Dissection of the effects that govern thioglucoside and thiomannoside reactivity

Article abstract of DOI:10.1039/c7ob02968c

Neighboring group effects were investigated in gluco- and manno-configured thioglycosides under NIS/TfOH activation. Donors possessing a 2-O-benzoyl group that are capable (1,2-trans) and incapable (1,2-cis) of exerting nucleophilic push were compared wit

Full text of DOI:10.1039/c7ob02968c

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Dissection of the Effects that Govern Thioglucoside and Thiomannoside
Reactivity
Mads Heuckendorff, Lulu Teressa Poulsen, Christinne Hedberg and Henrik H. Jensen*
Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark,
hhj@chem.au.dk
Abstract: Neighboring group effects were investigated in glucoꢀ and mannoꢀconfigured thioglycosides
under NIS/TfOH activation. Donors possessing a 2ꢀOꢀbenzoyl group that are capable (1,2ꢀtrans) and
incapable (1,2ꢀcis) of performing neighboring group participation were compared with donors
possessing a participatory neutral 2ꢀOꢀbenzyl group. By using competition experiments between sets of
glycosyl donors the direct effect of neighboring group participation and the electron withdrawing effect
of the 2ꢀOꢀbenzoyl group could be separated. The study brings insight into how the stereochemistry of
the 1 and 2 position and how the nature of the aglycon (Ph or Et) have a pronounced effect on glycosyl
donor reactivity.

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Introduction
Even with modern modelling techniques, the number of possible effects, being either
electronical or sterical, makes it difficult to predict the reactivity of a given reaction in
organic chemistry. One of these effects describe when a substituent stabilizes a transition
state or an intermediate by becoming temporary covalently attached to the reaction center.
This is known as neighboring group participation, which often implicates that the
stereochemical outcome of the reaction is affected by the substituent’s involvement.1 In
certain cases, a rate enhancement of the reaction can be observed due to neighboring group
participation, and the effect is then referred to as anchimeric assistance.2 Research into
neighboring group participation was pioneered by Winstein in the 1940s,3 whereas effects in
carbohydrate chemistry was later led by Lemieux.4 Aside from the earlier work on the
solvolysis of glycosyl halides, acetolysis of glycosyl esters and hydrolysis of glycosides,5
only little is known about the degree to which neighboring group participation influences the
rate of modern, synthetically relevant glycosylation reactions.
From our recent work on the soꢀcalled electronically superarmed glycosyl donors,6 having
the 2ꢀOꢀbenzoylꢀ3,4,6ꢀtriꢀOꢀbenzyl protecting group pattern,7 we became surprised that the
high reactivity reported for an SBox donor with DMTST activation was not general as
anticipated.
The effect by the 2ꢀOꢀbenzoyl group is deactivating (disarming)8 due to its electron
withdrawing properties and its closeness to the reaction center. However, it can also have an
accelerating effect due to anchimeric assistance. The balance between these two effects of
opposite direction apparently varies depending on reaction conditions.6
By using reactivity measurements in a competition setting between various glycosyl
donors, we here describe our attempts to dissect activating and deactivating effects caused by
changes in the 2ꢀOꢀprotecting group and the anomeric configuration to obtain further inꢀdepth
insight into the intricate nature of glycosylation chemistry.
Competition Experiments and Discussion
To separate the deactivating effect from the activating effect of the electron withdrawing 2ꢀ
Oꢀbenzoyl group, it was necessary to study both 1,2ꢀtrans and 1,2ꢀcis configured donors of
which the latter can only be expected to experience a deactivating effect, since anchimeric
assistance is not possible. Specifically, the reactivity was studied in a series of competition
experiments involving SPh and SEt functionalized glucoꢀ and mannoꢀpyranosyl donors with
2

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NIS/TfOH activation, given the fact that these constitute an oftenꢀused set of reaction
conditions and that the steric and electronic nature varies significantly between SPh and SEt.
All donors were synthesized by standard methods and prior to performing the competition
experiments, evaluated separately in reaction with Lꢀmenthol as acceptor to ensure that good
and reproducible yields could be obtained.9
The competition experiments were performed by having two donors (1 equiv. of each)
competing for the acceptor Lꢀmenthol (5 equiv.) in presence of triflic acid (TfOH, 10 mol%)
with a limiting amount of NIS (1 equiv.). Prior to each reaction, the ratio of mixed donors
was ensured to be 1.0:1.0 by recording a 13CꢀNMR spectrum with a high signalꢀtoꢀnoise ratio
and comparing the anomeric carbon intensities.10 After ended reaction with NIS/TfOH and
standard reaction workꢀup, another 13CꢀNMR spectrum was recorded of the crude reaction
mixture and the anomeric signals of the unreacted donors were again compared. The reported
data were found to be highly reproducible.
The consumption of each donor is an expression of its reactivity related to the competing
counterpart. The higher the proportion of unreacted donor, the less reactive it is. In the
following, we treat the obtained ratio as a ratio of rate constants, however, in reality this is
not entirely correct since there is a ‘catching up effect’ by the slower reacting donor due to
the consumption of the faster reacting species. This imperfection inherent to the experimental
protocol is also present in measurements conducted by Wong and coꢀworkers in their much
11
celebrated work with Sꢀtolyl functionalized donors.
Table 1. Competition experiments with SPh and SEt glucopyranosyl donors (conditions:
1 equiv. NIS, 0.1 equiv. TfOH and 5 equiv. Lꢀmenthol).
3

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Ratio of unreacted donors
R’=Ph (left), R’=Et (right)
Entry
1
Competition experiment
1 : 2
1 : 2
2
1 : 12
1 : 60
3
4
1 : 4
1 : 2
1 : 1.1
1 : 20
Competition experiments in the glucopyranosyl series were initially performed. As seen from
Table 1 (Entry 1) and as previously established,6 there is a twoꢀfold reactivity difference
between SPh donors 1 and 2, favoring the tetraꢀOꢀbenzylated donor 1, meaning that donor 2
is not superarmed let alone as reactive as 1. The same result was observed for the analogous
competition experiment between SEt functionalized donors 5 and 6. This lower reactivity of
2ꢀOꢀbenzoylated donors 2 and 6 suggests that the rate acceleration achieved by anchimeric
assistance is not large enough to override the deactivating effect originating from the electron
withdrawing effect of the 2ꢀOꢀbenzoyl group. A competition experiment between the
corresponding donors 3/4 and 7/8 in the αꢀseries (Entry 2), shows an even greater reactivity
difference (12ꢀfold for SPh donors and 60ꢀfold for SEt donors) in favor of the tetraꢀOꢀ
benzylated donors (3 and 7). This finding is in accordance with the fact that the 2ꢀOꢀbenzoyl
group of 4 and 8 is incapable of performing neighboring group participation12/nucleophilic
4

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push due to their 1,2ꢀcis relationship.13 The reason for the larger difference in reactivity
between the SEt functionalized donors is not clear.
Next, the reactivity difference between αꢀ and βꢀconfigured tetraꢀOꢀbenzylated donors 1/3
and 5/7 were evaluated under the same conditions (Entry 3). To our surprise, the phenyl αꢀ
thioglycoside 3 was established to be fourꢀfold more reactive its anomer (βꢀthioglycoside 1),
while the SEt anomers 5 and 7 were found to be almost equally reactive. We assumed that the
equatorially oriented βꢀconfigured donors (1 and 5) would be more reactive than their αꢀ
anomers based on the expectation of 3 and 7 would have a lower ground state energy, due to
stabilization by the endo anomeric effect,14 as opposed to 1 and 5. Bols and coꢀworkers have
earlier published an identical result for the SPh donors in a competition experiment without
commenting on the reactivity difference.15
For acid catalyzed hydrolysis of Oꢀmethyl glucopyranosides the βꢀanomer is approximately
2ꢀfold more reactive than its αꢀamomer16 and the anomeric effect is typically given as an
explanation of this fact.17 A similar explanation has been given as the cause of the observed
αꢀselectivity in the famous in situ anomerization procedure, where a βꢀhalide is speculated to
be the reactive intermediate.18
In contrast to Oꢀmethyl glucosides, however, the equatorial βꢀanomer of Oꢀphenyl
glucosides19 is known to hydrolyze at a slower rate than its αꢀanomer in accordance with the
order of reactivity measured for thioglucosides 1 and 3.
The difference in reactivity between α and β configured donors possessing a 2ꢀOꢀbenzoyl
group (2/4 and 6/8) is shown in Entry 4. In both cases the βꢀconfigured donors were the most
reactive in accordance with the possibility of anchimeric assistance. In case of the SEt set of
donors, however, the difference in reactivity was found to be far greater (1:20) than for the
analogous set of SPh donors (1:2).
We assume that there are three major features that govern the reactivity of the studied
donors: i) the anchimeric effect of a 1,2ꢀtrans oriented 2ꢀOꢀbenzoyl is activating, and ii) the
presence of a strongly electron withdrawing 2ꢀOꢀbenzoyl group is deactivating, and iii) the
effect of anomeric configuration. With the values reported in Table 1 in hand it ispossible to
obtain intimate knowledge in relation to the balance between i), ii) and iii) for thioglucosides
under NIS/TfOH activation.
First, for the tetraꢀOꢀbenzylated SPh donors 3 and 1 (Entry 3) there is a 4ꢀfold reactivity
difference caused by anomeric configuration in favor of the αꢀconfigured donor 3. By
5

