Chemical Glucosylation of Labile Natural Products Using a (2-Nitrophenyl)acetyl-Protected Glucosyl Acetimidate Donor

Article abstract of DOI:10.1002/ejoc.201800260

The synthesis of (2-nitrophenyl)acetyl (NPAc)-protected glucosyl donors is described that were designed for the neighboring-group assisted glucosylation of base-labile natural products also being sensitive to hydrogenolysis. Glycosylation conditions were optimized using a trichloroacetimidate glucosyl donor, and cyclohexylmethanol and (+)-menthol as model acceptors. The approach was then extended to a one-pot procedure for the synthesis of 1,2-trans-glycosides. This method was finally applied for improved synthesis of the masked mycotoxin T2-O-β,d-glucoside.

Full text of DOI:10.1002/ejoc.201800260

A Journal of
Accepted Article
Title: Chemical Glucosylation of Labile Natural Products using a (2-
Nitrophenyl)acetyl-Protected Glucosyl Acetimidate Donor
Authors: Julia Weber, Markus Schwarz, Andrea Schiefer, Christian
Hametner, Georg Häubl, Johannes Fröhlich, and Hannes
Mikula
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800260
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800260
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10.1002/ejoc.201800260
European Journal of Organic Chemistry
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Chemical Glucosylation of Labile Natural Products using
a (2-Nitrophenyl)acetyl-Protected Glucosyl Acetimidate Donor
Julia Weber,[a] Markus Schwarz,[a] Andrea Schiefer,[a] Christian Hametner,[a] Georg Häubl,[b] Johannes
Fröhlich,[a] and Hannes Mikula*[a]
Abstract: The synthesis of (2-nitrophenyl)acetyl (NPAc)-protected
glucosyl donors is described that were designed for the neighboring-
group assisted glucosylation of base-labile natural products also
being sensitive to hydrogenolysis. Glycosylation conditions were
glycosylation of natural products that are not stable under
hydrogenolytic conditions (e.g. compounds containing carbon-
carbon double or triple bonds). There are only very few glycosyl
donor systems known so far that might be applied for the
glycosylation of natural products being sensitive to both basic
conditions and hydrogenolysis. For the synthesis of (-)-cassiode
a fully PMB-protected sulfoxide glucosyl donor was used, which
surprisingly even showed enhanced diastereoselectivity toward β-
glycosylation.12 Heuckendorff et al.13 used a similar strategy
(PMB-protected thioglycosyl donor) and showed that the
selectivity of β-glycosylation is strongly dependent on the
acceptor. A fully TBDMS-protected sulfoxide glucosyl donor was
applied for the synthesis of glycopeptides14 and a fully TIPS-
protected thioethyl glucosyl donor was described by Okada et
al.,15 with both showing good β-selectivities in glycosylation
reactions with cyclohexylmethanol due to the restricted twist-boat
conformation. However, in case of more complex alcohols as
acceptors a decreased diastereoselectivity was observed when
using this glucosyl donor.16 Hence, a reliable strategy for the
glycosylation of complex and labile natural products is still missing.
To the best of our knowledge, no donor system has been reported
so far making use of neighboring group participation for
diastereoselective 1,2-trans glycosylation of base-labile natural
products containing at least one carbon-carbon double bond.
In the course of ongoing research in the field of phase II
metabolites of mycotoxins, we have become interested in the
development of glucosyl donors that can be used for the
glucosylation of T2-toxin (1, Fig. 1a), a compound that contains
ester groups and a carbon-carbon double bond. T2-toxin is a
potent inhibitor of the eukaryotic protein synthesis and represents
a contaminant of considerable concern to human and animal
health.17 Masked T2-toxins, especially glycosides, can emerge
after metabolization in plants and fail to be recognized in
conventional analyses.2 As hydrolysis to the parent toxin can
occur during digestion,18,19 these masked toxins present a risk
considering the underestimation of the total mycotoxin content in
routine screenings. For the development of routine analyses
including masked mycotoxins20 such as T2-glucoside (2, Fig. 1b)
and further studies regarding toxicity and structure elucidation,
there is an urgent need for sufficient amounts of reference
materials.
optimized using
a
trichloroacetimidate glucosyl donor, and
cyclohexylmethanol and (+)-menthol as model acceptors. The
approach was then extended to a one-pot procedure for the synthesis
of 1,2-trans-glycosides. This method was finally applied for improved
synthesis of the masked mycotoxin T2-O-β,D-glucoside.
Introduction
Glycosides are widespread in nature, often found as secondary
metabolites formed in plants or mammals during xenobiotic
metabolism.1,2 A variety of glycosylated bioactive natural products
is known with the sugar part playing a pivotal role regarding
biological activity and recognition of cellular targets.3,4
Considering the limited availability of glycosides from biological
sources and the need of significant amounts of these materials for
biological, medicinal and pharmacological studies, the chemical
synthesis of glycoconjugates is of high interest.5 However, the
glycosylation of complex natural products still remains
a
challenging task as there is no general procedure known so far
for the diastereoselective synthesis of glycoconjugates.6 The use
of peracetylated glycosyl donors represents the most commonly
applied method exploiting the neighboring participating effect of
the acetyl group for the formation of 1,2-trans glycosides.7,8
However, in case of
a base-labile natural product (e.g.
compounds containing ester groups), these donors fail as soon
as it comes to deprotection of the acetyl groups on the sugar
moiety. To circumvent this problem, several strategies have been
developed and reported including benzyl-protected donors with a
neighboring participating group at position 2 such as AZMB,9
MSc,10 or picolinyl.11 These donors can efficiently be used for the
diastereoselective glycosylation of base-sensitive acceptor
molecules. However, these donors are inapplicable for the
[a]
J. Weber, M. Schwarz, A. Schiefer, C. Hametner, J. Fröhlich and
H. Mikula*
Institute of Applied Synthetic Chemistry
Vienna University of Technology (TU Wien)
Getreidemarkt 9, 1060 Vienna, Austria
E-mail: hannes.mikula@tuwien.ac.at
G. Häubl
[b]
Romer Labs
Technopark 1, 3430 Tulln/Donau, Austria
Figure 1. Chemical structure of (a) T2-toxin and (b) its glycosylated metabolite
T2-O-β,D-glucoside.
