Reversing Reactivity: Stereoselective Desulfurative 1,2- trans- O-Glycosylation of Anomeric Thiosugars with Carboxylic Acids under Copper or Cobalt Catalysis

Article abstract of DOI:10.1021/acs.joc.0c00766

We have discovered a new mode of reactivity of 1-thiosugars in the presence of Cu(II) or Co(II) for a stereoselective O-glycosylation reaction. The process involves the use of a catalytic amount of Cu(acac)2 or Co(acac)2 and Ag2CO3 as an oxidant in α,α,α-trifluorotoluene. Moreover, this protocol turned out to have a broad scope, allowing the preparation of a wide range of complex substituted O-glycoside esters in good to excellent yields with an exclusive 1,2-trans-selectivity. The late-stage modification of pharmaceuticals by this method was also demonstrated. To obtain a closer insight into the reaction mechanism, cyclic voltammetry was performed.

Full text of DOI:10.1021/acs.joc.0c00766

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Article
Reversing reactivity: stereoselective desulfurative 1,2-trans-O-glycosylation
of anomeric thiosugars with carboxylic acids under copper or cobalt catalysis
Nedjwa Bennai, Amelie Chabrier, Maha Fatthalla, Christine Tran, Expédite Yen-
Pon, Mohamed Belkadi, Mouad Alami, Laurence Grimaud, and Samir Messaoudi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00766 • Publication Date (Web): 11 Jun 2020
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The Journal of Organic Chemistry
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Reversing reactivity: stereoselective desulfurative 1,2-trans-
O-glycosylation of anomeric thiosugars with carboxylic acids
under copper or cobalt catalysis
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Nedjwa Bennai,[a][b]† Amélie Chabrier,[a]† Maha I. Fatthalla,[a][c] Christine Tran,[a] Expédite Yen-Pon,[a]
Mohamed Belkadi,[b] Mouâd Alami,[a] Laurence Grimaud[d] and Samir Messaoudi*[a]
[a] Université Paris-Saclay, CNRS, BioCIS, 92290, Châtenay-Malabry, France.
[b] Université des sciences et de la technologie d’Oran-Mohamed-Boudiaf, Algeria
[c] Department of Chemistry, Faculty of Science, Helwan University, 11795 Ain Helwan, Cairo, Egypt
[d] Laboratoire des biomolécules (LBM), Sorbonne Université – Ecole Normale Supérieure – CNRS, 24 rue Lhomond, 75005,
Paris, France.
† contributed equally.
KEYWORDS. thiosugars • β-O-glycosylation • β-O-glycosyl esters • copper • cobalt • carbohydrates
ABSTRACT: We have discovered a new mode of reactivity of 1-thiosugars in the presence of Cu(II) or Co(II) for a stereoselective
O-glycosylation reaction. The process involves the use of a catalytic amount of Cu(acac)2 or Co(acac)2 and Ag2CO3 as an oxidant in
α,α,α-trifluorotoluene (TFT). Moreover, this protocol turned out to have a broad scope, allowing to prepare a wide range of com-
plex substituted O-glycoside esters in good to excellent yields with an exclusive 1,2-trans-selectivity. The late-stage modification of
pharmaceuticals by this method was also demonstrated. To get a closer insight into the reaction mechanism, cyclic voltammetry
(CV) was performed.
Introduction
Sugars are a very important family of biomolecules that play a
pivotal role in living organisms. Their inherent structural
complexity enables them to interact with myriad of biological
receptors.1 To understand the role of saccharides in biological
systems, chemists need to prepare well-defined chemical gly-
cosides. β-Acyl O-glycosides (AGs) is one of the common
motif found in natural products or bioactive compounds such
as phyllanthoside,2 neurosporaxanthin,3 cephasinenoside,4
macrophylloside D5, celecoxib acyl-β-D-glucuronide metabo-
lite6 (Figure 1) and the immunoadjuvant QS-21A7. Numerous
members of the ellagitannin family also have
a 1-
acylglycoside unit, such as sanguiin H-4 and sanguiin H-5.8
The use of AGs as surfactants also appeared to be an interest-
ing strategy to increase the lignocellulosic biomass value.9
Recently mannosamine lipid esters (Ac4ManNAz lipid ester,
Figure 1) were used as chemical tools for metabolic cell label-
ing strategy.10 Moreover, β-1-acyl glucuronides are the major
metabolites of most carboxylic acid containing drugs.11 Sever-
al β-1-acyl glucosides were also identified as metabolites of
bile acids and important bio-markers for patients with hepatic
diseases.12 More importantly, glycoacylation has been pointed
out as an attractive pathway to target cancer cells exploiting
the Warburg effect.13 This antitumor strategy that gained much
more attention in the last decades, is based on the use of sev-
eral glucose-based conjugates to more specifically deliver the
attached drug to cancer cells. There have been many examples
of glucose-conjugated drugs in preclinical or clinical evalua-
tion (paclitaxel,14 adriamycin,15 DNA alkylating agent
Figure 1. Examples of natural products and bioactive compounds
bearing a 1-acyl sugar moiety.
including chlorambucil,16 platinum17 and cyclophospha-
mide18).
Despite the high added-value of these substrates, a general
catalytic-stereoselective acylation method of sugars has not
been yet developed. Thus, it has become critical to stereose-
lectively prepare β-1-acyl glycosides. In vertebrates, acyl O-
glucuronide are synthesized by the conjugation of carboxylic
acids with uridine diphosphate glucuronic acid (UDPGA)
mediated by various glucuronosyl transferases (UDPGTs)
(Figure 2).19 From a synthetic point-of-view, usually, these
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furative 1,2-trans-glycosylation process to afford stereoselec-
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tively a variety of functionalized acyl- 1,2-trans-glycosides.
One of the advantages of this approach in addition to the broad
scope tolerance, is the availability of thiosugars: these sub-
strates are commercially available or may be synthesized
easily from the peracetylated precurssors in three-steps. 25
During the course of investigating the reactivity of various
thiosugars toward C–H activation processes26 we subjected
tetra-O-acetylated-1-thio-β-D-glucopyranose 1a and aliphatic
amide 4a to the Cu-catalyzed functionalization of unactivated
Csp3−H bonds under previously reported conditions.27 Rather
than obtaining the expected Csp3−S bond formation (com-
pound 6a), an O-glycosylation process was serendipitously
discovered leading to compound 7a in 10% yield as a pure β-
isomer (Scheme 1).
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Scheme 1: Unexpected O-glycosylation observed when using
β-thioglucose 1a with benzoic acid 5a.
We hypothesized that formation of 7a resulted from reaction
of sodium benzoate, which was used in a catalytic amount (20
mol %), with the β-thioglucose 1a. We therefore decided to
explore the viability of this unusual O-glycosylation of thio-
sugars. Herein, we report the optimization of this reaction
Figure 2. Strategies for O-glycosylation to access to acyl-O-
glycosides.
derivatives were prepared by treating benzoic acid derivatives
with sugar lactols through an SN2 Mitsunobu reaction20 (Fig-
ure 2, path A). However a mixture of anomers were obtained
in several cases. Some specific acyl glucuronides can be pre-
pared through β-acylation of allyl glucuronate with carboxylic
acids catalyzed by HATU21 and then mild deprotection after
treatment with Pd(PPh3)4 in the presence of morpholine. How-
ever, the use of glycosyl lactols in all these strategies remains
problematic because of the difficulty to prepare well-defined
α– or β–anomers. Another way to prepare acyl-O-glycosides
is the use of glycosyl donors such as glycocosyl halides, thio-
glycosides, glycosyl diethyl phosphates and glycosyl trichlo-
roacetimidates as partners in the glycosylation reaction with
carboxylic acids22 (Figure 2, path B). However, these methods
suffer from several drawbacks such as the limited scope to
non-functionalized substrates, the need for lengthy multisteps
preparation of the donor, and the low stereoselectivity of C1
conformation.
One different approach toward acyl-glycoside is the directed
dynamic kinetic stereoselective acylation of anomeric hydrox-
yl groups by using a chiral catalyst23 (Figure 2, path C). Re-
cently, Walczak group reported an elegant method to acylate
glycosyl stannane donors24 (Path D). This copper-mediated O-
glycosylation reaction involved the coupling of anomeric
stannane nucleophiles with carboxylic acids resulting in exclu-
sive anomeric selectivities. Although this method showed a
broad scope, it however requires a multi-steps procedures to
prepare the 1-stanylated sugar substrates. Moreover, the tox-
icity of the organic tin species remain always a major concern.
Because of all these drawbacks, developing complementary
alternatives are highly desirable for this seemingly simple
transformation. In this work we showed for the first time, that
thiosugars and acids can be joined together through a desul-
which appears as
a new method for the 1,2-trans-
stereoselective O-glycosylation of thiosugars.
