Synthesis of Glycoconjugated Phthalonitriles for New Phthalocyanine-Based Photosensitizers

Article abstract of DOI:10.1080/07328303.2015.1050106

Excellent photophysical and photochemical properties completed by magnificent take-up rates in malignant tissues attracted a great deal of interest to the application of glycosylated and glycoconjugated phthalocyanines in photodynamic therapy. In this stu

Full text of DOI:10.1080/07328303.2015.1050106

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Synthesis of Glycoconjugated
Phthalonitriles for New Phthalocyanine-
Based Photosensitizers
Göran Cruciusa, Michael Hanacka & Thomas Zieglera
a Institute of Organic Chemistry, University of Tuebingen,, Tübingen,
72076, Germany
Published online: 01 Jul 2015.
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To cite this article: Göran Crucius, Michael Hanack & Thomas Ziegler (2015): Synthesis of
Glycoconjugated Phthalonitriles for New Phthalocyanine-Based Photosensitizers, Journal of
Carbohydrate Chemistry, DOI: 10.1080/07328303.2015.1050106
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Journal of Carbohydrate Chemistry, 0:1–40, 2015
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Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2015.1050106
Synthesis of Glycoconjugated
Phthalonitriles for New
Phthalocyanine-Based
Photosensitizers
Go¨ran Crucius, Michael Hanack, and Thomas Ziegler
Institute of Organic Chemistry, University of Tuebingen, Auf der Morgenstelle 18
72076, Tu¨bingen, Germany
GRAPHICAL ABSTRACT
Excellent photophysical and photochemical properties completed by magnificent take-
up rates in malignant tissues attracted a great deal of interest to the application of
glycosylated and glycoconjugated phthalocyanines in photodynamic therapy. In this
study we describe the concise synthesis and full characterization of 16 differently 3,6-
bisglycoconjugated phthalonitriles 3, 5, 6, 8, and 48–59, which are precursors for a
new generation of photosensitizers, namely, nonperipheral glycoconjugated phthalo-
cyanines. The first example for the synthesis of a nonperipheral glycoconjugated zinc
phthalocyanine 60 from phthalonitrile 48 is also presented in this work.
Keywords Glycoconjugated phthalonitrile; Photosensitizer; Carbohydrate tosylate;
Hydroquinone; Zinc phthalocyanine
Received February 16, 2015; accepted May 6, 2015.
Address correspondence to Thomas Ziegler, Institute of Organic Chemistry, Univer-
sity of Tuebingen, Auf der Morgenstelle 18, 72076, Tuebingen, Germany. E-mail:
thomas.ziegler@uni-tuebingen.de
1

G. Crucius et al.
2
INTRODUCTION
Nowadays, photodynamic therapy (PDT) is a well-accepted method for the
treatment of age-related macular degeneration, for some forms of cancer in-
cluding skin and early lung cancer, and for antiviral and antibacterial applica-
tions.[1–3] The efficacy of PDT is based on the interaction of three components:
photosensitizer, light, and molecular oxygen. After intravenous injection and
accumulation of the photosensitizer in the malignant tissue, the photothera-
peutic effect is activated by irradiation with light to generate highly reactive
singlet oxygen from readily available triplet oxygen in the cells. These reac-
tive oxygen species evoke a toxic response in the malignant tissue, ending,
ultimately, in cell death.[4–6] Due to their absorbance in the red region of the
visible spectrum, high stability during light exposure, and longer triplet-state
lifetimes, phthalocyanines, especially their metalated diamagnetic complexes
(MPc’s, M = Zn, Al, etc.), turned out to be potential candidates for use in photo-
dynamic processes.[4,7] However, one considerable problem of phthalocyanine-
based photosensitizers (PSs) is the poor solubility of their hydrophobic skele-
ton in physiological media. Therefore, scientific attention has been focused on
the development of water-soluble PSs.[8–13] The combination of the hydrophobic
macrocycles with hydrophilic carbohydrate moieties has attracted a great deal
of attention, mainly due to the fact that several carbohydrates have a specific
recognition for cancer cells.[14–16] In addition, these carbohydrate residues en-
hance the solvation properties of the photosensitizer to ensure more effective
photocytotoxic activity.[17–28]
In previous studies we have synthesized and fully characterized a series of
peripheral glycosylated and glycoconjugated zinc (II) phthalocyanines bearing
galactose, glucose, mannose, maltose, or cellobiose residues at the macrocyclic
skeleton. Connection of the glycosides with the aromatic system was carried
out via an oxygen or sulfur atom at C-1 or C-6 of the appropriated carbo-
hydrate using nucleophilic aromatic displacement reactions at the phthaloni-
trile stages.[29–35] The achieved glycosylated and glycoconjugated zinc phthalo-
cyanine species with excellent solubility in water, absorption maxima beyond
700 nm, and high triplet quantum yields ranging from 0.68 to 0.88 fulfilled the
basic requirements for the successful application in PDT.[36,37]
Herein, we present the synthesis and full characterization of 3,6-
bisglycosylated and 3,6-bisglycoconjugated phthalonitriles, which are neces-
sary starting materials for the formation of new nonperipheral glycosylated
and glycoconjugated phthalocyanines.
RESULTS AND DISCUSSION
As mentioned before, the concept of nucleophilic aromatic displacement
reaction was successfully applied for the synthesis of monoglycosylated

Glycoconjugated Phthalonitriles
3
phthalonitriles—position three or four of the aromatic dinitrile is substituted
by one sugar residue—as well as for the 4,5-bisglycosylated and the 3,4,5,6-
tetraglycoconjugated phthalonitriles.[13,29–35] Additionally, we could show that
3,6-bisglycoconjugated phthalonitriles also have been accessible by nucle-
ophilic aromatic displacement of two fluorine atoms or triflyl groups via a
carbohydrate anion. Although the target structures were obtained, we devel-
oped a new and much more simple and efficient route for 3,6-bisglycosylated
phthalonitriles using reaction conditions described by Oyo Mitsunobu for the
formation of ethers starting from primary and secondary alcohols.[39]
Therefore, 2,3-dicyanohydroquinone (1) was reacted with 1,2:3,4-di-
O-isopropylidene-α-D-galactopyranose (2) in toluene using Ph3P and di-
ethyl azodicarboxylate (DEAD) as reagents to afford 3,6-bis(1,2:3,4-di-
O-isopropylidene-α-D-galactopyranos-6-yl)phthalonitrile (3) in a 47% yield
(Sch. 1). Driven by the successful formation of glycoconjugate 3, hydroquinone
1 was also treated with 2,3,4,6-tetra-O-benzyl-α-D-glucopyranose (4) under
similar reaction conditions to give 3,6-bis(2,3,4,6-tetra-O-benzyl-β-D-gluco-1-
yl)phthalonitrile (5) in a yield of 77% within 3 h (Sch. 2). No α-anomer of 5
could be detected.
Scheme 1: Formation of glycoconjugate 3 catalyzed by Ph3Ph and DEAD.
Scheme 2: Formation of bisglycoside 5 catalyzed by PPh3 and DEAD.

G. Crucius et al.
Both phthalonitriles 3 and 5 were easily accessible from simple precursors
4
like hydroquinone 1 and the corresponding carbohydrates 2 or 4, protected by
base-abiding groups to ensure stability during the subsequent transformation
process of the metal phthalocyanine (MPc) under basic conditions, and serve
as useful examples for the powerful application of DEAD and Ph3P in the syn-
thesis of ortho bis-substituted sugar dinitriles.
Taking into account that cleavage of benzyl groups at the phthalocya-
nine stage would become a challenging task,[31] we treated compound 5 with
Pd/C under an atmosphere of hydrogen to yield 3,6-bis-(β-D-glucopyranosyl)-
phthalonitrile (6) (Sch. 3). Although reaction conditions were diversified in
terms of solvent and amount of Pd/C and so forth, incomplete cleavage of
the benzyl protecting groups of sugar nitrile 5 occurred. However, 6 was
synthesized following another strategy. Hydroquinone (1), 2,3,4,6-tetra-O-
acetyl-α-D-glucopyranosyl bromide (7), and potassium carbonate were refluxed
in dry acetonitrile (ACN) for 36 h to give 3,6-bis-2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosyl phthalonitrile (8) in a yield of 60%. Subsequent deprotection
of 8 under Zemple´n conditions yielded 83% of dinitrile 6 (Sch. 3). To the
best of our knowledge, compounds 5, 6, and 8 are the first examples for 3,6-
disubstituted glyconitriles in which the carbohydrate moieties were anomeri-
cally linked to the aromatic system. All analytical data were in full agreement
with the expected results. Configurational aspects were determined by using
mono- and multidimensional NMR spectroscopy. Due to the evaluated coupling
constants of the 1H-1H- and 1H-13C-signals, we assigned an all β-configuration
Scheme 3: Synthesis of dinitrile 6.

