GlucoSiFA and LactoSiFA: New Types of Carbohydrate-Tagged Silicon-Based Fluoride Acceptors for 18F-Positron Emission Tomography (PET)

Article abstract of DOI:10.1055/s-0037-1611656

GlucoSiFA derivatives bearing an azide or alkynyl side chain were obtained from peracetyl- d -glucose using as key step a tosylate substitution by a SiFA thiolate obtained from 4-(di- tert -butylfluorsilyl)benzenethiol. In analogy, two-fold SiFA-substituted maltose and lactose derivatives were synthesized via bistosylates. Introduction of an acetal-protecting group in β- d -azidolactose allowed the synthesis of a LactoSiFA derivative bearing only one SiFA moiety.

Full text of DOI:10.1055/s-0037-1611656

SYNTHESIS
0
0
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9
-
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8
1
1
4
3
7
-
2
1
0
X
Georg Thieme Verlag Stuttgart · New York
2019, 51, A–K
feature
A
en
A. Wiegand et al.
Feature
Synthesis
GlucoSiFA and LactoSiFA: New Types of Carbohydrate-Tagged
Silicon-Based Fluoride Acceptors for 18F-Positron Emission
Tomography (PET)
Anja Wieganda
Vera Wiesea
Britta Glowackib
F
F
Si
Si
Ljuba Iovkovaa
OH
HO
S
S
Ralf Schirrmacher*c
Klaus Jurkschat*b
Norbert Krause*a
O
O
O
HO
HO
O
HO
0
0
0
0-0
0
0
1-9
9
3
0-8
5
8
X
X
N3
HO
HO
HO
HO
OCH C CH)
GlucoSiFA (X = N3,
LactoSiFA
2
a Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie,
Lehrstuhl für Organische Chemie, Otto-Hahn-Strasse 6, 44227 Dortmund,
Germany
norbert.krause@tu-dortmund.de
b Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie,
Lehrstuhl für Anorganische Chemie II, Otto-Hahn-Strasse 6, 44227 Dortmund,
Germany
klaus.jurkschat@tu-dortmund.de
c Department of Oncology, University of Alberta, 6820 116 Street, Edmonton,
Alberta T6G 2R3, Canada
Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue
Received: 11.12.2018
Accepted: 17.12.2018
Published online: 24.01.2019
DOI: 10.1055/s-0037-1611656; Art ID: ss-2018-z0819-fa
proved to be an elegant and non-invasive method to eluci-
date in vivo biochemistry. It allows metabolic tracking of
bioactive compounds and quantification of biochemical
and/or enzymatic processes in living organisms. Among
commonly used radioactive isotopes such as 11C, 13N, 15O,
18F, 64Cu, and 68Ga,2 the use of fluorine-18 has become rath-
er popular due to its favorable physical properties such as a
half-life of 109.7 minutes that allows for longer synthesis
times and remote shipment to local imaging facilities and a
low positron energy leading to PET images of highest reso-
lution.
License terms:
Abstract GlucoSiFA derivatives bearing an azide or alkynyl side chain
were obtained from peracetyl-D-glucose using as key step a tosylate
substitution by a SiFA thiolate obtained from 4-(di-tert-butylfluorsi-
lyl)benzenethiol. In analogy, two-fold SiFA-substituted maltose and lac-
tose derivatives were synthesized via bistosylates. Introduction of an
acetal-protecting group in β-D-azidolactose allowed the synthesis of a
LactoSiFA derivative bearing only one SiFA moiety.
There are different strategies for incorporating 18F into
radiopharmaceuticals. On the one hand, fluorination at car-
bon atoms in both aromatic and aliphatic compounds can
be achieved by electrophilic as well as nucleophilic reac-
tions and a variety of appropriate reagents has been devel-
oped for this purpose.2,3 Alternatively, 18F can also be bound
via isotopic exchange to non-carbon elements such as
boron, aluminum, silicon, and phosphorus.3a These non-
canonical labeling concepts got momentum in the last two
decades although some of the labeling principles have al-
ready been introduced to the literature as early as 19584 but
remained dormant for many years. The progress achieved
in these types of chemistry was regularly summarized in
review articles.3a,5 Aryldialkylsilicon fluorides, ArR2SiF, in
which the silicon atom is sufficiently protected with R =
isopropyl6 or tert-butyl7a substituents are stable under
physiological conditions and undergo 19F to 18F isotopic
exchange with good radiochemical yields. The tert-butyl-
Key words carbohydrates, silicon-based fluoride acceptors, nucleo-
philic substitution, tosylation, regioselectivity
The introduction of positron emission tomography
(PET) as a non-invasive method for medical diagnostic in
vivo imaging has become an indispensable tool in precision
medicine development.1 PET not only helps to understand
the complex interplay between biological targets such as
receptors and enzymes and their cognate ligands but fur-
thermore assists devising new therapeutic regimens based
on non-invasive biological target validation. Besides PET, a
straightforward example for diagnostic imaging is the use
of X-rays that has revolutionized medicine. However, this
method only yields anatomic/structural information
whereas PET and related radioisotope-based imaging meth-
odologies look directly at dynamic biological processes
without interference. PET, in addition to magnetic reso-
nance imaging (MRI) and computed tomography (CT), has
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

B
A. Wiegand et al.
Feature
Synthesis
substituted variant is now widely known as SiFA methodol-
ogy and has become popular in several research groups
(Equation 1).7b–e
One last problem when using SiFA-substituted biomole-
cules for PET applications is the high lipophilicity caused by
the organosilicon moiety. Sugars such as glucose are water-
soluble and carbon-bound 18F-derivatives such a 2-[18F]fluo-
rodeoxyglucose ([18F]FDG) are applied as PET radiotrac-
ers.7e,f With this in mind and the intention to increase the
water-solubility of the SiFA moiety, herein we report the
synthesis and characterization of SiFA-substituted sugar de-
18F–/Kryptofix 222/K+
X
Si 19F
X
Si 18F
–
19F–
Equation 1 Isotope exchange in silicon-based fluoride acceptors (SiFA)
Biographical Sketches
Anja Wiegand studied chemistry at the Facul-
ty of Chemistry and Chemical Biology of TU
Dortmund. She obtained her B.Sc. in 2012 and
her M.Sc. in 2014. In 2018, she finished her
Ph.D. work on carbohydrate-based NHC-gold
complexes and SiFA compounds under the
supervision of Prof. Dr. Norbert Krause.
Ralf Schirrmacher obtained his Ph.D. in nucle-
ar chemistry from the University of Mainz in
1999. After a brief postdoctoral stay at the Uni-
versity of Pennsylvania, he continued research
at the University of Mainz as a civil servant until
2007. In 2008 he was appointed Head of Radio-
chemistry and Director of Cyclotron at the Mc-
Connell Brain Imaging Center at the Montreal
Neurological Institute (MNI) of McGill Universi-
ty. During his time at McGill University he held
a Canada Research Chair in Molecular Imaging
and Radiochemistry. He is currently a Full Pro-
fessor in Oncologic Imaging at the Faculty of
Medicine at the MICF and Cross Cancer Center
at the University of Alberta at Edmonton. His
research group develops new imaging agents
for Positron Emission Tomography (PET) imag-
ing in the field of oncology and neurology using
a variety of different radionuclides such as car-
bon-11, fluorine-18, gallium-68, different ra-
dioisotopes of iodine and copper-64.
Chemistry at the Technische Universität. He
was a Guest Professor at Universite Bordeaux 1
(2000) and Universite Rennes 1 (2012). He is
Editor-in-Chief of the journal ‘Main Group
Metal Chemistry’ and author of approximately
320 publications. The chemistry of hypercoordi-
nate main group element compounds in all its
facets is in the center of his research interests.
Vera Wiese studied chemical biology at the
Faculty of Chemistry and Chemical Biology of
TU Dortmund. She obtained her B.Sc. in 2015
and her M.Sc. in 2018. For her Master’s thesis,
she worked on the synthesis of discchararide-
based SiFA compounds under the supervision
of Prof. Dr. Norbert Krause.
Norbert Krause graduated from TU Braunsch-
weig in 1984 and received his Ph.D. in 1986.
After postdoctoral stays at the ETH Zürich and
Yale University, he joined TU Darmstadt and
obtained his Habilitation in 1993. In 1994, he
moved to the University of Bonn as Associate
Professor, before being appointed to his pres-
ent position as Full Professor at TU Dortmund
in 1998. He was a Fellow of the Japan Society
for the Promotion of Science (JSPS) in 2003,
2009, and 2015, and Guest Professor at the
Université Catholique de Louvain (2007), at the
University of California, Santa Barbara, U.S.A.
(2009), and at the École Supérieure de Phy-
sique et de Chimie Industrielles de la Ville de
Paris (ESPCI), France (2009). He was a member
of the Editorial Board of the European Journal
of Organic Chemistry (2006–2013). His re-
search focuses on sustainable coinage metal
(copper, silver, and gold) catalysis, in particular
with water as bulk solvent.
Britta Glowacki studied chemistry at the Fac-
ulty of Chemistry and Chemical Biology of TU
Dortmund. She obtained her B.Sc. in 2011 and
her M.Sc. in 2013. In 2018, she finished her
Ph.D. work on amino alcoholate derivatives of
group XIV elements under the supervision of
Prof. Dr. Klaus Jurkschat.
Klaus Jurkschat received his Ph.D. from Martin
Luther University Halle-Wittenberg, Germany,
in 1980 and habilitated in 1987 at the same
university. After postdoctoral work with Jean-
Bernard Robert at CENG Grenoble, France, and
Marcel Gielen/Rudolph Willem at VUB Brussels,
Belgium, and staying as visiting researcher at
SUNY Albany (with Henry G. Kuivila), N.Y., USA,
and Deakin University Geelong (with Dainis
Dakternieks), Vic. Australia, he went to Dort-
mund, Germany, where from 1994 to 2018 he
was employed as a Full Professor for Inorganic
Ljuba Iovkova was born in Sofia, Bulgaria and
moved to Germany to study pharmacy and
chemistry. In 2006, she obtained her Diploma
from the TU Dortmund. She carried out gradu-
ate work at the same university under the su-
pervision of Prof. Dr. Klaus Jurkschat, earning a
Ph.D. in chemistry in 2010. After researcher
positions in the academic and industrial field
she joined again the Faculty of Chemistry and
Chemical Biology at the TU Dortmund in 2014
as Akademische Rätin.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

C
A. Wiegand et al.
Feature
Synthesis
rivatives that also contain a variety of functional groups
that hold potential for subsequent protein conjugation by
click-type chemistry.