Results and Discussion
When conducting the reaction of 1a with 1 equivalent of ben-
zoic acid 5a in the absence of the amide 4a, O-glycosylation
was still observed and the β-O-acyl glucoside 7a was isolated
in 29% yield (Table 1, entry 2). The exact structure of 7a,
including its 1,2-diaxial geometry, was determined by 1D and
2D NMR spectroscopy and unambiguously confirmed by
crystal structure analysis (Figure S10 in SI). Then, an optimi-
zation study was carried out using β-thioglucose 1a and ben-
zoic acid 5a as substrates (details can be found in Table S1 in
the Supporting Information). To understand the observed O-
glycosylation reaction and to verify that the outcome was
derived from a catalytic process, several control studies were
performed (Table 1). These studies led us to identify the best
reaction conditions as the use of 5 mol % Cu(acac)2 and 3
equivalents of Ag2CO3 in trifluorotoluene (TFT, 0.1 M) at 130
°C under microwave irradiation for 15 minutes. Under these
conditions, the desired phenyl acylglycoside 7a, was isolated
in 79% yield (Table 1, entry 1). Running the reaction in oil
bath at 130 °C for 1h instead of microwave irradiation led to
the desired product in only 45% yield (entry 3). Moreover,
performing the reaction in oil bath at 150°C for 1h furnished
7a in 74% yield (entry 4). Interestingly, we observed during
the optimization that the copper catalyst Cu(acac)2 can be
replaced by Co(acac)2 without affecting the yield (77% yield,
entry 8). We also confirmed that Ag2CO3 is required to ac-
complish O-glycosylation; without Ag2CO3 (entry 5,6) or
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Table 2. Scope of commercial carboxylic acids 5a-z in the O-
performing the reaction with other bases (K2CO3 or Cs2CO3)
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8
instead of silver carbonate, no reaction occurred (entries 6 and
11). Interestingly, control experiment showed also that this
reaction could be performed without catalyst, but 7a was iso-
lated in a lower yield (52%, entry 7). In addition, reaction with
Cu(I) was less efficient and gave product 7a in a yield similar
to the reaction without catalyst (46%, entry 9). We also
checked whether the copper salt could act as a Lewis acid by
performing the reaction in the presence of a catalytic amount
of the Lewis acid AlCl3 (5 mol%) instead of the copper cata-
lyst Cu(acac)2 (entry 10). However under these conditions,
only 59% yield of the desired product were obtained, suggest-
ing that this pathway plays only a minor role. Finally, when
the reaction was performed in the poorly absorbing toluene
solvant, compound 7a was obtained in a lower yield (67%
instead 79% with TFT, entry 12 vs entry 1). This difference
maybe is due to the particular properties of trifluorotoluene
(dielectric constants and dipole moments) which are more
adaptable to the microwave activation mode.
glycosylation of β-thioglucose 1a
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Table 1 Reaction conditions optimization for the O-glycosylation of
tetra-O-acetylated-1-thio-β-D-glucopyranose 1a with phenylbenzoïc
acid 5a.a
Yield
Entry
Deviation from the standard conditions
(%)b
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0
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none
12 h at 150 °C (oil bath)
1 h at 130 °C (oil bath)
1 h at 150 °C (oil bath)
without Cu-catalyst and Ag2CO3
without Ag2CO3
0
without Cu-catalyst
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77c
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Co(acac)2 instead of Cu(acac)2
CuI instead of Cu(acac)2
AlCl3 (5 mol%) Lewis acid instead
of Cu(acac)2
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K2CO3 or Cs2CO3 instead of Ag2CO3
0
67
Toluene instead of TFT
a
TFT = trifluorotoluene Conditions: 1a (1.5 equiv), 5a (1 equiv), metal
source (5 mol%), base (3 equiv), TFT [0.1 M] were heated in a sealed tube
b
under argon atmosphere. Yield of isolated 7a. c 1h reaction time under
thermal heating (at 150 °C).
Prompted by these exciting results, we subsequently investi-
gated the substrate scope for the catalytic O-glycosylation of
tetra-O-acetylated-1-thio-β-D-glucopyranose 1a with various
commercial carboxylic acids 5a-z, 5aa-ac using either
Cu(acac)2 or Co(acac)2. In most examples, yields arising from
Cu- and Co-catalysis are provided, otherwise, in other cases,
only one catalyst was used. Overall, the method works well
and tolerates a large variety of acid partners (Table 2), and
comparable yields were obtained with both copper and cobalt
catalysts (Table 2). Benzoïc acids having electron-donating
groups (5b-h) led to the formation of corresponding glycosyl
esters 7b-h in good yields, up to 85%. Delightfully, this proto-
col was efficient starting from benzoïc acids bearing free
hydroxyl and amino groups on the aromatic ring (compounds
[a] Reactions conditions: procedure (A) with Cu : carboxylic acids 5 (1
equiv), O-acetylated 1-thio-β-D-glucose 1a (1.5 equiv), Cu(acac)2 (5 mol
%), Ag2CO3 (3 equiv), TFT [0.1 M] in a sealed tube under argon at 130 °C
under microwave irradiation for 15 min. Procedure (B) with Co: carbox-
ylic acids 5 (1 equiv), O-acetylated 1-thio-β-D-glucose 1a (1.5 equiv),
Co(acac)2 (5 or 10 mol %), Ag2CO3 (3 equiv), TFT [0.1 M] in a sealed
tube under argon at 150 °C for 1 hour under thermal conditions. b yield for
the isolated product. c diastereomeric mixture 1:1 calculated by 1H NMR.
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7g, 7h, 7q and 7r). Likewise, 1-thio-β-D-glucose 1a was read- unprotected thiosugars are not tolerated under our reaction
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ily coupled with carboxylic acids derivatives bearing electron-
withdrawing group (e.g., –NO2, –F, –Cl, –Br, –I) to give the
O-glycosylated products 7i-r, which may be useful for further
regioselective cross-coupling reaction concerning the halogen-
ated substrates (Table 2). Vinyl carboxylic acids 5s,t are also
well tolerated in this coupling leading to the acrylic O-acyl
glycosides 7s,t in 78% yield. Importantly, heterocyclic acids
such as thiophene, quinoleine and benzofuran reacted well
with 1a, leading to products 7u-w in 83%, 50% and 60%
yields, respectively. Finally, the synthetic potential of this
protocol was well illustrated by its application on substrates
containing alkyl groups. Thus, the tridecanoic acid 5x, cyclo-
propyl carboxylic acid 5y as well as tetrahydronaphthalene-1-
carboxylic 5z were good partners leading to glycosyl esters
7x-z in good to excellent yields (55-79%). Interestingly, the
disaccharide ester 7aa was obtained through this approach in
60% yield when the sugar carboxylic acid 5aa was used.
After having demonstrated an excellent reactivity with simple
substrates, we then examined if the O-glycosylation reaction
could be extended to drug-like small molecules through a late
stage modification process. In this context, Bumetanide
(Bumex®), a marked-loop diuretic used to treat heart failure,
and probenecide (benemide®), an uricosuric agent that inhibits
the renal excretion, were successfully converted in one step
into the corresponding β-acylglucosyl analogues 7ab and 7ac
in synthetically useful yields (33 % and 56% yields, respec-
tively). These new acyl glycosides may be considered as use-
ful tool metabolites for studying their potential role in drug
toxicity. They can be also deacetylated by using literature
methods.28
conditions.
Table 3. Scope of 1 thio-β-glycosyls 1b-g a
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[a] Conditions: procedure (A) with Cu: carboxylic acids 5c or 5k (1
equiv), thiosugars 1b-g (1.5 equiv), Cu(acac)2 (5 mol %), Ag2CO3 (3
equiv), TFT [0.1 M] in a sealed tube under argon at 130 °C under
microwave irradiation for 15 min. Procedure (B) with Co: carboxylic
acids 5 (1 equiv), O-acetylated 1-thio-β-D-glucose 1a (1.5 equiv),
Co(acac)2 (10 mol %), Ag2CO3 (3 equiv), TFT [0.1 M] in a sealed
To further demonstrate the generality of this reaction, we
applied the optimized conditions to carboxylic acid, 5c and 5m
and structurally diverse mono-thiosugars 1b-g (Table 3). This
O-glycosylation appeared to be not limited to 1-thio-β-D-
glucose: thiosugars derived from β-D-galactopyranose (1b),
and β-D-fucose (1d) were also coupled with 5c or 5m to pro-
vide the corresponding β-O-glycosylated esters 8a,b, 8d in
good yields from either Cu- or Co-catalysts. Of note, the cou-
pling of β-D-mannopyranose (1c) led as expected, to the α-O-
glycosylated ester 3c in which we observed the inversion of
the anomeric configuration. In addition, this methodology
tolerates other protecting groups such OBz in the disarmed
donor (1e) and OMe ether (1f). Importantly, in the case of
thioGlc(OMe)4 (1f), a 1:1 mixture of both /β anomers was
obtained indicating that the anomeric stereochemistry is con-
trolled by the neighboring participant group at the C2 position.