Supporting information for this article is given via a link at the end of
the document.
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As described previously, glycosylation of T2-toxin was achieved
under thioglycosylation conditions using
a TIPS-protected
thioethyl glucosyl donor as developed by Okada et al.,15 leading
to an isomeric 5:1 mixture of β- and α-glucoside. The aim to
improve this reaction considering the reduction of elaborate
purification steps and increased versatility of the glycosylation
reaction led us to the development of a new glucosyl donor
system using (2-nitrophenyl)acetyl (NPAc) as
neighboring
participating group (Fig. 2). NPAc has been developed by
Daragics et al.21 for the protection of hydroxy groups and seemed
to us to be the perfect choice as its cleavage can be carried out
under very mild reductive conditions. Moreover, NPAc can be
introduced using commercially available nitrophenylacetic acid
and it was already shown that this protective group provides a
participation effect in glycosylation reactions leading to formation
of 1,2-trans glycosides.21
Scheme 1. Synthesis of 2,3,4,6-tetra-O-NPAc protected glucosyl donors 4
(bromosugar) and 6 (trichloroacetimidate).
Herein, we present the synthesis and application of a glucosyl
donor that is suitable for the glycosylation of base-labile natural
products that are not compatible with hydrogenolytic removal of
protecting groups.
To investigate glycosylation applying the NPAc-protected donors
4 and 6, cyclohexylmethanol was used as model acceptor with a
primary OH-group. Selected data of reaction optimization and
screening is shown in Table 1. Königs Knorr glycosylation using
bromosugar 4 as donor activated by various silver salts resulted
in no conversion after 24h (for examples see Entry 1 and Entry 2),
while Lewis-acid mediated glycosylation applying donor 6 and
.
BF3 Et2O as promotor led to formation of product 7, but only in low
yield (Entry 3). Further screening was carried out considering
various Lewis acids, number of equivalents of reactants and
promotor, solvent, etc., to obtain an improved protocol using
TMSOTf as activator for the trichloroacetimidate donor 6 to obtain
7 in 80% yield (Entry 4). Encouraged by the results we tested the
applicability of the optimized procedure towards secondary
alcohols using (+)-menthol as a model acceptor, and were able to
obtain compound 8 in 64% (Entry 5).
Figure 2. NPAc-protected glucosyl donors for glycosylation of labile acceptors.
Table 1. Glycosylation of cyclohexylmethanol (CyMeOH) and (+)-menthol using
glycosyl donors 4 and 6
Results and Discussion
Starting from D-glucose 1,2,3,4,6-NPAc-protected glucose 3 was
prepared applying a slightly modified protocol as described by
Daragics et al.21 using coupling of (2-nitrophenyl)acetic acid to the
OH-groups of the sugar mediated by 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDC) and catalytic amounts
of 4-dimethylaminopyridine (DMAP). 3 was reacted with HBr in
acetic acid5 to obtain bromosugar 4 that can be used for Königs-
Knorr glycosylation. Hydrolysis of the anomeric center with silver
carbonate in acetone/water22 yielded the 1-hydroxy sugar 5 that
was subsequently reacted with trichloroacetonitrile and 1,8-
Entry Donor
(equiv.)
Acceptor
(equiv.)
Activation
(equiv.)
Solvent
Yield[a] [%]
(product)
1
2
3
4
5
4 (1.0) CyMeOH (1.2)
4 (1.0) CyMeOH (1.2)
6 (1.0) CyMeOH (1.2)
6 (1.2) CyMeOH (1.0)
Ag2O (1.5)
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0 (7)
0 (7)
diazabicyclo[5,4,0]-undec-7-ene
(DBU)23
to
obtain the
Ag2CO3 (1.5)
trichloroacetimidate donor 6 for Schmidt glycosylation (Scheme
1). Notably, first attempts to introduce the imidoyl group by
reacting 5 with trichloroacetonitrile and potassium carbonate24
failed, while using DBU as a base led to full conversion after 16h
affording 6 in 76%. In contrast to the report of Jacquinet et al.
describing modification of NPAc groups in the presence of DBU
and Cl3CCN,25 we have not observed any side reaction.
.
BF3 Et2O (0.1)
5 (7)
TMSOTf (0.1)
80 (7, β/α=6:1)
64 (8, β/α=8:1)
6 (1.2) (+)-Menthol (1.0) TMSOTf (0.1)
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[a] Non-isolated yield as determined by HPLC (using standard addition
for quantification).
Unexpectedly, even though glucosyl donor 6 is equipped with a
neighboring participating group at O2, all Schmidt glycosylation
reactions led to a mixture of 1,2-trans and 1,2-cis glycosides.
However, the formation of ß-glucosides was still favored with a
ß/α ratio of up to 8:1. We hypothesize that the conformation of the
sugar and/or the intermediate oxocarbenium species (after
activation) is influenced due to steric hindrance of the four NPAc
groups thus preventing more efficient participation.
Scheme 3. Glycosylation of T2-toxin (1) and subsequent deprotection of the
crude intermediate to obtain T2-O-β,D-glucoside (2).