OAc
HC CCH2OH
OAc
BF3•OEt2/MeCN
O
AcO
AcO
O
AcO
AcO
O
76%
AcO
AcO
Our synthesis of the β-D-azido-substituted GlucoSiFA
derivative 5 (Scheme 1) started with peracetyl-D-glucose
(1; mixture of anomers), which was first brominated at the
anomeric center with HBr/AcOH. The resulting α-D-glycosyl
bromide underwent clean substitution with sodium azide
to afford β-D-glycosyl azide 2. Both steps proceeded in ex-
cellent yield, as did the subsequent deprotection with sodi-
um methoxide. A selective monotosylation at the primary
hydroxy group of the unprotected β-D-azidoglucose gave
the difunctionalized monosaccharide 3 in 72% yield. Finally,
the desired GlucoSiFA derivative 5 was obtained in 74%
yield (51% over 5 steps) by nucleophilic substitution of the
tosylate with deprotonated 4-(di-tert-butylfluorsilyl)ben-
zenethiol (4).8 Due to the pronounced base sensitivity of
SiFA derivatives, this step has to be carried out with bulky,
less nucleophilic bases. In the event, potassium tert-butox-
ide in DMSO gave the best results.
OAc
6
1
1. NaOMe/MeOH
2. pTsCl/pyridine
99%, 84%
F
Si
OTs
4
O
tBuOK/DMSO
HO
HO
S
O
52%
HO
O
HO
HO
O
7
HO
8
Scheme 2 Synthesis of β-D-alkynyl-substituted GlucoSiFA derivative 8
sylated products at low yield, or no product at all. We then
shifted our attention to maltose and lactose as starting di-
saccharides and first prepared two-fold SiFA-substituted
derivatives (Scheme 3).
OAc
1. HBr/AcOH/DCM
2. NaN3/DMF
OAc
O
AcO
AcO
O
Whereas the tosylation of β-azido-D-maltose (9a) with
pTsCl in pyridine proceeded rather sluggishly, the reactivity
was strongly increased in the presence of zinc bromide.9
Under these conditions, complete conversion was observed
after 1 hour at –20 °C, and the bistosylate 10a was isolated
in 50% yield. Both leaving groups could be replaced with
SiFA moieties under standard conditions using 4 and tBuOK
to afford the target molecule 11a in 67% yield. The corre-
sponding SiFA-tagged β-alkynyl-D-maltose 11b was ob-
tained in the same manner from 9b via bistosylate 10b in
31% and 55% yield, respectively.
Similar to the maltose derivatives, the corresponding β-
azido- and alkynyl-substituted D-lactoses 12a/b could not
be selectively monotosylated at one of the two primary hy-
droxy groups. Rather, the bistosylates 13a/b were obtained
in 44% and 36% yield, which were converted into the two-
fold SiFA-modified lactoses 14a/b in moderate yields
(33/36%).
It is evident from these results that a protection of one
of the two primary hydroxy groups is required for the syn-
thesis of a disaccharide bearing only one SiFA unit. Gratify-
ingly, the presence of an axial OH group in the galactose
ring of β-D-azidolactose 12a allows a selective acetalization
to afford product 15 in 74% yield (Scheme 4).10 For this sub-
strate, the selectivity of the tosylation was examined in de-
tail (Table 1).
With 4 equivalents of zinc bromide and 5 equivalents of
tosyl chloride in pyridine at –20 °C, a mixture of the desired
monotosylate 16 (41% yield) and the bistosylate 17 (21%
yield) was obtained after 10 minutes (Table 1, entry 1).
Thus, not only the primary, but also the secondary hydroxy
group at C-4′ are reactive under these conditions. As ex-
AcO
AcO
N3
97%, 99%
AcO
AcO
OAc
2
1
1. NaOMe/MeOH
2. pTsCl/pyridine
quant., 72%
HS
Si F
F
Si
OTs
4
O
tBuOK/DMSO
HO
HO
S
N3
74%
HO
O
HO
HO
N3
3
HO
5
Scheme 1 Synthesis of β-D-azido-substituted GlucoSiFA derivative 5
Starting point of the synthesis of the β-D-alkynyl-sub-
stituted GlucoSiFA derivative 8 (Scheme 2) was the Lewis
acid catalyzed substitution of the anomeric acetyl group of
peracetyl-D-glucose (1) with propargyl alcohol, which pro-
vided β-D-glycoside 6 in 76% yield. The following steps via
monotosylate 7 proceeded as before and gave target mole-
cule 8 in 33% yield over four steps.
In order to further increase the hydrophilicity of carbo-
hydrate-tagged SiFA derivatives, we next used disaccharides
as starting material. Here, serious reactivity and selectivity
issues were encountered. For example, even though β-D-az-
idogalactose can be monotosylated selectively at the prima-
ry hydroxy group, all attempts of a monotosylation of β-D-
azidomelibiose (which also contains only one primary hy-
droxy group) failed and provided either mixtures of bisto-
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

D
A. Wiegand et al.
Feature
Synthesis
F
Si
OH
OTs
4
pTsCl/ZnBr2
pyridine
O
O
F
HO
HO
HO
HO
Si
tBuOK/DMSO
OH
OTs
S
HO
HO
a: 50%
b: 31%
O
O
O
a: 67%
b: 55%
HO
HO
O
HO
O
HO
S
X
X
HO
HO
HO
O
HO
O
HO
9a (X = N3)
10
X
OCH2C CH)
9b (X =
11
F
Si
OH
OTs
HO
F
HO
4
pTsCl/ZnBr2
pyridine
Si
OH
OTs
tBuOK/DMSO
O
O
O
O
S
HO
O
O
HO
HO
a: 44%
b: 36%
a: 33%
b: 36%
S
X
X
HO
HO
HO
HO
O
HO
HO
O
O
HO
12a (X = N3)
12b (X = OCH2C CH)
13
X
HO
HO
HO
14
Scheme 3 Synthesis of two-fold SiFA-substituted maltose and lactose derivatives 11 and 14
Ph
Ph
PhCH(OMe)2
p-TsOH•H2O
O
O
OH
HO
pTsCl/ZnBr2
pyridine
OH
O
O
O
DMF
OH
OTs
O
O
HO
O
O
74%
49% (16)
31% (17)
N3
HO
HO
O
O
O
O
HO
HO
HO
N3
N3
HO
HO
HO
HO
12a
HO
HO
4/tBuOK
15
DMSO
16
61%
Ph
+
Ph
F
F
O
Si
Si
O
O
80% aq. AcOH
64%
O
OH
HO
OTs
S
S
O
O
O
HO
O
O
O
O
TsO
O
O
HO
HO
N3
HO
HO
N3
N3
HO
19
HO
HO
HO
HO
HO
18
17
Scheme 4 Synthesis of β-D-azido-substituted LactoSiFA derivative 19
pected, increasing the reaction time up to 40 minutes fa-
vored the formation of the bistosylate 17 (entries 2–4); the
best yield of the monotosylate 16 (49%) was obtained after
30 minutes and decreased to 30% after 40 minutes. Smaller
amounts of pTsCl afforded a higher selectivity in favor of
the monotosylate 16 (entries 5 and 6), which was isolated
as the sole product in the presence of 1.3 equivalents of
pTsCl (entry 6), albeit in a low yield of 30%. Interestingly,
the tosylation of the corresponding lactose derivative bear-
ing a propargyl glycoside instead of the azido group gave
only a bistosylate bearing the tosyl groups at the 2-CH2
group and C-4. At this point, it is not clear which factors
govern the regioselectivity of these transformations. Unfor-
tunately, attempts to introduce other leaving groups
(mesylate, 4-bromophenylsulfonate, bromide) failed.
The structural assignment of tosylation products 16 and
17 is based on extensive NMR studies. Moreover, both prod-
ucts were isolated in crystalline form and characterized by
single crystal X-ray diffraction analysis. The quality of the
crystals of monotosylate 16 was rather low and allowed
only the structural assignment of the constitution, but not
of the absolute stereochemistry of the acetal stereocenter.
In contrast to this, the acetal stereocenter of the major iso-
mer (87%) of bistosylate 17 (Figure 1) shows S-configura-
tion as estimated by the twin law of the measured crystal.11
The X-ray diffraction analysis also proved the presence of
the two tosyl groups at the 2-CH2 and 4′ positions.
The protected monotosylated β-azido-D-lactose deriva-
tive 16 obtained in 49% yield under the conditions of Table
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

E
A. Wiegand et al.
Feature
Synthesis
Table 1 Tosylation of Disaccharide 15a
procedures for the monofunctionalization of suitable car-
bohydrates, as well as, the synthesis of carbohydrate-tagged
SiFA derivatives bearing different handles for protein conju-
gation.
Entry ZnBr2·2 H2O (equiv)pTsCl (equiv)Time (min) 16 (Yield %) 17 (Yield %)
1
2
3
4
5
6
4
5
10
20
30
40
40
40
41
38
49
30
39
30
21
30
31
34
24
0
4
5
4
5
Reactions were carried out under argon atmosphere using oven- or
flame-dried glassware. Air- and moisture-sensitive reagents were
transferred via syringe. All reagents were obtained commercially and
used without further purification. THF, Et2O, CH2Cl2, and MeCN were
dried using a MB-SPS-800 system (M. Braun). Reactions were moni-
tored by TLC using silica gel 60 plates provided by Merck and
Macherey-Nagel. Visualization was accomplished with UV light (254
nm), ceric ammonium molybdate, KMnO4, or anisaldehyde.
4
5
1.5
4
2
1.3
a In pyridine at –20 °C.
1H, 13C, 19F, and 29Si NMR spectra were recorded with Bruker Avance III
HD (400–600 MHz) and calibrated against residual solvent peaks. IR
spectra were obtained with a PerkinElmer Spectrum Two UATR spec-
trophotometer. Mass spectra were recorded with a Thermo Fisher
Scientific TSQ (LCMS-ESI) and a Thermo Electron LTQ Orbitrap spec-
trometer (HPLC-ESI).