Glycosyl donors protected with tert-butyldimethylsilyl (TBS)
group were well known to have superior reactivity and selec-
tivity than other sugar donors.29 This enhanced reactivi-
ty/selectivity was correlated to the stereoelectronic effects
associated with the conformation change induced by the silyl
groups. Inspired by this above literature, we were wondering
whether the selectivity in our glycosylation reaction will be
impacted by this conformation change. To this end, we pre-
pared the conformationally super armed OTBS-protected
thiosugar (1g) and we carried out the Cu-catalyzed glycosyla-
tion reaction in the presence of phenylbenzoic acid. Interest-
b
c
tube under argon at 150 °C for 1 hour. yields of isolated product.
diastereomeric mixture 1:1 calculated by 1H NMR.
Having demonstrated the efficacy of our method with various
thiosugars, we next turned our attention to the validation of the
method with respect to more complex and biologically rele-
vant saccharides (Scheme 2). We were pleased to find that di-
and trisaccharide derivatives cellobiose 1h and maltotriose 1i,
readily undergo O-glycosylation in this transformation. The
desired O-acyl glycosides 8h,i were isolated in 58% and 45%
yields, respectively. Moreover, the O-acyl trisaccharide 8j,k
which are commonly used in bacterial imaging30 were isolated
in synthetically useful yields.
To broaden the synthetic applications of this method, we car-
ried out studies on whether the iodinated substrate 7l could be
used as a suitable platform for introducing molecular diversity
via cross coupling reactions. Thus, the glycosyl ester 9a bear-
ing both C–O and C–S β-glycosidic bonds was easily prepared
through this O-glycosylation approach (Scheme 3A) followed
by the functionalization of the C–I bond by the coupling with
the thioGluNAc 1j under our previously reported Pd-catalyzed
methodology.31 We have also shown that this process was
effective replacing thiosugar by a commercial NHAc-Cys,
delivering the glycoamino acid 9b in 68% yield (Scheme 3B).
1
ingly, under our standard conditions the desired C4 glycoside
8g was obtained in good 70% yield and 2:1 β-anomeric selec-
tivity although no participating group was installed at C-2
position. This result evidenced the effect of conformation
change on the glycosylation selectivity. One can note that
With these encouraging results in hand, we next turned our
attention to examine the reactivity of other thiols such as al-
kylthiols instead of thiosugars. Pleasantly, reaction of the
commercially available N-acetylcysteamine with benzoic acid
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unambiguously that the ester-group comes from the acid func-
tion and not from a decarboxylative/carboxylation sequence
with CO2 arising from the thermal decomposition of silver
carbonate.32
Scheme 2. Scope of complex 1 thio-β-glycosyls 1h,ia
Scheme 4. Mechanistic investigations.
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[a] Conditions: procedure (A) with Cu: carboxylic acids 5c or 5m (1
equiv), thiosugars 1h,i (1.5 equiv), Cu(acac)2 (5 mol %), Ag2CO3 (3
equiv), TFT [0.1 M] in a sealed tube under argon at 130 °C under
microwave irradiation for 15 min. Procedure (B) with Co: carboxylic
acids 5 (1 equiv), O-acetylated 1-thio-β-D-glucose 1a (1.5 equiv),
Co(acac)2 (10 mol %), Ag2CO3 (3 equiv), TFT [0.1 M] in a sealed
tube under argon at 150 °C for 1 hour. b yields of isolated product.
5m provided the ester product 10a in a 68 % yield (Scheme
3C). The study of reactivity of a large variety of alkylthiols in
this reaction is currently under progress in our group.
Scheme 3. Application of the methodology to molecular di-
versity
[a] Conditions: path A: O-acetylated 1-thio-β-D-glucose 1a (1.5
equiv), iodophenylbenzoic acid 5l (1 equiv), Cu(acac)2 (10 mol %),
Ag2CO3 (3 equiv), TFT [0.1 M] in a sealed tube under argon at 150
°C for 15 min under MW irradiation. path B: 7j (1 equiv), 1j or
NHAcCys (1.2 equiv), PdG3 XantPhos (5 mol %), Et3N (3 equiv),
Dioxane [0.1 M] at rt for 20 min. path C: a commercially available N-
acetylcysteamine (1.5 equiv), benzoic acid 5m (1 equiv), Co(acac)2
(10 mol %), Ag2CO3 (3 equiv), TFT [0.1 M] in a sealed tube under
argon at 150 °C for 1 hour.
[a] Conditions: O-acetylated 1-thio-β-D-glucose 1a or its dimer 11a
or S-methylated 12a or 13a (1.5 equiv), benzoic acid 2a or sodium
benzoate (1 equiv), Cu(acac)2 (5 mol %) or Co(acac)2 (10 mol %),
Ag2CO3 (3 equiv), solvent [0.1 M] in a sealed tube under argon.
Because the formation of the disulfide 11a (Scheme 4, eq.2)
was observed during all the reactions (isolated and character-
ized), we were wondering if 11a must be regarded as a by-
product which may hamper the glycosylation process, or in
contrary may be involved in the reaction pathway. In this
context, we performed a series of control experiments with the
disulfide 11a (Scheme 4, eq.2). Thus, heating 11a with benzo-
To gain further insight into the origin of this unconventional
thiol- to-acid two nucleophiles coupling, we performed the
C(13) isotope incorporation experiment conditions by using a
13C labeled benzoic acid (99 atom % 13C) (Scheme 4, eq 1).
The incorporation of 13C in the phenylglycosyl ester 7a proves
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ic acid 2a at 150 °C for 1 h in the presence of silver carbonate result with glycosyl lactol 13a as a sugar donor (Scheme 4, eq.
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8
furnished the desired β-O-glycoside 7a in a 57 % yield when
the Co-catalyst was used, and 99 % yield with Cu(acac)2 as a
catalyst (Scheme 4, eq. 2). Interestingly, omitting to add the
catalyst led also to the same product 7a in 68 % yield. This
result clearly indicates that disulfide 11a may be involved in
the catalytic cycle. In addition, performing the reaction of 11a
with sodium benzoate in TFT at 150 °C did not furnish 7a and
only the starting material was recovered unchanged (Scheme
4, eq.3). This result indicates that a pathway including a sim-
ple nucleophilic substitution is discarded. In another way, the
glycosylation reaction was completely inhibited when the thiol
function of the sugar was protected (S-methyl glucose 12a)
(Scheme 4, eq. 4). It was also found that addition of the radical
inhibitor TEMPO, had no significant effect on the reaction,
suggesting that a radical species may not be involved in the
catalytic cycle (Scheme 4, eq. 5). Finally, the importance of
the sulfhydryl (−SH) group was further demonstrated by the
Figure 3. Cyclic voltammetry (CV) experiments
6). Under the standard conditions, no desired product was
observed by using 13a.
The lack of any precedent for oxidative addition of thiols to
Cu-catalyst makes a traditional oxidative addition-reductive
elimination pathway for this new reaction unlikely. To get a
closer insight into the reaction mechanism, cyclic voltammetry
(CV) was performed (see SI). Cu(OTf)2 was selected as Cu(II)
sources and as expected no characteristic oxidation peak could
be detected towards oxidation potentials as shown with the
dashed line CV (Figure 3). Just after addition of 2 equiv. of
thiosugar 1a, the zero current potential of the solution was
shifted by 180 mV towards negative potentials and an oxida-
tion peak at + 1V vs SCE clearly evidenced the formation of
Cu(I) as thiol is not electroactive in this range of potentials
(see SI, Figure S1). A similar behavior was observed starting
with Cu(acac)2 but the CV of the metal salt alone is less in-
formative (see SI, Figure S1). The formation of Cu(I) under
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0
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0
-20
-20
-0.4
0.0
0.4
0.8
1.2
-0.4
0.0
0.4
0.8
1.2
E (V) vs SCE
E (V) vs SCE
CV performed in MeNO2 towards oxidation potentials containing CV performed towards oxidation potentials of a 2 mM solution
n-Bu4NBF4 (0.1 M) at a steady GC electrode (d = 3 mm), at the of Cu(OTf)2 in MeNO2 containing n-Bu4NBF4 (0.1 M) at a
scan rate of 0.5 V.s-1, at 20 °C. Black dashed line: Cu(OTf)2 (2 steady GC electrode (d = 3 mm), at the scan rate of 0.5 V.s-1, at
mM), blue line Cu(OTf)2 (2 mM) with 2 equiv of thiol 1a, red 20 °C.
line: Cu(OTf)2 (2 mM) with 2 equiv. of thiol 1a and 1 equiv of
AgOAc.
