %) of compound 13. Mp 121 °C, ref.43 127-
128 °C; [α]D20 = + 31.6 (c =1.0, CHCl3), ref.43 [α]D20 = + 25.6 (c =1.5, CHCl3); 1H-
NMR (400 MHz,CDCl3): δ=7.75-7.21 (m, 13H, Ph), 5.49 (s, 1H, PhCH), 4.82(d, 1H,
J1,2 3.5 Hz, H-1), 3.41 (dd, 1H, J1,2 3.5, J2,3 9.5 Hz, H-2), 3.74 (dd, 1H, J2,3 = J3,4 9.5
Hz, H-3), 3.48 (dd, 1H, J3,4 9.5, J4,5 10.0 Hz, H-4), 3.77 (ddd, 1H, J4,5 = J5,6ax 10.0,
J5,6eq 4.5 Hz, H-5), 3.71 (dd, 1H, J5,6ax = J6ax,6eq 10.0 Hz, H-6ax), 4.27 (dd, 1H, J5,6eq
4.5, J6ax,6eq 10.0 Hz, H-6eq), 3.44 (s, 3H, OCH3), 4.20-4.12 (m, 4H, CH2OTs), 4.07-
19

ACCEPTED MANUSCRIPT
3.98 and 3.90-3.79 (each m, each 2C, OCH2), 2.42, 2.40 (s, 6H, CH3Ts). 13C-NMR
(100 MHz, CDCl3): δ= 99.01 (C-1), 80.46 (C-2), 79.24 (C-3), 81.93 (C-4), 62.19 (C-
5), 69.40 (C-6), 55.37 (OCH3), 78.84, 72.64 (2C, OCH2), 70.07, 69.04 (2C,
CH2OTs), 21.63 (2C, CH3Ts), 101.25 (PhCH), 143.51-132.99 and 129.89-126.01
(18C, Ph).
4.3.12. 4 ,4´-Ditosylamino-diphenylmethane (17)
4, 4´-Diamino-diphenylmethane (15.0 g, 75.7 mmol) dissolved in
anhydrous pyridine (250 mL) was cooled to – 20°C and portion wise treated
with p-toluenesulfonyl chloride (33.2 g, 174 mmol). After 3 days the solution
was poured onto ice water (250 mL), extracted twice with diethyl ether (each
300 mL), the organic solvent successively washed with cold HCl (2N, 300 mL)
and ice water (300 mL), dried over Na2SO4, decolorized with active charcoal and
evaporated. The residue was recrystallized from dichloromethane/methanol 1 :
1 to give 23.9 g (62 %) of compound 17. Mp 167 °C; 1H-NMR (400 MHz, DMSO):
δ = 10.10 (s, 2H, NHTs), 7.63and 7.34 (m, each 4H, Ph), 7.03-6.98 (m, 8H, Ph),
2.55 (s, 6H, CH3Ts). Calcd. for C27H26N2O4S2 (506.7): C, 64.01; H, 5.17; N, 5.53; S,
12.66. Found: C, 63.60; H, 5.15; N, 5.42; S, 12.66.
4.3.13. Methyl 4, 6-O-benzylidene-2, 3-O-(6, 9-ditosyl-3, 12-dioxa-6, 9-diaza-
tetradecanylene)-α-D-glucopyranoside (18)
Compound 3 (2.75 g, 5.57 mmol), ethylene bis-toluenesulfonamide (14)
(2.05 g, 5.57 mmol), and cesium carbonate (5.3 g, 16.5 mmol) in DMF (40 mL)
were treated according to GP3 for 2 days at 80°C. Workup as in GP3 and
20

ACCEPTED MANUSCRIPT
separation by flash chromatography (toluene/ethyl acetate 1 : 1) gave 2.72 g
(62 %) of compound 18. Glass temperature 81 °C; [α]D20 = + 21.4 (c =1.0, CHCl3);
1H-NMR (400 MHz,CDCl3): δ = 7.75-7.18 (m, 13H, Ph), 5.52 (s, 1H, PhCH), 4.75
(d, 1H, J1,2 4.0 Hz, H-1), 3.89-3.23 (m, 25H, H-2, -3, -4, -5, -6ax, OCH2, CH2NTs),
4.26 (dd, 1H, J5,6eq 4.0, J6ax,6eq 10.0 Hz, H-6eq), 3.38 (s, 3H, OCH3), 2.43, 2.42 (s,
6H, CH3Ts). 13C-NMR (100 MHz, CDCl3): δ= 98.95 (C-1), 82.01, 80.36, 79.02 (C-2,
C-3, C-4), 62.30 (C-5), 55.28 (OCH3), 71.92, 71.71, 70.94, 70.77, 70.63, 69.12
(7C, C-6, OCH2), 50.31, 50.22, 49.74, 49.58 (4C, CH2NTs), 21.58 (2C, CH3Ts),
101.39 (PhCH), 143.37-136.15 and 129.79-126.10 (18C, Ph). Calcd. for
C38H50N2O12S2 (791.0): C, 57.71; H, 6.37; N, 3.54; S, 8.11. Found: C, 58.51; H,
6.52; N, 3.38; S, 8.36. FAB-MS found [M+H+] 791 (40%), [M+-OCH3] 759 (20%),
[M+-CH3C6H4SO2] 635 (100%).