Glycoconjugated Phthalonitriles
5
to compounds 5 and 8. Although the synthesis of the corresponding zinc ph-
thalocyanines is not a part of the present work, we can state that these new
3,6-bisglycosylated phthalonitriles will be potential precursors for new gly-
cophotosensitizers with excellent photophysical properties.
Consequently, we were also focused on systems with the same substi-
tution pattern but, as an additional aspect, with spacers between the aro-
matic and the carbohydrate moiety. Alkyl chains like ethyl, propyl, butyl, and
pentyl seemed to be the best choice for the spacer part because three advan-
tages could be expected. First, electron-donating alkyl chains would result in
a bathochromic shift of the absorption maxima in the zinc macrocycle. Second,
due to a lower steric hindrance, formation of the zinc phthalocyanine should
be favored. Finally, spacers should create a more bulky atmosphere around the
macrocycle, resulting in a lower aggregation behavior, which in turn is a basic
requirement for the successful application in PDT.
To acknowledge our assumption, we first had to consider the synthesis
of the appropriated carbohydrates. Special attention was paid to two main
requirements. On the one hand, the sugars had to be protected with base-
abiding groups that endure the harsh reaction conditions during the forma-
tion of phthalocyanines. On the other hand, protecting groups had to be labile
enough to be cleaved at the macrocyclic stage. Additionally, the spacer had
to carry a leaving group that is suitable for a subsequent nucleophilic substi-
tution reaction with hydroquinone (1) and potassium carbonate to form the
corresponding 3,6-bisglycoconjugated phthalonitriles. Therefore, D-galactose
2 (Sch. 4), D-glucose 10 (Sch. 5), and D-mannose 9 (Sch. 6), all of which
were protected with isopropylidene acetals, were reacted with alkyl bromides
1,2-dibromoethane (11), 1,3-dibromopropane (12), 1,4-dibromobutane (13), and
1,5-dibromopentane (14).
Treatment of pyranose 2 with halogen bromides 13 or 14 in dry
DMF catalyzed by sodium hydride yielded 6-O-(5-bromopentyl)-1,2:3,4-di-O-
isopropylidene-α-D-galactopyranose (15, 59%) and 6-O-(4-bromobutyl)-1,2:3,4-
di-O-isopropylidene-α-D-galactopyranose (16, 55%), respectively. Introducing
3-bromopropyl and 2-bromoethyl moieties at galactoside 2 with alkyl dibro-
mides 11 and 12 was not successful. Instead of the target compound 6-
O-(3-bromopropyl)-1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (17), 6-O-
allyl-1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (18) was isolated in a
27% yield from the reaction of carbohydrate 2, 1,3-dibromopropane (12), and
sodium hydride in dry DMF (Sch. 4). Due to the electronic effect and steric hin-
drance of 1,2-dibromoethane (11), no substitution products with galactopyra-
nose 2 were obtained. 1,2:3,4-di-O-Isopropylidene-α-D-galactopyranose (2) was
recovered quantitatively after workup (Sch. 4).
Likewise, 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (10) was treated
with alkyl bromides 11, 12, 13, and 14 in dry DMF using NaH as base
(Sch. 5). 3-O-(5-Bromopentyl)-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose

G. Crucius et al.
6
Scheme 4: Introduction of spacers to 2 to prepare 15, 16, and 18.
(19) and 3-O-(4-bromobutyl)-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose
(20) as well as an elimination product 3-O-allyl-1,2:5,6-di-O-isopropylidene-
α-D-glucofuranose (21) were obtained in yields of 53%, 50%, and 30%,
respectively. As previously mentioned for compound 17, 3-O-(2-bromoethyl)-
1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (22) was not accessible either
by nucleophilic substitution of 1,2-dibromoethane with an anion of glycoside
10.
1-O-(5-Bromopentyl)-2,3:5,6-di-O-isopropylidene-α-D-galactopyranose
(23),
1-O-(4-bromobutyl)-2,3:5,6-di-O-isopropylidene-α-D-galactopyranose
(24), and 1-O-allyl-2,3:5,6-di-O-isopropylidene-α-D-galactopyranose (25) were
synthesized from mannoside (9) and alkyl bromides 11, 12, or 13 using a phase
transfer system of THF/water (99.5/0.5; v/v), 18-crown-6 ether, and KOH at
ambient temperature (Sch. 6). Compounds 23, 24, and 25 were obtained in
90%, 73%, and 41% yields, respectively, after chromatographic purification.
As previously described for sugar derivatives 2 and 10, no reaction between
1,2-dibromoethane (11) and 2,3:5,6-di-O-isopropylidene-α-D-mannofuranose

Glycoconjugated Phthalonitriles
7
Scheme 5: Introduction of 5-bromopentyl, 4-bromobutyl, and allyl spacers to 10.
(9) was detected, but 9 was recovered from the reaction mixture after standard
workup.
Recapitulating, only compounds 15, 19, and 23 with 5-bromopentyl spacer
as well as 16, 20, and 24 with 4-bromobutyl spacer were accessible by nu-
cleophilic substitution of 1,5-dibromopentane (14) or 1,4 dibromobutane (13)
using the anions of galactopyranose 2, glucopyranose 10, and mannofuranose
9. Consequently, we chose another system that gave us access to both pentyl
and butyl derivatives of 2, 9, and 10 and additionally the opportunity to syn-
thesize propyl- and ethyl-prolonged sugars as well. Alkyl bistosylates, which
are widely used in synthetic organic chemistry, such as the synthesis of crown
ethers,[43] acetals,[44] and macrocycles,[45] seemed to be promising starting ma-
terials. 1,5-Pentanediyl bistosylate (26), 1,4-butanediyl bistosylate (27), 1,3-
propanediyl bistosylate (28), and 1,2-ethanediyl bistosylate (29) were obtained
by reactions of the corresponding diols with p-toluenesulfonyl chloride in dry
pyridine.[44] Subsequently, all four alkyl spacers of different lengths were suc-
cessfully introduced to galactose 2, mannofuranose 9, and glucofuranoside 10

G. Crucius et al.
8
Scheme 6: Synthesis of compounds 23, 24, and 25.
using bistosylates 26–29 as starting materials. As shown in Scheme 7, man-
nosides 30–33 were obtained in 62% to 78% yields. Reaction conditions were
similar to those described for the transformation of 9 with halogen bromides
11–14. Contrary to dibromides 11 and 12, tosylates 28 and 29 granted access
to ethyl- and propyl-modified mannosides 32 and 33.
Similarly, glycosides 34, 35, 38, and 39 were obtained from treatment of
galactose 2 and glucose 10 with tosylates 26 and 27 in dry DMF after addi-
tion of sodium hydride followed by smooth heating (Sch. 8 and 9). In addition,
compounds 36, 37, 40, and 41 were prepared using a phase transfer system of
benzene, benzyltriethylammonium chloride, and aqueous potassium hydrox-
ide, which was established previously for nucleophilic substitution of tosylates
by nucleophiles.[47] Although the isolated yields were moderate for 40 and 41
(30% to 38%) and low for 36 and 37 (15% to 16%), alkyl tosylates 28 and 29
granted access to both ethyl and propyl prolonged derivates of 2 and 10 (Sch. 8
and 9).
Moreover, because of the low yields for tosylates 36 and 37, we devel-
oped a multistep synthesis to enhance quantities of the given target struc-
tures (Sch. 10). Therefore, galactose 2 was reacted with 2-benzyloxyethyl to-
sylate (42) or 3-benzyloxypropyl tosylate (43) to form benzyloxides 44 and 45,
respectively. Subsequent reduction of 44 and 45 yielded alcohols 46 and 47,
which were finally tosylated using p-toluenesulfonyl chloride and DABCO in

Glycoconjugated Phthalonitriles
9
Scheme 7: Synthesis of mannose derivatives 30–33.
dry ethyl acetate. With these additional synthetic steps, product quantities in-
creased and overall yields of 55% for 36 and 34% for 37 were obtained.
With the prepared carbohydrate bromides as well as carbohydrate tosy-
lates available, we were able to synthesize a set of 3,6-bisglycoconjugated ph-
thalonitriles, which became essential starting materials for new nonperiph-
eral glycoconjugated phthalocyanines. The general procedure for the nucle-
ophilic substitution reaction of bromo-functionalized glycosides 15, 16, 19, 20,
23, and 24 or for tosylates 30–41 with hydroquinone 1 in dry DMF under ba-
sic conditions is depicted in Scheme 11. Reaction times, yields, and chemical
structures of the formed 3,6-bisglycoconjugated phthalonitriles 48–59 are sum-
marized in Table 1. Both carbohydrate bromides and carbohydrate tosylates
were suitable precursors for the formation of glycoconjugated phthalonitriles,
in which dicyanohydroquinone 3- and 6-positions were substituted by sugar
moieties.
The bromide precursors 15, 16, 19, 20, 23, and 24 tended to be more reac-
tive than their corresponding tosylates 30–41. This finding could be ascribed to
a higher leaving tendency of bromide ions in nucleophilic reactions in compar-
ison to tosylates. With the exception of compound 55 (38%), target compounds

G. Crucius et al.
10
Table 1: Time, yields, and product structures of reactions listed in Scheme 11
Sugar
Component
Reaction
Time
Product
Yield
15 or 34
18 h
91% or 76%
16 or 35
18 h
70% or 57%
36
18 h
91%
37
19 or 38
24 h
18 h
51
78%
57% or 53%
(Continued on next page)

Glycoconjugated Phthalonitriles
11
Table 1: Time, yields, and product structures of reactions listed in Scheme 11
(Continued)
Sugar Component Reaction Time
Product
Yield
20 or 39
18 h
85% or 59%
40
41
18 h
36 h
54
56%
36%
23 or 30
18 h
79% or 76%
24 or 31
18 h
65% or 62%
(Continued on next page)