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0
0
-20
-20
-0.4
0.0
0.4
0.8
1.2
E (V) vs SCE
-0.4
0.0
0.4
0.8
1.2
E (V) vs SCE
CV performed towards oxidation potentials of a 2 mM solution CV performed towards oxidation potentials of a 2 mM solution
of Cu(OTf)2 (2 mM) with 2 equiv of thiol in MeNO2 containing of Cu(OTf)2 (2 mM) with 2 equiv of thiol and 1 equiv of AgO-
n-Bu4NBF4 (0.1 M) at a steady GC electrode (d = 3 mm), at the Ac in MeNO2 containing n-Bu4NBF4 (0.1 M) at a steady GC
scan rate of 0.5 V.s-1, at 20 °C.
electrode (d = 3 mm), at the scan rate of 0.5 V.s-1, at 20 °C
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The Journal of Organic Chemistry
the reaction of 2a was performed with the disulfide 11a in the
these conditions is in agreement with previous reports in the
literature.33 After addition of 1 equiv of AgOAc, this oxidation
peak completely disappears and a black solid precipitated,
which was identified to be Ag2S.34 No further changes could
be detected in the presence of a larger excess of 1a and AgO-
Ac even in the presence of sodium benzoate (see SI, Figure
S2). One can be noted that the disulfide is not electroactive in
the range of potentials scanned for this study nor in the pres-
ence of a stoichiometric amount of Cu(II) (see SI, Figure S3).
Based on all these experiments, we propose the following
mechanistic path (Figure 4). The first step involves the oxida-
tion of thiosugar 1a by the Cu(II) catalyst to give the corre-
sponding disulfide 11a (Path.1) which has a great affinity for
silver. We propose that the strong complexation with silver in
complex (II) weakened the carbon–sulfur anomeric bond and
generated a good leaving group allowing the formation of the
acetoxonium ion. The latter is trapped by the carboxylate to
give the desired product 7. Along this process, we propose that
a second silver cation was involved to form the sulfonium (IV)
which can be reduced by Cu(I) to regenerate Cu(II) and one
thiol with formation of silver sulfide (Ag2S) which precipitat-
ed out from the solution (see supporting information). The
intermediate (IV) might regenerate 11a by reaction with thio-
sugar 1a without the need of Cu-catalyst. This step led also to
the formation of the silver sulfide (Ag2S).
Regarding the result obtained in the absence of the catalyst
(Table 1, entry 7), we proposed a concomitant pathway
(Path.2, Figure 3) mediated by Ag2CO3. The disulfide 11a
might be formed in the presence of silver carbonate as an
oxidant. Following a strong coordination of a second silver
cation (Ag+), the complex (II) led to the formation of an ace-
toxonium ion intermediate (if having a neighboring participat-
ing group at position 2). In the presence of carboxylate nucle-
ophiles, the 1,2-trans-glycoside ester (7) could be formed
producing the complex (III). This later evolves to (IV)
through a second coordination with silver ion, and finally
might react with 1a to regenerate the disulfide key intermedi-
ate 11a and the formation of the Ag2S. This hypothesis is in
agreement with the result highlighted in Scheme 4, Eq.3; when
presence of only Ag2CO3 (yield of 7a = 68%), thus suggesting
that this path may be involved in the mechanism. However,
when performed with a catalytic amount (10 mol%) of the
disulfide 11a and 1.5 equiv. of 1a in the presence of 2a and
Ag2CO3, without adding the Cu-catalyst (Scheme 4, eq. 7), the
reaction proceeded with only 53% yield of 7a (see supporting
information). The improvement observed in the presence of
copper salt led us to propose an alternative path for the evolu-
tion of IV. The latter can react with Cu(I) to release Ag2S
regenerating the Cu(II) catalyst.
In conclusion, we reported an unconventional thiol- to-acid
two nucleophiles coupling method for the diastereoselective
synthesis of 1,2-trans-O-glycosylated esters through a Cu(II)- or
Co(II)-catalyzed activation of glycosyl thiols. This approach
tolerates a wide range of functional groups, offers a unique
strategy to access 1,2-trans-O-glycosylated esters, and stream-
lines synthesis of pharmaceutically important compounds.
Furthermore, efforts to expand the scope of this transformation
are undergoing.
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EXPERIMENTAL SECTION
General Procedure
The coupling products were all identified by usual physical
1
1
methods, e.g., H NMR, 13C NMR, IR, MS. H and 13C NMR
spectra were measured in CDCl3, with a Bruker Avance-300.
1H chemical shifts are reported in ppm from an internal stand-
ard TMS or of residual chloroform (7.26 ppm). The following
abbreviations are used: m (multiplet), s (singlet), bs (broad
singlet), d (doublet), t (triplet), dd (doublet of doublet), td
(triplet of doublet), q (quadruplet), qui (quintuplet), sex (sex-
tuplet). 13C chemical shift are reported in ppm from central
peak of deuteriochloroform (77.14). IR spectra were measured
on a Bruker Vector 22 spectrophotometer and are reported in
wave numbers (cm-1). MS were recorded on a Micromass
spectrometer. Analytical TLC was performed on Merck pre-
coated silica gel 60F plates. Merck silica gel 60 (0.015–0.040
mm) was used for column chromatography. Melting points
were recorded on a Büchi B-450 apparatus (accuracy: up to
100 °C (±0.3 °C); up to 250 °C (±0.5 °C); up to 400 °C (±0.8
°C). High resolution mass spectra (HR-MS) were recorded on
a Bruker MicroTOF spectrometer, using ESI or APCI with
methanol as the carrier solvent. Biotage - microwave reaction
vial (2-5 mL, ref.351521) and (10-5 mL, ref.354833) for large
scale were used. Nominal and exact m/z values are reported in
Daltons. Unless otherwise noted, other materials are obtained
from commercial suppliers were used without further purifica-
tion. Solvents used were used as received without further
purification. Thiosugars were prepared following the literature
procedure.25, 31
Figure 4. Proposed mechanism
General Procedure (A) for Cu-Catalyzed glycosylation
with 1-thiosugars
A flame-dried microwave reaction vial (2-5 mL) was
charged with Cu(acac)2 (5 mol%), Ag2CO3 (0.53 mmol, 3.0
equiv.), commercial acid carboxylic (0.19 mmol, 1.0 equiv.)
and the thiosugar (0.29 mmol, 1.5 equiv.). Then, the reaction
mixture was flushed under Argon for 10 minutes. Tri-
fluorotoluene (2 mL) was added and the tube was sealed with
a Teflon screwcap, and the mixture was stirred at 130 °C
under microwave irradiation until completion. The resulting
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The Journal of Organic Chemistry
suspension was cooled to room temperature. The reaction
Page 8 of 20
1
2
3
4
5
6
7
8
mixture was then filtered through a small pad of Celite and
rinsed three times with DCM:MeOH 9:1 (3x10 mL). After
concentration under reduced pressure, the residue was purified
by silica gel column chromatography to afford the desired
product.
Compound 7b was prepared by using both general procedures
(A) (reaction time: 15 min), and (B) (reaction time: 1h), with
commercial 2-methoxybenzoic acid 5b (29.2 mg, 0.19 mmol,
1.0 equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.), which
afforded the product as a white solid (with Cu-catalyst 0.133
mmol, 70% yield, with Co-catalyst 0.0836 mmol, 44% yield)
after column chromatography EtOAc/Cyclohexane 3:7): TLC
Rf = 0.36 (EtOAc/Cyclohexane, 1:1, SiO2); mp: 91.9 – 93.0
1.2 General Procedure (B) for Co-Catalyzed glycosylation
with 1-thiosugars
19
A flame-dried sealed tube was charged with Co(acac)2 (10
mol%), Ag2CO3 (0.53 mmol, 3.0 equiv.), commercial acid
carboxylic (0.19 mmol, 1.0 equiv.) and the thiosugar (0.29
mmol, 1.5 equiv.).Then, the reaction mixture was flushed
under Argon for 10 minutes. Trifluorotoluene (2 mL) was
added and the tube was sealed with a Teflon screwcap, and the
mixture was stirred at 150 °C until completion. The resulting
suspension was cooled to room temperature. The reaction
mixture was then filtered through a small pad of Celite and
rinsed three times with EtOAc (3x10 mL). After concentration
under reduced pressure, the residue was purified by silica gel
column chromatography to afford the desired product.