Cleavage of NPAc-groups was finally achieved under reductive
conditions with zinc and ammonium chloride21 supported by
ultrasonic irradiation, and thus under reaction conditions
compatible with ester functionalities and unsaturated carbon-
carbon bonds. As the NPAc-protected glycosides 7 and 8 were
obtained in a complex product mixture, purification of these
intermediates turned out to be very laborious. To avoid this time-
consuming step, we developed a ‘one-pot’ procedure (only
including filtration and concentration of the crude glycosylation
reaction mixture) using cyclohexylmethanol and (+)-menthol as
acceptors, leading to the deprotected glucosides 9 and 10 in
overall yields of 40 and 45%, respectively (Scheme 2).
Conclusions
In summary, we were able to develop a new glycosyl donor
system that can be applied for the synthesis of glycosides of base-
labile acceptors that furthermore contain unsaturated carbon-
carbon bonds, and thus cannot be glycosylated using previously
described methods that make use of participating protecting
groups that are cleaved by hydrogenolysis. Reaction conditions
for the glycosylation step were optimized using model acceptors
(primary and secondary alcohols) and finally simplified to obtain a
‘one-pot’ procedure to avoid laborious purification of the protected
intermediates. Applying this optimized procedure, we could
facilitate the synthesis of T2-O-β,D-glucoside and achieved an
enhancement of the selectivity of the glycosylation reaction
towards the ß-isomer of the intermediate. Due to the ease and
low-cost preparation of the glucosyl donor using commercially
available reagents, we are convinced that this new donor system
represents a valuable tool for complex glycosylation reactions.
Experimental Section
All reactions were performed under an argon atmosphere. Anhydrous
solvents (dichloromethane, tetrahydrofuran, methanol and diethyl ether)
were dried using a PURESOLV facility of it-innovative technology.
Molecular sieves (3 Å) were activated under vacuum at 200 °C. Reaction
progress was monitored by LC-ESI-MS/MS performed on an HCT ion trap
mass spectrometer (Bruker, Germany) in full scan mode.
Chromatographic separation was done using a 1200 series HPLC system
(Agilent Technologies, Germany) and a Luna RP-C18 column (3.0 x 150
mm, 3 µm particle size, Phenomenex, Germany). Preparative column
chromatography was performed on silica gel 60 (Merck, 40-63 µm) using
a Büchi SepacoreTM Flash System. Preparative HPLC separation was
done on a Büchi Reveleris Prep system using a Luna Prep C18(2), 10 µm,
250x10 mm column (Phenomenex). NMR spectra were recorded on a
Bruker Avance IIIHD 600Mhz spectrometer equipped with a Prodigy BBO
cryo probe or on a Bruker Avance DRX-400 MHz spectrometer at 20°C.
Data were recorded and evaluated using TOPSPIN 3.5 (Bruker Biospin).
All chemical shifts are given in ppm relative to tetramethylsilane. The
calibration was done using residual solvent signals. T2-toxin was provided
by Romer Labs (Tulln) and all other chemicals were purchased from ABCR
(Germany) or Sigma-Aldrich (Austria/Germany). HRMS analysis was
carried out by analyzing acetonitrile solutions (concentration: 10 ppm) on
an Agilent 6230 AJS ESI–TOF mass spectrometer after chromatographic
separation on an Agilent 1100/1200 HPLC (Agilent Technologies,
Waldbronn, Germany).
Scheme 2. ‘One-pot’ procedure for glycosylation using the NPAc-protected
glucosyl trichloroacetimidate donor 6.
Applying this method, we were able to synthesize T2-O-β,D-
glucoside starting from T2-toxin. Following the optimized
Schmidt-glycosylation procedure the protected intermediate could
be obtained in a crude mixture of isomers in a β/α ratio of 8:1 (as
determined by HPLC). Subsequent deprotection (after filtration
and concentration of the crude reaction mixture) under reductive
conditions and purification by reversed-phase column
chromatography afforded T2-O-β,D-glucoside (2) in an overall
yield of 29%.
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1,2,3,4,6-Penta-O-(2-nitrophenyl)acetyl-D-glucopyranoside (3)
1C), 46.99 (d, 1C), 38.28 (t, 1C), 16.45 (t, 3C), 16.24 (t, 1C); ESI-MS calcd
for C38H32BrN4O17+ [M+H]+ 895.1, found 895.1.