(3R,4S,5R,6R)-6-(Acetoxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetra-
yltetraacetate (1),12 (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-bromo-
tetrahydro-2H-pyran-3,4,5-triyltriacetate,13 (2R,3R,4S,5R,6R)-2-(acet-
oxymethyl)-6-azidotetrahydro-2H-pyran-3,4,5-triyltriacetate (2),14
(2R,3R,4S,5S,6R)-2-azido-6-(hydroxymethyl)tetrahydro-2H-pyran-
3,4,5-triol,15
yloxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate
(2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(prop-2-yn-1-
(6),16
(2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(prop-2-yn-1-yloxy)tetra-
hydro-2H-pyran-3,4,5-triol,17 (2S,3R,4S,5R,6R)-6-(acetoxymethyl)-5-
{[(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)-tetrahydro-
2H-pyran-2-yl]oxy}tetrahydro-2H-pyran-2,3,4-triyltriacetate,18
(2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-{[(2R,3R,4S,5R,6R)-4,5-diacet-
oxy-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3-yl]oxy}tetra-
hydro-2H-pyran-3,4,5-triyltriacetate,19
(2R,3R,4S,5R,6R)-2-(acet-
Figure 1 X-ray crystal structure of bistosylate 17
oxymethyl)-6-{[(2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-
azidotetrahydro-2H-pyran-3-yl]oxy}tetrahydro-2H-pyran-3,4,5-tri-
yltriacetate,20 (2R,3R,4S,5S,6R)-2-{[(2R,3S,4R,5R,6R)-6-azido-4,5-di-
hydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-6-(hy-
1, entry 3, was treated with the thiolate formed by depro-
tonation of 4-(di-tert-butylfluorsilyl)benzenethiol (4) with
tBuOK. The SiFA-tagged lactose derivative 18 was isolated in
61% yield. Finally, acetal cleavage was achieved by heating
18 with 80% aqueous acetic acid to 70 °C for 4 hours. This
afforded the desired β-D-azido-substituted LactoSiFA deriv-
ative 19 in 64% yield (14% over 4 steps from 12a) (Scheme
4).
In conclusion, this work demonstrates the utility of car-
bohydrates for the synthesis of hydrophilic SiFA derivatives.
The GlucoSiFA derivatives 5 and 8 bearing an azide or
alkynyl handle for peptide and protein conjugation via 1,3-
dipolar cycloaddition were obtained in a straightforward
manner from peracetyl-D-glucose in 51% and 36% overall
yield, respectively. The key step is the substitution of a to-
sylate by a SiFA thiolate obtained from 4-(di-tert-butylflu-
orsilyl)benzenethiol (4). In analogy, the two-fold SiFA-sub-
stituted maltose and lactose derivatives 11 and 14 are read-
ily accessible in overall yields between 13% and 34%.
Introduction of an acetal protecting group in β-D-azidolac-
tose 12a allowed the synthesis of the LactoSiFA derivative
19 in 14% overall yield. Further work is devoted to improved
droxymethyl)tetrahydro-2H-pyran-3,4,5-triol
(9a),21
(2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-{[(2R,3R,4S,5R,6R)-4,5-diacet-
oxy-2-(acetoxymethyl)-6-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran-
3-yl]oxy}tetrahydro-2H-pyran-3,4,5-triyltriacetate,22
(2R,3R,4S,5S,6R)-2-{[(2R,3S,4R,5R,6R)-4,5-dihydroxy-2-(hydroxymeth-
yl)-6-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran-3-yl]oxy}-6-(hydroxy-
methyl)tetrahydro-2H-pyran-3,4,5-triol (9b),23 (3R,4S,5R,6R)-6-(acet-
oxymethyl)-5-{[(2S,3R,4S,5S,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)-
tetrahydro-2H-pyran-2-yl]oxy}tetrahydro-2H-pyran-2,3,4-triyltriac-
etate,24 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-{[(2R,3R,4S,5R,6R)-4,5-
diacetoxy-2-(acetoxymethyl)-6-bromtetrahydro-2H-pyran-3-yl]oxy}-
tetrahydro-2H-pyran-3,4,5-triyltriacetate,19 (2R,3S,4S,5R,6S)-2-(acet-
oxymethyl)-6-{[(2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-
azidotetrahydro-2H-pyran-3-yl]oxy}tetrahydro-2H-pyran-3,4,5-tri-
yltriacetate,20 (2S,3R,4S,5R,6R)-2-{[(2R,3S,4R,5R,6R)-6-azido-4,5-di-
hydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]oxy}-6-(hy-
droxymethyl)tetrahydro-2H-pyran-3,4,5-triol
(12a),25
(2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-{[(2R,3R,4S,5R,6R)-4,5-diacet-
oxy-2-(acetoxymethyl)-6-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran-
3-yl]oxy}tetrahydro-2H-pyran-3,4,5-triyltriacetate,26
(2S,3R,4S,5R,6R)-2-{[(2R,3S,4R,5R,6R)-4,5-dihydroxy-2-(hydroxymeth-
yl)-6-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran-3-yl]oxy}-6-(hydroxy-
methyl)tetrahydro-2H-pyran-3,4,5-triol (12b),26 and (4aR,6S,7R,8R)-
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

F
A. Wiegand et al.
Feature
Synthesis
6-{[(2R,3S,4R,5R,6R)-6-azido-4,5-dihydroxy-2-(hydroxymethyl)tetra-
hydro-2H-pyran-3-yl]oxy}-2-phenylhexahydropyrano[3,2-d][1,3]di-
oxin-7,8-diol (15)10 are known compounds and were prepared ac-
cording to literature procedures.
1H NMR (600 MHz, CDCl3): δ = 7.52 (d, J = 8.1 Hz, 2 H, ArH), 7.39 (d, J =
8.1 Hz, 2 H, ArH), 4.59 (d, J = 8.4 Hz, 1 H, β-H1), 3.69–3.66 (m, 1 H),
3.59–3.48 (m, 4 H), 3.34 (t, J = 8.5 Hz, 1 H), 3.31 (dd, J1 = 14.1 Hz, J2 = 7
Hz, 1 H), 1. 05 [s, 18 H, 2 × C(CH3)3].
13C NMR (150 MHz, CDCl3): δ = 138.4 (s, Ar), 134.5 (d, J = 4.1 Hz, Ar),
130.8 (s, J = 13.8 Hz, Ar), 127.2 (d, Ar), 90.0 (d, CHN3), 76.9, 76.4, 73.5,
72.5 (4 d, CH), 34.5 (t, CH2S), 27.3 [q, C(CH3)3], 20.3 [s, J = 12.4 Hz,
C(CH3)3].
19F NMR (565 MHz, CDCl3): δ = –188.9 (d, J = 297.8 Hz).
29Si NMR (119 MHz, CDCl3): δ = 15.3 (d, J = 297.8 Hz).
[(2R,3S,4S,5R,6R)-6-Azido-3,4,5-trihydroxytetrahydro-2H-pyran-
2-yl]methyl 4-Methylbenzolsulfonate (3)
A solution of (2R,3R,4S,5S,6R)-2-azido-6-(hydroxymethyl)tetrahydro-
2H-pyran-3,4,5-triol (585 mg, 2.85 mmol, 1.0 equiv) in anhyd pyri-
dine (6 mL) was cooled to 0 °C and treated with pTsCl (706 mg, 3.71
mmol, 1.3 equiv) in anhyd pyridine (3 mL). The mixture was stirred at
rt for 24 h. The solvent was removed under reduced pressure, and the
crude product was purified by column chromatography (silica gel,
EtOAc); yield: 742 mg (72%); colorless solid.
HRMS (ESI): m/z calcd for C20H33FN3O4SSi [M + H]+: 458.19396; found:
458.19396.
[(2R,3S,4S,5R,6R)-3,4,5-Trihydroxy-6-(prop-2-yn-1-yloxy)tetrahy-
dro-2H-pyran-2-yl]methyl 4-Methylbenzolsulfonate (7)
IR (ATR): 3354, 3290, 2115, 1347, 1248, 1188, 1167, 1106, 1079, 1057,
1012, 967, 894, 813, 781, 705, 663, 552, 505 cm–1
.
A solution of (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(prop-2-yn-1-
yloxy)tetrahydro-2H-pyran-3,4,5-triol (847 mg, 3.88 mmol, 1.0
equiv) in anhyd pyridine (7 mL) was cooled to 0 °C and treated with
pTsCl (962 mg, 5.05 mmol, 1.3 equiv) in anhyd pyridine (3 mL). The
mixture was stirred at rt for 24 h. The solvent was removed under re-
duced pressure, and the crude product was purified by column chro-
matography (silica gel, EtOAc); yield: 1.22 g (84%); colorless solid.
1H NMR (600 MHz, DMSO-d6): δ = 7.78 (d, J = 8.3 Hz, 2 H, ArH), 7.48
(d, J = 8.2 Hz, 2 H, ArH), 5.57 (d, J = 5.6 Hz, 1 H, CHOH), 5.34 (d, J = 5.7
Hz, 1 H, CHOH), 5.23 (d, J = 5.3 Hz, 1 H, CHOH), 4.51 (d, J = 8.7 Hz, 1 H,
β-H1), 4.24 (dd, J1 = 10.8 Hz, J2 = 1.7 Hz, 1 H), 3.52 (ddd, J1 = 9.8 Hz, J2 =
6.5 Hz, J3 = 1.7 Hz, 1 H), 3.16 (td, J1 = 8.9 Hz, J2 = 5.2 Hz, 1 H), 3.04 (td,
J1 = 9.4 Hz, J2 = 5.6 Hz, 1 H), 2.95 (td, J1 = 8.8 Hz, J2 = 5.6 Hz, 1 H), 2.43
(s, 3 H, ArCH3).
IR (ATR): 3325, 2899, 1596, 1446, 1356, 1188, 1176, 1080, 1046, 997,
13C NMR (150 MHz, DMSO-d6): δ = 132.6 (s, ipso-Ar), 130.6, 128.1 (2
d, Ar), 90.1 (d, CHN3), 76.5 (d, CHCH2), 75.7, 73.5, 70.3 (3 d, CHOH),
69.5 (t, CH2OH), 21.6 (q, ArCH3).
925, 833, 814, 687, 656, 620, 550, 502 cm–1
.
1H NMR (600 MHz, CD3OD): δ = 7.81 (d, J = 8.3 Hz, 2 H, ArH), 7.45 (d,
J = 8.1 Hz, 2 H, ArH), 4.37 (d, J = 7.8 Hz, 1 H, β-H1), 4.34 (dd, J1 = 10.9
Hz, J2 = 1.8 Hz, 1 H), 4.29–4.26 (m, 1 H), 4.21 (s, 1 H), 4.19–4.15 (m, 1
H), 3.39 (ddd, J1 = 9.8 Hz, J2 = 5.9 Hz, J3 = 1.9 Hz, 1 H), 3.30–3.28 (m, 1
H), 3.22–3.19 (m, 1 H), 3.11 (dd, J1 = 9.2 Hz, J2 = 7.9 Hz, 1 H), 2.46 (s, 3
H, ArCH3). OH groups were not detected.