4.3.14. Methyl 2, 3-O-(6, 9-ditosyl-3, 12-dioxa-6, 9-diaza-tetradecanylene)-α-
D-glucopyranoside (19)
Compound 18 (1.13 g, 1.43 mmol) was dissolved in methanol (100 mL),
HCl (0.5 M, 5 mL) added and heated to 70 °C for 1h. The mixture was
neutralized with Na2CO3, evaporated to dryness, and the residue extracted with
dichloromethane (200 mL). The organic phase was washed twice with water
(each 50 mL) then dried over Na2SO4 and evaporated to give 902 mg (90 %) of
1
compound 19. Glass temperature 72-75 °C, [α]D20 = + 32.1 (c =1.0, CHCl3); H-
NMR (400 MHz,CDCl3): δ = 7.74-7.32 (m, 8H, Ph), 4.75 (d, 1H, J1,2 3.5 Hz, H-1),
4.21-3.20 (m, 26H, H-2, -3, -4, -5, -6a, -6b, OCH2, CH2NTs), 3.40(s, 3H, OCH3),
2.43 (s, 6H, CH3Ts), 2.77 (d, 1H, J4,OH 1.5 Hz, OH-4), 2.11 (dd, 1H, J6,OH 6.1 Hz,
OH-6). 13C-NMR (100 MHz, CDCl3): δ= 97.78 (C-1), 81.82, 80.43, 70.64, 70.49 (C-
2, C-3, C-4, C-5), 62.49 (C-6), 55.17 (OCH3), 72.06, 71.38, 71.16, 70.86, 70.33,
21

ACCEPTED MANUSCRIPT
69.63 (6C, OCH2), 50.53, 49.91, 49.68, 49.66 (4C, CH2NTs), 21.53 (2C, CH3Ts),
143.45-135.79 and 129.73-127.32 (8C, Ph). Calcd. for C31H46N2O12S2 (702.8): C,
52.98; H, 6.60; N, 3.99; S, 9.12. Found: C, 52.70; H, 6.65; N, 3.90; S, 9.12. FAB-
MS found [M+Na+] 725 (100%), [M +H+] 703 (10%), [M+-CH3C6H4SO2] 672 (40%).