°C ; [α]D = - 12.7 (c, 1.00 in CHCl3); IR (neat, cm-1) 2974,
1
9
2920, 1758, 1601, 1492, 1366, 1206, 1079, 1037; H NMR
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60
(300 MHz, CDCl3) δ (ppm) 7.86 (d, J = 8.2 Hz, 1H), 7.52 (t,
J = 7.9 Hz, 1H), 6.99 (t, J = 7.2 Hz, 2H), 5.95 (d, J = 8.0 Hz,
1H), 5.32 (dd, J = 5.4, 3.3 Hz, 2H), 5.23 – 5.14 (m, 1H), 4.31
(dd, J = 12.5, 4.4 Hz, 1H), 4.12 (dd, J = 12.5, 2.1 Hz, 1H),
3.95 – 3.91 (m, 1H), 3.90 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H),
2.03 (s, 3H), 2.00 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
(ppm) 170.8 (Cq), 170.3 (Cq), 169.6 (Cq), 169.5 (Cq), 163.5
(Cq), 160.4 (Cq), 135.1 (CH), 132.7 (CH), 120.4 (CH), 117.6
(Cq), 112.2 (CH), 92.0 (CH), 73.0 (CH), 72.9 (CH), 70.4 (CH),
68.1 (CH), 61.7 (CH2), 56.0 (CH3), 20.8 (CH3), 20.7 (3 x
CH3); HRMS (ESI) (M
C22H26O12Na 505.1322, found 505.1324.
+
Na)+ m/z calculated for
NMR Data for the glycosyl esters 7a-z, 7aa, 7ab, 7ac, 8af
β-D-Glucopyranose, 2,3,4,6-tetraacetate 1-benzoate [7a]
Compound 7a was prepared by using both general procedures
(A) (reaction time: 15 min), and (B) (reaction time: 1h), with
commercial benzoic acid 5a (23.4 mg, 0.19 mmol, 1.0 equiv.)
and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.), which afforded the
product as a white solid (with Cu-catalyst 0.15 mmol, 79%
yield, with Co-catalyst 0.142 mmol, 77% yield) after column
chromatography EtOAc/Cyclohexane 3:7);
β-D-Glucopyranose,
dimethoxybenzoate) [7c]
2,3,4,6-tetraacetate
1-(2,6-
Compound 7c was prepared by using both general procedures
(A) (reaction time: 15 min), and (B) (reaction time: 1h), with
commercial 2,6-dimethoxybenzoic acid 5c (35.0 mg, 0.19
mmol, 1.0 equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.),
which afforded the product as a white solid (with Cu-catalyst
0.185 mmol, 70% yield, with Co-catalyst 0.0855 mmol, 45%
yield) after column chromatography EtOAc/Cyclohexane 3:7):
TLC Rf = 0.32 (EtOAc/Cyclohexane, 1:1, SiO2); mp: 185.7 –
1 mmol scale protocol: A flame-dried microwave reaction
vial (10-20 mL) was charged with Cu(acac)2 (5 mol%),
Ag2CO3 (3 mmol, 3.0 equiv.), commercial acid carboxylic (1
mmol, 1.0 equiv.) and the thiosugar (1.5 mmol, 1.5
equiv.).Then, the reaction mixture was flushed under Argon
for 10 minutes. Trifluorotoluene (10 mL) was added and the
tube was sealed with a Teflon screwcap, and the mixture was
stirred at 130 °C under microwave irradiation until comple-
tion. The resulting suspension was cooled to room tempera-
ture. The reaction mixture was then filtered through a small
pad of Celite and rinsed three times with DCM:MeOH 9:1
(3x10 mL). After concentration under reduced pressure, the
residue was purified by silica gel column chromatography to
afford the desired product 7a in 75% yield. TLC Rf = 0.54
(EtOAc/Cyclohexane, 1:1, SiO2); mp: 132.3 – 134.3 °C ;
[α]D19 = - 16.2 (c, 1.00 in CHCl3); IR (neat, cm-1) 2964, 2905,
20
187.2 °C ; [α]D = - 4.7 (c, 1.00 in CHCl3); IR (neat, cm-1)
2954, 2841, 1759, 1597, 1477, 1366, 1258, 1235, 1133, 1024;
1H NMR (300 MHz, CDCl3) δ (ppm) 7.30 (d, J = 8.4 Hz,
1H), 6.54 (s, 1H), 6.52 (s, 1H), 6.07 (d, J = 8.2 Hz, 1H), 5.34 –
5.25 (m, 1H), 5.23 – 5.13 (m, 2H), 4.33 (dd, J = 12.4, 4.5 Hz,
1H), 4.19 – 4.10 (m, 1H), 3.90 (ddd, J = 9.9, 4.6, 2.4 Hz, 1H),
3.78 (s, 6H), 2.07 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 2.01 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 170.8 (Cq),
170.3 (Cq), 169.5 (Cq), 169.3 (Cq), 164.3 (Cq), 157.9 (2 x Cq),
132.1 (CH), 111.3 (Cq), 104.1 (2 x CH), 92.2 (CH), 73.2 (CH),
73.1 (CH), 70.7 (CH), 68.0 (CH), 61.8 (CH2), 56.1 (2 x CH3),
20.8 (CH3), 20.7 (3 x CH3); HRMS (ESI) (M + Na)+ m/z
calculated for C23H28O13Na 535.1428, found 535.1431.
1
1759, 1367, 1243, 1086, 1066, 1033; H NMR (300 MHz,
β-D-Glucopyranose,
2,3,4,6-tetraacetate
1-(2,5-
CDCl3) δ (ppm) 8.03 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 7.3 Hz,
1H), 7.45 (t, J = 7.7 Hz, 2H), 5.92 (dd, J = 5.6, 2.5 Hz, 1H),
5.34 (dd, J = 5.7, 3.1 Hz, 2H), 5.25 – 5.10 (m, 1H), 4.32 (dd, J
= 12.5, 4.4 Hz, 1H), 4.13 (dd, J = 12.6, 2.3 Hz, 1H), 3.94 (ddd,
J = 9.9, 4.5, 2.3 Hz, 1H), 2.06 (s, 3H), 2.04 (s, 3H), 2.03 (s,
3H), 1.98 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ (ppm)
170.7 (Cq), 170.2 (Cq), 169.5 (Cq), 169.4 (Cq), 164.6 (Cq),
134.1 (CH), 130.3 (2 x CH), 128.7 (2 x CH), 128.5 (Cq), 92.4
(CH), 72.9 (CH), 72.8 (CH), 70.3 (CH), 68.0 (CH), 61.6
(CH2), 20.8 (CH3), 20.7 (3 x CH3); HRMS (ESI) (M + Na)+
m/z calculated for C21H24O11Na 475.1211, found 475.1198.
dimethoxybenzoate) [7d]
Compound 7d was prepared by using both general procedures
(A) (reaction time: 15 min), and (B) (reaction time: 1h), with
commercial 2,5-dimethoxybenzoic acid 5d (35.0 mg, 0.19
mmol, 1.0 equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.),
which afforded the product as a white solid (with Cu-catalyst
0.138 mmol, 70% yield, with Co-catalyst 0.060 mmol, 32%
yield) after column chromatography EtOAc/Cyclohexane 3:7):
TLC Rf = 0.25 (EtOAc/Cyclohexane, 1:1, SiO2); mp: 126.0 –
20
127.2 °C ; [α]D = - 2.4 (c, 1.00 in CHCl3); IR (neat, cm-1)
1
2964, 2929, 1757, 1502, 1367, 1238, 1080, 1039; H NMR
(300 MHz, CDCl3) δ (ppm) 7.39 (d, J = 3.2 Hz, 1H), 7.08
(dd, J = 9.1, 3.2 Hz, 1H), 6.92 (d, J = 9.1 Hz, 1H), 5.93 (dd, J
= 5.2, 2.9 Hz, 1H), 5.32 (dd, J = 5.6, 3.2 Hz, 2H), 5.24 – 5.14
β-D-Glucopyranose,
methoxybenzoate) [7b]
2,3,4,6-tetraacetate
1-(2-
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The Journal of Organic Chemistry
Compound 7g was prepared by using both general proce-
(m, 1H), 4.32 (dd, J = 12.5, 4.5 Hz, 1H), 4.13 (dd, J = 12.5,
1
2
3
4
5
6
7
8
2.4 Hz, 1H), 3.92 (ddd, J = 10.1, 4.4, 2.1 Hz, 1H), 3.86 (s,
3H), 3.80 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.01
(s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 170.8 (Cq),
170.2 (Cq), 169.6 (Cq), 169.5 (Cq), 163.2 (Cq), 154.9 (Cq),
153.1 (Cq), 121.9 (CH), 117.8 (Cq), 116.1 (CH), 113.9 (CH),
92.1 (CH), 72.9 (2 x CH), 70.4 (CH), 68.1 (CH), 61.7 (CH2),
56.6 (CH3), 56.0 (CH3), 20.9 (CH3), 20.8 (3 x CH3); HRMS
(ESI) (M + Na)+ m/z calculated for C23H28O13Na 535.1428,
found 535.1434.