13C NMR (150 MHz, CD3OD): δ = 146.7, 134.6 (2 s, Ar), 131.2, 129.3 (2
d, Ar), 102.1 (d, CHOCH2), 80.0 (s, C≡C), 77.9 (d, CH), 76.5 (s, C≡C),
75.2, 74.8, 71.2 (2 d, CH), 70.8 (t, CH2OTs), 56.7 (t, CH2C≡C), 21.8
(ArCH3).
4-(Di-tert-butylfluorsilyl)benzenethiol (4)
The procedure published previously8 was improved as follows. A solu-
tion of tBuLi in pentane (8.05 mL, 1.9 M, 15.3 mmol, 2.0 equiv) was
added dropwise under magnetic stirring to a –78 °C cold solution of
(4-bromophenylsulfanyl)-tert-butyldimethylsilane
(2.32 g,
7.65 mmol, 1.0 equiv) in Et2O (50 mL). After stirring the reaction mix-
ture for 25 min at –78 °C, di-tert-butyldifluorosilane (1.52 g,
8.41 mmol, 1.1 equiv) was added dropwise. The reaction mixture was
allowed to warm up to rt over a period of 24 h and brine (50 mL) was
added. The organic layer was separated, and the aqueous layer was
extracted with Et2O (4 × 50 mL). The combined organic layers were
dried (MgSO4). The filtrate was concentrated in vacuo to give 1-(tert-
butyldimethylsilanylsulfanyl)-4-(di-tert-butylfluorosilanyl)benzene
as a yellow oil that solidified (2.58 g, 6.70 mmol, 88%). The subse-
quent deprotection to afford 4 was carried out as described previous-
ly.8
HRMS (ESI): m/z calcd for C16H20O8SNa [M + Na]+: 395.07711; found:
395.07671.
(2S,3S,4S,5R,6R)-2-({[4-(Di-tert-butylfluorosilyl)phenyl]thio}meth-
yl)-6-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran-3,4,5-triol (8)
A solution of 4 (50 mg, 0.18 mmol, 1.2 equiv) in anhyd DMSO (1 mL)
was treated with tBuOK (20 mg, 0.18 mmol, 1.2 equiv). The mixture
was stirred at 50 °C for 30 min. After the addition of 7 (56 mg, 0.15
mmol, 1 equiv) in anhyd DMSO (1 mL), the mixture was stirred at
50 °C for 24 h. Cooling to rt was followed by addition of excess aq 1 M
HCl. The mixture was dissolved in Et2O and washed with aq 1 M HCl
(3 × 20 mL) and H2O (3 × 20 mL). After drying (MgSO4), the solvent
was removed under reduced pressure, and the crude product was pu-
rified by column chromatography (silica gel) using a gradient starting
with pentane/Et2O (15:1) and ending with Et2O/MeOH (20:1); yield:
36.8 mg (52%); colorless powder.
(2R,3R,4S,5S,6S)-2-Azido-6-({[4-(di-tert-butylfluorosilyl)phe-
nyl]thio}methyl)tetrahydro-2H-pyran-3,4,5-triol (5)
A solution of 4 (50 mg, 0.18 mmol, 1.2 equiv) in anhyd DMSO (1 mL)
was treated with tBuOK (20 mg, 0.18 mmol, 1.2 equiv). The mixture
was stirred at 50 °C for 30 min. After the addition of 3 (54 mg, 0.15
mmol, 1 equiv) in anhyd DMSO (1 mL), the mixture was stirred at
50 °C for 24 h. Cooling to rt was followed by addition of excess aq 1 M
HCl. The mixture was dissolved to Et2O and washed with aq 1 M HCl
(3 × 20 mL) and H2O (3 × 20 mL). After drying (MgSO4), the solvent
was removed under reduced pressure, and the crude product was pu-
rified by column chromatography (silica gel) using a gradient starting
with pentane/Et2O (15:1) and ending with Et2O/MeOH (20:1); yield:
51.1 mg (74%); colorless powder.
IR (ATR): 3347, 3293, 2934, 2859, 1582, 1470, 1387, 1365, 1262, 1180,
1066, 1007, 824, 811, 740, 716, 645 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.57–7.49 (m, 2 H, ArH), 7.39–7.36 (m,
2 H, ArH), 4.50 (d, J = 7.3 Hz, 1 H, β-H1), 4.36 (dd, J1 = 15.7 Hz, J2 = 2.4
Hz, 1 H), 4.25 (dd, J1 = 15.9 Hz, J2 = 2.2 Hz, 1 H), 3.61–3.48 (m, 4 H),
3.46–3.41 (m, 1 H), 3.17 (dd, J1 = 14.2 Hz, J2 = 7.3 Hz, 1 H), 2.48 (t, J =
2.4 Hz, 1 H), 1.60 (br s, 3 H, CHOH), 1. 05 [s, 18 H, 2 × C(CH3)3].
IR (ATR): 3354 (br), 2933, 2859, 2117, 1582, 1471, 1386, 1365, 1245,
1064, 1011, 969, 936, 836, 824, 811, 740, 715, 646, 599 cm–1
.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

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A. Wiegand et al.
Feature
Synthesis
13C NMR (100 MHz, CDCl3): δ = 138.8 (s, Ar), 134.4 (d, Ar), 130.4 (s,
Ar), 127.1 (d, Ar), 100.1 (d, CHOCH2), 77.2 (s, C≡C), 76.3 (d, CH), 75.4
(s, C≡C), 75.3, 73.6, 72.9 (3 d, CH), 55.9 (t, CH2C≡C), 34.5 (t, CH2S), 27.3
[q, C(CH3)3], 20.3 [s, J = 12.5 Hz, C(CH3)3].
19F NMR (565 MHz, CDCl3): δ = –188.9 (d, J = 297.6 Hz).
29Si NMR (119 MHz, CDCl3): δ = 15.3 (d, J = 297.8 Hz).
12.3 Hz, 1 H), 3.49–3.41 (m, 3 H), 3.25–3.20 (m, 1 H), 3.16–3.11 (m, 1
H), 3.09–3.05 (m, 1 H), 3.03–3.00 (m, 1 H), 1.00–0.94 [m, 36 H, 4 ×
C(CH3)3].
13C NMR (150 MHz, DMSO-d6): δ = 140.0, 139.7 (2 s, Ar), 133.9 (d, J =
4.1 Hz, Ar), 133.8 (d, J = 3.9 Hz, Ar), 128.6 (s, J = 13.8 Hz, Ar), 128.4 (s,
J = 13.8 Hz, Ar), 126.4, 125.9 (2 d, Ar), 101.4 (d, CHO), 89.6 (d, CHN3),
82.6, 75.8, 75.5, 72.8, 72.7, 72.5, 72.3, 72.1 (8 d, CH), 59.7 (t, CH2S),
39.0 (t, CH2S), 28.0 [q, J = 6.1 Hz, C(CH3)3], 27.0 [q, J = 6.6 Hz, C(CH3)3],
19.8 [s, J = 12.4 Hz, C(CH3)3], 19.7 [s, J = 12.4 Hz, C(CH3)3].
HRMS (ESI): m/z calcd for C23H35FO5SSiNa [M + Na]+: 493.18507;
found: 493.18476.
19F NMR (565 MHz, DMSO-d6): δ = –187.5 (d, J = 297.8 Hz).
29Si NMR (119 MHz, DMSO-d6): δ = 15.4 (d, J = 297.8 Hz).
HRMS (ESI): m/z calcd for C40H63F2N3O8S2Si2Na [M + H + Na]+:
((2R,3S,4S,5R,6R)-6-{[(2R,3S,4R,5R,6R)-6-Azido-4,5-dihydroxy-2-
[(tosyloxy)methyl]tetrahydro-2H-pyran-3-yl]oxy}-3,4,5-trihy-
droxytetrahydro-2H-pyran-2-yl)methyl 4-Methylbenzenesulfon-
ate (10a)
894.34609; found: 894.34644.
A solution of 9a (100 mg, 0.27 mmol, 1.0 equiv) in anhyd pyridine (2.4
mL) was cooled to –20 °C and treated with ZnBr2·2 H2O (243 mg, 1.08
mmol, 4.0 equiv) and then with pTsCl (257 mg, 1.35 mmol, 5.0 equiv)
in anhyd pyridine (1 mL). The mixture was stirred at –20 °C for 1 h.
The reaction was carried out three times in separate flasks. The reac-
tion mixtures were combined, the solvent was removed under re-
duced pressure, and the crude product was purified by column chro-
matography (silica gel, EtOAc); yield: 367 mg (50%); colorless solid.
((2R,3S,4S,5R,6R)-6-{[(2R,3S,4R,5R,6R)-4,5-Dihydroxy-6-(prop-2-
yn-1-yloxy)-2-[(tosyloxy)methyl]tetrahydro-2H-pyran-3-yl]oxy}-
3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl 4-Methylben-
zenesulfonate (10b)
A solution of 9b (100 mg, 0.26 mmol, 1.0 equiv) in anhyd pyridine
(2.4 mL) was cooled to –20 °C and treated with ZnBr2·2 H2O (237 mg,
1.05 mmol, 4.0 equiv) and then with pTsCl (248 mg, 1.3 mmol, 5.0
equiv) in anhyd pyridine (1 mL). The mixture was stirred at –20 °C for
1 h. The reaction was carried out twice in separate flasks. The reac-
tion mixtures were combined, the solvent was removed under re-
duced pressure, and the crude product was purified by column chro-
matography (silica gel, EtOAc); yield: 115 mg (31%); colorless solid.
IR (ATR): 3375, 2363, 2330, 2119, 1598, 1450, 1353, 1190, 1173, 1141,
1071, 973, 928, 812, 688, 660, 551, 502 cm–1
.
1H NMR (500 MHz, CD3OD): δ = 7.82–7.77 (m, 4 H, ArH), 7.44 (d, J =
7.1 Hz, 4 H, ArH), 4.97 (d, J = 3.7 Hz, 1 H, α-H1′), 4.43 (d, J = 8.7 Hz, 1 H,
β-H1), 4.32–4.30 (m, 2 H), 4.19–4.16 (m, 2 H), 3.71–3.68 (m, 1 H),
3.63–3.60 (m, 1 H), 3.52 (m, 2 H), 3.36–3.33 (m, 1 H), 3.25 (t, J = 9.5
Hz, 1 H), 3.07 (t, J = 9 Hz, 1 H), 2.46 (d, J = 5.3 Hz, 6 H, ArCH3). OH
groups were not detected.