4.3.15. Methyl 4, 6-di-O-acetyl-2, 3-O-(6, 9-ditosyl-3, 12-dioxa-6, 9-diaza-
tetradecanylene)-α-D-glucopyranoside (20)
Compound 19 (63 mg, 90 µmol) dissolved in pyridine (5 mL) was treated
with acetic acid anhydride (64 mg, 0.6 mmol) for 24h at 20 °C. Co-distillation
with toluene and purification by flash chromatography (toluene/ethyl acetate
1:1) gave 65 mg (92 %) of compound 20. Glass temperature 63-68 °C, [α]D20 = +
1
37.8 (c =1.0, CHCl3); H-NMR (400 MHz,CDCl3): δ = 7.76-7.32 (m, 8H, Ph), 4.78
(d, 1H, J1,2 3.5 Hz, H-1), 3.41 (dd, 1H, J1,2 3.5, J2,3 9.5 Hz, H-2), 3.67 (dd, 1H, J2,3 =
J3,4 9.5 Hz, H-3), 4.95 (dd, 1H, J3,4 = J4,5 9.5 Hz, H-4), 3.77 (ddd, 1H, J4,5 9.5, J5,6a
5.0, J5,6b 2.0 Hz, H-5), 4.21 (dd, 1H, J5,6a 5.0, = J6a,6b 12.0 Hz, H-6a), 4.05 (dd, 1H,
J5,6b 2.0, J6a,6b 12.0 Hz, H-6b), 3.40 (s, 3H, OCH3), 4.05-3.98, 3.81-3.75 and 3.72-
3.68 (each m, each 1H, OCH2), 3.63-3.18 (m, 17H, OCH2, CH2NTs), 2.44 (s, 6H,
CH3Ts), 2.07, 2.05 (s, 6H, CH3CO). 13C-NMR (100 MHz, CDCl3): δ= 97.90 (C-1),
80.31 (C-2), 79.71 (C-3), 69.91 (C-4), 67.46 (C-5), 62.492 (C-6), 55.39 (OCH3),
72.07, 71.63, 71.18, 71.00, 70.57, 70.47 (6C, OCH2), 50.46, 50.31, 49.99, 49.78
(4C, CH2NTs), 21.57 (2C, CH3Ts), 20.86, 20.80 (2C, CH3CO), 170.77, 169.50 (2C,
CH3CO), 143.39-136.19 and 129.80-127.39 (12C, Ph). C35H50N2O14S2 (786.9):
FAB-MS found [M+Na+] 809 (100%), [M +H+] 787 (30%), [M+-CH3C6H4SO2] 631
(40%).
22

ACCEPTED MANUSCRIPT
4.3.16. Methyl 4, 6-O-benzylidene-2, 3-O-(6, 9, 12-tritosyl-3, 15-dioxa-6, 9, 12-
triaza-heptadecanylene)-α-D-glucopyranoside (21)
Compound 3 (760 mg, 1.53 mmol), diethylenetriamino tris-
toluenesulfonamide (15)44,45 (868 mg, 1.53 mmol), and potassium carbonate
(1.1 g, 7.7 mmol) in DMF (10 mL) were treated according to GP3 for 4 days at
80°C. Workup as in GP3 and separation by flash chromatography (toluene/ethyl
acetate 1 : 1) gave 625 mg (41 %) of compound 21. Glass temperature 81-86 °C;
1
[α]D20 = + 6.0 (c =1.0, CHCl3); H-NMR (400 MHz,CDCl3): δ = 7.77-7.16 (m, 17H,
Ph), 5.54 (s, 1H, PhCH), 4.69 (d, 1H, J1,2 3.5 Hz, H-1), 3.73-3.32 (m, 29H, H-2, -3, -
4, -5, -6ax, OCH2, CH2NTs), 4.25 (dd, 1H, J5,6eq 4.5, J6ax,6eq 10.0 Hz, H-6eq), 3.40 (s,
3H, OCH3), 2.42, 2.41 (s, 9H, CH3Ts). 13C-NMR (100 MHz, CDCl3): δ= 98.40 (C-1),
81.50, 79.69, 78.64 (C-2, C-3, C-4), 61.86 (C-5), 54.75 (OCH3), 71.33, 70.83,
70.46, 70.29, 69.89, 69.67, 68.50 (7C, C-6, OCH2), 49.75, 49.46, 49.32, 49.22,
48.92, 48.77 (6C, CH2NTs), 21.06 (3C, CH3Ts), 100.80 (PhCH), 143.05-135.31 and
129.35-125.66 (24C, Ph). Calcd. for C47H61N3O14S3 (988.2): C, 57.13; H, 6.22; N,
4.25; S, 9.73. Found: C, 58.00; H, 6.35; N, 4.00; S, 9.16. FAB-MS found [M+H+]
988 (20%), [M+-OCH3] 956 (20%), [M+-CH3C6H4SO2] 832 (100%).