To a solution of glucose (1.0 g, 5.6 mmol, 1 eq.) and 2-nitrophenylacetic
acid (6.1 g, 33.6 mmol, 6 eq.) in dry dichloromethane (50 mL) (4-
dimethylamino)pyridine (1.1 g, 5.6 mmol, 1 eq.) and EDC (6.4 g, 5.6 mmol,
6 eq.) were added. The reaction mixture was stirred at room temperature
for 16 hours, washed with 1N HCl (2x50 mL) and saturated NaHCO3-
solution (2x50 mL), dried over Na2SO4, filtered and concentrated. The
crude product was purified by flash chromatography (CH2Cl2/EtOAc,
gradient elution 100:1 to 20:1) to obtain the title compound as a white foam
(3.0 g, 53 %). According to NMR analysis, a 4:1 (α:β) mixture of anomers
was obtained; 1H NMR (400 MHz, CDCl3): α-(4): δ 8.20-8.11 (m, 4H), 8.09
(dd, J = 8.2, 1.2 Hz, 1H), 7.70-7.57 (m, 5H), 7.56-7.46 (m, 8H), 7.43 (td, J
= 7.8, 1.3, 1H), 7.34 (dd, J = 7.6, 1.3 Hz, 1H), 6.37 (d, J = 3.5 Hz, 1H), 5.59
(t, J = 9.9 Hz, 1H), 5.14 (t, J = 9.9 Hz, 1H), 5.08 (dd, J = 10.1, 3.9 Hz, 1H),
4.39 (dd, J = 12.3, 1.4 Hz, 1H), 4.32-4.09 (m, 9H), 4.08-3.93 (m, 3H); β-
(4): δ 8.20-8.11 (m, 4H), 8.09 (dd, J = 8.2, 1.2 Hz, 1H), 7.70-7.57 (m, 5H),
7.56-7.46 (m, 8H), 7.43 (td, J = 7.8, 1.3, 1H), 7.34 (dd, J = 7.6, 1.3 Hz, 1H),
5.79 (d, J = 8.2 Hz, 1H), 5.43 (t, J = 9.7 Hz, 1H), 5.22 (dd, J = 9.7, 8.2 Hz,
1H), 5.14 (t, J = 9.7 Hz, 1H), 4.36 (dd, J = 12.5, 4.6 Hz, 1H), 4.32-4.09 (m,
9H), 4.08-3.93 (m, 3H); 13C NMR (100 MHz, CDCl3): α-(4): δ 169.81 (s,
2C), 169.62 (s, 1C), 169.29 (s, 1C), 168.50 (s, 1C), 148.75 (s, 1C), 148.57
(s, 1C), 148.56 (s, 1C), 148.52 (s, 1C), 148.49 (s, 1C), 134.42 (d, 1C),
134.32 (d, 1C), 134.25 (d, 1C), 134.15 (d, 1C), 134.12 (d, 3C), 133.91 (d,
1C), 133.76 (d, 1C), 133.73 (d, 1C), 130.11 (s, 1C), 129.88 (s, 1C), 129.80
(s, 1C), 129.59 (s, 1C), 129.52 (s, 1C), 129.07 (d, 1C), 128.89 (d, 1C),
128.87 (d, 1C), 128.77 (d, 1C), 128.65 (d, 1C), 125.54 (d, 1C), 125.35 (d,
2C), 125.31 (d, 1C), 125.25 (d, 1C), 89.29 (d, 1C), 70.18 (d, 1C), 70.10 (d,
1C), 69.84 (d, 1C), 68.11 (d, 1C), 62.48 (t, 1C), 39.84 (t, 1C), 39.74 (t, 1C),
39.69 (t, 1C), 39.55 (t, 1C), 39.50 (t, 1C); β-(4): δ 169.69 (s, 1C), 169.66
(s, 1C), 169.24 (s, 1C), 169.18 (s, 1C), 168.86 (s, 1C), 148.56 (s, 1C),
148.52 (s, 1C), 148.49 (s, 1C), 148.46 (s, 1C), 148.42 (s, 1C), 134.56 (d,
1C), 134.45 (d, 1C), 134.25 (d, 1C), 134.15 (d, 1C), 134.12 (d, 3C), 133.82
(d, 1C), 133.76 (d, 1C), 133.73 (d, 1C), 130.06 (s, 1C), 129.88 (s, 1C),
129.83 (s, 1C), 129.55 (s, 1C), 129.46 (s, 1C), 129.00 (d, 1C), 128.89 (d,
1C), 128.87 (d, 1C), 128.80 (d, 1C), 128.61 (d, 1C), 125.42 (d, 1C), 125.35
(d, 2C), 125.31 (d, 1C), 125.25 (d, 1C), 91.97 (d, 1C), 72.86 (d, 1C), 72.37
(d, 1C), 70.51 (d, 1C), 68.32 (d, 1C), 62.15 (t, 1C), 39.62 (t, 1C), 39.55 (t,
1C), 33.91 (t, 1C), 25.67 (t, 1C), 24.99 (t, 1C); HRMS calcd for
C46H37N5NaO21+ [M+Na]+ 1018.1873, found 1018.1875.
2,3,4,6-Tetra-O-(2-nitrophenyl)acetyl-D-glucopyranose (5)
To a solution of compound 4 (1.45 g, 1.67 mmol, 1 eq.) in acetone (9 mL)
water (30 µl) and Ag2CO3 (0.52 g, 1.84 mmol, 1.1 eq.) were added. After
stirring at room temperature for 20 h in the dark, the reaction mixture was
filtered over celite and the filtrate was concentrated under reduced
pressure. The residue was dissolved in DCM and filtered over a short pad
of silica gel (elution with EtOAc/hexanes, 1:1) to obtain a 4:1 (α:β) mixture
1
of anomers of 5 (1.1 g, 79 %); H NMR (400 MHz, CDCl3): α-(6): δ 8.21-
8.08 (m, 4H), 7.68-7.54 (m, 5H), 7.53-7.41 (m, 6H), 7.36-7.30 (m, 1H), 5.65
(t, J = 9.9 Hz, 1H), 5.43 (d, J = 3.5 Hz, 1H), 5.03 (t, J = 9.8 Hz, 1H), 4.94
(dd, J = 10.1, 3.5 Hz, 1H), 4.35-4.26 (m, 2H), 4.25-4.18 (m, 2H), 4.18-4.11