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assuming that this difference also holds for comparing donors 2 and 4, which both have the
electron withdrawing 2ꢀOꢀbenzoyl group, the reactivity factor of 2 in favor of βꢀconfigured
donor 2 then must mean that the rate acceleration due to the anchimeric effect is
approximately 8ꢀfold (Scheme 1).
Scheme 1. Overview of approximate magnitude of effects that are decisive for the level of reactivity of
phenyl thioglucosides with NIS/TfOH activation.
A comparison of the reactivity differences between the two αꢀconfigured donors 3 and 4
(Entry 2), where no achimeric assistance is possible and the major variation can be assumed
to stem from the electron withdrawing power of the 2ꢀOꢀbenzoyl group, a factor of 12ꢀfold
was measured in favor of the tetraꢀOꢀbenzylated donor 3. The difference in reactivity
between 1 and 2 (Entry 1), measured to be 2ꢀfold, roughly agrees with an 8ꢀfold rate
enhancement due to achimeric assistance and a 12ꢀfold reactivity decrease caused by the
larger electron withdrawing power of a 2ꢀOꢀbenzoyl group (Scheme 1).
A similar analysis was performed for the SEt functionalized donors (5ꢀ8) with the results
listed in Table 1. The tetraꢀOꢀbenzyl donor 5 in competition with the 2ꢀOꢀbenzoyl counterpart
6 was found to be 2ꢀfold more reactive, which is the identical ratio obtained for the analogous
SPh functionalized donor pair 1 and 2 (Entry 1). Upon dissection of the cause of this
reactivity difference, the SEt donors (5 and 6) clearly behave markedly different fromthe
corresponding SPh donors (1 and 2).
For obtaining a value for the anchimeric effect for SEt donors, again the effect of anomeric
configuration (a factor of 1.1, Entry 3) was multiplied by the effect of having anchimeric
assistance, as opposed to not having this possibility (a factor of 20, Entry 4). Hereby, the
value arrives at a 22ꢀfold increase being much more pronounced than in the analogous SPh
functionalized donor system (Scheme 2).
6

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Scheme 2. Overview of approximate magnitude of effects that are decisive for the level of reactivity of
ethyl thioglucosides with NIS/TfOH activation.
The large activating anchimeric effect (22ꢀfold) is more than offset by an even larger
deactivating effect (60ꢀfold), caused by the presence of the electron withdrawing 2ꢀOꢀbenzoyl
group compared to the less electron withdrawing 2ꢀOꢀbenzyl group, which largely accounts
for an observed difference in reactivity of 2ꢀfold between 5 and 6.
Recently, Zhu and coꢀworkers published a letter entitled: “Investigation of αꢀThioglycoside
Donors: Reactivity Studies toward ConfigurationꢀControlled Orthogonal Activation in Oneꢀ
Pot Systems”20 studying glycosylation rates of SEt functionalized thioglucosides. The authors
used 2ꢀOꢀacetylated donor analogues of donor 6 and 8 and obtained a difference in reactivity
of 1:>19, which is in agreement with our result (cf. 1:20, Entry 4, Table 1). Given the great
reactivity difference between αꢀ and βꢀanomers in the SEt system, they were able to
chemoselectively couple the 2ꢀOꢀacetylated analogue of 6 to its anomer having a free 6ꢀOH.
Our results suggest that a similar coupling would have failed for SPh bearing glucosyl
donors.
Table 2. Competition experiments with SPh mannopyranosyl donors (conditions: 1
equiv. NIS, 0.1 equiv. TfOH and 5 equiv. Lꢀmenthol).
7

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Ratio of unreacted donors
Entry
1
Competetion Experiment
1 : 13
2
3
1 : 24
1 : 2.5
4
1 : 1.2
In the study by Zhu and coꢀworkers,20 the donor analogous to 6 is claimed to be
superarmed21 under activation by NIS/TMSOTf(cat). The authors, however, fail to
demonstrate this statement and our present results brings this into question.
Having established the effect of a 2ꢀOꢀbenzoyl and 2ꢀOꢀbenzyl group on glucosylation rates
a study of the behavior in the mannose system with its axial 2ꢀO substituent was undertaken.
We started out with comparing tetraꢀOꢀbenzylated donor 9 and its 2ꢀOꢀbenzoyl protected
analogue 10 both having a 1,2ꢀtrans relationship as in the study of thioglucosides. As in the
glucose case, the tetraꢀOꢀbenzylated donor (9) was found to be the most reactive, but this
time the difference between the pair of donors had increased to 13ꢀfold (cf. 2ꢀfold) (Table 2,
Entry 1). For the analogous βꢀcase (Entry 2), devoid of the possibility of neighboring group
participation from the 2ꢀOꢀbenzoyl functionality, the difference was even greater (24ꢀfold)
again in favor of the tetraꢀOꢀbenzyl protected donor.
Studying the role of anomeric configuration by a competition experiment between the βꢀ
and αꢀconfigured tetraꢀOꢀbenzylated donors (11 and 9, Entry 3) the equatorial thiomannoside
11 was established to be more reactive (by 2.5ꢀfold) in opposition to the case for
thioglucosides, where the axial thioglucoside was the most reactive. This reversed order of
reactivity could be caused by a greater stabilization of the axial anomer in the thiomannoside
ground state and possibly be a result of the ꢁ2ꢀeffect.22 Lastly, it was found that the
αꢀconfigured 2ꢀOꢀbenzoyl protected donor (10) was 1.2ꢀfold less reactive than its
corresponding βꢀanomer (12). (Entry 4).
8

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For the two cases, where two anomeric donors are compared (Entry 3 and 4), there could be
a dipole influence on the reactivity difference, which would be different compared to the
glucopyranosyl case where the 1 and 2 substituents are arranged in a gauche relationship as
opposed to being in an anti relationship for the αꢀanomeric mannopyranosyl cases. This
effect is included in the effect of anomeric configuration.
Analyzing the overall results as above makes it evident, that the glucosylꢀ and mannosyl
behavior is highly dissimilar (Scheme 3). From Entry 3, Table 2 the effect of anomeric
configuration is 2.5ꢀfold making the anchimeric effect only 2ꢀfold, which is a factor of 4 less
than for the phenyl thioglucosyl system. This means, that the electron withdrawing effect of
the 2ꢀOꢀbenzoyl compared to that of a 2ꢀOꢀbenzyl is 12ꢀfold, which is in good agreement
with the measured factor of 13ꢀfold (Entry 1).
Scheme 3. Overview of approximate magnitude of effects that are decisive for the level of reactivity of
thiomannosides with NIS/TfOH activation.
In the above, the level of anchimeric assistance/neighboring group participation has been
estimated using Entries 3 and 4 of Table 1 and Table 2. Alternatively, another number to
estimate this effect can be obtained from Entries 1 and 2 of the same tables, as the latter entry
is a measure of the electron withdrawing capacity of the 2ꢀOꢀbenzoyl substituent. The
anchimeric effects then amounts to 6, 30 and 1.8ꢀfold (cf. 8, 22 and 2.1ꢀfold) for the phenyl
glucopyranoside, ethyl glucopyranoside and phenyl mannopyranoside, respectively.
Disaccharide Synthesis
Given the significant reactivity difference between mannosyl donors 9 and 10 (a factor of 13)
it was decided to demonstrate that a reactivity controlled chemoselective activation could be
performed and attain a disaccharide in an acceptable yield. Removal of a benzyl ether is
expected only to have little influence on the reactivity of the glycosyl donor.11
9

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First, an analogue of the less reactive thiomannopyranoside 10 was prepared to act as an
23
acceptor in coupling with donor 9. Specifically, this was achieved by acetolysis of 10 to
obtain 13 in 60% yield, which was subsequently deacetylated under acidic conditions to
obtain the acceptor 14 still possessing a donor function (Scheme 4). Glycosylation of 14 with
the more reactive donor 9 indeed resulted in disaccharide 15 as a mixture of anomers (α/β
1:2) in 81% yield demonstrating how the determined reactivity values have synthetic utility.
We note that a similar coupling most likely fail in the glucose series as a consequence of the
much smaller reactivity difference in reactivity between 1/5 and a monoꢀdeprotected
derivative of 2/6, respectively.
Scheme 4. Synthesis of disaccharide by chemoselective activation of 9 over 14.
Conclusion
By the use of competition experiments we have investigated the degree to which anomeric
configuration, neighboring group participation/anchimeric assistance and electron
withdrawing effects influence glycosyl donor reactivity for ethylꢀ and phenyl thioglucosides
and phenyl thiomannosides with NIS/TfOH activation. Using rough estimations, it was
possible to arrive at meaningful numbers with respect to reactivity differences suggesting that
the above mentioned structural features are the main factors deciding thioglycoside reactivity
under NIS/TfOH activation.
Of the three sets of donors investigated, the axial anomer was most reactive for the phenyl
thioglucoside, while it was found to be the equatorial anomer for the phenyl thiomannoside.
For the ethyl thioglucosides an almost equal reactivity was found between the two anomers.
A significant reactivity difference of a factor of 13 was noted for a set of mannopyranosyl
donors that were not present in the analogous glucopyranosyl congeners. This insight was
10

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used to perform a mannosylation of a derivative of the less reactive donor possessing an
acceptor functionality.
The present study offers new detailed insight into the degree of glycosyl donors
armament/disarmament, which is crucial for being able to perform chemoselective
thioglycoside activation and thereby reactivity controlled oneꢀpot glycosylations.
General Methods
All reagents were used as purchased without further purification. High purity NIS was
bought from Chempur (004499, Nꢀiodosuccinimide/98%+). Dry solvents were taken from a
solvent purification system. Glassware used for waterꢀfree reactions were dried for 12 h at
120 °C before use. Columns were packed with silica gel 60 (230–400 mesh) as the stationary
phase. TLC plates were visualized by 10% H2SO4 in EtOH and heating until spots appeared.
1HꢀNMR and 13CꢀNMR spectra were recorded on a 400 MHz spectrometer. Chemical shifts
(δ) are reported in ppm relative to the residual solvent signal. Highꢀresolution mass spectral
(HRMS) data were obtained on an electrospray (ES) mass spectrometer analyzing timeꢀofꢀ
flight.
Experimental Section
General procedure for glycosylations
A mixture of glycosyl donor (0.10 mmol), glycosyl acceptor (0.15 mmol), and freshly
activated molecular sieves (3 Å, 100 mg) in CH2Cl2 (2 mL) was stirred under argon for 1 h.
The solution was cooled to –78 °C using a dry ice/acetone bath. NIS (0.11 mmol) and TfOH
(0.1 mL of a 0.1 M solution of TfOH in CH2Cl2) were added. Lumps of dry ice were removed
from the acetone bath and the reaction was slowly allowed to reach 0 °C (over approximately
3 hours). After having reached 0 °C, the solids were filtered off and the filtrate was washed
with aqueous 10% Na2S2O3 solution. The organic layer was separated, dried over MgSO4,
and concentrated in vacuo. The residue was purified by flash column chromatography on
silica gel to afford the corresponding glycoside. Anomeric ratios were measured by
1
comparison of integral intensities of the anomeric protons and anomeric carbons from Hꢀ
NMR and 13CꢀNMR spectra of crude reaction mixtures.
11