4.3.17. Methyl 4, 6-O-benzylidene-2, 3-O-(6, 15-ditosyl-3, 9, 12, 18-tetraoxa-6,
15-diaza-icosanylene)-α-D-glucopyranoside (22)
Compound 3 (700 mg, 1.41 mmol), 1, 8-ditosylamino-3, 6-dioxaoctane
(16)44,45 (645 mg, 1.41 mmol), and potassium carbonate (976 mg, 7.1 mmol) in
DMF (10 mL) were treated according to GP3 for 3 days at 80°C. Workup as in
GP3 and separation by flash chromatography (toluene/ethyl acetate 2 : 1) gave
553 mg (45 %) of compound 22. Glass temperature 60-63 °C; [α]D20 = + 18.7 (c
1
=1.0, CHCl3); H-NMR (400 MHz,CDCl3): δ = 7.71-7.18 (m, 13H, Ph), 5.52 (s, 1H,
23

ACCEPTED MANUSCRIPT
PhCH), 4.78 (d, 1H, J1,2 3.5 Hz, H-1), 3.90-3.30 (m, 33H, H-2, -3, -4, -5, -6ax,
OCH2, CH2NTs), 4.26 (dd, 1H, J5,6eq 4.0, J6ax,6eq 10.0 Hz, H-6eq), 3.41 (s, 3H, OCH3),
2.42, 2.39 (s, 6H, CH3Ts). 13C-NMR (100 MHz, CDCl3): δ= 99.09 (C-1), 81.87,
80.37, 79.00 (C-2, C-3, C-4), 62.33 (C-5), 55.25 (OCH3), 72.26, 71.09, 70.70,
70.45, 70.35, 70.20, 69.08 (11C, C-6, OCH2), 49.36, 49.18, 49.15 (4C, CH2NTs),
21.49, 21.46 (2C, CH3Ts), 101.33 (PhCH), 143.22-136.82 and 129.67-125.30
(18C, Ph). Calcd. for C42H58N2O14S2 (879.1): C, 57.39; H, 6.65; N, 3.19; S, 7.29.
Found: C, 57.27; H, 6.57; N, 3.02; S, 7.21. FAB-MS found [M+Cs+] 1012 (70%),
[M+Rb+] 964 (45%), [M+H+] 880 (25%), [M+-OCH3] 847 (35%), [M+-CH3C6H4SO2]
723 (90%).
4.3.18. Methyl 4, 6-O-benzylidene-2, 3-O-[bis-N-(4, 4´-ditosylamino-
diphenylmethane)-3-oxapentyl]-α-D-glucopyranoside (23)
Compound 3 (500 mg, 1.0 mmol), 4, 4´-ditosylamino-diphenylmethane
(17)44,45 (562 mg, 1.1 mmol), and cesium carbonate (1.62 g, 5.0 mmol) in DMF
(10 mL) were treated according to GP3 for 2 days at 80°C. Workup as in GP3
and separation by flash chromatography (toluene/ethyl acetate 1 : 1) gave 479
mg (52 %) of compound 23. Glass temperature 79-87 °C; [α]D20 = + 24.9 (c =1.0,
1
CHCl3); H-NMR (400 MHz,CDCl3): δ = 7.52-6.92 (m, 21H, Ph), 5.48 (s, 1H,
PhCH), 4.73 (d, 1H, J1,2 3.5 Hz, H-1), 3.21 (dd, 1H, J1,2 3.5, J2,3 9.0 Hz, H-2), 3.58
(dd, 1H, J2,3 = J3,4 9.0 Hz, H-3), 3.43 (dd, 1H, J3,4 9.0, J4,5 9.5 Hz, H-4), 3.71 (ddd,
1H, J4,5 = 9.5. J5,6ax 10.0, J5,6eq 4.5 Hz, H-5), 3.69 (dd, 1H, J5,6ax = J6ax,6eq 10.0 Hz, H-
6ax), 4.25 (dd, 1H, J5,6eq 4.5, J6ax,6eq 10.0 Hz, H-6eq), 3.38 (s, 3H, OCH3), 3.90 (s,
2H, PhCH2Ph), 3.75-3.14 (m, 16H, OCH2, CH2NTs), 2.42, 2.40 (s, 6H, CH3Ts). 13C-
NMR (100 MHz, CDCl3): δ= 99.04 (C-1), 80.82 (C-2), 78.91 (C-3), 81.55 (C-4),
62.37 (C-5), 69.05 (C-6), 55.29 (OCH3), 72.84, 71.01, 70.39, 70.11, 69.82, 69.42
24

ACCEPTED MANUSCRIPT
(6C, OCH2), 50.52, 50.39 (2C, CH2NTs), 41.31 (PhCH2Ph), 21.55 (2C, CH3Ts),
101.43 (PhCH), 143.37-135.92 and 129.43-125.30 (30C, Ph). Calcd. for
C49H56N2O12S2 (929.1): C, 63.34; H, 6.08; N, 3.02; S, 6.90. Found: C, 64.11; H,
6.25; N, 2.84; S, 6.69. FAB-MS found [M+H+] 929 (100%), [M+-OCH3] 897 (30%),
[M+-CH3C6H4SO2] 774 (100%).