G. Crucius et al.
12
Table 1: Time, yields, and product structures of reactions listed in Scheme 11
(Continued)
Sugar Component
32
Reaction Time
18 h
Product
Yield
63%
33
36 h
80%
48–54 and 56–59 were obtained in good to excellent yields (53% to 91%). All
synthesized compounds were fully characterized by spectroscopic techniques
and elemental analysis, respectively. Analytical data were in agreement with
the expected results.
As a short outline of our ongoing work, Scheme 12 depicts the synthesis
of one nonperipheral glycoconjugated zinc phthalocyanine 61, which was ob-
tained from cross-condensation of phthalonitrile (60), sugar derivative 48, and
zinc bromide in 2-dimethylaminoethanol (DMAE) at 100◦C. The deep green
macrocycle was isolated in a 16% yield after chromatographic purification and
showed excellent photophysical properties, that is, absorption maxima beyond
700 nm. The syntheses and photophysical properties of other nonperipheral
octaglycosylated zinc phthalocyanines will be published elsewhere.
Summary
In this report, we summarized the recent progress that we made on the
synthesis of new water-soluble phthalocyanine-based photosensitizers for the
application in photodynamic therapy. In the first part of this work, we pre-
sented the synthesis of four unknown 3,6-bisglycosylated phthalonitriles 3, 5,

Glycoconjugated Phthalonitriles
13
Scheme 8: Synthesis of galactose tosylates 34–37 starting from 2.
and 6, which were obtained from dicyanohydroquinone (1) and sugars 2, 4, and
7. Additionally, starting from protected sugars 2, 9, and 10, we subsequently
synthesized a set of new spacer-prolonged sugar bromides and tosylates 15, 16,
19, 20, 23, 24, and 30–41. Treatment of these bromides and tosylates with hy-
droquinone yielded phthalonitriles 48–59, which are the starting materials for
the preparation of new nonperipheral substituted sugar phthalocyanines with
good photophysical properties and solubility in physiological media. Moreover,
the first nonperipheral glycoconjugated zinc phthalocyanine 61 was prepared
from 48 via cross-condensation with phthalonitrile and zinc bromide as the
metal source.

G. Crucius et al.
14
Scheme 9: Reaction of glucose 10 and tosylates 26–29.
EXPERIMENTAL
General Methods
Starting materials and reagents were purchased from ABCR GmbH (1,5-
dibromopentane, 1,4-dibromobutane, 1,3-dibromopropane, 1,2-dibromoethane)
and were of the highest purity available. DMF was distilled from phosphorous
˚
pentoxide. All solvents were stored over molecular sieve 3A under an atmo-
sphere of nitrogen until used. Silica gel 60 (particle size 0.04–0.063 mm) was
used for column chromatography. NMR spectra were recorded on a Bruker
Avance 400. UV-vis spectra were recorded on a Perkin Elmer Lambda 25 using
a 1-cm quartz cell. Melting points were determined with a Bu¨chi Melting Point

Glycoconjugated Phthalonitriles
15
Scheme 10: Multistep synthesis of 46 and 47.
M-560. Elemental analyses were performed on a HEKAtech Euro EA Analyzer.
FT-ICR-MS spectra were recorded on a Bruker Daltonic Apex 2. ESI-TOF spec-
tra were determined with a Bruker Daltonics Maxis G4.

G. Crucius et al.
16
Scheme 11: Reaction of modified sugars 15, 16, 19, 20, 23, 24, and 30–41 with 1 in dry DMF.
Scheme 12: Synthesis of zinc phthalocyanine 61.
General procedure GP1: introduction of bromoalkyl chains using NaH
A suspension of 1.00 eq. of the protected sugar in dry DMF was cooled to
0◦C under an atmosphere of nitrogen. Next, 1.30 eq. of sodium hydride was
added to the suspension and cooling was removed. The mixture was stirred for
an additional hour at rt before 5.00 eq. of the corresponding dibromide was
added in one portion. The mixture was stirred for 12 h at 60◦C. Next, the mix-
ture was cooled to rt, diluted with water, and extracted with three portions of
DCM. The combined organic layers were dried over MgSO4 and the solvents
were removed under reduced pressure. The crude product was purified by col-
umn chromatography.
General procedure GP2: introduction of bromoalkyl/tosylalkyl chains using
KOH and [18]-crown-6 in THF
A solution of 1.00 eq. of saccharide, 4.00 eq. potassium hydroxide, and 0.01
eq. [18]-crown-6 ether in THF/water (99.5/0.5; v/v) was stirred for 1 h at rt.

Glycoconjugated Phthalonitriles
17
Next, 5.00 eq. of the corresponding dibromide or bistosylate were added at
once and stirring was continued for 24 to 72 h. The mixture was neutralized
with saturated aqueous ammonium chloride and extracted several times with
DCM, and the combined organic layers were dried over MgSO4. The solvents
were evaporated under reduced pressure and the residue was purified by col-
umn chromatography.
General procedure GP3: introduction of tosyl-spacers using DMF and sodium
hybrid
A solution of 1.00 eq. of saccharide in dry DMF was cooled to 0◦C under
an atmosphere of nitrogen. Next, 1.20 eq. of sodium hydride was added to the
solution and stirring was continued for 60 min. Next, 4.00 eq. of bistosylate
was added to the mixture and stirring was continued for an additional 4 h at
rt. The reaction was quenched by addition of a saturated aqueous solution of
ammonium chloride and extracted with three portions of DCM, and the com-
bined organic layers were dried over sodium sulfate. After evaporation of the
solvents, the residue was purified by column chromatography.
General procedure GP4: introduction of tosyl-spacers using benzene and benzyl
triethylammonium chloride
To a solution of 1.00 eq. of saccharide in benzene was added at rt 5.00 eq.
of sodium hydroxide (50% in water) as well as 100 mg of benzyl triethylammo-
nium chloride. The suspension was stirred for an additional hour before 4.00
eq. of tosylate was added at once and stirring was continued for 18 h. The solu-
tion was neutralized with a saturated aqueous solution of ammonium chloride
and the aqueous phase was extracted three times using DCM. The combined
organic layers were dried over magnesium sulfate, the solvents were removed
under reduced pressure, and the residue was purified by column chromatogra-
phy.
General procedure GP5: synthesis of 3,6-bisglycoconjugated
phthalonitriles
A solution of 1.00 eq. 2,3-dicyanohydroquinone, 12.00 eq. potassium car-
bonate, and 2.20 eq. saccharide was suspended in dry DMF and heated to 60◦C.
Stirring was continued for 18 to 36 h at 60◦C. The mixture was cooled to rt,
water was added, and the phases were separated. The aqueous phase was ex-
tracted several times with DCM. The combined organic layers were dried upon
magnesium sulfate and the solvent was evaporated under reduced pressure.
The residue was purified using column chromatography.

G. Crucius et al.
18
3,6-Bis(1,2:3,4-di-O-isopropylidene-α-D-galactopyranos-6-yl)-
phthalonitrile
(3)
A solution of 27.40 mL (60 mmol) DEAD (40% in toluene) was added
dropwise over a period of 5 min to a suspension of 3.20 g (20 mmol) 2,3-
dicyanohydroquinone[40] and 15.70 g (60 mmol) PPh3 in 180 mL of dry toluene.
The mixture was stirred at rt until all solids were dissolved. Next, 15.60 g
(60 mmol) 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose dissolved in dry
toluene was added to the deeply red solution and the mixture was heated to
110◦C for 24 h. The solution was cooled to rt and the solvent was evaporated
under reduced pressure. The viscous oily residue was purified by column chro-
matography using a mixture of chloroform and methanol (250:1). Compound
3 was obtained by crystallization from acetone. Colorless solid (5.90 g, 47%);
m.p. 180–182◦C (acetone); [α]D = –98.8 (c 1.0, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.25 (s, 2 H, Ar-H), 5.52 (d, J1,2 = 5.1 Hz, 2 H, H-1), 4.67 (dd, J3,4
= 7.8 Hz, 2 H, H-3), 4.42 (d, J4,5 = 8 Hz, 2 H, H-4), 4.35 (dd, J2,3 = 2.3 Hz, 2
H, H-2), 4.26–4.18 (m, 6 H, H-5, H-6a, H-6b), 1.54, 1.43, 1.34, 1.33 (4s, 12H,
-CH3); 13C NMR (100.6 MHz, CDCl3) δ 155.2 (2 C, Ar-C), 119.2 (2 C, Ar-C),
112.8 (2 C, Ar-C), 109.5 (2 C, 2 × -C(CH3)2), 109.0 (2 C, 2 × -C(CH3)2), 105.5 (2
C, 2 × -CN), 96.2 (2 C, C-1), 70.6 (2 C, C-2),∗ 70.5 (2 C, C-4),∗ 70.5 (2 C, C-3),∗
68.8 (2 C, C-6), 66.3 (2 C, C-5), 26.2, 26.1, 25.0, 24.4 (8 C, 8 × -CH3); IR (Neat)
20
1
v˜max 2988, 2938, 2232, 1579, 1488, 1454, 1385, 1214, 1009, 920, 810, 514 cm−1
;
Anal. calcd. for C32H40N2O12: C 59.62; H 6.25; N 4.35; Found: C 59.52; H 6.41;
N 4.11.
∗Signals could be reversed.
3,6-Bis(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)phthalonitrile
(5)
A solution of 1.00 mL (2.20 mmol) DEAD (40% in toluene) was added
dropwise over a period of 5 min to a suspension of 0.16 g (1.00 mmol) 2,3-
dicyanohydroquinone[40] and 0.58 g (2.20 mmol) PPh3 in 30 mL of dry THF
and the mixture was stirred for 10 min at rt. Next, 1.19 g (2.20 mmol) 2,3,4,6-
tetra-O-benzyl-α-D-glucopyranose dissolved in 10 mL of dry THF was added
to the deeply red solution and the mixture was heated under reflux for 3 h.
The solution was cooled to rt and the solvent was evaporated under reduced
pressure. The residue was purified by column chromatography using a mix-
ture of toluene and acetone (25:1). Compound 5 was obtained by recrystalliza-
tion from ethanol/acetone as colorless needles (0.93 g, 77%); m.p. 138–140◦C
20
1
(ethanol/acetone); [α]D = –58.4 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3):
δ 7.42–7.40 (m, 4 H, Ar-H), 7.36–7.26 (m, 32 H, Ar-H), 7.22–7.19 (m, 6H, Ar-
H), 5.16 (d, 2 H, -CH2Ph), 5.02 (d, 2 H, -CH2Ph), 4.99 (d, J1,2 = 7.3 Hz, 2 H,