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Competition Experiments
The two glycosyl donors (0.10 mmol each) were dissolved in CDCl3 (1 mL) and the ratios of
1
donors were checked to be 1.0:1.0 by H NMR and 13C NMR. The solvent was evaporated
and dry CH2Cl2 (2 mL), Lꢀmenthol (0.5 mmol) and freshly activated molecular sieves (3 Å,
100 mg) were added. The mixture was stirred under argon for 1 h. The solution was cooled to
−78 °C and NIS (0.10 mmol) and TfOH (0.1 mL of a 0.1 M solution of TfOH in CH2Cl2)
were added. Lumps of dry ice were removed from the acetone bath and the reaction was
slowly allowed to reach 0 °C (over approximately 3 h). Upon completion, the solids were
filtered off and the filtrate was washed with aqueous 10% Na2S2O2 solution. The organic
layer was separated, dried over MgSO4, and concentrated in vacuo. The crude mixture was
dissolved in CDCl3 (1 mL) and 1H NMR and 13C NMR was measured. Anomeric ratios were
measured by comparison of integral intensities of the anomeric protons and anomeric carbons
from 1HꢀNMR and 13CꢀNMR spectra of crude reaction mixtures.
Phenyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (1)
Phenyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (21.8 g, 49.7 mmol, 1 equiv.) was
dissolved in MeOH and sodium methoxide solution (25 wt. % in MeOH) was added until a
pHꢀvalue of approximately 10 was reached. The reaction mixture was stirred for 30 h at rt,
then neutralized with DOWEX® Acidic Cation Exchanger Resin in MeOH. The resin was
filtered off by suction and the product mixture was concentrated in vacuo. The crude product
was dissolved in anhydrous DMF (60 mL) and cooled to 0 °C. NaH (60 % (w/w) dispersion
in mineral oil, 15.9 g, 397 mmol, 8 equiv.) was added and the mixture was stirred for 10 min
prior to dropwise addition of BnBr (35.5 mL, 298 mmol, 6 equiv.). The resulting mixture was
stirred for 18 h at rt then quenched by cautiously transferring the mixture into a large volume
of H2O at 0 °C. The aqueous phase was extracted with CH2Cl2 (three times) and the
combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography (pentane/EtOAc 4:1) to afford the product (19.9 g,
31.4 mmol, 63 %) as a white solid. Rf 0.66 (pentane/EtOAc 5:1). [α]D295K +3.2 (c 1.0, CHCl3).
lit. +3 (CHCl3).24 Mp (uncorr.) 91.5 – 92.5 °C. lit. 91 – 92 °C.1 1H NMR (400 MHz, CDCl3)
δH 7.57 – 7.52 (m, 2H, ArH), 7.37 – 7.14 (m, 23H, ArH), 4.86 (d, J 10.9 Hz, 1H, CHHPh),
4.85 (d, J 10.2 Hz, 1H, CHHPh), 4.81 (d, J 10.8 Hz, 1H, CHHPh), 4.79 (d, J 10.8 Hz, 1H,
CHHPh), 4.69 (d, J 10.3 Hz, 1H, CHHPh) 4.63 (d, J 9.8 Hz, 1H, H1), 4.57 (d, J 12.0 Hz, 1H,
CHHPh), 4.55 (d, J 10.8 Hz, 1H, CHHPh), 4.50 (d, J 12.0 Hz, 1H, CHHPh) 3.75 (dd, J 9.8
12