13C NMR (125 MHz, CD3OD): δ = 146.8, 146.6, 134.5, 134.4 (4 s, Ar),
131.3, 131.2, 129.4, 129.3 (4 d, Ar), 103.0 (d, CHO), 91.7 (d, CHN3),
80.7, 77.6, 75.6, 74.9, 74.0, 73.8, 72.4, 70.7 (8 d), 70.5, 70.4 (2 t,
CH2OTs), 21.8 (q, ArCH3).
IR (ATR): 3284, 2924, 1731, 1598, 1354, 1173, 993, 928, 812, 691, 660,
551 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.79–7.71 (m, 4 H, ArH), 7.46 (ddd,
J1 = 10.0 Hz, J2 = 8.6 Hz, J3 = 0.6 Hz, 4 H, ArH), 5.54 (d, J = 3.2 Hz, 1 H,
OH), 5.49 (d, J = 6.4 Hz, 1 H, OH), 5.33 (d, J = 5.4 Hz, 1 H, OH), 5.23 (d,
J = 5.8 Hz, 1 H, OH), 5.03 (d, J = 5.1 Hz, 1 H, OH), 4.93 (d, J = 3.7 Hz, 1 H,
α-H1′), 4.29–4.23 (m, 2 H), 4.22–4.19 (m, 1 H), 4.14–4.06 (m, 4 H),
3.51–3.56 (m, 1 H), 3.48 (t, J = 2.5 Hz, 2 H), 3.37 (d, J = 3.2 Hz, 1 H),
3.26–3.30 (m, 1 H), 3.21–3.26 (m, 1 H), 3.13–3.18 (m, 1 H), 3.08 (dd,
J1 = 9.7 Hz, J2 = 5.7 Hz, 1 H), 2.96 (dd, J1 = 5.3 Hz, J2 = 1.1 Hz, 1 H), 2.41
(s, 6 H, ArCH3).
13C NMR (125 MHz, DMSO-d6): δ = 145.0, 144.9, 132.4, 132.3 (4 s, Ar),
130.1, 127.7, 127.5 (3 d, Ar), 100.7 (d), 100.4 (d), 79.5 (d), 78.9 (d),
77.6 (s), 75.8, 72.8, 72.4 (3 d), 71.9 (t, CH2OTs), 71.5 (d), 70.4 (t,
CH2OTs), 69.3, 68.8 (2 d), 55.1 (t, CH2C≡CH), 21.2 (q, ArCH3).
HRMS (ESI): m/z calcd for C26H33N3O14S2Na [M + Na]+: 698.12962;
found: 698.12955.
(2S,3R,4S,5S,6S)-2-{[(2S,3S,4R,5R,6R)-6-Azido-2-({[4-(di-tert-butyl-
fluorosilyl)phenyl]thio}methyl)-4,5-dihydroxytetrahydro-2H-
pyran-3-yl]oxy}-6-({[4-(di-tert-butylfluorsilyl)phenyl]thio}meth-
yl)tetrahydro-2H-pyran-3,4,5-triol (11a)
A solution of 4 (192.2 mg, 0.71 mmol, 2.4 equiv) in anhyd DMSO (3
mL) was treated with tBuOK (79.7 mg, 0.71 mmol, 2.4 equiv). The
mixture was stirred at 50 °C for 30 min. After the addition of 10a (200
mg, 0.30 mmol, 1 equiv) in anhyd DMSO (1 mL), the mixture was
stirred at 50 °C for 48 h. Cooling to rt was followed by addition of ex-
cess aq 1 M HCl. The mixture was dissolved in Et2O and washed with
aq 1 M HCl (3 × 20 mL) and H2O (3 × 20 mL). After drying (MgSO4), the
solvent was removed under reduced pressure, and the crude product
was purified by column chromatography (silica gel) using a gradient
starting with cyclohexane/EtOAc (3:1) and ending with EtOAc/MeOH
(10:1); yield: 174 mg (67%); colorless solid.
HRMS (ESI): m/z calcd for C29H37O15S2 [M + H]+: 689.15684; found:
689.15570.
(2S,3S,4S,5R,6S)-2-({[4-(Di-tert-butylfluorsilyl)phenyl]thio}meth-
yl)-6-{[(2S,3S,4R,5R,6R)-2-({[4-(di-tert-butylfluorsilyl)phe-
nyl]thio}methyl)-4,5-dihydroxy-6-(prop-2-yn-1-yloxy)tetrahydro-
2H-pyran-3-yl]oxy)}tetrahydro-2H-pyran-3,4,5-triol (11b)
A solution of 4 (144.1 mg, 0.53 mmol, 2.4 equiv) in anhyd DMSO (3
mL) was treated with tBuOK (59.8 mg, 0.53 mmol, 2.4 equiv). The
mixture was stirred at 50 °C for 30 min. After the addition of 10b
(152.9 mg, 0.22 mmol, 1 equiv) in anhyd DMSO (1 mL), the mixture
was stirred at 50 °C for 2 d. Cooling to rt was followed by addition of
excess aq 1 M HCl. The mixture was dissolved in Et2O and washed
with aq 1 M HCl (3 × 20 mL) and H2O (3 × 20 mL). After drying (Mg-
SO4), the solvent was removed under reduced pressure, and the crude
product was purified by column chromatography (silica gel) using a
gradient starting with cyclohexane/EtOAc (3:1) and ending with
EtOAc/MeOH (10:1); yield: 109 mg (55%); colorless solid.
IR (ATR): 3325, 2934, 2859, 2117, 1715, 1582, 1470, 1373, 1250, 1056,
1012, 939, 816, 740, 645, 600, 504 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 7.42–7.36 (m, 6 H, ArH), 7.25 (d, J =
8 Hz, 2 H, ArH), 5.84–5.83 (m, 1 H), 5.75 (d, J = 6.3 Hz, 1 H), 5.66 (d, J =
5.5 Hz, 1 H), 5.32 (d, J = 5.8 Hz, 1 H), 5.13–5.08 (m, 2 H), 4.57 (d, J = 8.7
Hz, 1 H, β-H1), 3.79 (t, J = 7.2 Hz, 1 H), 3.70–3.67 (m, 1 H), 3.56 (d, J =
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

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A. Wiegand et al.
Feature
Synthesis
IR (ATR): 3298, 2933, 2859, 1732, 1582, 1471, 1365, 1245, 1062, 1012,
824, 812, 741, 646, 601, 504, 430 cm–1
0.21 mmol, 1 equiv) in anhyd DMSO (1 mL), the mixture was stirred
at 50 °C for 48 h. Cooling to rt was followed by addition of excess aq 1
M HCl. The mixture was dissolved in Et2O and washed with aq 1 M
HCl (3 × 20 mL) and H2O (3 × 20 mL). After drying (MgSO4), the solvent
was removed under reduced pressure, and the crude product was pu-
rified by column chromatography (silica gel) using a gradient starting
with cyclohexane/EtOAc (3:1) and ending with EtOAc; yield: 61 mg
(33%); colorless solid.
.
1H NMR (600 MHz, DMSO-d6): δ = 7.44–7.39 (m, 4 H, ArH), 7.36 (d,
J = 8.1 Hz, 2 H, ArH), 7.26 (d, J = 8.1 Hz, 2 H, ArH), 5.72 (d, J = 2.6 Hz, 1
H, OH), 5.64 (d, J = 6.6 Hz, 1 H, OH), 5.34–5.29 (m, 2 H, 2 × OH), 5.13
(d, J = 3.7 Hz, 1 H, α-H1′), 5.06 (d, J = 5.1 Hz, 1 H, OH), 4.93 (td,
J1 = 6.5 Hz, J2 = 3.9 Hz, 1 H), 4.29 (d, J = 7.7 Hz, 1 H, β-H-1), 4.11 (d,
J = 2.6 Hz, 1 H), 3.99 (d, J = 13.6 Hz, 1 H, H-7b), 3.80–3.77 (m, 1 H, H-
3), 3.53–3.44 (m, 2 H), 3.43–3.34 (m, 7 H), 3.23–3.18 (m, 1 H), 3.14–
3.08 (m, 1 H), 3.08–2.98 (m, 2 H), 0.97 [d, J = 8.1 Hz, 36 H, 4 × C(CH3)3].
IR (ATR): 3371, 2935, 2860, 2117, 1582, 1470, 1366, 1249, 1054, 936,
816, 741, 646, 600, 505 cm–1
.
13C NMR (150 MHz, DMSO-d6): δ = 140.0, 139.8 (2 s, Ar), 133.9 (d,
J = 4.1 Hz, Ar), 133.8 (d, J = 4.1 Hz, Ar), 128.5 (s, J = 13.9 Hz, Ar), 128.3
(s, J = 13.9 Hz, Ar), 126.4 (d, Ar), 125.8 (d, Ar), 101.2 (d), 100.5 (d),
82.9 (d), 79.3 (s), 77.5 (s), 76.0, 74.2 (2 d), 72.8 (d, J = 7.1 Hz), 72.6,
72.3 (2 d), 72.01 (d, J = 3.4 Hz), 68.8 (d), 58.3 (d), 54.7 (t), 31.4, 28.0 (2
t), 27.0 [q, C(CH3)3], 19.8, 19.7 [2 s, J = 4.7 Hz, C(CH3)3].
1H NMR (600 MHz, DMSO-d6): δ = 7.49–7.44 (m, 4 H, ArH), 7.39–7.33
(m, 4 H, ArH), 5.75 (d, J = 5.6 Hz, 1 H), 5.33 (d, J = 5 Hz, 1 H), 4.93 (d, J =
5.6 Hz, 1 H), 4.88 (d, J = 5 Hz, 1 H), 4.70 (d, J = 1.9 Hz, 1 H), 4.59 (d, J =
8.7 Hz, 1 H), 4.36 (d, J = 7.8 Hz, 1 H), 4.03 (q, J = 7.1 Hz, 1 H), 3.80–3.71
(m, 3 H), 3.65 (t, J = 6.7 Hz, 1 H), 3.45–3.41 (m, 3 H), 3.23–3.11 (m, 3
H), 1.01–1.00 [m, 36 H, 4 × C(CH3)3].
19F NMR (565 MHz, CDCl3): δ = –187.5, –187.5 (2 d, J = 297.8 Hz).
29Si NMR (119 MHz, CDCl3): δ = 15.5, 13.0 (2 d, J = 298.1 Hz).