Glycoconjugated Phthalonitriles
19
H-1), 4.91–4.85 (m, 6 H, -CH2Ph), 4.59–4.47 (m, 6 H, -CH2Ph), 3.85 (dd, J2,3
= 8.8 Hz, 2 H, H-2), 3.79–3.74 (m, 4 H, H-3, H-6a), 3.70–3.61 (m, 6 H, H-4,
H-5, H-6b); 13C NMR (100.6 MHz, CDCl3): δ 154.2, 138.2, 137.9, 137.7, 137.7,
128.5, 128.5, 128.4, 128.3, 128.0, 128.0, 127.9, 127.8, 127.7, 121.0, 112.8 (54 C,
Ar-C), 105.8 (2 C, -CN), 101.2 (2 C, C-1), 84.3 (2 C, C-3), 81.4 (2 C, C-2), 77.3 (2
C, C-4), 75.8 (2 C, -CH2-), 75.5 (2 C, C-5), 75.4 (2 C, -CH2-), 75.2 (2 C, -CH2-),
73.5 (2 C, -CH2-), 68.7 (2 C, C-6); IR (Neat) v˜max 3089, 3062, 3030, 2867, 2230,
1497, 1482, 1453, 1363, 1274, 1209, 1071, 1027, 813, 736 cm−1; Anal. calcd. for
C76H72N2O12: C 75.73; H 6.02; N 2.32; Found: C 75.92; H 6.00; N 2.30.
3,6-Bis-(β-D-glucopyranosyl)-phthalonitrile (6)
A solution of sodium methanolate in methanol (5.4 M, 150 μL ) was added
at rt to a suspension of 8.41 g (10.25 mmol) of compound 8 in 100 mL methanol.
Stirring at rt was continued until TLC showed the complete disappearance of
the starting material. Dowex H+ ion exchange resin was added and subse-
quently removed by filtration. Methanol was removed under reduced pressure
20
1
to yield an amorphous solid (4.11 g, 83%); [α]D = –34.7 (c 0.5, MeOH); H
NMR (400 MHz, MeOH-d4): δ 7.64 (s, 2 H, Ar-H), 5.10 (d, J1,2 = 7.6 Hz, 2 H, H-
1), 3.88 (dd, J5,6a = 2.0 Hz, J6a,6b = 12.0 Hz, 2 H, H-6a), 3.68 (dd, J5,6b = 5.8 Hz,
2 H, H-6b), 3.55–3.37 (m, 8 H, H-2, H-3, H-4, H-5); 13C NMR (100.6 MHz,
MeOH-d4): δ = 156.0, 123.8, 114.1 (6 C, Ar-C), 106.6 (2 C, -CN), 102.5 (2 C,
C-1), 78.7 (2 C, C-3),∗ 78.2 (2 C, C-2),∗ 74.7 (2 C, C-4),∗ 71.2 (2 C, C-5),∗ 62.6 (2
C, C-6); IR (Neat) v˜max 3385, 2917, 2242, 1638, 1582, 1485, 1403, 1281, 1076,
924, 890, 825, 753, 703 cm−1; Anal. calcd. for C20H24N2O12: C 49.59; H 4.99; N
5.78; Found: C 49.23; H 5.76; N 5.43.
∗Signals could be reversed.
3,6,-Bis-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)phthalonitrile
(8)
A suspension of 3.14 g (21.20 mmol) of 2,3-dicyanohydroquinone,[40] 18.20 g
(44.60 mmol) 2,3,4,6-tetra-O-acetyl-α-D-glucopyranososyl bromide (7), and
17.28 g (125.20 mmol) K2CO3 in 200 mL of dry acetonitrile was heated under
reflux for 36 h. The yellow suspension was cooled to rt, filtered, and concen-
trated. The filter cake was washed with acetonitrile and the combined solvents
were concentrated under reduced pressure. Chromatography of the residue on
silica gel using a mixture of n-hexane and ethyl acetate (1:1, v/v) and sub-
sequent crystallization from methanol yielded 8 as a colorless solid (10.40 g,
60%); m.p. 216◦C; [α]D = –75.7 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3):
δ 7.51 (s, 2 H, Ar-H), 5.30–5.23 (m, 4 H, H-2, H-3), 5.19–5.14 (m, 2 H, H-4),
5.06–5.04 (m, 2 H, H-1), 4.28–4.20 (m, 4 H, H-6a, H-6b), 3.85–3.81 (m, 2 H,
H-5), 2.11, 2.08, 2.04, 2.02 (4s, 24 H, 8 × -CH3); 13C NMR (100.6 MHz, CDCl3):
20
1

G. Crucius et al.
20
δ 170.5, 170.2, 169.5, 169.4 (8 C, -OCOCH3), 154.6, 124.9, 111.7 (6 C, Ar-C),
108.5 (2 C, -CN), 100.6 (2 C, C-1), 72.7 (2 C, C-5), 72.7 (2 C, C-3),∗ 70.4 (2 C,
C-2),∗ 67.9 (2 C, C-4), 61.5 (2 C, C-6), 20.8, 20.7, 20.6 (8 C, -COCH3); IR (Neat)
v˜max 3455, 2240, 1758, 1637, 1481, 1432, 1379, 1236, 1074, 1039, 904 cm−1
;
Anal. calcd. for C36H40N2O20: C 52.68; H 4.91; N 3.41; Found: C 52.82; H 4.90;
N 3.26.
∗Signals could be reversed.
6-O-(5-Bromopentyl)-1,2:3,4-di-O-isopropylidene-α-D-
galactopyranose (15)
Pursuant to general procedure GP1, 1.40 g (5.38 mmol) of saccharide
2, 168 mg (7.00 mmol) sodium hydride, and 3.64 mL (27.00 mmol) 1,5-
dibromopentane (14) in 60 mL of dry DMF and chromatographic purification
on silica gel using a mixture of toluene/acetone (30:1) gave compound 15 as a
colorless oil (1.26 g, 59%). Analytical data were in accordance with the litera-
ture.[41]
6-O-(4-Bromobutyl)-1,2:3,4-di-O-isopropylidene-α-D-
galactopyranose (16)
Pursuant to general procedure GP1, 2.80 g (10.76 mmol) of saccharide
2, 336 mg (13.99 mmol) sodium hydride, and 6.40 mL (54.00 mmol) 1,4-
dibromobutane (13) in 60 mL of dry DMF and chromatographic purification
on silica gel using a mixture of toluene/acetone (30:1) gave compound 16 as a
colorless oil (3.34 g, 55%). Analytical data were in accordance with the litera-
ture.[41]
6-O-Allyl-1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (18)
Pursuant to general procedure GP1, 2.80 g (10.76 mmol) of saccharide
2, 337 mg (14.04 mmol) sodium hydride, and 5.48 mL (54.00 mmol) 1,3-
dibromopropane (12) in 60 mL of dry DMF and chromatographic purification
on silica gel using a mixture of toluene/acetone (30:1) gave compound 18 as a
colorless oil (0.89 g, 27%). Analytical data were in accordance with the litera-
ture.[42]
3-O-(5-Bromopentyl)-1,2:5,6-di-O-isopropylidene-α-D-
glucofuranose (19)
Pursuant to general procedure GP1, 5.20 g (20.00 mmol) of saccharide
10, 624 mg (26.00 mmol) sodium hydride, and 13.47 mL (100.00 mmol) 1,5-
dibromopentane (14) in 75 mL of dry DMF and chromatographic purification
on silica gel using a mixture of toluene/acetone (30:1) gave compound 19 as a