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Hz, 1H, H6a), 3.72 – 3.64 (m, 2H, H6b, H3/H4), 3.61 (t, J 9.2 Hz, 1H, H3/H4) 3.50 – 3.44
(m, 1H, H5), 3.47 (dd, J 9.5 Hz, 8.6 Hz, 1H, H2). 13C NMR (100 MHz, CDCl3) δC 138.4
(ArC), 138.3 (ArC), 138.0 (ArC), 133.8 (ArC), 132.0 – 127.5 (ArCH), 87.5 (C1), 86.8
(C3/C4), 80.6 (C2/C5), 79.1 (C2/C5), 77.8 (C3/C4), 75.9 (CH2Ph), 75.5 (CH2Ph), 75.1
(CH2Ph), 73.5 (CH2Ph), 69.0 (C6). HRMS (ES): calcd. for C40H40O5SNa+ 655.2494; found
655.2488. Spectral values were in accordance with previously reported data.25
Phenyl 2ꢀOꢀbenzoylꢀ3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀglucoyranoside (2)
Phenyl 3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀglucoyranoside (100 mg, 0.18 mmol, 1 equiv.) was
dissolved in anhydrous CH2Cl2 (3 mL) and DMAP (9 mg, 0.09 mmol, 0.5 equiv.), Et3N (0.13
mL, 0.92 mmol, 5 equiv.) and BzCl (0.08 mL, 0.74 mmol, 4 equiv.) were added. The mixture
was stirred at rt for 18 h. To quench excess BzCl the mixture was stirred with DMAPA26 (0.
09 mL, 0.74 mmol, 4 equiv.) for 10 min. The reaction mixture was washed with aq. 1M HCl
(x3), sat. aq. NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and
concentrated in vacuo. The resulting residue was purified by flash column chromatography
(pentane/EtOAc 10:1) yielding the product (86 mg, 0.14 mmol, 74 %) as a white solid. Rf
295K
0.35 (pentane/EtOAc 5:1). [α]D
+28.2 (c 1.0, CHCl3), lit. +21.7 (c 1.1, CHCl3).27
o
1
Mp (uncorr.) 128.4 – 129.1 C. H NMR (400 MHz, CDCl3) δH 8.09 – 8.03 (m, 2H, ArH),
7.63 – 7.09 (m, 23H, ArH), 5.30 (t, J 9.5 Hz, 1H, H2), 4.82 (dd, J 10.8 Hz, J 10.8 Hz, 2H,
CHHPh, CHHPh), 4.75 (d, J 11 Hz, 1H, H1), 4.67 – 4.56 (m, 4H, 2xCH2Ph), 3.86 (t, J 9.3
Hz, 1H, H3), 3.85 – 3.77 (m, 2H, H6a, H6b), 3.76 (t, J 8.8 Hz, 1H, H4), 3.67 – 3.60 (m, 1H,
H5). 13C NMR (101 MHz, CDCl3) δC 165.2 (C=O) 138.2 (ArC), 137.9 (ArC), 137.6 (ArC),
137.2 (ArC), 133.2 –127.6 (ArCH), 86.2 (C1), 84.3 (C3), 79.5 (C5), 77.8 (C4), 75.4 (CH2Ph),
75.1 (CH2Ph), 73.4 (CH2Ph), 72.4 (C2), 68.9 (C6). HRMS (ES): calcd. for C40H38O6S
[M+Na+] 669.2281; found 669.2288. Spectral values were in accordance with previously
reported data.27
Phenyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀ1ꢀthioꢀαꢀDꢀglucopyranoside (3)
1,2ꢀdiꢀOꢀAcetylꢀ3,4,6ꢀtriꢀOꢀbenzylꢀβꢀD
ꢀglucopyranose28 (3.5 g, 6.55mmol) was dissolved in
CH2Cl2 (20 mL). The solution was added PCl5 (1.5 g, 7.21 mmol) and finally a drop of
BF3·Et2O was added. After 5 minutes TLC analysis showed no more starting material and the
reaction mixture was transferred to a separatory funnel. The reaction mixture was washed
with ice water, cold saturated bicarbonate solution and finally with cold brine. The organic
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layer was dried over Na2SO4, filtered and evaporated to dryness. The crude compound was
dissolved in HMPA (5 mL) and added to a solution of thiophenol (1.34 mL, 0.013 mol) and
NaH (0.79 g, 0.02 mol) in HMPA (10 mL) at 0 °C. The reaction was stirred for 1 hour and
then quenched by addition of Ac2O. The reaction mixture was diluted with EtOAc and then
washed 5 times with water then brine followed by drying with MgSO4. The solution was
evaporated and the crude compound was subjected to column chromatography with pentane
as eluent with a gradient to EtOAc giving phenyl 2ꢀOꢀacetylꢀ3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀαꢀDꢀ
glucopyranoside as a waxy solid. (1 g, 26 %). Rf: 0.60 (pentane/EtOAc 5:1). [α]D295K +180 (c
1, CHCl3). 1H NMR (400 MHz, CDCl3): δH 7.39 – 7.05 (m, 20H, ArH), 5.80 (d, J 5.6 Hz, 1H,
H1), 5.00 (dd, J 10.1, 5.6 Hz, 1H, H2), 4.81 – 4.68 (m, 4H, CH2Ph), 4.52 (d, J 12.0 Hz, 1H,
CHHPh), 4.45 (d, J 10.8 Hz, 1H, CHHPh), 4.36 (d, J 12.0 Hz, 1H, CHHPh), 4.27 (dd, J 10.0,
2.0 Hz, 1H, H5), 3.86 (t, J 9.4 Hz, 1H, H3), 3.75 – 3.64 (m, 2H, H4, H6a), 3.56 (dd, J 10.8,
1.7 Hz, 1H, H6b), 1.96 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δC 170.2 (C=O), 138.5,
138.1, 138.0, 133.7, 131.9, 129.1, 128.6, 128.6, 128.5, 128.1, 128.0, 127.9, 127.9, 127.8,
127.7, 127.5, 85.7 (C1), 81.0 (C3), 77.8 (C4), 75.7 (CH2Ph), 75.3 (CH2Ph), 73.6 (C2), 73.5
+
(CH2Ph), 71.5 (C5), 68.5 (C6), 21.1 (CH3). HRMS (ES): calcd. for C35H36O6SNH4
602.2576; found 602.2575.
To a stirred solution of phenyl 2ꢀOꢀacetylꢀ3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀαꢀDꢀglucopyranoside (1
g, 1.71 mmol) in MeOH (10 mL) a catalytic amount of Na(s) was added until a pHꢀvalue of
10 was reached. The reaction mixture was stirred for 30 h at rt, then neutralized with
DOWEX® Acidic Cation Exchanger Resin in MeOH. The resin was filtered off by suction
and the product mixture was concentrated in vacuo, giving phenyl 3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀ
295K
αꢀDꢀglucopyranoside as a white solid. (0.93 g, 100%). Rf: 0.27 (pentane/EtOAc 5:1). [α]D
+217 (c 1, CHCl3). Mp. 126.5ꢀ127.5 °C lit. 123ꢀ125 °C.29 1H NMR (400 MHz, CDCl3): δH
7.61 – 7.18 (m, 20H, ArH), 5.67 (d, J 5.4 Hz, 1H, H1), 4.94 (d, J 11.2 Hz, 1H, CHHPh), 4.90
(d, J 11.2 Hz, 1H, CHHPh), 4.86 (d, J 10.8 Hz, 1H, CHHPh), 4.67 (d, J 12.0 Hz, 1H,
CHHPh), 4.57 (d, J 10.8 Hz, 1H, CHHPh), 4.51 (d, J 12.0 Hz, 1H, CHHPh), 4.37 (d, J 9.1
Hz, 1H, H5), 4.05 (dd, J 8.9, 5.4 Hz, 1H, H2), 3.86 (dd, J 10.8, 3.8 Hz, 1H, H6a), 3.79 – 3.67
(m, 3H, H3, H4, H6b). 13C NMR (100 MHz, CDCl3): δC 138.5, 138.1, 138.0, 134.2, 132.0,
129.2, 128.7, 128.6, 128.5, 128.1, 128.1, 128.0, 128.0, 127.9, 127.6 (Ar), 90.1 (C1), 83.6,
77.7, 75.6 (CH2Ph), 75.1 (CH2Ph), 73.6 (CH2Ph), 72.5 (C2), 72.1 (C5), 68.6 (C6). HRMS
+
(ES): calcd. for C32H34O5SNH4 560.2571; found 560.2469. Spectral values were in
accordance with those reported.29
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Phenyl 3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀαꢀDꢀglucopyranoside (400 mg, 0.74 mmol, 1 equiv.) was
dissolved in anhydrous DMF (15 mL) under N2 atmosphere and NaH (60% dispersion in
mineral oil, 59 mg, 1.11 mmol, 1.5 equiv.) was added at 0 °C. The mixture was stirred for 10
min prior to dropwise addition of BnBr (0.13 mL, 1.48 mmol, 2 equiv.). The reaction was
allowed to reach rt while stirring for 5 h. To quench the reaction sat. aq. NH4Cl was added
until gas development ceased. The reaction mixture was extracted with EtOAc (three times)
and the combined organic phases were washed with H2O (five times), dried over Na2SO4,
filtered and concentrated in vacuo. The resulting residue was purified by flash column
chromatography (pentane/EtOAc 10:1) yielding the product (420 mg, 0.66 mmol, 90%) as a
295K
white solid. Rf (EtOAc/pentane 4:1) 0.40, [α]D
+148 (c 1.0, CHCl3), lit. +142.7 (c 0.33,
o
CHCl3).30 Mp (uncorr.) 76.5 – 78.4 C, lit. 77 – 78 oC.6 1H NMR (400 MHz, CDCl3) δH 7.72
(dd, J 8.0, 1.4 Hz, 2H, ArH), 7.62 – 7.34 (m, 23H, ArH), 5.89 (d, J 4.5 Hz, 1H), 5.23 (d, J
10.8 Hz, 1H, CHHPh), 5.08 (d, J 10.8 Hz, 1H, CHHPh), 5.03 (d, J 10.8 Hz, 1H, CHHPh),
4.96 (d, J 11.8 Hz, 1H, CHHPh), 4.87 (d, J 11.8 Hz, 1H, CHHPh), 4.77 (d, J 12.0 Hz, 1H,
CHHPh), 4.72 (d, J 10.8 Hz, 1H, CHHPh), 4.63 – 4.56 (m, 1H, H5), 4.59 (d, J 12.0 Hz, 1H,
CHHPh), 4.18 – 4.10 (m, 2H, H2, H3), 3.98 (dd, J 10.7, 3.8 Hz, 1H, H6a), 3.96 – 3.88 (m,
1H, H4), 3.81 (dd, J 10.6, 1.6 Hz, 1H, H6b). 13C NMR (101 MHz, CDCl3) δC 138.9, 138.5,
138.1, 137.9, 134.8, 131.8, 129.2 ꢀ 127.3 (Ar), 87.2 (C1), 82.8 (C2/C3), 80.0 (C3/C2), 77.6
(C4), 76.0 (CH2Ph), 75.4 (CH2Ph), 73.6 (CH2Ph), 72.7 (CH2Ph), 71.4 (C5), 68.7 (C6).
+
HRMS (ES): calcd. for C40H40O5SNH4 650.2935; found 650.2942. Spectral values were in
accordance with those reported.30
Phenyl 2ꢀOꢀbenzoylꢀ3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀαꢀDꢀglucoyranoside (4)
Phenyl 3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀαꢀDꢀglucopyranoside (400 mg, 0.74 mmol, 1 equiv.) was
dissolved in anhydrous CH2Cl2 (10 mL) and DMAP (45 mg, 0.37 mmol, 0.5 equiv.), Et3N
(0.52 mL, 3.70 mmol, 5 equiv.) and BzCl (0.34 mL, 2.96 mmol, 4 equiv.) were added. The
mixture was stirred at rt for 5 h under N2 atmosphere. To quench excess BzCl the mixture
was stirred with DMAPA26 (0.37 mL, 2.96 mmol, 4 equiv.) for 10 min. The reaction mixture
was washed with aq. 1M HCl (three times), sat. aq. NaHCO3 and brine. The organic phase