HRMS (ESI): m/z calcd for C44H67F2O11S2Si2 [M + HCOO]–: 929.36259;
13C NMR (150 MHz, DMSO-d6): δ = 139.5, 139.0 (2 s, Ar), 134.1 (d, J =
4.1 Hz, Ar), 134.0 (d, J = 3.9 Hz, Ar), 128.8 (s, J = 13.8 Hz, Ar), 128.3 (s,
J = 13.8 Hz, Ar), 126.2, 125.9 (2 d, Ar), 103.2 (d, CHO), 89.4 (d, CHN3),
81.4, 75.4, 74.0, 73.3 (4 d, CH), 73.1 (d, J = 7.4 Hz, CH), 70.1, 69.2 (2 d,
CH), 32.4 (t, CH2S), 32.2 (t, CH2S), 28.0 [q, J = 6.1 Hz, C(CH3)3], 27.0 [q,
C(CH3)3], 19.8 [s, C(CH3)3], 19.7 [s, C(CH3)3].
found: 929.36097.
((2R,3R,4S,5R,6S)-6-{[(2R,3S,4R,5R,6R)-6-Azido-4,5-dihydroxy-2-
[(tosyloxy)methyl]tetrahydro-2H-pyran-3-yl]oxy}-3,4,5-trihy-
droxytetrahydro-2H-pyran-2-yl)methyl 4-Methylbenzolsulfonate
(13a)
19F NMR (565 MHz, DMSO-d6): δ = –187.4 (d, J = 297.5 Hz).
29SiNMR (119 MHz, DMSO-d6): δ = 15.6 (d, J = 297.5 Hz).
HRMS (ESI): m/z calcd for C40H64F2N3O8S2Si2 [M + H]+: 872.36359;
found: 872.36441.
A solution of 12a (100 mg, 0.27 mmol, 1.0 equiv) in anhyd pyridine
(2.4 mL) was cooled to –20 °C and treated with ZnBr2·2 H2O (243 mg,
1.08 mmol, 4.0 equiv) and then with pTsCl (257 mg, 1.35 mmol, 5.0
equiv) in anhyd pyridine (1 mL). The mixture was stirred at –20 °C for
15 min. The reaction was carried out twice in separate flasks. The re-
action mixtures were combined, the solvent was removed under re-
duced pressure, and the crude product was purified by column chro-
matography (silica gel) using a gradient starting with EtOAc/cyclo-
hexane (30:1) and ending with EtOAc/MeOH (10:1); yield: 160 mg
(44%); colorless solid.
((2R,3R,4S,5R,6S)-6-{[(2R,3S,4R,5R,6R)-4,5-Dihydroxy-6-(prop-2-
yn-1-yloxy)-2-[(tosyloxy)methyl]-tetrahydro-2H-pyran-3-yl]oxy}-
3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl 4-Methylben-
zolsulfonate (13b)
A solution of 12b (100 mg, 0.26 mmol, 1.0 equiv) in anhyd pyridine
(2.3 mL) was cooled to –20 °C and treated with ZnBr2·2 H2O (237 mg,
1.05 mmol, 4.0 equiv) and then with pTsCl (251 mg, 1.3 mmol, 5.0
equiv) in anhyd pyridine (1 mL). The mixture was stirred at –20 °C for
90 min. The reaction was carried out twice in separate flasks. The re-
action mixtures were combined, the solvent was removed under re-
duced pressure, and the crude product was purified by column chro-
matography (silica gel, EtOAc); yield: 130 mg (36%); colorless solid.
IR (ATR): 3369, 2912, 2116, 1728, 1598, 1451, 1352, 1255, 1173, 1060,
971, 811, 769, 689, 662, 550 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 7.83–7.76 (m, 4 H, ArH), 7.49–7.45
(m, 4 H, ArH), 5.82 (d, J = 5.6 Hz, 1 H), 5.16 (d, J = 3.8 Hz, 1 H), 4.96 (d,
J = 4.7 Hz, 1 H), 4.82 (d, J = 4.7 Hz, 1 H), 4.59–4.55 (m, 2 H), 4.46 (d, J =
9.9 Hz, 1 H), 4.20–4.10 (m, 3 H), 3.91 (t, J = 9.2 Hz, 1 H), 3.76–3.72 (m,
2 H), 3.30–3.23 (m, 3 H), 3.04–3.01 (m, 1 H), 2.42 (d, J = 1.5 Hz, 6 H, 2
× ArCH3). OH groups were not detected.
13C NMR (125 MHz, DMSO-d6): δ = 145.2, 144.9, 132.3, 131.8 (4 s, Ar),
130.3, 130.1, 127.9, 127.7 (4 d, Ar), 102.8 (d, CHO), 89.2 (d, CHN3),
78.5, 74.0, 73.3, 72.6, 72.4, 72.2 (6 d, CH), 69.9 (t, CH2OTs) 69.8 (d, CH),
69.2 (t, CH2OTs), 68.0 (d, CH), 21.2 (q, ArCH3).
IR (ATR): 3334, 2912, 1728, 1598, 1451, 1352, 1173, 1122, 1049, 1019,
971, 931, 836, 813, 769, 691, 661, 551 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.84–7.77 (m, 4 H, ArH), 7.50–7.46
(m, 4 H, ArH), 5.46 (d, J = 5.4 Hz, 1 H), 5.16 (d, J = 4.1 Hz, 1 H), 4.96 (d,
J = 5 Hz, 1 H), 4.82 (d, J = 4.9 Hz, 1 H), 4.54 (d, J = 2.1 Hz, 1 H), 4.47 (d,
J = 9.3 Hz, 1 H), 4.31 (d, J = 7.8 Hz, 1 H), 4.23–4.07 (m, 5 H), 4.02 (t, J =
6.8 Hz, 1 H), 3.91 (dd, J1 = 9.9 Hz, J2 = 8.5 Hz, 1 H), 3.78–3.76 (m, 1 H),
3.59–3.51 (m, 3 H), 3.27–3.24 (m, 3 H), 3.04–2.99 (m, 1 H), 2.43 (s, 6
H, 2 × ArCH3).
HRMS (ESI): m/z calcd for C26H33N3O14S2Na [M + Na]+: 698.12962;
found: 698.12936.
13C NMR (125 MHz, DMSO-d6): δ = 145.1, 144.8, 132.5, 131.8 (4 s, Ar),
130.3, 130.1, 127.9, 127.7 (4 d, Ar), 102.7 (d, CHO), 100.3 (d, CHOCH2),
79.6 (s, C≡CH), 77.6 (d, C≡CH), 74.0, 72.6, 72.5, 72.2, 71.4, 69.8, 69.4,
68.0 (8 d), 62.3 (t, CH2OTs), 55.0 (t, CHOCH2), 21.2 (q, ArCH3).
HRMS (ESI): m/z calcd for C29H37O15S2 [M + H]+: 689.15684; found:
689.15712.
(2R,3R,4S,5R,6S)-2-{[(2S,3S,4R,5R,6R)-6-Azido-2-({[4-(di-tert-bu-
tylfluorosilyl)phenyl]thio}methyl)-4,5-dihydroxytetrahydro-2H-
pyran-3-yl]oxy}-6-({[4-(di-tert-butylfluorsilyl)phenyl]thio}meth-
yl)tetrahydro-2H-pyran-3,4,5-triol (14a)
A solution of 4 (136 mg, 0.5 mmol, 2.4 equiv) in anhyd DMSO (3 mL)
was treated with tBuOK (57 mg, 0.5 mmol, 2.4 equiv). The mixture
was stirred at 50 °C for 30 min. After the addition of 13a (142 mg,
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

I
A. Wiegand et al.
Feature
Synthesis
(2S,3R,4S,5R,6R)-2-({[4-(Di-tert-butylfluorsilyl)phenyl]thio}meth-
yl)-6-{[(2S,3S,4R,5R,6R)-2-({[4-(di-tert-butylfluorsilyl)phenyl]-
thio}methyl)-4,5-dihydroxy-6-(prop-2-yn-1-yloxy)tetrahydro-2H-
pyran-3-yl]oxy}tetrahydro-2H-pyran-3,4,5-triol (14b)
4.99 (m, 2 H, OH), 4.63–4.56 (m, 2 H), 4.33 (d, J = 7.4 Hz, 1 H), 4.13
(dd, J1 = 11.0 Hz, J2 = 7.2 Hz, 1 H), 4.09–4.05 (m, 2 H), 3.96 (d, J = 12.2
Hz, 1 H), 3.79 (t, J = 8.3 Hz, 1 H), 3.58 (s, 1 H), 3.48–3.39 (m, 3 H), 3.36
(d, J = 9.5 Hz, 1 H), 3.03 (td, J1 = 8.6 Hz, J2 = 5.8 Hz, 1 H), 2.38 (s, 3 H,
ArCH3).
13C NMR (150 MHz, DMSO-d6): δ = 145.3 (s, Ar), 139.0 (s, Ar), 132.7 (s,
Ar), 130.5, 129.2 (2 d, Ar), 128.4 (d, Ar), 128.1, 126.7 (2 d, Ar), 102.8
(d), 100.2 (d), 89.7 (d), 77.5, 76.1, 74.6 73.9, 73.3, 72.0, 70.0 (7 d), 69.8,
68.9 (2 t), 66.8 (d), 21.6 ArCH3).
A solution of 4 (94 mg, 0.35 mmol, 2.4 equiv) in anhyd DMSO (1.5 mL)
was treated with tBuOK (39 mg, 0.35 mmol, 2.4 equiv). The mixture
was stirred at 50 °C for 30 min. After the addition of 13b (100 mg,
0.15 mmol, 1 equiv) in anhyd DMSO (1 mL), the mixture was stirred
at 50 °C for 2 d. Cooling to rt was followed by addition of excess aq 1
M HCl. The mixture was dissolved in Et2O and washed with aq 1 M
HCl (3 × 20 mL) and H2O (3 × 20 mL). After drying (MgSO4), the solvent
was removed under reduced pressure, and the crude product was pu-
rified by column chromatography (silica gel) using a gradient starting
with cyclohexane/EtOAc (3:1) and ending with EtOAc/MeOH (10:1);
yield: 47 mg (36%); colorless solid.
HRMS (ESI): m/z calcd for C26H32N3O12S [M + H]+: 610.17012; found:
610.17125.
17
Yield: 52 mg (31%); colorless solid.
IR (ATR): 3486, 3037, 2875, 2116, 1729, 1598, 1357, 1246, 1173, 1093,
IR (ATR): 3396, 2934, 2859, 1715, 1582, 1471, 1365, 1074, 825, 812,
1043, 963, 905, 868, 812, 697, 669, 552 cm–1
.