Glycoconjugated Phthalonitriles
21
colorless oil (4.33 g, 53%). Analytical data were in accordance with the litera-
ture.[41]
3-O-(4-Bromobutyl)-1,2:5,6-di-O-isopropylidene-α-D-
glucofuranose (20)
Pursuant to general procedure GP1, 5.20 g (20.00 mmol) of saccharide
10, 624 mg (26.00 mol) sodium hydride, and 11.81 mL (100.00 mmol) 1,4-
dibromobutane (13) in 75 mL of dry DMF and chromatographic purification
on silica gel using a mixture of toluene/acetone (30:1) gave compound 20 as a
colorless oil (3.93 g, 50%). Analytical data were in accordance with the litera-
ture.[41]
3-O-Allyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (21)
Pursuant to general procedure GP1, 1.72 g (6.62 mmol) of saccharide
10, 206 mg (8.60 mol) sodium hydride, and 3.36 mL (33.10 mmol) 1,3-
dibromopropane (12) in 50 mL of dry DMF and chromatographic purification
on silica gel using a mixture of toluene/acetone (30:1) gave compound 21 as a
colorless oil (0.58 g, 30%). Analytical data were in accordance with the litera-
ture.[41]
1-O-(5-Bromopentyl)-2,3:5,6-di-O-isopropylidene-α-D-
mannofuranose (23)
Pursuant to general procedure GP2, 7.00 g (26.92 mmol) of saccharide 9,
6.03 g (107.30 mmol) potassium hydroxide, 72 mg (0.27 mmol) [18]-crown-
6 ether, and 18.00 mL (134.50 mmol) 1,5-dibromopentane (15) in 250 mL
THF/water (99.5:0.5; v:v) and chromatographic purification on silica gel us-
ing a mixture of n-hexane/ethyl acetate (7:1) gave compound 23 as a colorless
20
1
oil (9.90 g, 90%); [α]D = +35.6 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3):
δ 4.97 (s, 1 H, H-1), 4.78 (dd, 1 H, J3,4 = 3.7 Hz, H-3), 4.58 (d, 1 H, J2,3
=
6.1 Hz, H-2), 4.43–4.38 (m, 1 H, H-5), 4.11 (dd, 1 H, J = 8.6 Hz, 6.3 Hz, H-
6a), 4.03 (dd, 1 H, J = 8.6 Hz, 4.4 Hz, H-6b), 3.92 (dd, 1 H, J4,5 = 7.8 Hz,
H-4), 3.66–3.60 (m, 1 H, Ha -OCH2-), 3.43–3.36 (m, 3 H, Hb -OCH2-, -CH2Br-),
1.91–1.84 (m, 2 H, -CH2-), 1.63–1.55 (m, 2 H, -CH2-), 1.52–1.48 (m, 2 H, -CH2-),
1.47, 1.46, 1.38, 1.32 (4s, 12 H, 4 × – -CH3); 13C NMR (100.6 MHz, CDCl3): δ
112.6, 109.2 (2 C, -C(CH3)2), 106.3 (1 C, C-1), 85.0 (1 C, C-2), 80.2 (1 C, C-4),
79.5 (1 C, C-3), 73.1 (1 C, C-5), 67.1 (1 C, -OCH2-), 66.9 (1 C, C-6), 33.6, 32.4,
28.53, 24.8 (4 C, 4 × -CH2-), 26.9, 25.9, 25.2, 24.5 (4 C, 4 × -CH3); MS (FAB):
m/z 409 [M+H]+, 393 [M-CH3]+, [M-C12H19O6]+; Anal. calcd. for C17H29BrO6:
C 49.88; H 7.14; Found: C 49.79; H 7.12.

G. Crucius et al.
22
1-O-(4-Bromobutyl)-2,3:5,6-di-O-isopropylidene-α-D-
mannofuranose (24)
Pursuant to general procedure GP2, 5.20 g (20.00 mmol) of saccharide
9, 4.48 g (80.00 mmol) potassium hydroxide, 53 mg (0.20 mmol) [18]-crown-
6 ether, and 11.80 mL (100.00 mmol) 1,4-dibromobutane (13) in 250 mL
THF/water (99.5:0.5; v:v) and chromatographic purification on silica gel us-
ing a mixture of n-hexane/ethyl acetate (7:1) gave compound 24 as a color-
less oil (5.75 g, 73%); [α]D = +39.5 (c 1.0, CHCl3); 1H NMR (400 MHz,
20
CDCl3): δ 4.97 (s, 1 H, H-1), 4.79 (dd, 1 H, J3,4 = 3.5 Hz, H-3), 4.58 (d,
1 H, J2,3 = 5.8 Hz, H-2), 4.43–4.38 (m, 1 H, H-5), 4.11 (dd, 1 H, J =
8.6 Hz, 6.3 Hz, H-6a), 4.03 (dd, 1 H, J = 8.6 Hz, 4.5 Hz, H-6b), 3.92 (dd,
1 H, J4,5 = 7.6 Hz, H-4), 3.69–3.63 (m, 1 H, Ha -OCH2-), 3.45–3.38 (m,
3 H, Hb -OCH2-, -CH2Br-), 1.96–1.89 (m, 2 H, -CH2-), 1.74–1.68 (m, 2 H,
-CH2-), 1.47, 1.46, 1.38, 1.33 (4s, 12 H, 4 × -CH3); 13C NMR (100.6 MHz,
CDCl3): δ 112.6, 109.2 (2 C, 2 × -C(CH3)2), 106.3 (1 C, C-1), 85.1 (1 C, C-2),
80.3 (1 C, C-4), 79.5 (1 C, C-3), 73.1 (1 C, C-5), 66.9 (1 C, C-6), 66.4 (1 C, -OCH2-
), 33.4, 29.5, 28.0 (3 C, 3 × -CH2-), 26.9, 25.9, 25.1, 24.1 (4 C, 4 × -CH3); MS
(FAB): m/z 395 [M+H]+, 379 [M-CH3]+; Anal. calcd. for C16H27BrO6: C 48.62;
H 6.88; Found: C 48.48; H 6.83.
1-O-Allyl-2,3:5,6-di-O-isopropylidene-α-D-mannofuranose (25)
Pursuant to general procedure GP2, 1.30 g (5.00 mmol) of saccharide 9,
1.12 g (20.00 mmol) potassium hydroxide, 13 mg (0.05 mmol) [18]-crown-6
ether, and 2.54 mL (25.00 mmol) 1,3-dibromopropane (12) in 50 mL THF/water
(99.5:0.5; v:v) and chromatographic purification on silica gel using a mixture of
n-hexane/ethyl acetate (7:1) gave compound 25 as an oily residue (0.62 g, 41%).
Analytical data were in accordance with literature.[48]
1-O-[(5-p-Toluenesulfonyl)-pentan-1-yl]-2,3:5,6-di-O-
isopropylidene-α-D-mannofuranose (30)
Pursuant to general procedure GP2, 4.30 g (16.52 mmol) of 9, 13.63 g
(33.04 mmol) 1,5-bis(p-toluenesulfonyl)pentane (26), 3.70 g (66.08 mmol)
KOH, and 45 mg (0.17 mmol) 18-crown-6 ether in 150 mL THF and chromato-
graphic purification on silica gel (toluene/acetone 25:1) gave 30 as a colorless
20
1
oil (5.16 g, 62%); [α]D = +27.8 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3): δ
7.80 (d, 2 H, Ar-H), 7.35 (d, 2 H, Ar-H), 4.94 (s, 1 H, H-1), 4.77 (dd, 1 H, J3,4
=
3,5 Hz, H-3), 4.56 (d, 1 H, J2,3 = 5.8 Hz, H-2), 4.40 (ddd, 1 H, J5,6a = 6.2 Hz,
J5,6b = 4.4 Hz, H-5), 4.12–4.09 (m, 1 H, H-6a), 4.04–4.00 (m, 3 H, H-6b, -CH2-),
3.90 (dd, 1 H, J4,5 = 7.6 Hz, H-4), 3.61–3.55 (m, 1 H, -CH2-), 3.35–3.29 (m, 1
H, -CH2-), 2.46 (s, 3 H, Ar-CH3), 1.70–1.63 (m, 2 H, -CH2-), 1.54–1.47 (m, 2 H,
-CH2-), 1.47, 1.45 (2s, 6 H, 2 × -CH3), 1.40–1.34 (m, 2 H, -CH2-), 1.38, 1.33 (2s,