4.3.19. Methyl 4, 6-O-benzylidene-2, 3-O-(4, 10-ditosyl-7-oxa-4, 10-diazatri-
decanylene)-α-D-glucopyranoside (25)
Compound 10 (262 mg, 0.63 mmol), diethyleneglycol ditosylate (24)44,45
(262 mg, 0.63 mmol), and cesium carbonate (977 mg, 3.0 mmol) in DMF (10
mL) were treated according to GP3 for 3 days at 80°C. Workup as in GP3 and
separation by flash chromatography (toluene/ethyl acetate 1 : 1) gave 383 mg
(78 %) of compound 25. Glass temperature 66-71 °C; [α]D20 = + 25.8 (c =1.0,
1
CHCl3); H-NMR (400 MHz,CDCl3): δ = 7.70-7.14 (m, 13H, Ph), 5.51 (s, 1H,
PhCH), 4.84 (d, 1H, J1,2 3.5 Hz, H-1), 3.90-3.13 (m, 18H, H-2, -4, OCH2, CH2NTs),
3.65 (dd, 1H, J2,3 = J3,4 9.0 Hz, H-3), 3.76 (ddd, 1H, J4,5 = 9.5. J5,6ax 10.0, J5,6eq 4.0
Hz, H-5), 3.71 (dd, 1H, J5,6ax = J6ax,6eq 10.0 Hz, H-6ax), 4.26 (dd, 1H, J5,6eq 4.0,
J6ax,6eq 10.0 Hz, H-6eq), 3.41 (s, 3H, OCH3), 1.99-1.78 (m, 4H, CH2), 2.42, 2.38 (s,
6H, CH3Ts). 13C-NMR (100 MHz, CDCl3): δ= 98.01 (C-1), 82.63, 79.64, 77.56 (C-2,
C-3, C-4), 62.20 (C-5), 55.24 (OCH3), 71.00, 70.80, 70.28, 69.05, 68.03 (5C, C-6,
OCH2), 49.23, 48.71, 47.76, 47.61 (4C, CH2NTs), 29.64, 29.32 (2C, CH2), 21.49,
21.45 (2C, CH3Ts), 101.23 (PhCH), 143.29-137.03 and 129.71-125.30 (18C, Ph).
Calcd. for C38H50N2O11S2 (775.0): C, 58.90; H, 6.50; N, 3.61; S, 8.27. Found: C,
59.87; H, 6.75; N, 3.48; S, 8.71. FAB-MS found [M+Na+] 797 (100%), [M+H+] 775
(90%).
25

ACCEPTED MANUSCRIPT
4.3.20. Methyl 4, 6-O-benzylidene-2, 3-O-(3, 6, 9-tritosyl-3, 6, 9-triiaza-
undecylene)-α-D-glucopyranoside (26)
Compound 13 (778 mg, 1.15 mmol), diethylenetriamino tris-
tuoluenesulfonamide (15)44,45 (650 mg, 1.15 mmol), and cesium carbonate (1.5
g, 4.6 mmol) in DMF (10 mL) were treated according to GP3 for 24 h at 80°C.