was dried over MgSO4, filtered and concentrated in vacuo. And the resulting residue purified
by flash column chromatography (pentane/EtOAc 10:1) yielding the product (368 mg, 0.57
mmol, 77%) as a white solid. Rf (EtOAc/pentane 4:1) 0.39. [α]D295K +149 (c 1.0, CHCl3). Mp
1
(uncorr.) 56.6 – 58.2 °C. H NMR (400 MHz, CDCl3) δH 8.27 – 8.24 (m, 2H, ArH), 7.69 (t, J
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7.4 Hz, 1H, ArH), 7.62 – 7.54 (m, 4H, ArH), 7.51 –7.31 (m, 18H, ArH), 6.21 (d, J 5.6 Hz,
1H, H1), 5.63 (dd, J 10.0, 5.6 Hz, 1H, H2), 5.08 – 4.99 (m, 2H, CHHPh, CHHPh), 5.04 (d, J
10.7, 1H, CHHPh), 4.78 (d, J 12.0 Hz, 1H, CHHPh), 4.74 (d, J 10.8 Hz, 1H, CHHPh), 4.68 –
4.62 (m, 1H, H5), 4.61 (d, J 12.1 Hz, 1H, CHHPh), 4.33 (t, J 9.5 Hz, 1H, H3), 4.05 (t, J 9.5
Hz, 1H, H4), 4.01 (dd, J 10.8, 3.7 Hz, 1H, H6a), 3.85 (dd, J 10.7, 1.4 Hz, 1H, H6b). 13C
NMR (101 MHz, CDCl3) δC 165.7 (C=O), 138.2, 138.0, 133.6, 133.6, 132.1, 130.1 – 127.6
(Ar), 86.1 (C1), 80.9 (C3), 77.9 (C4), 75.78 (CH2Ph), 75.4 (CH2Ph), 73.8 (C2), 73.6
+
(CH2Ph), 71.6 (C5), 68.6 (C6). HRMS (ES): calcd. for C40H38O6SNH4 664.2727; found
664.2732.
Ethyl 2ꢀOꢀbenzoylꢀ3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀαꢀDꢀglucopyranoside (7)
A solution of ethyl 3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀαꢀDꢀglucopyranoside (0.738 g, 1.49 mmol) in
CH2Cl2 (5 mL) was added Et3N (1 mL, 7.45 mmol), DMAP (90 mg, 0.75 mmol) and benzoyl
chloride (0.7 mL, 6 mmol). The reaction mixture was stirred overnight and then quenched by
addition of DMAPA26 (0.75 mL, 6 mmol). The mixture was washed once with aq. 1M HCl
solution then brine. The organic phase was dried over MgSO4, filtered and evaporated to
dryness. The compound was further purified by column chromatography with pentane as
eluent with a gradient to EtOAc giving the product as a syrup. (788 mg, 82%). Rf: 0.63
(pentane/EtOAc 7:1). [α]DRT +150 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3): δH 8.08 – 8.02
(m, 2H, ArH), 7.59 (t, J 7.4 Hz, 1H ArH), 7.46 (t, J 7.7 Hz, 2H, ArH), 7.41 – 7.27 (m, 8H,
ArH), 7.23 – 7.15 (m, 7H, ArH), 5.78 (d, J 5.7 Hz, 1H, H1), 5.35 (dd, J 10.0, 5.7 Hz, 1H,
H5), 4.09 (t, J 10.0 Hz, 1H, H3), 3.88 – 3.80 (m, 2H, H4, H6a), 3.72 (dd, J 10.8, 1.9 Hz, 1H,
H6b), 2.56 (m, 2H, SCH2), 1.23 (t, J 7.4 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): δC
165.6 (C=O), 138.2, 138.2, 138.0, 133.4, 129.9, 129.8, 128.6, 128.5, 128.4, 128.0, 128.0,
127.9, 127.8, 127.8 (Ar), 82.3 (C1), 80.9 (C3), 77.9 (C4), 75.7 (CH2Ph), 75.2 (CH2Ph), 73.8
(C2), 73.6 (CH2Ph), 70.8 (C5), 68.5 (C6), 24.3 (SCH2), 14.9 (CH3). HRMS (ES): calcd. for
+
C36H38O6SNH4 616.2727; found 616.2737.
Phenyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀ1ꢀthioꢀαꢀDꢀmannopyranoside (9)
Phenyl 1ꢀthioꢀαꢀDꢀmannopyranoside (872 mg, 3.20 mmol, 1 equiv.) was dissolved in
anhydrous DMF (20 mL) under N2 atmosphere and NaH (60% dispersion in mineral oil, 1.02
o
g, 25.60 mmol, 8 equiv.) was added at 0 C. The mixture was stirred for 10 min prior to
dropwise addition of BnBr (2.29 mL, 19.2 mmol, 6 equiv.). The reaction mixture was
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allowed to reach rt while stirring for 18 h. To quench the reaction aq. sat. NH4Cl was added
until gas development ceased. The reaction mixture was then extracted with EtOAc (three
times) and the organic phase was washed with H2O (five times, dried over Na2SO4, filtered
and concentrated in vacuo. The residue was purified by flash column chromatography
(pentane/EtOAc 25:1) affording the product (1.83 g, 2.89 mmol, 91%) as a colorless syrup.
+86.8 (c 1.0, CHCl3), lit. +10 (c 1.1, CHCl3)31. H
295K
1
Rf (EtOAc/pentane 4:1) 0.63, [α]D
NMR (400 MHz, CDCl3) δH 7.69 – 7.64 (m, 2H, ArH), 7.58 – 7.37 (m, 23H, ArH), 5.85 (d, J
1.3 Hz, 1H, H1), 5.13 (d, J 10.8 Hz, 1H, CPHHPh), 4.91 (d, J 12.3 Hz, 1H, CHHPh), 4.84 (d,
J 12.1 Hz, 1H, CHHPh), 4.83 – 4.78 (m, 3H, CH2Ph), 4.75 (d, J 10.8 Hz, 1H, CHHPh), 4.67
(d, J 12.0 Hz, 1H, CHHPh), 4.53 (ddd, J 9.7, 4.9, 1.5 Hz, 1H, H5) 4.32 (t, J 9.5 Hz, 1H, H4),
4.22 (dd, J 2.8, 1.8 Hz, 1H, H2), 4.10 (dd, J 9.3, 3.0 Hz, 1H, H3), 4.06 (dd, J 11.0, 5.1 Hz,
1H, H6a), 3.95 (dd, J 10.8, 1.6 Hz, 1H, H6b). 13C NMR (101 MHz, CDCl3) δC 138.7, 138.6,
138.4, 138.2, 134.7, 131.9, 129.3, 128.7 ꢀ 127.6 (Ar), 86.0 (C1, JC1ꢀH1 166.2 Hz
(characteristic of the αꢀanomer)7), 80.4 (C3), 76.5 (C2), 75.4 (CH2Ph), 75.2 (C4), 73.5
(CH2Ph), 73.0 (C5), 72.3 (CH2Ph), 72.1 (CH2Ph), 69.4 (C6). HRMS (ES): calcd. for
C40H40O5SNa+ 655.2489; found 655.2494. Spectral values were in accordance with
previously reported data.32
Phenyl 2ꢀOꢀbenzoylꢀ3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀαꢀDꢀmannopyranoside (10)
1,2ꢀOꢀAcetylꢀ3,4,6ꢀtriꢀOꢀbenzylꢀDꢀmannopyranose (5.2 g, 9.74 mmol, 1 equiv.) was
dissolved in anhydrous CH2Cl2 (50 mL) under inert atmosphere and thiophenol (2.00 mL,
.
19.5 mmol, 2 equiv.) and BF3 OEt2 (3.61 mL, 29.2 mmol, 3 equiv.) were added at 0 °C. The
ice bath was removed and the yellow mixture was stirred for 2 h. The reaction was quenched
by addition of sat. aq. NaHCO3, diluted with CH2Cl2 and washed with H2O and brine. The
organic phase was dried over Na2SO4, filtered and concentrated in vacuo leaving the crude
thiomannoside as an α/βꢀmixture. The thiomannosides were then dissolved in MeOH and
sodium methoxide solution (25 wt. % in MeOH) was added until a pHꢀvalue of
approximately 10 was reached. The reaction mixture was stirred for 18 h under inert
atmosphere then neutralized with DOWEX® acidic ion exchanger. The solid was filtered off
and filtrate was concentrated in vacuo leaving the crude 2ꢀhydroxyl mannosides. The 2ꢀ
hydroxyl mannoside was dissolved in anhydrous CH2Cl2 (35 mL) together with DMAP (287
mg, 2.34 mmol, 0.5 equiv.), Et3N (3.26 mL, 23.4 mmol, 5 equiv.) and BzCl (2.18 mL, 18.7
mmol, 4 equiv.). The mixture was stirred for 18 h at rt under N2 atmosphere. To quench
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excess BzCl the mixture was stirred with DMAPA26 (2.36 mL, 18.7 mmol, 4 equiv.) for 10
min. The reaction mixture was washed with aq. 1M HCl (three times), sat. aq. NaHCO3 and
brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The
resulting residue was purified by flash column chromatography (pentane/EtOAc 10:1)
yielding the product (2.33 g, 1.51 mmol, 37% over 3 steps) as a colorless syrup. Rf
ꢀ18.8 (c 1.0, CHCl3), lit. +69 (c 1.1, CHCl3)33, H NMR
295K
1
(EtOAc/pentane 4:1) 0.67. [α]D
(400 MHz, CDCl3) δH 8.10 – 8.04 (m, 2H, ArH), 7.56 (t, J 7.4 Hz, 1H, ArH), 7.53 – 7.46 (m,
2H, ArH), 7.40 – 7.21 (m, 20H, ArH), 5.88 (dd, J 2.7, 1.9 Hz, 1H, H2), 5.66 (d, J 1.5 Hz, 1H,
H1), 4.92 (d, J 10.8 Hz, 1H, CHHPh), 4.83 (d, J 11.3 Hz, 1H, CHHPh), 4.72 (d, J 11.9 Hz,
1H, CHHPh), 4.62 (d, J 11.3 Hz, 1H, CHHPh), 4.58 (d, J 10.8 Hz, 1H, CHHPh), 4.51 (d, J
11.9 Hz, 1H, CHHPh), 4.40 (ddd, J 9.7, 3.5, 1.3, 1H, H5) 4.18 (t, J 9.5 Hz, 1H, H4), 4.07 (dd,
J 9.3, 3.0 Hz, 1H, H3), 3.96 (dd, J 10.9, 4.0 Hz, 1H, H6a), 3.80 (dd, J 10.8, 1.6 Hz, 1H, H6b).
13C NMR (101 MHz, CDCl3) δC 165.6 (C=O), 138.4, 138.3, 137.7, 133.7, 133.3, 131.9,
130.0, 129.8, 129.1, 128.5 ꢀ 127.5 (Ar), 86.4 (C1, JC1ꢀH1 167.2 Hz (characteristic of the αꢀ
anomer34)), 78.6 (C3), 75.4 (CH2Ph), 74.5 (C4), 73.4 (CH2Ph), 72.6 (C5), 71.7 (CH2Ph), 70.6
(C2), 69.0 (C6). HRMS (ES): calcd. for C40H38O6SNa+ 669.2281; found 669.2289.
Phenyl 2,3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀmannopyranoside (11)
A solution of phenyl 3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (2.68 g, 5 mmol) in
CH2Cl2 (20 mL) was cooled to 0 °C and DessꢀMartin periodinane was added (2.50 g, 6
mmol). The reaction mixture was stirred for 3 hours while allowed to warm to rt. The
reaction mixture was quenched by addition of saturated aq. NaHCO3 and 10% Na2S2O2
solution while stirring vigorously for 1 hour. The organic phase was separated and dried over
MgSO4 and evaporated to dryness. The crude compound was dissolved in a 1:1 mixture of
MeOH and CH2Cl2 (30 mL). The solution was cooled to 0 °C and added NaBH4 (2.5 g, 70
mmol). The reaction mixture was stirred for 2 hours while allowed to warm to rt. The mixture
was diluted with CH2Cl2 and washed once with water, twice with aq. 1% citric acid solution