dures (A) (reaction time: 15 min), and (B) (reaction time: 1h),
with commercial 4-aminolbenzoic acid 5g (26.3 mg, 0.19
mmol, 1.0 equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.),
which afforded the product as a white solid (with Cu-catalyst
0.145 mmol, 50% yield, with Co-catalyst 0.1 mmol, 53%
yield) after column chromatography EtOAc/Cyclohexane 3:7):
TLC Rf = 0.28 (EtOAc/Cyclohexane, 1:1, SiO2); mp: 138.2 –
19
140.4 °C ; [α]D = - 5.6 (c, 1.00 in CHCl3); IR (neat, cm-1)
3487, 3384, 2964, 2924, 1758, 1602, 1366, 1210, 1065, 1037;
1H NMR (300 MHz, CDCl3) δ (ppm) 7.84 (d, J = 8.7 Hz,
2H), 6.63 (d, J = 8.7 Hz, 2H), 5.88 (dd, J = 6.0, 2.4 Hz, 1H),
5.36 – 5.27 (m, 2H), 5.23 – 5.12 (m, 1H), 4.32 (dd, J = 12.7,
4.2 Hz, 1H), 4.14 (d, J = 2.9 Hz, 1H), 3.92 (ddd, J = 10.3, 4.4,
2.2 Hz, 1H), 2.07 (s, 3H), 2.04 (s, 3H), 2.04 (s, 3H), 1.98 (s,
3H), no NH2 protons observed; 13C{1H} NMR (75 MHz,
CDCl3) δ (ppm) 170.8 (Cq), 170.2 (Cq), 169.6 (2 x Cq), 164.5
(Cq), 151.9 (Cq), 132.6 (2 x CH), 117.6 (Cq), 114.0 (2 x CH),
92.1 (CH), 72.9 (CH), 72.8 (CH), 70.4 (CH), 68.1 (CH), 61.7
(CH2), 20.8 (CH3), 20.7 (3 x CH3); HRMS (ESI) (M + Na)+
m/z calculated for C21H25NO11Na 490.1325, found 490.1327.
9
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12
13
14
15
16
17
18
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β-D-Glucopyranose,
2,3,4,6-tetraacetate
1-(3,4,5-
trimethoxybenzoate) [7e]
Compound 7e was prepared by using both general proce-
dures (A) (reaction time: 15 min), and (B) (reaction time: 1h),
with commercial 3,4,5-trimethoxybenzoic acid 5e (40.8 mg,
0.19 mmol, 1.0 equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5
equiv.), which afforded the product as a white solid (with Cu-
catalyst 0.100 mmol, 53% yield, with Co-catalyst 0.119 mmol,
67% yield) after column chromatography EtOAc/Cyclohexane
3:7): TLC Rf = 0.40 (EtOAc/Cyclohexane, 1:1, SiO2); mp:
20
89.7 – 90.7 °C ; [α]D = - 26.1 (c, 1.00 in CHCl3); IR (neat,
cm-1) 3496, 2949, 2841, 1757, 1590, 1504, 1336, 1206, 1126,
β-D-Glucopyranose,
2,3,4,6-tetraacetate
1-(4-
1
1031; H NMR (300 MHz, CDCl3) δ (ppm) 7.29 (s, 2H),
hydroxybenzoate) [7h]
5.85 (dd, J = 5.6, 2.4 Hz, 1H), 5.37 – 5.30 (m, 2H), 5.26 – 5.12
(m, 1H), 4.34 (dd, J = 12.5, 4.4 Hz, 1H), 4.17 – 4.08 (m, 1H),
3.99 – 3.91 (m, 1H), 3.90 (s, 3H), 3.89 (s, 6H), 2.06 (s, 3H),
2.04 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ (ppm) 170.7 (Cq), 170.1 (Cq), 169.6 (Cq),
169.5 (Cq), 164.2 (Cq), 153.2 (2 x Cq), 143.2 (Cq), 123.3 (Cq),
107.5 (2 x CH), 92.6 (CH), 72.9 (CH), 72.6 (CH), 70.3 (CH),
68.1 (CH), 61.6 (CH2), 61.1 (CH3), 56.4 (2 x CH3), 20.8
(CH3), 20.7 (3 x CH3); HRMS (ESI) (M + Na)+ m/z calculat-
ed for C24H30O14Na 565.1528, found 565.1534.
Compound 7h was prepared by using the general procedure
(B) (reaction time: 1h), with commercial 4-hydroxylbenzoic
acid 5h (26.5 mg, 0.19 mmol, 1.0 equiv.) and 1a[25] (104.9 mg,
0.29 mmol, 1.5 equiv.), which afforded the product as a white
solid (37.2 mg, 41% yield after column chromatography
EtOAc/Cyclohexane
3:7);
TLC
Rf
=
0.28
(EtOAc/Cyclohexane, 1:1, SiO2); mp: 178.3 – 179.6 °C ;
19
[α]D = - 7.3 (c, 1.00 in CHCl3); IR (neat, cm-1) 3418, 2969,
1
2910, 1757, 1609, 1367, 1212, 1067, 1038; H NMR (300
MHz, CDCl3) δ (ppm) 7.93 (dd, J = 7.0, 4.8 Hz, 2H), 6.85
(dd, J = 7.0, 4.8 Hz, 2H), 5.90 (dd, J = 5.8, 2.5 Hz, 1H), 5.39 –
5.27 (m, 2H), 5.26 – 5.11 (m, 1H), 4.33 (dd, J = 12.5, 4.3 Hz,
1H), 4.14 (dd, J = 12.5, 2.4 Hz, 1H), 3.94 (ddd, J = 10.1, 4.4,
2.2 Hz, 1H), 2.07 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 1.99 (s,
3H), no OH proton observed; 13C{1H} NMR (75 MHz,
CDCl3) δ (ppm) 170.9 (Cq), 170.3 (Cq), 169.8 (Cq), 169.7
(Cq), 164.3 (Cq), 161.1 (Cq), 132.8 (2 x CH), 120.8 (Cq), 115.6
(2 x CH), 92.3 (CH), 72.9 (CH), 72.8 (CH), 70.4 (CH), 68.1
(CH), 61.7 (CH2), 20.9 (CH3), 20.7 (3 x CH3); HRMS (ESI)
(M + Na)+ m/z calculated for C21H24O12Na 491.1165, found
491.1174.
β-D-Glucopyranose,
2,3,4,6-tetraacetate
1-(2,4,6-
trimethylbenzoate) [7f]
Compound 7f was prepared by using the general procedure
(B) (reaction time: 1h), with commercial
2,4,6-trimethylbenzoic acid 5f (31.5 mg, 0.19 mmol, 1.0
equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.), which af-
forded the product as a white solid (61.2 mg, 65% yield after
column chromatography EtOAc/Cyclohexane 3:7); TLC Rf =
0.60 (EtOAc/Cyclohexane, 1:1, SiO2); mp: 136.2 – 137.5 °C ;
20
[α]D = - 8.2 (c, 1.00 in CHCl3); IR (neat, cm-1) 2969, 2920,
1
1757, 1612, 1366, 1239, 1167, 1060, 1036; H NMR (300
MHz, CDCl3) δ (ppm) 6.84 (s, 2H), 5.99 (d, J = 8.1 Hz, 1H),
5.34 – 5.25 (m, 1H), 5.18 (dd, J = 20.4, 9.0 Hz, 2H), 4.32 (dd,
J = 12.4, 4.7 Hz, 1H), 4.19 – 4.11 (m, 1H), 3.95 – 3.87 (m,
1H), 2.27 (s, 3H), 2.26 (s, 6H), 2.07 (s, 3H), 2.04 (s, 3H), 2.02
(s, 3H), 2.01 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
(ppm) 170.7 (Cq), 170.3 (Cq), 169.5 (Cq), 169.2 (Cq), 168.1
(Cq), 140.3 (Cq), 135.7 (2 x Cq), 129.1 (Cq), 128.7 (2 x CH),
91.9 (CH), 73.3 (CH), 72.9 (CH), 70.3 (CH), 68.1 (CH), 61.7
(CH2), 21.3 (CH3), 20.8 (CH3), 20.7 (3 x CH3), 19.9 (2 x CH3);
HRMS (ESI) (M + Na)+ m/z calculated for C24H30O11Na
517.1686, found 517.1678; Elemental Analysis calculated: C,
58.29 %; H, 6.12 %; O, 35.59 %, found: C, 58.07 %; H, 6.17
%; O, 35.03 %.