(m, 3H), 4.10-4.00 (m, 3H), 3.95 (d, J = 17.6 Hz, 1H), 3.37 (bs, 1H); β-(6):
δ 8.21-8.08 (m, 4H), 7.68-7.54 (m, 5H), 7.53-7.41 (m, 6H), 7.36-7.30 (m,
1H), 5.39 (t, J = 9.9 Hz, 1H), 5.08 (t, J = 9.9 Hz, 1H), 4.97 (dd, J = 9.8, 8.2
Hz, 1H), 4.77 (d, J = 7.8 Hz, 1H), 4.35-4.26 (m, 2H), 4.25-4.18 (m, 2H),
4.18-4.11 (m, 3H), 4.10-4.00 (m, 3H), 3.95 (d, J = 17.6 Hz, 1H), 3.37 (bs,
1H); 13C NMR (100 MHz, CDCl3): α-(6): δ 169.88 (s, 1C), 169.67 (s, 1C),
169.57 (s, 1C), 169.43 (s, 1C), 148.52 (s, 4C), 134.37 (d, 1C), 134.18 (d,
1C), 134.10 (d, 4C), 133.95 (d, 1C), 133.78 (d, 1C), 130.23 (s, 1C), 129.98
(s, 2C), 129.67 (s, 1C), 128.89 (d, 1C), 128.86 (d, 1C), 128.75 (d, 2C),
125.46 (d, 1C), 125.44 (d, 1C), 125.35 (d, 1C), 125.28 (d, 1C), 90.14 (d,
1C), 71.78 (d, 1C), 70.07 (d, 1C), 69.05 (d, 1C), 67.24 (d, 1C), 62.91 (t,
1C), 39.95 (t, 1C), 39.82 (t, 2C), 39.77 (t, 1C); β-(6): 170.09 (s, 1C), 169.80
(s, 1C), 169.57 (s, 1C), 169.35 (s, 1C), 148.61 (s, 1C), 148.52 (s, 2C),
148.49 (s, 1C), 134.47 (d, 1C), 134.23 (d, 1C), 134.10 (d, 4C), 133.95 (d,
1C), 133.78 (d, 1C), 130.12 (s, 1C), 129.92 (s, 1C), 129.72 (s, 1C), 129.63
(s, 1C), 128.94 (d, 1C), 128.86 (d, 1C), 128.79 (d, 1C), 128.75 (d, 1C),
125.46 (d, 1C), 125.44 (d, 1C), 125.31 (d, 1C), 125.28 (d, 1C), 95.49 (d,
1C), 73.77 (d, 1C), 72.21 (d, 1C), 72.19 (d, 1C), 68.87 (d, 1C), 62.59 (t,
1C), 39.90 (t, 1C), 39.82 (t, 1C), 39.71 (t, 1C), 39.64 (t, 1C); HRMS calcd
for C38H32N4NaO18+ [M+Na]+ 855.1603, found 855.1604.
2,3,4,6-Tetra-O-(2-nitrophenyl)acetyl-α,D-glucopyranosyl
trichloroacetimidate (6)
To a solution of compound 5 (1.2 g, 1.4 mmol, 1 eq.) in dry CH2Cl2,
trichloroacetonitrile (43 µl, 4.3 mmol, 3 eq.) was slowly added at 0 °C,
followed by DBU (21 µl, 0.14 mmol, 0.1 eq.). The reaction mixture was
slowly warmed to room temperature and stirring was continued for 16 h.
The solution was concentrated under vacuum and the crude product was
purified by flash chromatography (EtOAc in hexanes, gradient elution) to
obtain the title compound as a lightly yellow foam (1.07 g, 76 %); 1H NMR
(600 MHz, CDCl3) δ 8.70 (s, 1H), 8.17 (dd, J = 8.3, 1.1 Hz, 1H), 8.15 (dd,
J = 8.0, 1.2 Hz, 1H), 8.12 (dd, J = 8.2, 1.2 Hz, 1H), 8.01 (dd, J = 8.2, 1.3
Hz, 1H), 7.69-7.56 (m, 4H), 7.54-7.41 (m, 7H), 7.31 (dd, J = 7.6, 1.2, 1H),
6.52 (d, J = 3.8 Hz, 1H), 5.71 (t, J = 9.8 Hz, 1H), 5.25 (t, J = 9.9 Hz, 1H),
5.22 (dd, J = 10.1, 3.7 Hz, 1H), 4.35 (dd, J = 12.6, 3.8 Hz, 1H), 4.31 (dd, J
= 12.6, 1.7 Hz, 1H), 4.24 (ddd; J = 10.5, 3.9, 2.1, 1H), 4.22 (d, J = 6.5 Hz,
1H), 4.20-4.14 (m, 3H), 4.09 (d, J = 16.9 Hz, 1H), 3.99 (d, J = 14.9 Hz, 1H),
3.96 (d, J = 14.1 Hz, 1H), 3.91 (d, J = 17.3 Hz, 1H); 13C NMR (150 MHz,
CDCl3) δ 169.76 (s, 1C), 169.69 (s, 1C), 169.50 (s, 1C), 168.24 (s, 1C),
160.61 (s, 1C), 148.76 (s, 1C), 148.56 (s, 1C), 148.48 (s, 1C), 148.44 (s,
1C), 143.43 (d, 1C), 134.21 (d, 2C), 134.10 (d, 1C), 134.08 (d, 1C), 133.69
(d, 2C), 133.65 (d, 1C), 130.14 (s, 1C), 129.64 (s, 1C), 129.57 (s, 1C),
129.47 (s, 1C), 128.97 (d, 1C), 128.90 (d, 1C), 128.83 (d, 1C), 128.66 (d,
1C), 125.44 (d, 1C), 125.35 (d, 1C), 125.31 (d, 2C), 92.96 (d, 1C), 90.80
(s, 1C), 70.33 (d, 1C), 70.27 (d, 1C), 69.93 (d, 1C), 67.80 (d, 1C), 62.10 (t,
1C), 39.76 (t, 1C), 39.69 (t, 1C), 39.52 (t, 1C), 39.49 (t, 1C); HRMS calcd
for C40H32Cl3N5NaO18+ [M+Na]+ 998.0700, found 998.0702.
1-Bromo-1-deoxy-2,3,4,6-tetra-O-(2-nitrophenyl)acetyl-α,D-
glucopyranose (4)
To
a solution of compound 3 (4.0 g, 4.02 mmol, 1 eq.) in dry
dichloromethane (3 mL) hydrogen bromide in acetic acid (30 % (wt), 5 mL)
was slowly added at 0 °C. The reaction was warmed to room temperature
and stirred for 4 h and then quenched by the addition of ice water (30 mL).