Workup as in GP3 and separation by flash chromatography (toluene/ethyl
acetate 4 : 1) gave 782 mg (76 %) of compound 26. Glass temperature 98 °C;
1
[α]D20 = + 11.4 (c =1.0, CHCl3); H-NMR (400 MHz,CDCl3): δ = 7.73-7.16 (m, 17H,
Ph), 5.52 (s, 1H, PhCH), 4.85 (d, 1H, J1,2 3.5 Hz, H-1), 4.07-3.14 (m, 21H, H-2, -3, -
4, -5, -6ax, OCH2, CH2NTs), 4.25 (dd, 1H, J5,6eq 4.5, J6ax,6eq 10.0 Hz, H-6eq), 3.39 (s,
3H, OCH3), 2.45, 2.44, 2.39 (s, 9H, CH3Ts). 13C-NMR (100 MHz, CDCl3): δ= 97.77
(C-1), 82.50, 78.49, 77.57 (C-2, C-3, C-4), 62.13 (C-5), 55.19 (OCH3), 71.82,
68.99, 68.08 (3C, C-6, OCH2), 50.98, 50.37, 49.75, 49.33 (6C, CH2NTs), 21.55 (3C,
CH3Ts), 101.28 (PhCH), 143.67-137.25 and 129.85-125.99 (24C, Ph). Calcd. for
C43H53N3O12S3 (900.1): FAB-MS found [M+Na+] 922(100%).
4.3.21. 2, 3´: 3, 2´-Bis-di-O-tosyl-(6-tosyl-3, 9-dioxa-6-aza-undecanylene)-bis-
[methyl 4, 6-O-benzylidene-α-D-glucopyranoside] (27) and 2, 2´: 3, 3´-Bis-di-O-
tosyl-(6-tosyl-3, 9-dioxa-6-aza-undecanylene)-bis-[methyl 4, 6-O-benzylidene-
α-D-glucopyranoside] (28)
Compounds 3 (224 mg, 0.44 mmol), 6 (334 mg, 0.44 mmol) and cesium
carbonate (1.4 g, 4.3 mmol) in DMF (10 mL) were treated according to GP3 for
4 days at 80°C. Workup as in GP3 and purification by flash chromatography
(toluene/ethyl acetate 3 : 1) gave 270 mg (52 %) of a mixture 27 + 28, which
1
could not be separated. Data of this mixture: H-NMR (400 MHz,CDCl3):
δ = 7.71-7.24 (m, 18H, Ph), 5.50 (s, 2H, PhCH, PhCH´), 4.82 (d, 2H, J1,2 = J1´,2´ 3.5
26

ACCEPTED MANUSCRIPT
Hz, H-1, -1´), 3.90-3.24 (m, 42H, H-2, -2´, -3, -3´, -4, -4´, -5, -5´, -6ax, -6ax´, OCH2,
CH2NTs), 4.28-4.25 (m, 2H, H-6eq, -6eq´), 3.41 (s, 6H, OCH3 ,OCH3´), 2.42, 2.34
(s, 6H, CH3Ts). 13C-NMR (100 MHz, CDCl3): δ= 99.15 (C-1, -1´), 81.88, 81.84,
80.49, 80.43, 79.11 (6 C, C-2, -2´, C-3, -3´, C-4, -4´), 62.32 (2C, C-5, -5´), 55.28
(2C, OCH3, OCH3´), 72.22, 71.22, 71.15, 70.82, 70.74, 70.63, 70.46, 70.36, 70.22,
70.14, 69.07 (14C, C-6, -6´, OCH2), 49.28, 49.11, 49.02, 48.96 (4C, CH2NTs),
21.48 (2C, CH3Ts), 101.32 (2C, PhCH, PhCH´), 143.42-137.47 and 129.69-126.08
(24C, Ph). Calcd. for C58H72N2O20S2 (1187.4): FAB-MS found [M+Na+] 1210
(100%).
4.3.22. 2, 3´: 3, 2´-Bis-di-O-(3-tosyl-3-aza-hexylene)-bis-[methyl 4, 6-O-
benzylidene-α-D-glucopyranoside] (29) and 2, 2´: 3, 3´-Bis-di-O-(3-tosyl-3-aza-
hexylene)-bis-[methyl 4, 6-O-benzylidene-α-D-glucopyranoside] (30)
Compounds 10 (585 mg, 0.83 mmol), 13 (563 mg, 0.83 mmol) and cesium
carbonate (1.35 g, 4.15 mmol) in DMF (10 mL) were treated according to GP3
for 2 days at 70°C. Workup as in GP3 and separation by flash chromatography
(toluene/ethyl acetate 1 : 1) gave compounds 29 and 30, the assignment of
which was ambiguous.