β-D-Glucopyranose, 2,3,4,6-tetraacetate 1-(2-bromobenzoate)
[7i]
Compound 7i was prepared by using both general procedures
(A) (reaction time: 15 min), and (B) (reaction time: 1h), with
commercial 2-bromobenzoic acid 5i (38.6 mg, 0.19 mmol, 1.0
equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.), which af-
forded the product as a white solid (with Cu-catalyst 0.091
mmol, 48% yield, with Co-catalyst 0.057 mmol, 30% yield)
after column chromatography EtOAc/Cyclohexane 3:7): TLC
Rf = 0.47 (EtOAc/Cyclohexane, 1:1, SiO2); mp: 103.3 – 105.2
20
°C ; [α]D = - 13.6 (c, 1.00 in CHCl3); IR (neat, cm-1) 2959,
1
1758, 1590, 1433, 1366, 1235, 1070, 1031; H NMR (300
MHz, CDCl3) δ (ppm) 7.93 – 7.83 (m, 1H), 7.75 – 7.61 (m,
1H), 7.38 (dd, J = 6.8, 3.5 Hz, 2H), 6.03 – 5.90 (m, 1H), 5.37
– 5.26 (m, 2H), 5.26 – 5.09 (m, 1H), 4.34 (dd, J = 12.5, 4.4
Hz, 1H), 4.14 (dd, J = 12.6, 2.2 Hz, 1H), 3.93 (ddd, J = 12.1,
4.4, 2.1 Hz, 1H), 2.08 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 2.02
β-D-Glucopyranose, 2,3,4,6-tetraacetate 1-(4-aminobenzoate)
[7g]
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The Journal of Organic Chemistry
Page 10 of 20
(s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 170.8 (Cq),
Compound 7l was prepared by using both general procedures
1
2
3
4
5
6
7
8
170.2 (Cq), 169.5 (2 x Cq), 163.4 (Cq), 135.1 (CH), 133.9
(CH), 132.5 (CH), 129.5 (Cq), 127.6 (CH), 123.0 (Cq), 92.6
(CH), 73.0 (CH), 72.9 (CH), 70.3 (CH), 67.9 (CH), 61.6
(CH2), 20.9 (CH3), 20.8 (CH3), 20.7 (2 x CH3); HRMS (ESI)
(M + Na)+ m/z calculated for C21H23BrO11Na 553.0321, found
553.0327.
(A) (reaction time: 15 min), and (B) (reaction time: 1h), with
commercial 4-iodobenzoic acid 5l (47.6 mg, 0.19 mmol, 1.0
equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.), which af-
forded the product as a white solid (with Cu-catalyst 0.123
mmol, 65% yield, with Co-catalyst 0.081 mmol, 43% yield)
after column chromatography EtOAc/Cyclohexane 3:7): TLC
Rf = 0.59 (EtOAc/Cyclohexane, 1:1, SiO2); mp: 149.0 – 151.6
19
β-D-Glucopyranose, 2,3,4,6-tetraacetate 1-(2-fluorobenzoate)
[7j]
°C ; [α]D = - 21.9 (c, 1.00 in CHCl3); IR (neat, cm-1) 2949,
1
1746, 1586, 1366, 1229, 1085, 1069; H NMR (300 MHz,
9
Compound 7j was prepared by using both general procedures
(A) (reaction time: 15 min), and (B) (reaction time: 1h), with
commercial 2-fluorobenzoic acid 5j (26.9 mg, 0.19 mmol, 1.0
equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.), which af-
forded the product as a white solid (with Cu-catalyst 0.114
mmol, 60% yield, with Co-catalyst 0.112 mmol, 59% yield)
after column chromatography EtOAc/Cyclohexane 3:7): TLC
Rf = 0.46 (EtOAc/Cyclohexane, 1:1, SiO2); mp: 116.6 – 118.0
CDCl3) δ (ppm) 7.83 (dd, J = 8.5, 2.1 Hz, 2H), 7.73 (dd, J =
8.5, 2.0 Hz, 2H), 5.89 (d, J = 6.8 Hz, 1H), 5.38 – 5.26 (m, 2H),
5.26 – 5.11 (m, 1H), 4.32 (dd, J = 12.6, 4.5 Hz, 1H), 4.13 (dd,
J = 12.5, 2.1 Hz, 1H), 3.93 (ddd, J = 10.0, 4.6, 2.3 Hz, 1H),
2.07 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ (ppm) 170.7 (Cq), 170.2 (Cq),
169.6 (Cq), 169.5 (Cq), 164.3 (Cq), 138.2 (2 x CH), 131.6 (2 x
CH), 128.0 (Cq), 102.4 (Cq), 92.6 (CH), 73.0 (CH), 72.7 (CH),
70.2 (CH), 68.0 (CH), 61.5 (CH2), 20.8 (CH3), 20.7 (3 x CH3);
HRMS (ESI) (M + Na)+ m/z calculated for C21H23IO11Na
601.0183, found 601.0183.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
°C ; [α]D = - 14.0 (c, 1.00 in CHCl3); IR (neat, cm-1) 3496,
1
2954, 1745, 1613, 1491, 1367, 1240, 1081, 1036 ; H NMR
(300 MHz, CDCl3) δ (ppm) 7.92 (t, J = 7.1 Hz, 1H), 7.56 (dd,
J = 12.6, 7.2 Hz, 1H), 7.18 (dt, J = 19.2, 8.6 Hz, 2H), 5.93 (dd,
J = 6.0, 0.9 Hz, 1H), 5.38 – 5.26 (m, 2H), 5.26 – 5.11 (m, 1H),
4.32 (dd, J = 12.5, 4.3 Hz, 1H), 4.14 (d, J = 12.3 Hz, 1H), 4.03
– 3.84 (m, 1H), 2.07 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.01 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 170.7 (Cq),
170.2 (Cq), 169.5 (Cq), 169.4 (Cq), 162.6 (d, JCF = 261.0 Hz,
Cq), 162.0 (d, JCF = 3.8 Hz, Cq), 135.7 (d, JCF = 9.0 Hz, CH),
132.5 (CH), 124.3 (d, JCF = 3.0 Hz, CH), 117.3 (Cq), 117.3 (d,
JCF = 21.8 Hz, CH), 92.4 (CH), 73.0 (CH), 72.8 (CH), 70.2
β-D-Glucopyranose,
2,3,4,6-tetraacetate
1-(3,5-
dichlorobenzoate) [7m]
Compound 7m was prepared by using both general proce-
dures (A) (reaction time: 15 min), and (B) (reaction time: 1h),
with commercial 3,5-dichlorobenzoic acid 5m (36.7 mg, 0.19
mmol, 1.0 equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.),
which afforded the product as a white solid (with Cu-catalyst
0.104 mmol, 55% yield, with Co-catalyst 0.157 mmol, 83%
yield) after column chromatography EtOAc/Cyclohexane 3:7):
TLC Rf = 0.59 (EtOAc/Cyclohexane, 1:1, SiO2); mp: 87.8 –
(CH), 68.0 (CH), 61.6 (CH2), 20.8 (CH3), 20.72 (3 x CH3); 19
F
NMR (376 MHz, CDCl3) δ (ppm) – 108.3 (CF); HRMS
(ESI) (M + Na)+ m/z calculated for C21H23FO11Na 493.1122,
found 493.1126.
20
89.5 °C ; [α]D = - 12.7 (c, 1.00 in CHCl3); IR (neat, cm-1)
1
2964, 2920, 1747, 1571, 1426, 1366, 1207, 1073, 1030; H
NMR (300 MHz, CDCl3) δ (ppm) 7.89 (d, J = 2.1 Hz, 2H),
7.57 (t, J = 2.1 Hz, 1H), 5.91 (dd, J = 5.0, 2.7 Hz, 1H), 5.39 –
5.25 (m, 2H), 5.17 (ddd, J = 9.3, 6.0, 3.1 Hz, 1H), 4.30 (dd, J
= 12.5, 4.5 Hz, 1H), 4.12 (dd, J = 12.6, 2.3 Hz, 1H), 3.92 (ddd,
J = 10.1, 4.6, 2.3 Hz, 1H), 2.06 (s, 3H), 2.04 (s, 3H), 2.03 (s,
3H), 1.99 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ (ppm)
170.7 (Cq), 170.2 (Cq), 169.5 (Cq), 169.3 (Cq), 162.5 (Cq),
135.7 (2 x Cq), 133.9 (CH), 131.4 (Cq), 128.6 (2 x CH), 92.9
(CH), 73.0 (CH), 72.6 (CH), 70.3 (CH), 67.9 (CH), 61.5
(CH2), 20.8 (CH3), 20.7 (3 x CH3); HRMS (ESI) (M + Na)+
m/z calculated for C21H22Cl2O11Na 543.0437, found 543.0432.