The mixture was diluted with CH2Cl2 and washed with saturated aqueous
NaHCO3 solution. The organic layer was dried over Na2SO4 and the
solvents were removed under reduced pressure to give the desired
product 4 as a yellow foam (2.9 g, 81%); 1H NMR (600 MHz, CDCl3) δ
8.19-8.14 (m, 3H), 8.09 (dd, J = 8.2, 1.2 Hz, 1H), 7.67-7.57 (m, 4H), 7.53-
7.47 (m, 5H), 7.46-7.42 (m, 2H), 7.31 (dd, J = 7.7, 0.9 Hz, 1H), 6.51 (d, J
= 4.1 Hz, 1H), 5.66 (t, J = 9.7 Hz, 1H), 5.21 (t, J = 9.8 Hz, 1H), 4.96 (dd, J
= 9.8, 3.9 Hz, 1H), 4.38 dd (J = 13.1, 4.2 Hz, 1H), 4.33-4.29 (m, 2H), 4.27
(d, J = 17.0 Hz, 1H), 4.22-4.14 (m, 3H), 4.08 (d, J = 17.0 Hz, 1H), 4.03 (d,
J = 17.0 Hz, 1H), 3.97 (d, J = 5.3 Hz, 1H), 3.95 (d, J = 5.6 Hz, 1H); 13C
NMR (150 MHz, CDCl3) δ 146.35 (s, 1C), 146.20 (s, 1C), 146.08 (s, 1C),
146.82 (s, 1C), 125.40 (s, 1C), 125.15 (s, 3C), 111.07 (d, 1C), 110.88 (d,
2C), 110.84 (d, 2C), 110.80 (d, 1C), 110.39 (d, 1C), 110.38 (d, 1C), 106.73
(s, 1C), 106.28 (s, 1C), 106.17 (s, 1C), 106.13 (s, 1C), 105.72 (d, 1C),
105.64 (d, 1C), 105.54 (d, 1C), 105.40 (d, 1C), 102.16 (d, 1C), 102.07 (d,
1C), 102.03 (d, 1C), 102.02 (d, 1C), 63.26 (d, 1C), 49.02 (d, 2C), 47.56 (d,
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10.1002/ejoc.201800260
European Journal of Organic Chemistry
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General Procedure A: Königs-Knorr Glycosylation
34.23 (t, 1C), 31.77 (d, 1C), 25.08 (d, 1C), 22.86 (t, 1C), 22.40 (q, 1C),
+
21.48 (q, 1C), 16.23 (q, 1C); HRMS calcd for C48H50N4NaO18 [M+Na]+
To a solution of alcohol (0.01 mmol, 1 eq.) and glucosyl donor 4 (80 mg,
0.013 mmol, 1.2 eq.) in dry CH2Cl2 or MeCN (1 mL) was added molecular
sieves (3Å, 0.1 g/ mL). After stirring at room temperature for 1 h, promotor
(0.017 mmol, 1.5 eq.) was added and the reaction mixture was stirred in
the dark for 24 h. A sample was taken and analyzed by HPLC. Standard
addition was used for quantification.
993.3012, found 993.3012.
General Procedure C: ‘One-pot’ Glycosylation/Deprotection
To a solution of alcohol (1 eq.) and glycosyl donor 6 (1.5 eq.) in dry CH2Cl2
(25 mL/mmol) was added molecular sieves (3 Å, 0.1 g/ mL), and the
reaction mixture was stirred at rt for 1 h. After cooling to 0 °C, TMSOTf
(0.15 eq.) was added and reaction mixture was stirred at 0 °C. After 2 h,
the reaction was quenched by the addition of Et3N (0.15 equiv), filtered
through Celite and concentrated. The crude product mixture was dissolved
in MeOH (17 mL/mmol), and zinc dust (20 equiv.) and ammonium chloride
(12 equ.) were added at rt. The reaction was treated with ultrasonic
irradiation for 2-4h at 25 °C, then filtered over celite and concentrated
under vacuum. Preparative HPLC (RP-C18, MeCN in H2O, gradient
elution) afforded the desired glycoside.
General Procedure B: Schmidt Glycosylation.
To a solution of alcohol (0.07 mmol, 1 eq.) and glucosyl donor 6 (80 mg,
0.08 mmol, 1.2 eq.) in dry CH2Cl2 (1 mL) molecular sieves (3Å, 0.1 g/mL)
was added, and the reaction mixture was stirred at rt for 1h. After cooling
the reaction mixture to 0 °C, TMSOTf (1.6 µl, 9 µmol, 0.15 eq.) was added.
The reaction mixture was stirred for 2 h, and then quenched by the addition
of Et3N (0.15 equiv). The reaction mixture was filtered through Celite and
concentrated. The crude product was purified by flash chromatography
(EtOAc in hexanes, gradient elution) to obtain the desired product.
Methylcyclohexyl-β,D-glucopyranoside (9)
1-Methylcyclohexyl-2,3,4,6-tetra-O-(2-nitrophenyl)acetyl-β,D-
glucopyranoside (7)
General procedure C; starting from cyclohexyl methanol (14.6 mg, 0.13
mmol) and glucosyl donor 6 (150 mg, 0.15 mmol) 9 was obtained as a
colorless solid (14 mg, 40%). According to NMR analysis, a 6:1 (β/α)
mixture of anomers was obtained; 1H NMR (400 MHz, CD3OD) δ 4.24 (d,
J = 7.4 Hz, 1H), 3.87 (dd, J = 12.2, 1.9 Hz, 1H), 3.73 (dd, J = 9.4, 6.6 Hz,
1H), 3.70-3.65 (m, 1H), 3.39-3.23 (m, 4H), 3.18 (dd, J = 8.8, 7.9 Hz, 1H),
1.91-1.78 (m, 2H), 1.77-1.58 (m, 4H), 1.38-1.15 (m, 3H), 1.07-0.90 (m,
2H); 13C NMR (100 MHz, CD3OD) δ 104.59 (d, 1C), 78.14 (d, 1C), 77.89
(d, 1C), 76.53 (t, 1C), 75.17 (d, 1C), 71.68 (d, 1C), 62.77 (t, 1C), 39.35 (d,
1C), 31.06 (t, 1C), 31.03 (t, 1C), 27.73 (t, 1C), 26.99 (t, 1C), 26.97 (t, 1C);
HRMS calcd for C14H25O8- [M+COOH]- 321.1555, found 321.1558.