Glycoconjugated Phthalonitriles
23
6 H, 2 × -CH3); 13C NMR (100.6 MHz, CDCl3): δ 144.7, 133.1, 129.8, 127.9 (6
C, Ar-C), 112.6, 109.2 (2 C, 2 × -C(CH3)2), 106.3 (1 C, C-1), 85.0 (1 C, C-2), 80.2
(1 C, C-4), 79.5 (1 C, C-2), 73.1 (1 C, C-5), 70.4 (1 C, -CH2-), 66.9, 66.9 (2 C, C-6,
-CH2-), 28.7, 28.6 (2 C, 2 × -CH2-), 26.9, 25.9, 25.1, 24.5 (4 C, 4 × -CH3), 22.1
(1 C, -CH2-), 21.6 (1 C, Ar-CH3); MS (FAB): m/z 523 [M+Na]+, 485 [M-CH3]+;
ESI-TOF-MS [M+Na]+ calcd. for C24H36NaO9S: 523.19722; Found: 523.19811.
1-O-[(4-p-Toluenesulfonyl)-butan-1-yl]-2,3:5,6-di-O-
isopropylidene-α-D-mannofuranose (31)
Pursuant to general procedure GP2, 5.40 g (20.00 mmol) of 9, 15.92 g
(40.00 mmol) 1,4-bis(p-toluenesulfonyl)butane (27), 4.48 g (80.00 mmol) KOH,
and 45 mg (0.17 mmol) 18-crown-6 ether in 150 mL THF and chromatographic
purification on silica gel (toluene/acetone 25:1) gave 31 as a colorless oil (7.56 g,
78%); [α]D = +30.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.80 (d, 2 H,
20
Ar-H), 7.36 (d, 2 H, Ar-H), 4.92 (s, 1 H, H-1), 4.75 (dd, 1 H, J3,4 = 3.5 Hz, H-3),
4.53 (d, 1 H, J2,3 = 5.8 Hz, H-2), 4.39 (ddd, 1 H, J5,6a = 6.3 Hz, J5,6b = 4.3 Hz,
H-5), 4.12–4.10 (m, 1 H, H-6a), 4.05 (t, 2 H, -CH2-), 4.02–3.99 (m, 1 H, H-6b),
3.88 (dd, 1 H, J4,5 = 7.6 Hz, H-4), 3.62–3.57 (m, 1 H, -CH2-), 3.35–3.29 (m, 1 H,
-CH2-), 2.46 (s, 3 H, Ar-CH3), 1.75–1.68 (m, 2 H, -CH2-), 1.62–1.57 (m, 2 H, -
CH2-), 1.46, 1.45, 1.38, 1.32 (4s, 12 H, 4 × -CH3); 13C-NMR (100.6 MHz, CDCl3):
δ 144.7, 133.1, 129.8, 127.9 (6 C, Ar-C), 112.6, 109.2 (2 C, 2 × -C(CH3)2), 106.3
(1 C, C-1), 85.0 (1 C, C-2), 80.3 (1 C, C-4), 79.5 (1 C, C-3), 73.1 (1 C, C-5), 70.1
(1 C, -CH2-), 66.9 (1 C, C-6), 66.4 (1 C, -CH2-), 26.9, 25.9 (2 C, 2 × -CH3), 25.8,
25.4 (2 C, 2 × -CH2-), 25.1, 24.5 (2 C, 2 × -CH3), 21.6 (1 C, Ar-CH3); MS (FAB):
m/z 471 [M-CH3]+; ESI-TOF-MS [M+Na]+ calcd. for C23H34NaO9S: 509.18227;
Found: 509.18157.
1-O-[(3-p-Toluenesulfonyl)-propan-1-yl]-2,3:5,6-di-O-
isopropylidene-α-D-mannofuranose (32)
Pursuant to general procedure GP2, 1.46 g (5.63 mmol) of 9, 10.80 g
(28.13 mmol) 1,3-bis(p-toluenesulfonyl)propane (28), 1.26 g (22.50 mmol)
KOH, and 16 mg (0.06 mmol) 18-crown-6 ether in 80 mL THF and chromato-
graphic purification on silica gel (toluene/acetone 25:1) and crystallization from
ethanol gave 32 as colorless crystals (2.00 g, 75%); mp 96–97◦C (EtOH); [α]D
20
= +21.6 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.80 (d, 2 H, H-aromat.),
7.36 (d, 2 H, Ar-H), 4.82 (s, 1 H, H-1), 4.73 (dd, 1 H, J3,4 = 3.5 Hz, H-3), 4.44
(d, 1 H, J2,3 = 5.8 Hz, H-2), 4.39–4.35 (m, 1 H, J5,6a = 4.6 Hz, J5,6b = 8.8 Hz,
H-5), 4.13–4.08 (m, 3 H, H-6a, -CH2-), 4.01 (dd, 1 H, H-6b), 3.86 (dd, 1 H, J4,5
= 7.6 Hz, H-4), 3.66–3.62 (m, 1 H, -CH2-), 3.39–3.33 (m, 1 H, -CH2-), 2.46 (s,
3 H, Ar-CH3), 1.95–1.83 (m, 2 H, -CH2-), 1.46, 1.45, 1.38, 1.32 (4s, 12 H, 4 ×

G. Crucius et al.
24
-C(CH3)2); 13C NMR (100.6 MHz, CDCl3): δ 144.8, 133.0, 129.8, 127.9 (6 C, Ar-
C), 112.6, 109.2 (2 C, 2 × -C(CH3)2), 106.3 (1 C, C-1), 84.9 (1 C, C-2), 80.4 (1 C,
C-4), 79.4 (1 C, C-3), 73.1 (1 C, C-5), 67.2 (1 C, C-6),∗ 66.9 (1 C, -CH2-),∗ 62.7 (1
C, -CH2-), 28.9 (1 C, -CH2-), 26.8, 25.9, 25.2, 24.5 (4 C, 4 × -C(CH3)2), 21.6 (1 C,
-CH3); MS (FAB): m/z 473 [M+H]+, 457 [M-CH3]+; Anal. calcd. for C22H32O9S:
C 55.92; H 6.83; S 6.79; Found: C 56.24; H 6.81; S 6.80.
∗Signals could be reversed.
1-O-[(2-p-Toluenesulfonyl)-ethan-1-yl]-2,3:5,6-di-O-
isopropylidene-α-D-mannofuranose (33)
Pursuant to general procedure GP2, 5.39 g (20.72 mmol) of 9, 23.00 g
(62.16 mmol) 1,3-bis(p-toluenesulfonyl)propane (29), 4.64 g (82.88 mmol)
KOH, and 55 mg (0.21 mmol) 18-crown-6 ether in 200 mL THF and chromato-
graphic purification on silica gel (toluene/acetone 25:1) gave 33 as an amor-
20
1
phous solid (6.31 g, 66%); [α]D = +41.1 (c 1.0, CHCl3); H NMR (400 MHz,
CDCl3): δ 7.80 (d, 2 H, Ar-H), 7.35 (d, 2 H, Ar-H), 4.90 (s, 1 H, H-1), 4.71 (dd,
1 H, J3,4 = 3.8 Hz, H-3), 4.47 (d, 1 H, J2,3 = 5.8 Hz, H-2), 4.36 (ddd, 1 H, J5,6a
= 4.6 Hz, J5,6b = 6.3 Hz, H-5), 4.21–4.11 (m, 2 H, -CH2-), 4.09 (dd, 1 H, H-6a),
3.98 (dd, 1 H, H-6b), 3.87 (dd, 1 H, J4,5 = 7.6 Hz, H–4), 3.78–3.73 (m, 1 H,
-CH2-), 3.62–3.57 (m, 1 H, -CH2-), 2.46 (s, 3 H, Ar-CH3), 1.44, 1.38, 1.31 (3s, 12
H, 4 × -CH3); 13C NMR (100.6 MHz, CDCl3): δ 144.8, 133.1, 129.8, 127.9 (6 C,
Ar-C), 112.6, 109.2 (2 C, 2 × -C(CH3)2), 106.3 (1 C, C-1), 84.8 (1 C, C-2), 80.5
(1 C, C-4), 79.3 (1 C, C-3), 73.0 (1 C, C-5), 68.7 (1 C, -CH2-), 66.8 (1 C, C-6),
64.6 (1 C, -CH2-), 26.8, 25.8, 25.2, 24.5 (4 C, 4 × -CH3), 21.6 (1 C, Ar-CH3);
MS (FAB): m/z 481 [M+Na]+, 443 [M-CH3]+; ESI-TOF-MS [M+Na]+ calcd. for
C21H30NaO9S: 481.15093; Found: 481.15027.
6-O-[5-(p-Toluenesulfonyl)-pentan-1-yl]-1,2:3,4-di-O-
isopropylidene-α-D-galactopyranose (34)
Pursuant to general procedure GP3, 2.60 g (10.00 mmol) 2, 288 mg
(12.00 mmol) sodium hydride, and 16.50
g (40.00 mmol) 1,5-bis(p-
toluenesulfonyl)pentane (26) and chromatographic purification on silica gel
20
(toluene/acetone 25:1) gave 34 as colorless oil (3.43 g, 69%); [α]D = –42.2 (c
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.79 (d, 2 H, J = 8.3 Hz, Ar-H), 7.35
(d, 2 H, J = 8.6 Hz, Ar-H), 5.53 (d, 1 H, J1,2 = 5.1 Hz, H-1), 4.59 (dd, 1 H, J3,4
=
8.1 Hz, H-3), 4.30 (dd, 1 H, J2,3 = 2.3 Hz, H-2), 4.23 (dd, 1 H, J4,5 = 1.8 Hz, H-
4), 4.02 (t, 2 H, J6a,6b = 6.6 Hz, H-6a, H-6b), 3.95–3.92 (m, 1 H, H-5), 3.62–3.52
(m, 2 H, -CH2-), 3.49–3.38 (m, 2 H, -CH2-), 2.45 (s, 3 H, Ar-CH3), 1.70–1.63
(m, 2 H, -CH2-), 1.56–1.49 (m, 5 H, -CH2-, -CH3), 1.44 (s, 3 H, -CH3), 1.41–1.36
(m, 2 H, -CH2-), 1.34, 1.33 (2s, 6 H, 2 × -CH3); 13C NMR (100.6 MHz, CDCl3):
δ 144.6, 133.2, 129.8, 127.9 (6 C, Ar-C), 109.2, 108.5 (2 C, 2 × -C(CH3)2), 96.3