Eluting first compound 29 (or 30): 283 mg (33 %); glass temperature 89-
1
95 °C; [α]D20 = + 40.7 (c =1.0, CHCl3); H-NMR (400 MHz,CDCl3): δ = 7.66-7.16
(m, 18H, Ph), 5.53 (s, 2H, PhCH, PhCH´), 4.80 (d, 2H, J1,2 = J1´,2´ 3.5 Hz, H-1, -1´),
3.90-3.11 (m, 26H, H-2, -2´, -3, -3´, -4, -4´, -5, -5´, -6ax, -6ax´, OCH2, CH2NTs),
4.27 (dd, 2H, J5,6eq = J5´,6eq´ 3.5, J6ax,6eq = J6ax´,6eq´ 10.0 Hz, H-6eq, -6eq´), 3.40 (s, 6H,
OCH3, OCH3´), 1.89-1.72 (m, 4H, CH2), 2.38, 2.34 (s, 6H, CH3Ts). 13C-NMR (100
MHz, CDCl3): δ= 98.35 (C-1, -1´), 82.43, 81.92, 80.10, 80.01, 78.68, 77.85 (6 C, C-
2, -2´, C-3, -3´, C-4, -4´), 62.32, 62.19 (2C, C-5, -5´), 55.34, 55.25 (2C, OCH3,
27

ACCEPTED MANUSCRIPT
OCH3´), 70.73, 70.34, 69.07, 68.39, 67.46 (6C, C-6, -6´, OCH2), 48.29, 48.28,
47.24, 45.53 (4C, CH2NTs), 29.63, 29.35 (2C, CH2), 21.47 (2C, CH3Ts), 101.39,
101.26 (2C, PhCH, PhCH´), 143.23-137.34 and 129.70-125.30 (18C, Ph). Calcd.
for C52H66N2O16S2 (1039.2): C, 60.10; H, 6.40; N, 2.70; S, 6.17. Found: C, 60.28;
H, 6.54; N, 2.75; S, 6.09. FAB-MS found [M+Cs+] 1171 (80%), [M+Na+] 1061
(100%).
Eluting second compound 30 (or 29): 297 mg (35 %); glass temperature
84-88 °C; [α]D20 = + 34.1 (c =1.0, CHCl3); H-NMR (400 MHz,CDCl3): δ = 7.70-7.14
1
(m, 18H, Ph), 5.49, 5.44 (s, 2H, PhCH, PhCH´), 4.84, 4.83 (d, 2H, J1,2 = J1´,2´ 3.5 Hz,
H-1, -1´), 3.90-3.05 (m, 26H, H-2, -2´, -3, -3´, -4, -4´, -5, -5´, -6ax, -6ax´, OCH2,
CH2NTs), 4.29-4.24 (m, 2H, H-6eq, -6eq´), 3.44, 3.43 (s, 6H, OCH3, OCH3´), 1.97-
1.90 and 1.78-1.69 (m, 4H, CH2), 2.42, 2.35 (s, 6H, CH3Ts). 13C-NMR (100 MHz,
CDCl3): δ= 98.44 (2C, C-1, -1´), 82.25, 81.79, 80.19, 79.76, 78.70, 77.92 (6 C, C-2,
-2´, C-3, -3´, C-4, -4´), 62.31, 62.30 (2C, C-5, -5´), 55.39, 55.31 (2C, OCH3, OCH3´),
71.32, 70.18, 69.06, 68.27 (6C, C-6, -6´, OCH2), 49.00, 48.28, 47.12, 46.30 (4C,
CH2NTs), 29.36, 29.35 (2C, CH2), 21.51 (2C, CH3Ts), 101.32, 101.23 (2C, PhCH,
PhCH´), 143.32-137.36 and 129.78-125.98 (18C, Ph). Calcd. for C52H66N2O16S2
(1039.2): FAB-MS found [M+Na+] 1061 (100%).
Acknowledgement
Partial support of these studies by the Deutsche Forschungsgemeinschaft (DFG)
and the Bundesministerium für Forschung und Technologie (BMFT) is gratefully
acknowledged.
References
1.
Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 2495-2496.
28