and then brine. The solution was dried over MgSO4 and evaporated to dryness.
Crystallization from diisopropyl ether gave the Phenyl 3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀ
mannopyranoside at colorless needles. (1.054 g, 39%). Rf: 0.59 (pentane/EtOAc 3:1).
[α]D295K ꢀ44 (c 1, CHCl3). Lit. ꢀ52, (c 1.5, CHCl3)35. Mp. 113ꢀ114 °C lit. 109ꢀ110 °C.35 1
H
NMR (400 MHz, CDCl3): δH 7.72 – 7.20 (m, 20H, ArH), 4.95 (d, J 10.9 Hz, 1H, CHHPh),
4.87 (s, 1H, H1), 4.81 (d, J 11.6 Hz, 1H, CHHPh), 4.73 (d, J 11.6 Hz, 1H, CHHPh), 4.71 –
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4.58 (m, 3H, CHPh), 4.36 (s, 1H), 3.90 (t, J 9.8 Hz, 2H), 3.79 (dd, J 10.9, 6.0 Hz, 1H), 3.72 –
3.66 (m, 1H), 3.63 – 3.54 (m, 1H), 2.77 (s, 1H, OH). 13C NMR (100 MHz, CDCl3): δC 138.3,
138.1, 137.5, 135.1, 130.8, 129.0, 128.6, 128.4, 128.3, 128.1, 128.1, 128.0, 127.8, 127.8,
127.6, 127.2 (Ar), 86.7 (C1), 82.7, 79.6, 75.2, 74.2, 73.5, 71.9, 69.9, 69.5. HRMS (ES):
calcd. for C33H34O5SNa+ 565.2019; found 565.2028. Spectral values were in accordance with
those reported.35
A solution of phenyl 3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀmannopyranoside (0.40 g, 0.74 mmol) in
DMF was cooled to 0 °C and added NaH (60 % (w/w) dispersion in mineral oil (59 mg,
1.48mmol) and BnBr (0.18 mL, 1.48 mmol). The solution was stirred overnight and
quenched by addition of water. The solution was diluted with EtOAc and washed 5 times
with water, then brine. The organic phase was dried over MgSO4 and evaporated to dryness.
The crude compound was purified by column chromatography with pentane as eluent with a
gradient to EtOAc giving the product as a white solid. (0.424 g, 91%). Rf: 0.4
(pentane/EtOAc 9:1). [α]D295K ꢀ44 (c 1, CHCl3). Lit. ꢀ4.1 (c 1, CHCl3).36 Mp. 114ꢀ115 °C. 1H
NMR (400 MHz, CDCl3): δH 7.60 – 7.50 (m, 4H, ArH), 7.43 – 7.18 (m, 21H, ArH), 5.09 (d, J
11.5 Hz, 1H, CHHPh), 4.93 (d, J 10.8 Hz, 1H, CHHPh), 4.91 (d, J 11.5 Hz, 1H, CHHPh),
4.82 (s, 1H, H1), 4.78 (d, J 11.8 Hz, 1H, CHHPh), 4.73 (d, J 11.8 Hz, 1H, CHHPh), 4.64 (m,
2H, CH2Ph), 4.59 (d, J 11.7 Hz, 1H, CHHPh), 4.19 (d, J 2.5 Hz, 1H, H2), 3.98 (t, J 9.6 Hz,
1H, H4), 3.89 (dd, J 10.9, 1.7 Hz, 1H, H6a), 3.79 (dd, J 10.9, 6.6 Hz, 1H, H6b), 3.68 (dd, J
9.4, 2.9 Hz, 1H, H3), 3.61 – 3.55 (m, 1H, H5). 13C NMR (100 MHz, CDCl3): δC 138.6, 138.4,
138.3, 138.1, 135.8, 130.7, 129.0, 128.6, 128.5, 128.4, 128.4, 128.3, 128.2, 127.9, 127.9,
127.9, 127.7, 127.5, 127.1 (Ar), 87.7 (C1), 84.5 (C3), 80.2 (C5), 77.6 (C2), 75.3, 75.2, 75.0,
+
73.6, 72.7 (CH2Ph), 69.9 (C6). HRMS (ES): calcd. for C40H40O5SNH4 650.2935; found
650.2933. Spectral values were in accordance with those reported.36
Phenyl 2ꢀOꢀbenzoylꢀ3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀmannopyranoside (12)
A solution of phenyl 3,4,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀmannopyranoside (0.40 g, 0.74 mmol) in
CH2Cl2 (5 mL) was added Et3N (0.51 mL, 3.7 mmol), DMAP (45 mg, 0.37 mmol) and
benzoyl chloride (0.34 mL, 3 mmol). The reaction mixture was stirred overnight and then
quenched by addition of DMAPA26 (0.37 mL, 3 mmol). The mixture was washed once with
aq. 1 M HCl solution then brine. The organic phase was dried over MgSO4, filtered and
evaporated to dryness. The compound was further purified by column chromatography with
pentane as eluent with a gradient to EtOAc giving the product as a syrup. (415 mg, 87%). Rf:
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1
0.42 (pentane/EtOAc 8:1). [α]D295K ꢀ67 (c 1, CHCl3). H NMR (400 MHz, CDCl3): δH 8.19
(d, J 7.2 Hz, 2H, ArH), 7.70 – 7.19 (m, 23H, ArH), 6.07 (d, J 3.1 Hz, 1H, H2), 4.99 (s, 1H,
H1), 4.92 (d, J 10.8 Hz, 1H, CHHPh), 4.90 (d, J 10.1 Hz, 1H, CHHPh), 4.79 (d, J 11.9 Hz,
1H, CHHPh), 4.66 (d, J 11.9 Hz, 1H, CHHPh), 4.61 (d, J 10.8 Hz, 1H, CHHPh), 4.59 (d, J
11.2 Hz, 1H, CHHPh), 4.00 (t, J 9.3 Hz, 1H, H4), 3.92 (m, 2H, H6), 3.83 (dd, J 9.3, 3.3 Hz,
1H, H3), 3.67 (ddd, J 9.7, 4.2, 2.7 Hz, 1H, H5). 13C NMR (100 MHz, CDCl3): δC 165.8
(C=O), 138.5, 138.2, 137.5, 134.3, 133.2, 131.1, 130.2, 129.7, 129.0, 128.4, 128.4, 128.4,
128.4, 128.3, 128.0, 127.8, 127.8, 127.5, 127.5, 127.4 (Ar), 85.5 (C1), 81.5 (C3), 79.9 (C5),
75.3 (CH2Ph), 74.1 (C4), 73.5 (CH2Ph), 71.7 (CH2Ph), 70.7 (C2), 69.5 (C6). HRMS (ES):
+
calcd. for C40H38O6SNH4 664.2727; found 664.2722.
LꢀMenthyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀαꢀDꢀglucopyranoside
295K
Appearance: Colorless oil. Rf 0.38 (pentane/EtOAc, 5:1). [α]D
+31 (c 1.0, CHCl3), lit. +
31.3 (c 1.1, CHCl3).37 1H NMR (400 MHz, CDCl3) δH 7.37 ꢀ 7.23 (m, 18H, ArH), 7.15 ꢀ 7.11
(m, 2H, ArH), 5.02 (d, J 3.6 Hz, 1H, H1), 4.98 (d, J 10.9 Hz, 1H, CHHPh), 4.84 (d, J 10.7
Hz, 1H, CHHPh), 4.82 (d, J 10.9 Hz, 1H, CHHPh), 4.72 (d, J 11.8 Hz, 1H, CHHPh), 4.68 (d,
J 12.3 Hz, 1H, CHHPh), 4.64 (d, J 12.3 Hz, 1H, CHHPh), 4.47 (d, J 12.1 Hz, 1H, CHHPh),
4.45 (d, J 10.7 Hz, 1H, CHHPh), 4.02 (t, J 9.5 Hz, H3), 4.00 – 3.93 (m, 1H, H5), 3.75 (dd, J
10.5, 3.7 Hz, 1H, H6a), 3.64 (t, J 9.4 Hz, 1H, H4), 3.64 (dd, J 10.5, 1.6 Hz, 1H, H6b), 3.55
(dd, J 19.8, 3.6 Hz, 1H, H2), 3.35 (dt, J 10.6, 4.3 Hz, 1H, OCH), 2.42 (dsep, J 6.9, 1.9 Hz,
1H, CH(CH3)2), 2.16 – 2.08 (m, 1H), 1.65 ꢀ 1.57 (m, 2H), 1.40 – 1.25 (m, 2H), 1.08 – 0.75
(m, 3H), 0.86 (d, J 6.4 Hz, 3H, CH3), 0.83 (d, J 7.1 Hz, 3H, CH3), 0.71 (d, J 6.9 Hz, 3H,
CH3). 13C NMR (101 MHz, CDCl3) δC 138.9, 138.4, 138.3, 138.0, 128.5 ꢀ 127.5 (Ar), 98.6
(C1), 82.0 (C3), 81.0 (OCH), 80.5 (C2), 78.1 (C4), 75.5 (CH2Ph), 75.1 (CH2Ph), 73.5
(CH2Ph), 73.2 (CH2Ph), 70.3 (C5), 68.6 (C6), 48.8, 43.1 (CH2), 34.3 (CH2), 31.7, 24.6
(CH(CH3)2), 22.9 (CH2), 22.3 (CH3), 21.1 (CH3), 16.1 (CH3). HRMS (ES): Calcd. for
+
C44H54O6NH4 696.4259; found 696.4273. Spectral values were in accordance with
previously reported data.37
LꢀMenthyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀβꢀDꢀglucopyranoside
Appearance: White solid. Rf 0.47 (pentane/EtOAc, 5:1). [α]D295K ꢀ16 (c 1.0, CHCl3), lit. ꢀ17.2
(c 1.05, CHCl3).38 1H NMR (400 MHz, CDCl3) δH 7.57 – 7.53 (m, 1H, ArH), 7.43 – 7.23 (m,
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19H, ArH), 5.01 (d, J 10.6 Hz, 1H, CHHPh), 4.98 (d, J 10.8 Hz, 1H, CHHPh), 4.88 (d, J 10.8
Hz, 1H, CHHPh), 4.85 (d, J 11.0 Hz, 1H, CHHPh), 4.74 (d, J 10.9 Hz, 1H, CHHPh), 4.67 (d,
J 12.0 Hz, 1H, CHHPh), 4.64 (d, J 10.4 Hz, 1H, CHHPh), 4.60 (d, J 12.2 Hz, 1H, CHHPh),
4.53 (d, J 7.8 Hz, 1H, H1), 3.75 (d, J 3.2 Hz, 2H, H6a, H6b), 3.70 (t, J 8.5 Hz, H3/H4), 3.65
(t, J 9.0 Hz, H3/H4), 3.56 (td, J 10.7, 4.2 Hz, 1H, OCH), 3.50 – 3.44 (m, 1H, H5), 3.47 (t, J
8.2 Hz, 1H, H2), 2.46 – 2.35 (m, 1H, CH(CH3)2), 2.20 (d, J 12.1 Hz, 1H), 1.72 (m, 2H), 1.46
– 1.28 (m, 2H), 1.11 – 0.92 (m, 3H), 0.98 (d, J 7.1 Hz, 3H, CH3), 0.96 (d, J 6.6 Hz, 3H, CH3),
0.88 (d, J 6.9 Hz, 3H, CH3). 13C NMR (101 MHz, CDCl3) δC 138.9, 138.6, 138.4, 138.3,
129.1 – 127.2 (Ar), 100.8 (C1), 85.0 (C3/C4), 82.3 (C5/C2), 78.0 (C4/C3), 77.8 (OCH), 75.7
(CH2Ph), 75.1 (CH2Ph), 74.9 (CH2Ph), 74.9 (C2/C5), 73.7 (CH2Ph), 69.4 (C6), 48.2, 41.0
(CH2), 34.5 (CH2), 31.5, 25.3 (CH(CH3)2), 23.3 (CH2), 22.3 (CH3), 21.2 (CH3), 16.0 (CH3).
Spectral values were in accordance with previously reported data.38
LꢀMenthyl 3,4,6ꢀtriꢀOꢀbenzylꢀ2ꢀOꢀbenzoylꢀβꢀDꢀglucopyranoside
295K
Appearance: White solid. Rf 0.50 (pentane/EtOAc 4:1). [α]D
ꢀ17 (c 1.0, CHCl3). Mp
o
1
(uncorr.) 68.0 – 70.0 C. H NMR (400 MHz, CDCl3) δH 7.95 ꢀ7.92 (m, 2H, ArH), 7.51 –
7.39 (m, 1H, ArH), 7.34 (t, J 7.7 Hz, 2H, ArH), 7.28 – 7.13 (m, 10H, ArH), 7.09 – 7.01 (m,
5H, ArH), 5.14 (t, J 8.5 Hz, 1H, H2), 4.76 (d, J 10.6 Hz, 1H, CHHPh), 4.66 (d, J 11.0 Hz,
1H, CHHPh), 4.58 (d, J 10.6 Hz, 1H, CHHPh), 4.56 (d, J 12.1 Hz, 1H, CHHPh), 4.55 (d, J
10.8 Hz, 1H, CHHPh), 4.49 (d, J 12.5 Hz, 1H, CHHPh), 4.48 (d, J 8.3 Hz, 1H, H1), 3.72 (t, J
9.0 Hz, 1H, H3), 3.70 – 3.62 (m, 3H, H4, H6a, H6b), 3.47 – 3.40 (m, 1H, H5), 3.31 (td, J
10.8, 4.1 Hz, 1H, OCH), 2.23 (dsep, J 6.9, 2.5 Hz, 1H, CH(CH3)2), 1.82 – 1.75 (m, 1H), 1.52
– 1.41 (m, 2H), 1.24 – 1.11 (m, 2H), 1.10 ꢀ 1.00 (m, 1H), 0.89 ꢀ 0.78 (m, 1H), 0.77 (d, J 7.1
Hz, 3H, CH3), 0.69 (d, J 6.8 Hz, 3H, CH3), 0.64 (d, J 6.6 Hz, 3H, CH3), 0.60 ꢀ 0.47 (m, 1H).
13C NMR (101 MHz, CDCl3) δC 165.3 (C=O), 138.5, 138.2, 138.1, 133.0, 130.4, 129.9,
129.2, 128.6 ꢀ 127.3 (Ar), 99.3 (C1), 83.1 (C3), 78.8 (OCH), 78.3 (C4), 75.4 (C5), 75.2