General procedure A; starting from cyclohexyl methanol (12.3 mg,
0.11 mmol) and glucosyl donor 6 (127 mg, 0.13 mmol) 7 was obtained as
a white solid (32 mg, 49%); 1H NMR (400 MHz, CDCl3) δ 8.21-8.04 (m,
4H), 7.68-7.42 (m, 10H), 7.41-7.29 (m, 2H), 5.33 (t, J = 9.6 Hz, 1H), 5.07
(t, J = 9.8 Hz, 1H), 4.99 (dd, J = 10.0, 7.7 Hz, 1H), 4.46 (d, J = 8.2 Hz, 1H),
4.38 (dd, J = 12.3, 1.8 Hz, 1H), 4.33-4.16 (m, 3H), 4.14-4.08 (m, 2H), 4.07-
3.81 (m, 4H), 3.70 (ddd, J = 9.9, 5.5, 1.8 Hz, 1H), 3.65 (dd, J = 9.4, 5.8 Hz,
1H), 3.26 (dd, J = 9.6, 6.8 Hz, 1H), 1.80-1.60 (m, 4H), 1.31-1.15 (m, 4H),
1.00-0.78 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 169.81 (s, 1C), 169.73
(s, 1C), 169.34 (s, 1C), 168.77 (s, 1C), 148.84 (s, 1C), 148.79 (s, 1C),
148.65 (s, 1C), 148.52 (s, 1C), 134.49 (d, 1C), 134.21 (d, 1C), 134.12 (d,
1C), 133.99 (d, 1C), 133.85 (d, 1C), 133.80 (d, 1C), 133.71 (d, 1C), 133.68
(d, 1C), 130.16 (s, 1C), 129.82 (s, 1C), 129.71 (s, 1C), 129.65 (s, 1C),
128.85 (d, 1C), 128.80 (d, 1C), 128.75 (d, 1C), 128.64 (d, 1C), 125.41 (d,
1C), 125.31 (d, 2C), 125.26 (d, 1C), 101.05 (d, 1C), 75.76 (t, 1C), 72.66 (d,
1C), 72.13 (d, 1C), 72.00 (d, 1C), 68.95 (d, 1C), 62.88 (t, 1C), 39.76 (t, 2C),
39.62 (t, 2C), 37.86 (d, 1C), 29.88 (t, 1C), 29.70 (t, 1C), 26.69 (t, 1C), 25.96
(t, 1C), 25.91 (t, 1C); HRMS calcd for C45H44N4NaO18+ [M+Na]+ 951.2543,
found 951.2536.
(+)-Menthyl-β,D-glucopyranoside (10)
General procedure C; starting from (+)-menthol (10.7 mg, 0.07 mmol) and
glucosyl donor 6 (80 mg, 0.08 mmol) 10 was obtained as a white solid (10
mg, 45%). According to NMR analysis, a 8:1 (β/α) mixture of anomers was
obtained; 1H NMR (400 MHz, CD3OD) δ 4.32 (d, J = 7.8 Hz, 1H), 3.85 (dd,
J = 11.9, 2.2 Hz, 1H), 3.67 (dd, J = 11.7, 5.1 Hz, 1H), 3.43 (td, J = 10.7,
4.3 Hz, 1H), 3.39-3.32 (m, 1H), 3.30-3.21 (m, 2H), 3.16 (t, J = 8.2 Hz, 1H),
2.45 (m, J = 13.9, 6.9, 2.4 Hz, 1H), 2.33-2.22 (m, 1H), 1.73-1.60 (m, 2H),
1.48-1.32 (m, 1H), 1.31-1.22 (m, 1H), 1.09-0.93 (m, 2H), 0.91 (d, J = 6.0
Hz, 3H), 0.90 (d, J = 7.6 Hz, 3H), 0.88-0.83 (m, 1H), 0.80 (d, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CD3OD) δ 105.69 (d, 1C), 82.44 (d, 1C), 78.19
(d, 1C), 77.74 (d, 1C), 75.59 (d, 1C), 71.68 (d, 1C), 62.81 (t, 1C), 50.23 (d,
1C), 44.74 (t, 1C), 35.60 (t, 1C), 32.94 (d, 1C), 25.71 (d, 1C), 24.00 (t, 1C),
22.72 (q, 1C), 21.63 (q, 1C), 16.31 (q, 1C); HRMS calcd for C16H29O6+ [M-
H]- 317.1970, found 317.1971.