Glycoconjugated Phthalonitriles
25
(1 C, C-1), 71.2 (1 C, C-4), 70.9 (1 C, -CH2-), 70.6 (1 C, C-3),∗ 70.6 (1 C, C-2),∗
70.5 (1 C, -CH2-), 69.4 (1 C, C-6), 66.7 (1 C, C-5), 28.8 (1 C, -CH2-), 28.6 (1 C,
-CH2-), 26.1, 26.0, 24.9, 24.4 (4 C, 4 × -CH3), 22.0 (1 C, -CH2-), 21.6 (1 C, Ar-
CH3); MS (FAB): m/z 523 [M+Na]+, 501 [M+H]+, 485 [M-CH3]+; FT-ICR-MS
[M+Na]+ calcd. for C24H36NaO9S: 523.19722; Found: 523.19712.
∗Signals could be reversed.
6-O-[4-(p-Toluenesulfonyl)-butan-1-yl]-1,2:3,4-di-O-
isopropylidene-α-D-galactopyranose (35)
Pursuant to general procedure GP3, 2.60 g (10.00 mmol) 2, 288 mg
(12.00 mmol) sodium hydride, and 15.94
g (40.00 mmol) 1,4-bis(p-
toluenesulfonyl)butane (27) and chromatographic purification on silica gel
20
(toluene/acetone 20:1) gave 35 as colorless oil (3.36 g, 69%); [α]D = –44.5 (c
1
1.0, CHCl3); H NMR (400 MHz, CDCl3): δ 7.79 (d, 2 H, Ar-H), 7.35 (d, 2 H,
Ar-H), 5.52 (d, 1 H, J1,2 = 5.1 Hz, H-1), 4.60 (dd, 1 H, J3,4 = 7.8 Hz, H-3), 4.30
(dd, 1 H, J2,3 = 2.3 Hz, H-2), 4.22 (dd, 1 H, J4,5 = 1.8 Hz, H-4), 4.06 (t, 2 H,
J = 6.3 Hz, -CH2-), 3.94–3.90 (m, 1 H, H-5), 3.60–3.52 (m, 2 H, H-6a, H-6b),
3.48–3.40 (m, 2 H, -CH2-), 2.45 (s, 3 H, Ar-CH3), 1.78–1.70 (m, 2 H, -CH2-),
1.63–1.58 (m, 2 H, -CH2-), 1.53, 1.44, 1.33 (3 s, 12 H, 4 × -CH3); 13C NMR
(100.6 MHz, CDCl3): δ 144.6, 133.2, 129.8, 127.5 (6 C, Ar-C), 109.2, 108.5 (2 C,
2 × -C(CH3)2), 96.3 (1 C, C-1), 71.1 (1 C, C-4), 70.6 (1 C, C-3), 70.5 (1 C, C-2),
70.4, 70.2 (2 C, 2 × -CH2-), 69.4 (1 C, C-6), 66.7 (1 C, C-5), 26.0, 25.9 (2 C, 2 ×
-CH3), 25.7, 25.5 (2 C, 2 × -CH2-), 24.9, 24.4 (2 C, 2 × -CH3), 21.6 (1 C, Ar-CH3);
MS (FAB): m/z 509 [M+Na]+, 471 [M-CH3]+; FT-ICR-MS [M+Na]+ calcd. for
C23H34NaO9S: 509.18157; Found: 509.18185.
6-O-[3-(p-Toluenesulfonyl)-propan-1-yl]-1,2:3,4-di-O-
isopropylidene-α-D-galactopyranose (36)
Method 1: Pursuant to general procedure GP4, 2.60 g (10.00 mmol)
2, 2.00 g (50.00 mmol) sodium hydroxide (50% in water), and 15.36 g
(40.00 mmol) 1,3-bis(p-toluenesulfonyl)-propane (28) and chromatographic pu-
rification (toluene/acetone 25:1) on silica gel gave 36 (0.70 g, 15%) as colorless
oil.
Method 2: To a solution of 4.20 g (13.20 mmol) 47 and 2.95 g (26.42 mmol)
DABCO in 100 mL of ethyl acetate was added 3.77 g (19.81 mmol) p-
toluenesulfonyl chloride at 0◦C, and the mixture was stirred for 1 h at 0◦C
and for 18 h at rt. The organic layer was washed with 5% aqueous HCl, sat-
urated aqueous sodium bicarbonate, and water. After drying over magnesium
sulfate, the solvent was removed under reduced pressure and the residue was
purified by column chromatography (toluene/acetone 25:1) on silica gel (4.12 g,
66%); [α]D = –43.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.79 (d, 2 H,
20

G. Crucius et al.
26
J = 8.3 Hz, Ar-H), 7.34 (d, 2 H, J = 8.1 Hz, Ar-H), 5.51 (d, 1 H, J1,2 = 5.1 Hz,
H-1), 4.58 (dd, 1 H, J3,4 = 7.8 Hz, H-3), 4.30 (dd, 1 H, J2,3 = 2.3 Hz, H-2), 4.18
(dd, 1 H, J4,5 = 1.8 Hz, H-4), 4.12–4.16 (m, 2 H, -CH2-), 3.87–3.91 (m, 1 H, H-5),
3.47–3.55 (m, 4 H, H-6a, H-6b, -CH2-), 2.45 (s, 3 H, Ar-CH3), 1.88–1.94 (m, 2
H, -CH2-), 1.53, 1.44, 1.33 (3s, 12 H, 4 × -CH3); 13C NMR (100.6 MHz, CDCl3):
δ 144.6, 133.2, 129.8, 127.9 (6 C, Ar-C), 109.2, 108.5 (2 C, 2 × -C(CH3)2), 96.3
(1 C, C-1), 71.1 (1 C, C-4), 70.6 (1 C, C-3), 70.5 (1 C, C-2), 69.6 (1 C, C-6),∗ 67.8
(1 C, -CH2-), 66.7 (1 C, -CH2-),∗ 66.6 (1 C, C-3), 29.2 (1 C, -CH2-), 26.0, 25.9,
24.9, 24.4 (4 C, 4 × -CH3), 21.6 (1 C, Ar-CH3); MS (FAB): m/z 473 [M+H]+, 457
[M-CH3]+, 185 [M-C14H23O6]; FT-ICR-MS [M+Na]+ calcd. for C22H32NaO9S:
495.16592; Found: 495.16543.
∗Signals could be reversed.
6-O-[2-(p-Toluenesulfonyl)-ethan-1-yl]-1,2:3,4-di-O-
isopropylidene-α-D-galactopyranose (37)
Method 1: Pursuant to general procedure GP4, 5.20 g (20.00 mmol)
2, 4.00 g (100.00 mmol) sodium hydroxide (50% in water), and 29.60 g
(80.00 mmol) 1,2-bis(p-toluenesulfonyl)-ethane (29) and chromatographic pu-
rification (toluene/acetone 25:1) on silica gel gave 37 (1.50 g, 16%) as a colorless
oil.
Method 2: Treatment of a solution of 3.84 g (12.63 mmol) 46 and 2.87 g
(25.63 mmol) DABCO in 100 mL ethyl acetate with 3.61 g (18.95 mmol) p-
toluenesulfonyl chloride and workup as described for the preparation of 36
20
(method2) gave 37 (2.30 g, 40%) as a colorless oil; [α]D = –47.4 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3): δ 7.80 (d, 2 H, Ar-H), 7.35 (d, 2 H, Ar-H), 5.51 (d,
1 H, J1,2 = 5.1 Hz, H-1), 4.58 (dd, 1 H, J3,4 = 8.0 Hz, H-3), 4.31 (dd, 1 H, J2,3
=
2.5 Hz, H-2), 4.18 (dd, 1 H, J4,5 = 1.8 Hz, H-4), 4.16 (t, 2 H, -CH2-), 3.93–3.90
(m, 1 H, H-5), 3.76–3.62 (m, 3 H, H-6a, -CH2-), 3.58–3.53 (m, 1 H, H-6b), 2.45
(s, 3 H, Ar-CH3), 1.54, 1.43, 1.33 (3s, 12 H, 4 × -CH3); 13C NMR (100.6 MHz,
CDCl3): δ 144.7, 133.0, 129.8, 128.0 (6 C, Ar-C), 109.2, 108.6 (2 C, -C(CH3)2),
96.3 (1 C, C-1), 71.0 (1 C, C-4), 70.6 (1 C, C-3), 70.5 (1 C, C-2), 70.1 (1 C, C-6),
69.1, 68.7 (2 C, 2 × -CH2-), 66.9 (1 C, C-6), 26.0, 25.9, 24.9, 24.4 (4 C, 4 × -CH3),
21.6 (1 C, Ar-CH3); MS (FAB): m/z 481.1 [M+Na]+, 459.1 [M+H]+; FT-ICR-MS
[M+Na]+ calcd. for C21H30NaO9S: 481.15046; Found: 481.15027.
3-O-[5-(p-Toluenesulfonyl)propan-1-yl]-1,2:3,4-di-O-
isopropylidene-α-D-glucofuranose (38)
Pursuant to general procedure GP3, 2.60 g (10.00 mmol) 10, 288 mg
(12.00 mmol) sodium hydride, and 16.50
g (40.00 mmol) 1,5-bis(p-
toluenesulfonyl)-pentane (26) and chromatographic purification on silica gel
20
(toluene/acetone 30:1) gave 38 as viscous oil (3.76 g, 77%); [α]D = –20.1 (c