(CH2Ph), 74.9 (CH2Ph), 74.2 (C2), 73.9 (CH2Ph), 69.3 (C6), 47.5, 41.1 (CH2), 34.3 (CH2),
31.4, 25.1, 23.1 (CH(CH3)2), 22.2 (CH3), 21.1 (CH3), 15.9 (CH3). HRMS (ES) Calcd. for Cꢀ
+
44H52O7NH4 710.4071 found; 710.4062.
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LꢀMenthyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀ2ꢀOꢀbenzoylꢀαꢀDꢀmannopyranoside
295K
1
Appearance: Colorless oil. Rf (pentane/EtOAc 6:1) 0.55. [α]D
ꢀ89.2 (c 1.0, CHCl3). H
NMR (400 MHz, CDCl3) δH 7.31 – 7.16 (m, 18H, ArH), 7.12 – 7.07 (m, 2H, ArH), 4.82 (d, J
10.7 Hz, 1H, CHHPh), 4.80 (d, J 1.4 Hz, 1H, H1), 4.66 (d, J 12.6 Hz, 1H, CHHPh), 4.61 (d, J
12.8 Hz, 1H, CHHPh), 4.59 (d, J 12.2 Hz, 1H, CHHPh) 4.58 (d, J 12.0 Hz, 1H, CHHPh),
4.53 (d, J 11.8 Hz, 1H, CHHPh), 4.45 (d, J 12.8 Hz, 1H, CHHPh), 4.42 (d, J 10.9 Hz, 1H,
CHHPh), 3.91 – 3.77 (m, 3H, H3, H4, H5), 3.72 (dd, J 10.6, 4.5 Hz, 1H, H6a), 3.65 (dd, J
10.8, 1.0 Hz, 1H, H6b), 3.62 – 3.58 (m, 1H, H2), 3.17 (td, J 10.6, 4.3 Hz, 1H, OCH), 2.07 (d,
J 12.0 Hz, 1H), 1.69 (dsep, J 7.0, 2.3 Hz, 1H, CH(CH3)2), 1.55 – 1.43 (m, 2H), 1.31 – 1.18
(m, 1H), 1.06 – 0.99 (m, 1H), 0.91 – 0.64 (m, 3H), 0.75 (d, J 7.0 Hz, 3H, CH3), 0.74 (d, J 6.5
Hz, 3H, CH3), 0.56 (d, J 6.9 Hz, 3H, CH3). 13C NMR (101 MHz, CDCl3) δC 138.6, 138.6,
138.5, 138.3, 128.4 – 127.4 (Ar), 99.9 (C1, JC1ꢀH1 166.6 Hz (characteristic of the αꢀproduct)7),
81.1 (OCH), 80.1 (C3), 75.3 (C4/C5), 75.2 (CH2Ph), 74.4 (C2), 73.3 (CH2Ph), 72.4 (CH2Ph),
72.3 (CH2Ph), 71.8 (C5/C4), 69.5 (C6), 48.7, 42.9 (CH2), 34.3 (CH2), 31.6, 25.7 (CH(CH3)2),
23.2, 22.2 (CH3), 21.1 (CH3), 16.3 (CH3). HRMS (ES): calcd. for C44H54O6Na+ 701.3813;
found 701.3832.
LꢀMenthyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀ2ꢀOꢀbenzoylꢀβꢀDꢀmannopyranoside
295K
1
Appearance: Colorless oil. Rf (pentane/EtOAc 6:1) 0.65. [α]D
ꢀ23.4 (c 1.0, CHCl3). H
NMR (400 MHz, CDCl3) δH 7.44 – 7.40 (m, 2H, ArH), 7.31 – 7.18 (m, 18H, ArH), 4.94 (d, J
12.4 Hz, 1H, CHHPh), 4.88 (d, J 10.8 Hz, 1H, CHHPh), 4.81 (d, J 12.4 Hz, 1H, CHHPh),
4.64 (d, J 11.9 Hz, 1H, CHHPh), 4.54 (d, J 11.0 Hz, 1H, CHHPh), 4.52 (d, J 11.9 Hz, 1H,
CHHPh), 4.48 (d, J 10.8 Hz, 1H, CHHPh), 4.47 (s, 1H, H1), 4.43 (d, J 11.5 Hz, 1H, CHHPh),
3.84 (t, J 9.6 Hz, 1H, H4), 3.80 – 3.70 (m, 3H, H2, H6a, H6b), 3.56 – 3.47 (m, 2H, OCH,
H3), 3.42 – 3.36 (m, 1H, H5), 2.38 (dsep, J 7.0, 2.3 Hz, 1H, CH(CH3)2), 1.95 (d, J 12.0 Hz,
1H), 1.67 – 1.57 (m, 2H), 1.38 – 1.27 (m, 1H), 1.26 – 1.17 (m, 1H), 1.03 – 0.81 (m, 2H), 0.87
(d, J 6.6 Hz, 3H, CH3), 0.86 (d, J 7.2 Hz, 3H, CH3), 0.79 (d, J 6.8 Hz, 3H, CH3). 13C NMR
(101 MHz, CDCl3) δC 139.1, 138.7, 138.5, 138.4, 128.4 – 127.3 (Ar), 98.0 (C1, JC1ꢀH1 154.1
Hz (characteristic of the βꢀproduct)7), 82.7 (C3), 76.3 (OCH), 76.1 (C5), 75.2 (C4), 75.1
(C2), 74.9 (CH2Ph), 73.9 (CH2Ph), 73.7 (CH2Ph), 71.3 (CH2Ph), 70.1 (C6), 48.3, 40.5 (CH2),
34.5 (CH2), 31.4, 25.3 (CH(CH3)2), 23.1 (CH2), 22.4 (CH3), 21.3 (CH3),16.0 (CH3). HRMS
(ES): calcd. for C44H54O6Na+ 701.3813; found 701.3842.
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DOI: 10.1039/C7OB02968C
LꢀMenthyl 3,4,6ꢀtriꢀOꢀbenzylꢀ2ꢀOꢀbenzoylꢀβꢀDꢀmannopyranoside
Colorless oil, 59 mg, 79%.
295K
1
Rf (pentane/EtOAc 5:1) 0.60. [α]D
ꢀ18.8 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) δH
8.12 – 8.07 (m, 2H, ArH), 7.59 – 7.53 (m, 1H, ArH), 7.43 – 7.20 (m, 17H, ArH), 5.53 (d, J
1.7 Hz, 1H, H2), 5.05 (d, J 1.4 Hz, 1H, H1), 4.91 (d, J 10.7 Hz, 1H, CHHPh), 4.81 (d, J 11.5
Hz, 1H, CHHPh), 4.76 (d, J 12.0 Hz, 1H, CHHPh), 4.62 (d, J 11.5 Hz, 1H, CHHPh), 4.55 (d,
J 11.6 Hz, 1H, CHHPh), 4.16 – 4.01 (m, 3H, H3, H4, H5), 3.92 (dd, J 10.6, 3.9 Hz, 1H, H6a),
3.79 (dd, J 10.6, 1.2 Hz, 1H, H6b), 3.43 – 3.34 (m, 1H, OCH), 2.21 (d, J 11.8 Hz, 1H), 2.14 –
2.02 (m, 1H), 1.68 – 1.58 (m, 2H), 1.44 – 1.30 (m, 1H), 1.30 – 0.80 (m, 3H), 0.94 (d, J 7.0
Hz, 3H, CH3), 0.87 (d, J 6.4 Hz, 3H, CH3), 0.80 (d, J 6.9 Hz, 3H, CH3). 13C NMR (101 MHz,
CDCl3) δC 165.9 (C=O), 138.5, 138.4, 138.1, 133.1, 130.1 – 127.5 (Ar), 99.4 (C1, JC1ꢀH1
164.8 Hz (characteristic of the αꢀproduct)7), 81.9 (OCH), 78.0 (C3/C4), 75.4 (CH2Ph), 74.6
(C3/C4), 73.4 (CH2Ph), 71.7 (C5), 71.5 (CH2Ph), 69.6 (C2), 69.2 (C6), 48.5, 42.7 (CH2), 34.3
(CH2), 31.6, 26.0, 23.4 (CH2), 22.3 (CH3), 21.0 (CH3), 16.4 (CH3). HRMS (ES): calcd. for
C44H52O7Na+ 715.3605; found 715.3617.
Phenyl 6ꢀOꢀacetylꢀ2ꢀOꢀbenzoylꢀ3,4ꢀdiꢀOꢀbenzylꢀ1ꢀthioꢀαꢀDꢀmannopyranoside (13)
Thioglycoside 10 (0.963 g, 1.49 mmol) was dissolved in Ac2O (8.5 mL). TsOH*H2O (0.370
g, 1.95 mmol, 1.3 equiv.) was added. The reaction mixture was stirred at 70 °C for 2.5 h
before it was poured into H2O. The mixture was extracted thrice with EtOAc and the
resulting organic phase was washed with sat. aq. NaHCO3 and brine, dried over MgSO4,
filtered and concentrated in vacuo. The crude residue was purified by flash column
chromatography (pentane/AcOEt 20:1ꢀ6:1) to give 13 (0.538 g, 0.90 mmol, 60%) as a
298K
1
colorless oil. Rf (pentane/AcOEt 8:1) 0.30. [α]D
+106.5 (c 2.0, CHCl3). H NMR (400
MHz, CDCl3) δH 8.14ꢀ8.10 (m, 2H, ArH), 7.62 (tt, Jortho 7.4 Hz, Jmeta 1.3 Hz, 1H, ArH), 7.55ꢀ
7.45 (m, 4H, ArH), 7.42ꢀ7.21 (m, 13H, ArH), 5.90 (dd, J2,3 2.9 Hz, J2,1 1.8 Hz, 1H, H2), 5.64
(d, 1H, H1), 4.96 (d, Jgem 10.9 Hz, 1H, CHHPh), 4.87(d, Jgem 11.2 Hz, 1H, CHHPh), 4.67 (d,
Jgem 10.9 Hz, 1H, CHHPh), 4.65 (d, Jgem 11.2 Hz, 1H, CHHPh), 4.49 (ddd, J5,4 9.6 Hz, J5,6a
4.6 Hz, J5,6b 2.4 Hz, 1H, H5), 4.44 (dd, J6a,6b 11.7 Hz, 1H, H6a), 4.39 (dd, 1H, H6b), 4.13 (dd,
J
3,4 9.2 Hz, 1H, H3), 4.00 (t, 1H, H4), 2.06 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δC
170.7, 165.5 (C=O), 137.9, 137.5 (ArC), 133.4 (ArCH), 133.3 (ArC), 132.3, 129.9 (ArCH),
129.8 (ArC), 129.2, 128.5ꢀ128.0 (ArCH), 86.3 (C1), 78.7 (C3), 75.3 (CH2Ph), 73.9 (C4), 71.7
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(CH2Ph), 70.8 (C5), 70.4 (C2), 63.4 (C6), 20.9 (CH3). HRMS (ES): calcd. for
+
C35H34O7SNH4 616.2363; found 616.2374.
Phenyl 2ꢀOꢀbenzoylꢀ3,4ꢀdiꢀOꢀbenzylꢀ1ꢀthioꢀαꢀDꢀmannopyranoside (14)
Acetate 13 (0.125 gm 0.21 mmol) was dissolved in dry CH2Cl2 (4 mL) and dry MeOH (4
mL). AcCl (0.2 mL, 2.8 mmol, 13 equiv.) was added. The reaction mixture was stirred at 6 h
at rt before removal of volatiles under reduced pressure. The crude residue was purified by
flash column chromatography (pentane/AcOEt 5:1ꢀ3:1) to give 14 (0.105 g, 0.19 mmol,
298K
90%) as a colorless oil. Rf (pentane/AcOEt 3:1) 0.47. [α]D
+87.8 (c 1.0, CHCl3), lit. +82
(c 1.72, CHCl3).1 1H NMR (400 MHz, CDCl3) δH 8.12ꢀ8.07 (m, 2H, ArH), 7.61 (tt, Jortho 7.5
Hz, Jmeta 1.2 Hz, 1H, ArH), 7.54ꢀ7.44 (m, 4H, ArH), 7.42ꢀ7.23 (m, 13H, ArH), 5.88 (t, J2,1/3
1.5 Hz, 1H, H2), 5.63 (d, 1H, H1), 4.98 (d, Jgem 10.9 Hz, 1H, CHHPh), 4.84 (d, Jgem 11.4 Hz,
1H, CHHPh), 4.72 (d, Jgem 10.9 Hz, 1H, CHHPh), 4.65 (d, Jgem 11.4 Hz, 1H, CHHPh), 4.30ꢀ
4.25 (m, 1H, H5), 4.13ꢀ4.06 (m, 2H, H3, H4), 3.93ꢀ3.85 (m, 2H, H6a, H6b), 1.88 (s, 1H,
OH). 13C NMR (101 MHz, CDCl3) δC 165.7 (C=O), 138.2, 137.7 (ArC), 133.5 (ArCH), 133.3
(ArC), 132.3, 130.0 (ArCH), 129.8 (ArC), 129.3 (ArCH), 128.6ꢀ127.9 (ArCH), 86.5 (C1),
78.5 (C3), 75.5 (CH2Ph), 74.1 (C5), 73.1 (C4), 71.8 (CH2Ph), 70.8 (C2), 62.0 (C6). Spectral
+
39
values were in accordance with earlier reported. HRMS (ES): calcd. for C33H32O6SNH4
574.2258; found 574.2267.
Phenyl
6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀα/βꢀDꢀmannopyranosyl)ꢀ2ꢀOꢀbenzoylꢀ3,4ꢀdiꢀOꢀ
benzylꢀ1ꢀthioꢀαꢀDꢀmannopyranoside (15)
Acceptor 14 (0.056 g, 0.10 mmol, 1 equiv.) and donor 9 (0.081 g, 0.13 mmol, 1.3 equiv.)
were dissolved in dry CH2Cl2 (2 mL). 3 Å molecular sieves (0.100 g) were added and the
reaction mixture was stirred 1 h at rt before it was cooled to ꢀ78 °C in an acetoneꢀdry ice
bath. NIS (0.030 g, 0.13 mmol, 1.3 equiv.) and TfOH (0.13 mL of a 0.1 M solution in
CH2Cl2, 0.013 mmol, 0.1 equiv.) were added. Lumps of dry ice were removed, and the
cooling bath was allowed to reach 0 °C over 3 h and 15 min. The reaction mixture was
filtered and 10% aq. Na2S2O3 was added. The mixture was extracted with CH2Cl2 (x3). The
resulting organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude
residue was purified by flash column chromatography (CH2Cl2/Et2O 200:1ꢀ100:1) to give
15 (0.088 g, 0.082 mmol, 81%, α/β 1:2) as a colorless oil.
24