741, 646, 601, 505, 430 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 7.82 (d, J = 8.2 Hz, 2 H, ArH), 7.74
(d, J = 8.2 Hz, 2 H, ArH), 7.42 (d, J = 8.2 Hz, 2 H, ArH), 7.39–7.35 (m, 5
H, ArH), 7.29–7.26 (m, 2 H, ArH), 5.76 (d, J = 5.5 Hz, 1 H, OH), 5.61 (d,
J = 5.5 Hz, 1 H, OH), 5.35 (s, 1 H), 5.04 (d, J = 3.1 Hz, 1 H, OH), 4.62–
4.51 (m, 4 H), 4.48 (d, J = 7.6 Hz, 1 H), 4.25 (d, J = 3.4 Hz, 1 H), 4.03–
4.09 (m, 2 H), 3.99–3.95 (m, 1 H), 3.78–3.73 (m, 1 H), 3.70 (s, 1 H),
3.54 (ddd, J1 = 9.5 Hz, J2 = 7.9 Hz, J3 = 5.5 Hz, 1 H), 3.43–3.36 (m, 2 H,),
3.01 (td, J1 = 8.5 Hz, J2 = 5.8 Hz, 1 H), 2.38 (d, J = 3.7 Hz, 6 H, 2 × ArCH3).
1H NMR (600 MHz, DMSO-d6): δ = 7.46 (dd, J1 = 19.8 Hz, J2 = 8.1 Hz, 4
H ArH), 7.38 (d, J = 8.2 Hz, 2 H, ArH), 7.34 (d, J = 8.2 Hz, 2 H, ArH), 5.38
(d, J = 5.3 Hz, 1 H, OH), 5.30 (d, J = 4.8 Hz, 1 H, OH), 4.91 (d, J = 5.4 Hz,
1 H, OH), 4.86 (d, J = 4.9 Hz, 1 H, OH), 4.64 (d, J = 1.8 Hz, 1 H, OH),
4.37–4.32 (m, 2 H), 4.19 (dd, J1 = 15.6 Hz, J2 = 2.4 Hz, 1 H), 4.11–4.04
(m, 2 H), 3.77–3.70 (m, 2 H), 3.67–3.64 (m, 1 H), 3.59–3.54 (m, 1 H),
3.43–3.37 (m, 4 H), 3.26–3.21 (m, 1 H), 3.16–3.08 (m, 3 H), 1.00 [d,
J = 5.0 Hz, 36 H, 4 × C(CH3)3].
13C NMR (150 MHz, DMSO-d6): δ = 145.1 (s, Ar), 144.9 (s, Ar), 138.1 (s,
Ar), 134.0 (s, Ar), 132.3 (s, Ar), 130.2, 130.0, 129.1, 128.2 (4 d, Ar),
127.8 (d, J = 13.6 Hz, Ar), 126.2 (d, Ar), 102.8 (d), 100.2 (d), 89.7 (d),
77.5, 76.1, 74.6 73.9, 73.3, 72.0, 70.0 (7 d), 69.8, 68.9 (t), 66.8 (d), 21.6
(q, ArCH3).
13C NMR (150 MHz, DMSO-d6): δ = 140.2, 139.6 (2 s, Ar), 134.6 (d,
J = 4.4 Hz, Ar), 134.4 (d, J = 4.4 Hz, Ar), 129.2 (s, J = 14.3 Hz, Ar), 128.7
(s, J = 14.3 Hz, Ar), 126.7, 126.4 (2 d, Ar), 103.6 (d), 100.9 (d), 82.2 (d),
79.9 (s), 77.9, 74.6, 74.4, 73.7 (4 d), 73.5 (d, J = 2.2 Hz), 70.5 (d), 69.7
(d), 67.7 (d, J = 12.1 Hz), 55.3 (t), 33.0, 32.8 (2 t), 27.5 [q, C(CH3)3], 20.2
[s, J = 12.1 Hz, C(CH3)3].
LRMS (ESI): m/z calcd for C26H31N3O12SNa [M + Na]+: 786.16; found:
19F NMR (565 MHz, CDCl3): δ = –187.4, –187.4 (2 d, J = 297.8 Hz).
29Si NMR (119 MHz, CDCl3): δ = 15.5, 13.6 (2 d, J = 297.6 Hz).
HRMS (ESI): m/z calcd for C43H66F2O9S2Si2 [M + Na]+: 907.35471;
786.32.
X-ray Crystal Data11
Intensity data for the colorless crystal of compound 17 were collected
on a D8 Venture Bruker Diffractometer, SC-XRD using Cu-Kα radia-
tion at 173(2) K. The molecular structure was solved with direct
methods using SHELXS-2014/7 or SHELXT-2014/7 and refinements
were carried out against F2 by using SHELXL-2014/727 or OLEX2.28
The data obtained by the measurement were treated in the refine-
ment procedure as a 2-component twin. Applying the TwinRotMat
option in the program PLATON29 revealed a twin law (BASF 0.
0.13258).
found: 907.35541.
((2R,3S,4R,5R,6R)-6-Azido-3-{[(4aR,6S,7R,8R)-7,8-dihydroxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy}-4,5-dihy-
droxytetrahydro-2H-pyran-2-yl)methyl4-Methylbenzensulfonate
(16) and (4aR,6S,7R,8R)-6-{[(2R,3S,4R,5R,6R)-6-Azido-4,5-dihy-
droxy-2-[(tosyloxy)methyl]tetrahydro-2H-pyran-3-yl]oxy}-7-hy-
droxy-2-phenylhexahydropyran[3,2-d][1,3]dioxin-8-yl 4-
Methylbenzenesulfonate (17)
A solution of 15 (100 mg, 0.22 mmol, 1.0 equiv) in anhyd pyridine (2
mL) was cooled to –20 °C and treated with ZnBr2·2 H2O (198 mg, 0.88
mmol, 4.0 equiv) and then with pTsCl (209 mg, 1.1 mmol, 5.0 equiv)
in anhyd pyridine (1 mL). The mixture was stirred at –20 °C for 30
min. The solvent was removed under reduced pressure, and the crude
product was purified by column chromatography (silica gel) using a
gradient starting with EtOAc/cyclohexane (1:1, + 1% Et3N) and ending
with EtOAc/MeOH (30:1, + 1% Et3N).
(4aR,6S,7R,8R)-6-{[(2S,3S,4R,5R,6R)-6-Azido-2-({[4-(di-tert-butyl-
fluorsilyl)phenyl]thio}methyl)-4,5-dihydroxytetrahydro-2H-
pyran-3-yl]oxy}-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7,8-
diol (18)
A solution of 4 (110 mg, 0.41 mmol, 1.2 equiv) in anhyd DMSO (3 mL)
was treated with tBuOK (45.8 mg, 0.41 mmol, 1.2 equiv). The mixture
was stirred at 50 °C for 30 min. After the addition of 16 (207 mg, 0.34
mmol, 1 equiv) in anhyd DMSO (1 mL), the mixture was stirred at
50 °C for 2 d. Cooling to rt was followed by addition of excess aq 1 M
HCl. The mixture was dissolved in Et2O and washed with aq 1 M HCl
(3 × 20 mL) and H2O (3 × 20 mL). After drying (MgSO4), the solvent
was removed under reduced pressure, and the crude product was pu-
rified by column chromatography (silica gel) using a gradient starting
with cyclohexane/EtOAc (2:1) and ending with EtOAc; yield: 146 mg
(61%); colorless solid.
16
Yield: 66 mg (49%); colorless solid.
IR (ATR): 3334, 2911, 2113, 1598, 1359, 1248, 1174, 1095, 1033, 994,
964, 903, 839, 810, 774, 741, 698, 670, 597, 554, 520, 481 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 7.76 (d, J = 8.1 Hz, 2 H, ArH), 7.44
(dd, J1 = 6.1 Hz, J2 = 2.4 Hz, 2 H, ArH), 7.41–7.35 (m, 5 H, ArH), 5.74 (d,
J = 5.6 Hz, 1 H, OH), 5.56 (s, 1 H), 5.19 (d, J = 4.1 Hz, 1 H, OH), 5.06–
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

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A. Wiegand et al.
Feature
Synthesis
IR (ATR): 3385, 2934, 2933, 2859, 2115, 1733, 1582, 1471, 1365, 1245,
1163, 1027, 901, 812, 740, 699, 647, 601, 505, 431 cm–1
Supporting Information
.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611656.
1H NMR (600 MHz, DMSO-d6): δ = 7.47 (d, J = 7.7 Hz, 4 H, ArH), 7.42–
7.35 (m, 5 H, ArH), 5.70 (d, J = 5.5 Hz, 1 H, OH), 5.58 (s, 1 H), 5.47 (d,
J = 4.4 Hz, 1 H, OH), 5.13–5.07 (m, 1 H, OH), 4.83–4.77 (m, 1 H, OH),
4.64 (d, J = 8.4 Hz, 1 H), 4.50–4.46 (m, 1 H), 4.11 (d, J = 2.6 Hz, 2 H),
4.00 (d, J = 12.1 Hz, 1 H), 3.85–3.81 (m, 1 H), 3.75 (br s, 1 H), 3.65 (s, 1
H), 3.54–3.47 (m, 2 H), 3.45–3.43 (m, 2 H), 3.18–3.08 (m, 2 H), 1.01 [s,
18 H, 2 × C(CH3)3].
13C NMR (150 MHz, DMSO-d6): δ = 139.8, 138.9, 135.3 (3 s, Ar), 134.4
(d, J = 4.4 Hz, Ar), 129.1, 128.3, 126.6, 126.2 (4 d, Ar), 103.7 (d, C-1′),
100.1 (d), 89.9 (d), 82.3, 76.1, 75.8, 74.5, 73.7, 72.2, 70.3 (7 d), 68.8 (t),
66.8 (d), 32.7 (t), 28.4, 27.4 [2 q, C(CH3)3)], 20.2 [d, J = 12.1 Hz,
C(CH3)3].
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References
(1) Shukla, A. K.; Kumar, U. J. Med. Phys. 2006, 31, 13.
(2) (a) Ametamey, S. M.; Honer, M.; Schubiger, P. A. Chem. Rev.
2008, 108, 1501. (b) Schirrmacher, R.; Wängler, C.;
Schirrmacher, E. Mini-Rev. Org. Chem. 2007, 4, 317. (c) Miller, P.
W.; Long, N. J.; Vilar, R.; Gee, A. D. Angew. Chem. Int. Ed. 2008, 47,
8998.