Glycoconjugated Phthalonitriles
27
1
1.0, CHCl3); H NMR (400 MHz, CDCl3): δ 7.79 (d, 2 H, Ar-H), 7.35 (d, 2 H,
Ar-H), 5.86 (d, 1 H, J1,2 = 3.5 Hz, H-1), 4.50 (d, 1 H, H-2), 4.28–4.23 (m, 1 H,
H-5), 4.09 (dd, 1 H, J4,5 = 7.8 Hz, H-4), 4.07–3.96 (m, 4 H, H-6a, H-6b, -CH2-),
3.83 (d, 1 H, J3,4 = 2.8 Hz, H-3), 3.60–3.46 (m, 2 H, -CH2-), 2.46 (m, 3 H, Ar-
CH3), 1.71–1.64 (m, 2 H, -CH2-), 1.57–1.50 (m, 5 H, -CH2-, -CH3), 1.44–1.38
(m, 5 H, -CH2-, -CH3), 1.33 (s, 6 H, 2 × -CH3); 13C NMR (100.6 MHz, CDCl3):
δ 144.7, 133.1, 129.8, 127.9 (6 C, Ar-C), 111.7, 108.9 (2 C, 2 × -C(CH3)2), 105.2
(1 C, C-1), 82.5 (1 C, C-2), 82.1 (1 C, C-3), 81.1 (1 C, C-4), 72.4 (1 C, C-5),
70.4, 70.1 (2 C, 2 × -CH2-), 67.3 (1C, C-6), 29.0, 28.6 (2 C, 2 × -CH2-), 26.8,
26.7, 26.2, 25.4 (4 C, 4 × -CH3), 22.0 (1 C, -CH2-), 21.6 (1 C, Ar-CH3); MS
(FAB): m/z 523.1 [M+Na]+, 485.1 [M-CH3]+; FT-ICR-MS [M+Na]+ calcd. for
C24H36NaO9S: 523.19722; Found: 523.19708.
3-O-[4-(p-Toluenesulfonyl)butan-1-yl]-1,2:3,4-di-O-
isopropylidene-α-D-glucofuranose (39)
Pursuant to general procedure GP3, 5.20 g (20.00 mmol) 10, 576 mg
(24.00 mmol) sodium hydride, and 31.88
g (80.00 mmol) 1,4-bis(p-
toluenesulfonyl)-butane (27) and chromatographic purification on silica gel
20
(toluene/acetone 30:1) gave 39 as viscous oil (4.68 g, 48%); [α]D = –21.3 (c
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.79 (d, 2 H, Ar-H), 7.36 (d, 2 H, Ar-
H), 5.84 (d, 1 H, J1,2 = 3.5 Hz, H-1), 4.50 (d, 1 H, H-2), 4.25–4.20 (m, 1 H, H-5),
4.08–4.04 (m, 4 H, H-4, H-6a, -CH2-), 3.98–3.95 (m, 1 H, H-6b), 3.80 (d, 1 H,
J3,4 = 3.0 Hz, H-3), 3.62–3.57 (m, 1 H, -CH2-), 3.51–3.46 (m, 1 H, -CH2-), 2.46
(s, 3 H, -CH3), 1.80–1.72 (m, 2 H, -CH2-), 1.64–1.57 (m, 2 H, -CH2-), 1.50, 1.41,
1.32 (3s, 12 H, 4 × -CH3); 13C NMR (100.6 MHz, CDCl3): δ 144.7, 133.1, 129.8,
127.9 (6 C, Ar-C), 111.8, 109.0 (2 C, -C(CH3)2), 105.2 (1 C, C-1), 82.4 (1 C, C-2),
82.1 (1 C, C-3), 81.1 (1 C, C-4), 72.3 (1 C, C-5), 70.2, 69.4 (2 C, 2 × -CH2-), 67.4
(1 C, C-6), 26.8 (2 C, 2 × -CH3), 26.2 (1 C, -CH3), 25.7 (2 C, -CH2-), 25.3 (1 C,
-CH3), 21.6 (1 C, Ar-CH3); MS (FAB): m/z 509.1 [M+Na]+,487.2 [M+H]+ 471.1
[M-CH3]+; FT-ICR-MS [M+Na]+ calcd. for C23H34NaO9S: 509.18112; Found:
509.18157.
3-O-[3-(p-Toluenesulfonyl-)propan-1-yl]-1,2:3,4-di-O-
isopropylidene-α-D-glucofuranose (40)
Pursuant to general procedure GP4, 5.20 g (20.00 mmol) 10, 4.00 g
(100.00 mmol) sodium hydroxide (50% in water), and 30.72 g (80.00 mmol)
1,3-bis(p-toluenesulfonyl)-propane (28) and chromatographic purification
20
(toluene/acetone 25:1) on silica gel gave 40 as colorless oil (2.82 g, 30%); [α]D
= –26.9 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.80 (d, 2 H, Ar-H), 7.36
(d, 2 H, Ar-H), 5.80 (d, 1 H, J1,2 = 3.5 Hz, H-1), 4.48 (d, 1 H, H-2), 4.21–4.02
(m, 5 H, -CH2-, H-4, H-5, H-6a), 3.97–3.94 (m, 1 H, H-6b), 3.81 (d, 1 H, J3,4
=

G. Crucius et al.
28
3.0 Hz, H-3), 3.72–3.67 (m, 1 H, -CH2-), 3.60–3.55 (m, 1 H, -CH2-), 2.46 (s, 3 H,
Ar-CH3), 1.49, 1.41, 1.32 (3s, 12 H, 4 × -CH3); 13C NMR (100.6 MHz, CDCl3): δ
144.8, 133.1, 129.9, 127.9 (6 C, Ar-C), 111.8, 109.0 (2 C, 2 × -C(CH3)2), 105.2 (1
C, C-1), 82.3 (1 C, C-3),∗ 83.2 (1 C, C-2),∗ 81.1 (1 C, C-4), 72.3 (1 C, C-5), 67.3 (1
C, -CH2-), 67.2 (1 C, C-6), 65.6 (1 C, -CH2-), 29.2 (1 C, -CH2-), 26.8, 26.8, 26.2,
25.3 (4 C, 4 × -CH3), 21.6 (1 C, Ar-CH3); MS (FAB): m/z 495.2 [M+Na]+, 473.1
[M+H]+ 457.1 [M-CH3]+; FT-ICR-MS [M+Na]+ calcd. for C22H32NaO9S: 495.
16592; Found: 495.16591.
∗Signals could be reversed.
3-O-[2-(p-Toluenesulfonyl)-ethan-1-yl]-1,2:3,4-di-O-
isopropylidene-α-D-glucofuranose (41)
Pursuant to general procedure GP4, 2.60 g (10.00 mmol) 10, 2.00 g
(50.00 mmol) sodium hydroxide (50% in water), and 14.80 g (40.00 mmol)
1,2-bis(p-toluenesulfonyl)-ethane (29) and chromatographic purification
20
(toluene/acetone 20:1) on silica gel gave 41 as colorless oil (1.76 g, 38%); [α]D
= –18.3 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.80 (d, 2 H, Ar-H), 7.35
(d, 2 H, Ar-H), 5.80 (d, 1 H, J1,2 = 3.8 Hz, H-1), 4.45 (d, 1 H, H-2), 4.18–4.14
(m, 3 H, H-5, -CH2-), 4.05 (dd, 1 H, J4,5 = 8.1 Hz, H-4), 4.03 (dd, 1 H, J5,6a
=
6.3 Hz, H-6a), 3.94 (dd, 1 H, J5,6b = 5.6 Hz, H-6b), 3.86 (d, 1 H, J3,4 = 3.0 Hz,
H-3), 3.82–3.79 (m, 2 H, -CH2-), 2.46 (s, 3 H, Ar-CH3), 1.49, 1.40, 1.32, 1.31 (4s,
12 H, 4 × -CH3); 13C NMR (100.6 MHz, CDCl3): δ 144.9, 132.9, 129.8, 127.9
(6 C, Ar-C), 111.9, 109.0 (2 C, 2 × -C(CH3)2), 105.2 (1 C, C-1), 82.8 (1 C, C-3),
82.6 (1 C, C-2), 81.0 (1 C, C-4), 72.3 (1 C, C-5), 68.9, 68.3 (2 C, -CH2-), 67.3 (1
C, C-6), 26.8, 26.2, 25.3 (4 C, 4 × -CH3), 21.6 (1 C, Ar-CH3); MS (FAB): m/z
481.1 [M+Na]+, 459.1 [M+H]+ 443.0 [M-CH3]+; FT-ICR-MS [M+Na]+ calcd.
for C21H30NaO9S: 481.15062; Found: 481.15027.
6-O-(2-Benzyloxyethyl)-1,2:3,4-di-O-isopropylidene-α-D-
galactopyranose (44)
A suspension of 5.28 g (20.30 mmol) of 2 and 461 mg (19.20 mmol) sodium
hydride in 130 mL of dry THF was stirred for 1 h at 60◦C. Next, 7.45 g
(24.40 mmol) 2-benzyloxyethyl-p-toluenesulfonate (42) dissolved in 25 mL of
dry THF was added and the mixture refluxed for 36 h under an atmosphere
of nitrogen. After cooling to rt, water was added. The aqueous phase was ex-
tracted several times with DCM and the combined organic phases were dried
over magnesium sulfate and concentrated. Chromatographic purification of the
residue on silica gel (toluene/acetone 30:1) gave 44 as a colorless oil (7.26 g,
20
1
91%); [α]D = –52.7 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3): δ 7.37–7.26
(m, 5 H, Ar-H), 5.54 (d, 1 H, J1,2 = 5.1 Hz, H-1), 4.60 (dd, 1 H, J3,4 = 7.8 Hz, H-
3), 4.58 (s, 2 H, -CH2-Ph), 4.31 (dd, 1 H, J2,3 = 2,4 Hz, H-2), 4.27 (dd, 1 H, J4,5