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DOI: 10.1039/C7OB02968C
1
Rf (Pentane/EtOAc 4:1) 0.61. H NMR (400 MHz, CDCl3) δH 8.06ꢀ8.00 (m, 4H, 2ArHꢀα,
2ArHꢀβ), 7.51ꢀ7.43 (m, 6H, 3ArHꢀα, 3ArHꢀβ), 7.40ꢀ7.10 (m, 70H, 35ArHꢀα, 35ArHꢀβ), 5.85
(dd, J2,3 3.1 Hz, J2,1 1.7 Hz, 1H, H2ꢀβ), 5.82 (dd, J2,3 3.0 Hz, J2,1 1.7 Hz, 1H, H2ꢀα), 5.64 (d,
1H, H1ꢀβ), 5.56 (d, 1H, H1ꢀα), 4.99 (d, J1’,2’ 1.5 Hz, 1H, H1’ꢀα), 4.96ꢀ4.84 (m, 5H,
2xCHHPhꢀα, 3xCHHPhꢀβ), 4.81 (d, Jgem 11.3 Hz, 1H, CHHPhꢀβ), 4.79 (d, Jgem 11.0 Hz, 1H,
CHHPhꢀα), 4.73 (d, Jgem 12.3 Hz, 1H, CHHPhꢀβ), 4.69ꢀ4.31 31 (m, 20H, 9xCHHPhꢀα,
7xCHHPhꢀβ, 2xHꢀα, 2xHꢀβ), 4.28 (s, 1H, H1’ꢀβ), 4.08 (dd, J3,4 9.2 Hz, J3,2 3.2 Hz, 1H, H3ꢀ
β), 4.05ꢀ3.66 (m, 13H, 6xHꢀβ, 8xHꢀα), 3.62 (dd, Jgem 10.7 Hz, J6b/b’,5/5’ 1.4 Hz, 1H, H6b/b’ꢀα),
3.44ꢀ3.38 (m, 1H, H5’ꢀβ), 3.38 (dd, J3’,4’ 9.4 Hz, J3’,2’ 3.3 Hz, 1H, H3’ꢀβ). 13C NMR (101
MHz, CDCl3) δC 165.8 (C=O, β), 165.7 (C=O, α), 102.3 (C1’ꢀβ), 98.3 (C1’ꢀα), 86.5 (C1ꢀβ),
86.4 (C1ꢀα), 82.3 (C3’ꢀβ), 80.1 (C3’ꢀα), 78.8 (C3ꢀα), 78.8 (C3ꢀβ), 76.1 (C5’ꢀβ), 75.3
(CH2Phꢀα), 75.2 (CH2Phꢀβ), 75.2 (CH2Phꢀβ), 75.2 T, 75.1 (CH2Phꢀα), 75.0 (Cꢀα), 75.0 (Cꢀβ),
74.9 (Cꢀβ), 74.6 (Cꢀα), 74.2 (CH2Phꢀβ), 74.1 (Cꢀβ), 73.6 (CH2Phꢀβ), 73.3 (CH2Phꢀα), 72.7
(Cꢀβ), 72.7 (CH2Phꢀα), 72.2 (Cꢀα), 72.1 (CH2Phꢀα), 72.1 (Cꢀα), 71.8 (CH2Phꢀβ), 71.8
(CH2Phꢀα), 71.4 (CH2Phꢀβ), 71.0 (C2ꢀβ), 70.9 (C2ꢀα), 69.9 (C6/C6’ꢀα), 69.2 (C6+C6’ꢀβ),
+
66.4 (C6/C6’ꢀα). HRMS (ES): calcd. for C67H66O11SNH4 1096.4664; found 1096.4679.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the publications website:
Glycosylation results under a nonꢀcompetitive setting and 1H and 13C spectra of compounds.
Corresponding Author
*Email: hhj@chem.au.dk
ACKNOWLEDGMENT
We are grateful for financial support from The Villum Foundation (VKR023110)
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