(3) (a) Ying, L. Sci. China Chem. 2013, 56, 1682. (b) Gao, Z.;
Gouverneur, V.; Davis, B. G. J. Am. Chem. Soc. 2013, 135, 13612.
(c) Brust, P.; Van den Hoff, J.; Steinbach, J. Neurosci. Bull. 2014,
30, 777. (d) Liang, S. H.; Vasdev, N. Angew. Chem. Int. Ed. 2014,
53, 2. (e) Fehler, S. K.; Maschauer, S.; Höfling, S. B.; Bartuschat,
A. L.; Tschammer, N.; Hübner, H.; Gmeiner, P.; Prante, O.;
Heinrich, M. R. Chem. Eur. J. 2014, 20, 370. (f) Van der Born, D.;
Pees, A.; Poot, A. J.; Orru, R. V. A.; Windhorst, A. D.; Vugts, D. J.
Chem. Soc. Rev. 2017, 46, 4709. (g) Jakobsson, J. E.; Grønnevik,
G.; Riss, P. J. Chem. Commun. 2017, 53, 12906.
19F NMR (565 MHz, CDCl3): δ = –187.4 (d, J = 296.5 Hz).
29Si NMR (119 MHz, CDCl3): δ = 15.6 (d, J = 297.1 Hz).
HRMS (ESI): m/z calcd for C34H47FN3O11SSi [M + HCOO]–: 752.26791;
found: 752.26732.
(2S,3R,4S,5R,6R)-2-{[(2S,3S,4R,5R,6R)-6-Azido-2-({[4-(di-tert-bu-
tylfluorsilyl)phenyl]thio}methyl)-4,5-dihydroxytetrahydro-2H-
pyran-3-yl]oxy}-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-
triol (19)
(4) Gens, T. A.; Wethongton, J. A.; Brosi, A. R. J. Phys. Chem. 1958, 62,
1593.
A mixture of 18 (124 mg, 0.18 mmol, 1.0 equiv) and 80% aq AcOH (4
mL) was stirred at 70 °C for 4 h. After cooling to rt, the mixture was
extracted with toluene (3 × 20 mL). After drying (MgSO4), the solvent
was removed under reduced pressure, and the crude product was pu-
rified by column chromatography (silica gel) using a gradient starting
with EtOAc and ending with EtOAc/MeOH (10:1); yield: 71 mg (64%);
colorless solid.
(5) (a) Smith, G. E.; Sladen, H. L.; Biagini, S. C. G.; Blower, P. J. Dalton
Trans. 2011, 40, 6196. (b) Chansaenpak, K.; Vabre, B.; Gabbai, F.
P. Chem. Soc. Rev. 2016, 45, 954. (c) Gauthier, V. B.; Bailey, J. J.;
Liu, Z.; Wängler, B.; Wängler, C.; Jurkschat, K.; Perrin, D. M.;
Schirrmacher, R. Bioconjugate Chem. 2016, 27, 267. (d) Wilson,
T. C.; Cailly, T.; Gouverneur, V. Chem. Soc. Rev. 2018, 47, 6990.
(e) Schirrmacher, R.; Bernard-Gauthier, V.; Schirrmacher, E.;
Bailey, J. J.; Jurkschat, K.; Wängler, C.; Wängler, B. In Fluorine in
Life Sciences: Pharmaceuticals, Medicinal Diagnostics, and Agro-
chemicals; Haufe, G., Ed.; Elsevier: Amsterdam, 2019, Chap. 15.
(6) Mu, L. J.; Hohne, A.; Schubiger, R. A.; Ametamey, S. M.; Graham,
K.; Cyr, J. E.; Dinkelborg, L.; Stellfeld, T.; Srinivasan, A.;
Voigtmann, U.; Klar, U. Angew. Chem. Int. Ed. 2008, 47, 4922.
(7) (a) Schirrmacher, R.; Bradtmöller, G.; Schirrmacher, E.; Thews,
O.; Tillmanns, J.; Siessmeier, T.; Buchholz, H. G.; Bartenstein, P.;
Wängler, B.; Niemeyer, C. M.; Jurkschat, K. Angew. Chem. Int. Ed.
2006, 45, 6047. (b) Tietze, L. F.; Schmuck, K. Synlett 2011, 1697.
(c) Joyard, Y.; Azzouz, R.; Bischoff, L.; Papamicaël, C.; Labar, D.;
Bol, A.; Bol, V.; Vera, P.; Grégoire, V.; Levacher, V.; Bohn, P.
Bioorg. Med. Chem. 2013, 21, 3680. (d) Jana, S.; Al-huniti, M. H.;
Yang, B. Y.; Lu, S.; Pike, V. W.; Lepore, S. D. J. Org. Chem. 2017, 82,
2329. (e) Tisseraud, M.; Schulz, J.; Vimont, D.; Berlande, M.;
Fernandez, P.; Hermange, P.; Fouquet, E. Chem. Commun. 2018,
54, 5098. (f) Boutureira, O.; Bernardes, G. J. L.; D’Hooge, F.;
Davis, B. G. Chem. Commun. 2011, 47, 10010.
IR (ATR): 3359, 2933, 2859, 2121, 1583, 1366, 1245, 1172, 1068, 1034,
878, 814, 778, 741, 700, 645, 599, 503, 437 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 7.53–7.30 (m, 4 H, Ar), 5.69 (d,
J = 5.5 Hz, 1 H, OH), 5.33–5.25 (m, 1 H, OH), 4.88–4.82 (m, 2 H), 4.67
(t, J = 5.0 Hz, 1 H, OH), 4.62 (d, J = 8.4 Hz, 1 H), 4.55 (d, J = 4.8 Hz, 1 H),
4.44 (br. s., 1 H, OH), 4.28 (d, J = 7.7 Hz, 1 H), 3.82–3.77 (m, 1 H), 3.73–
3.68 (m, 1 H), 3.63 (br s, 1 H), 3.57–3.45 (m, 3 H), 3.40–3.34 (m, 4H),
3.15–3.06 (m, 2 H), 1.02–0.95 [m, 18 H, 2 × C(CH3)3].
13C NMR (150 MHz, DMSO-d6): δ = 139.5 (s, Ar), 134.1 (d, J = 4.4 Hz,
Ar), 128.3 (s, J = 13.2 Hz, Ar), 126.0 (d, Ar), 104.3 (d), 89.5 (d), 83.1,
75.8, 75.4, 74.6, 73.5, 73.1, 70.6, 68.3 (8 d), 60.5 (t), 32.4 (t), 28.1, 27.2
[2 q, C(CH3)3], 19.9 [s, J = 13.2 Hz, C(CH3)3].
19F NMR (565 MHz, CDCl3): δ = –187.4 (d, J = 297.2 Hz).
29Si NMR (119 MHz, CDCl3): δ = 15.6 (d, J = 297.3 Hz).
HRMS (ESI): m/z calcd for C26H42FN3O9SSiNa [M + Na]+: 642.22873;
found: 642.22877.
(8) Iovkova, L.; Wängler, B.; Schirrmacher, E.; Schirrmacher, R.;
Quandt, G.; Boening, G.; Schürmann, M.; Jurkschat, K. Chem. Eur.
J. 2009, 15, 2140.
Funding Information
(9) Yamamura, H.; Kawasaki, J.; Saito, H.; Araki, S.; Kawai, M. Chem.
Lett. 2001, 30, 706.
Natural Sciences and Engineering Research Council of Canada
(NSERC) research grant to R.S.()
(10) Ying, L.; Gervay-Hague, J. Carbohydr. Res. 2003, 338, 835.
(11) CCDC 1866515 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
Acknowledgment
The
Cambridge
Crystallographic
Data
Centre
via
We thank Matthias Mawick for synthesizing compound 4.
www.ccdc.cam.ac.uk/getstructures.
(12) Lai, Y.-C.; Luo, C.-H.; Chou, H.-C.; Yang, C.-J.; Lu, L.; Chen, C.-S.
Tetrahedron Lett. 2016, 57, 2474.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

K
A. Wiegand et al.
Feature
Synthesis
(13) Bernardes, G. J. L.; Marston, J. P.; Batsanov, A. S.; Howard, J. A. K.;
Davis, B. G. Chem. Commun. 2007, 3145.
(22) Ma, D.-L.; Shum, T. Y.-T.; Zhang, F.; Che, C.-M.; Yang, M. Chem.
Commun. 2005, 4675.
(14) Jha, A. K.; Jain, N. Tetrahedron Lett. 2013, 54, 4738.
(15) Liu, F.; Tang, P.; Ding, R.; Liao, L.; Wang, L.; Wang, M.; Wang, J.
Dalton Trans. 2017, 46, 7515.
(16) Tong, Z.; Pu, S.; Xiao, Q.; Liu, G.; Cui, S. Tetrahedron Lett. 2013,
54, 474.
(23) Maki, T.; Ishida, K. J. Org. Chem. 2007, 72, 6427.
(24) Sun, B.; Jiang, H. Tetrahedron Lett. 2012, 53, 5711.
(25) Calatrava-Pérez, E.; Bright, S. A.; Achermann, S.; Moylan, C.;
Senge, M. O.; Veale, E. B.; Williams, D. C.; Gunnlaugsson, T.;
Scanlan, E. M. Chem. Commun. 2016, 52, 13086.
(17) Mauceri, A.; Borocci, S.; Galantini, L.; Giansanti, L.; Mancini, G.;
Martino, A.; Manni, L. S.; Sperduto, C. Langmuir 2014, 30, 11301.
(18) Chatterjee, D.; Paul, A.; Yadav, R.; Yadav, S. RSC Adv. 2015, 5,
29669.
(19) Yuan, X.; Cheng, S.; Shi, Y.; Xue, W. Synthesis 2014, 46, 331.
(20) Okafor, I. S.; Wang, G. Carbohydr. Res. 2017, 451, 81.
(21) Eisink, N. N. H. M.; Lohse, J.; Witte, M. D.; Minnaard, A. J. Org.
Biomol. Chem. 2016, 14, 4859.
(26) Abellán Flos, M.; García Moreno, M. I.; Ortiz Mellet, C.; García
Fernández, J. M.; Nierengarten, J.-F.; Vincent, S. P. Chem. Eur. J.
2016, 22, 11450.
(27) Sheldrick, G. M. Acta Crystallogr., Sect. C 2015, 71, 3.
(28) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. J. Appl. Cryst. 2009, 42, 339.
(29) Spek, A. L. Acta Crystallogr., Sect. D 2009, 65, 148.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K