1-(+)-Menthyl-2,3,4,6-tetra-O-(2-nitrophenyl)acetyl-β,D-
glucopyranoside (8)
General procedure A; starting from (+)-menthol (10.7 mg, 0.06 mmol) and
glucosyl donor 6 (80 mg, 0.08 mmol) 8 was obtained as a slightly yellow
solid (18 mg, 31 %); 1H NMR (400 MHz, CDCl3) δ 8.18-8.05 (m, 4H), 7.65-
7.40 (m, 10H), 7.35 (dd, J = 7.8, 1.6 Hz, 1H), 7.32 (dd, J = 7.4, 1.2 Hz, 1H),
5.36 (t, J = 9.6 Hz, 1H), 5.07 (t, J = 9.7 Hz, 1H), 5.03 (dd, J = 9.8, 7.8 Hz,
1H), 4.61 (d, J = 8.2 Hz, 1H), 4.44 (dd, J = 12.1, 1.9 Hz, 1H), 4.27 (d, J =
17.6 Hz, 1H), 4.22-4.03 (m, 6H), 3.92 (d, J = 17.2 Hz, 1H), 3.76 (d, J =
17.6 Hz, 1H), 3.74 (ddd, J = 10.1, 5.9, 2.0 Hz, 1H), 3.42 (td, J = 10.7, 4.3
Hz, 1H), 2.25-2.07 (m, 2H), 1.73-1.50 (m, 3H), 1.41-1.23 (m, 3H), 1.12-
1.01 (m, 1H), 0.95 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H) 0.83 (d, J =
7.0 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) δ 169.89 (s, 1C), 169.73 (s, 1C),
169.42 (s, 1C), 168.74 (s, 1C), 148.87 (s, 1C), 148.83 (s, 1C), 148.68 (s,
1C), 148.57 (s, 1C), 134.49 (d, 1C), 134.22 (d, 1C), 134.05 (d, 1C), 133.92
(d, 1C), 133.86 (d, 1C), 133.68 (d, 1C), 133.67 (d, 1C), 133.61 (d, 1C),
130.15 (s, 1C), 129.80 (s, 1C), 129.70 (s, 1C), 129.59 (s, 1C), 128.94 (d,
1C), 128.74 (d, 1C), 128.69 (d, 1C), 128.66 (d, 1C), 125.51 (d, 1C), 125.31
(d, 1C), 125.26 (d, 1C), 125.19 (d, 1C), 101.82 (d, 1C), 82.31 (d, 1C), 72.88
(d, 1C), 72.50 (d, 1C), 71.82 (d, 1C), 69.13 (d, 1C), 63.13 (t, 1C), 48.27 (d,
1C), 43.07 (t, 1C), 39.66 (t, 1C), 39.65 (t, 1C), 39.56 (t, 1C), 39.47 (t, 1C),
T2-O-β,D-glucoside (2)
General procedure C; starting from T2-toxin (30 mg, 0.06 mmol) and
glucosyl donor 6 (94 mg, 0.096 mmol) T2-β,D-glucoside (2) was obtained
as a white solid (11 mg, 29%); 1H NMR (600 MHz, CD3OH) δ 5.98 (d, J =
3.2 Hz, 1H), 5.78 (dt, J = 6.0; 1.0 Hz, 1H), 5.33 (d, J = 5.6 Hz, 1H), 4.48
(dd, J = 5.0, 3.0 Hz, 1H), 4.45 (d, J = 7.9 Hz, 1H), 4.39 (d, J = 6.7 Hz, 1H),
4.38 (d, J = 12.9 Hz, 1H), 4.09 (d, J = 12.7, 1H), 3.84 (dd, J = 12.0, 2.0 Hz,
1H), 3.72 (d, J = 5.0 Hz, 1H), 3.65 (dd, J = 12.1, 5.7 Hz, 1H), 3.35 (t, J =
9.0 Hz, 1H), 3.29 (t, J = 8.8 Hz, 1H), 3.25 (dd, J = 8.9, 7.5 Hz, 1H), 3.21
(ddd, J = 9.5, 5.7, 2.5 Hz, 1H), 3.04 ( d, J = 3.8 Hz, 1H), 2.87 (d, J = 3.8
Hz, 1H), 2.38 (dd, J = 15.2, 5.9 Hz, 1H), 2.16 (dd, J = 7.0, 2.3 Hz, 2H),
2.09 (s, 3H), 2.07 (s, 3H), 2.06 - 2.03 (m, 1H), 1.94 (d, J = 15.3 Hz, 1H),
1.75 (s, 3H), 0.97 (d, J = 4.5 Hz, 3H), 0.96 (d, J = 4.4 Hz, 3H), 0.74 (s, 3H);
13C NMR (150 MHz, CD3OH) δ 173.97 (1C), 172.27 (1C), 172.19 (1C),
137.37 (1C), 125.07 (1C), 103.78 (1C), 83.84 (1C), 81.17 (1C), 80.48 (1C),
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European Journal of Organic Chemistry
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78.34 (1C), 78.06 (1C), 74.79 (1C), 71.43 (1C), 69.32 (1C), 68.49 (1C),
65.38 (1C), 65.26 (1C), 62.59 (1C), 50.07 (1C), 47.86 (1C), 44.50 (1C),
44.32 (1C), 28.76 (1C), 26.94 (1C), 22.77 (1C), 22.71 (1C), 21.21 (1C),
20.80 (1C), 20.44 (1C), 7.04 (1C); HRMS calcd for C31H45O16- [M+COOH]-
673.2713, found 673.2716.
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Entry for the Table of Contents
FULL PAPER
Glycosylation
Julia Weber, Markus Schwarz,
Andrea Schiefer, Christian Hametner,
Georg Häubl, Johannes Fröhlich, and
Hannes Mikula*
Page No. – Page No.
(2-Nitrophenyl)acetyl (NPAc)-protected glucosyl donors have been prepared and
investigated towards the chemical glucosylation of natural products. The reductive
conditions for deprotection of NPAc-groups are compatible with many functional
groups including ester functionalities and unsaturated carbon-carbon bonds. The
development of a convenient ‘one-pot’ procedure finally enabled the synthesis of a
glucosylated metabolite of T2-toxin.
Chemical Glucosylation of Labile
Natural Products using a
(2-Nitrophenyl)acetyl-Protected
Glucosyl Acetimidate Donor
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