β-D-Glucopyranose, 2,3,4,6-tetraacetate 1-(4-fluorobenzoate)
[7k]
Compound 7k was prepared by using the general procedure
(B) (reaction time: 1h), with commercial 4-fluorobenzoic acid
5k (26.9 mg, 0.19 mmol, 1.0 equiv.) and 1a (104.9 mg, 0.29
mmol, 1.5 equiv.), which afforded the product as a white solid
(55.5 mg, 62% yield after column chromatography
EtOAc/Cyclohexane
3:7);
TLC
Rf
=
0.57
(EtOAc/Cyclohexane, 1:1, SiO2); mp: 157.3 – 159.7 °C ;
[α]D20 = - 11.0 (c, 1.00 in CHCl3); IR (neat, cm-1) 2964, 2924,
1
1759, 1604, 1509, 1366, 1242, 1067, 1034; H NMR (300
MHz, CDCl3) δ (ppm) 8.05 (dd, J = 8.8, 5.4 Hz, 2H), 7.13 (t,
J = 8.6 Hz, 2H), 5.90 (dd, J = 4.9, 3.3 Hz, 1H), 5.33 (dd, J =
5.6, 3.1 Hz, 2H), 5.27 – 5.09 (m, 1H), 4.32 (dd, J = 12.5, 4.4
Hz, 1H), 4.13 (dd, J = 12.6, 2.4 Hz, 1H), 3.93 (ddd, J = 9.9,
4.5, 2.2 Hz, 1H), 2.07 (s, 3H), 2.04 (s, 3H), 2.04 (s, 3H), 1.98
(s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 170.7 (Cq),
170.2 (Cq), 169.6 (Cq), 169.5 (Cq), 166.5 (d, JCF = 254.3 Hz,
Cq), 163.7 (Cq), 133.0 (d, JCF = 9.0 Hz, 2 x CH), 124.8 (d, JCF
= 3.0 Hz, Cq), 116.1 (d, JCF = 21.8 Hz, 2 x CH), 92.5 (CH),
72.9 (CH), 72.7 (CH), 70.3 (CH), 68.0 (CH), 61.6 (CH2), 20.8
(CH3), 20.7 (3 x CH3); 19F NMR (376 MHz, CDCl3) δ (ppm)
– 103.4 (CF); HRMS (ESI) (M + Na)+ m/z calculated for
C21H23FO11Na 493.1122, found 493.1120.
β-D-Glucopyranose,
2,3,4,6-tetraacetate
1-(2,4-
dichlorobenzoate) [7n]
Compound 7n was prepared by using the general procedure
(A) (reaction time: 15min), with commercial
2,3-dichlorobenzoic acid 5n (36.7 mg, 0.19 mmol, 1.0 equiv.)
and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.), which afforded the
product as a amorphos solid (0.097 mmol, 55% yield after
column chromatography EtOAc/Cyclohexane 4:6); Rf (40%
25
EtOAc/Cyclohexane)
=
0.50; [α]D
=
−37.27 (c 0,011
CH2Cl2); IR (neat, cm-1) 3460, 1745, 1711, 1584, 1376, 1207,
1071, 1021; H NMR (300 MHz, CDCl3) δ (ppm) 7.85 (d, J
1
= 8.5 Hz, 1H), 7.49 – 7.45 (m, J = 1.4 Hz, 1H), 7.31 (d, J = 8.5
Hz, 1H), 5.92 (d, J = 7.5 Hz, 1H), 5.29 (t, J = 6.6 Hz, 2H),
5.16 (t, J = 9.3 Hz, 1H), 4.31 (dd, J = 12.5, 4.3 Hz, 1H), 4.15 –
4.07 (m, 1H), 3.95 – 3.88 (m, 1H), 2.05 (s, 3H), 2.02 (s, 3H),
2.01 (s, 3H), 1.99 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
(ppm) 170.52(Cq), 170.00(Cq), 169.35(Cq), 169.29(Cq),
β-D-Glucopyranose, 2,3,4,6-tetraacetate 1-(4-iodobenzoate)
[7l]
ACS Paragon Plus Environment

Page 11 of 20
The Journal of Organic Chemistry
25
161.96(Cq), 139.68(Cq), 136.07(Cq), 133.26(CH), 131.41(CH),
(40% EtOAc/Cyclohexane) = 0.38 ; mp: 213-219 °C; [α]D
=
−19.6 (c 0,0051 in CH2Cl2); IR (neat, cm-1) 3371, 2925, 1756,
1730, 1442, 1368, 1245, 1111, 1083, 1032; H NMR (300
1
2
3
4
5
6
7
8
127.30(CH), 125.77(Cq), 92.45(CH), 72.86(CH), 72.63(CH),
70.12(CH), 67.73(CH), 61.37(CH2), 20.66(CH3), 20.54 (3 x
1
CH3); HRMS (ESI) (M + Na)+
m/z calculated for
C21H22O11NaCl2Na: 543.0437, found 543.0432.
MHz, CDCl3) δ (ppm) 7.73 (s, 1H), 6.00 (d, J = 7.9 Hz, 1H),
5.27 (t, 1H), 5.21 (d, J = 9.3 Hz, 1H), 5.15 (d, J = 5.8 Hz, 2H),
4.30 (dd, J = 12.5, 4.6 Hz, 1H), 4.19 – 4.08 (m, 2H), 3.95 –
3.87 (m, 1H), 2.06 (s, 3H), 2.03 (s, 6H), 2.00 (s, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ (ppm) 170.53(Cq), 170.06(Cq),
169.27(Cq), 169.16(Cq), 163.88(Cq), 144.48(Cq), 138.34(CH),
132.37(Cq), 115.83(Cq), 110.31(Cq),, 109.00(Cq), 92.71(CH),
73.05(CH), 72.75(CH), 69.99(CH), 67.69(CH), 61.32(CH2),
20.67(CH3), 20.54 (3 x CH3); HRMS (ESI) (M + Na)+ m/z
calculated for C21H22NO11ClBr2Na: 679.9140, found 679.9109.
β-D-Glucopyranose,
difluorobenzoate) [7o]
2,3,4,6-tetraacetate
1-(2,5-
Compound 7o was prepared by using the general procedure A
(reaction time: 15min), with commercial 2,5-difluorobenzoic
acid 5o (36.7 mg, 0.19 mmol, 1.0 equiv.) and 1a (104.9 mg,
0.29 mmol, 1.5 equiv.), which afforded the product as a white
solid (0.118 mmol, 62% yield after column chromatography
EtOAc/Cyclohexane 4:6); Rf (40% EtOAc/Cyclohexane) =
0.39; mp: 105-112 °C; [α]D25= −37.73 (c 0,0053 in CH2Cl2);
IR (neat, cm-1) 1758, 1739, 1496, 1381, 1209, 1185, 1077,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
β-D-Glucopyranose, 2,3,4,6-tetraacetate 1-(3,5-diiodo, 4-
aminobenzoate) [7r]
1
1035; H NMR (300 MHz, CDCl3) δ (ppm) 7.64 – 7.55 (m,
1H), 7.30 – 7.21 (m, 1H), 7.16 – 7.10 (m, J = 9.3, 4.1 Hz, 1H),
5.91 (d, J = 7.4 Hz, 1H), 5.33 – 5.27 (m, J = 3.4 Hz, 2H), 5.21
– 5.12 (m, J = 9.5 Hz, 1H), 4.30 (dd, J = 12.5, 4.4 Hz, 1H),
4.13 (d, J = 12.1 Hz, 1H), 3.96 – 3.89 (m, J = 9.8 Hz, 1H),
2.06 (s, 3H), 2.03 – 2.00 (m, 9H); 13C{1H} NMR (75 MHz,
Compound 7r was prepared by using the general procedure
(B) (reaction time: 1h), with commercial 4-amino-3,5-
diiodobenzoic acid 5r (74.7 mg, 0.19 mmol, 1.0 equiv.) and 1a
(104.9 mg, 0.29 mmol, 1.5 equiv.), which afforded the product
as a white solid (64.4 mg, 47% yield after column chromatog-
CDCl3) δ(ppm)
169.15(Cq), 161.00(Cq), 160.15(Cq), 159.59(Cq), 156.31(Cq),
122.29(CH), 118.55(CH), 118.21(CH), 92.50(CH),
170.55(Cq), 170.06(Cq), 169.35(Cq),
raphy EtOAc/Cyclohexane 3:7); TLC Rf
=
0.52
(EtOAc/Cyclohexane, 1:1, SiO2); mp: 151.8 – 152.5 °C ;
20
72.85(CH), 72.59(CH), 70.00(CH), 67.75(CH), 61.40(CH2),
20.65(CH3), 20.55(2 x CH3), 20.48(CH3); 19F NMR (376
MHz, CDCl3) δ (ppm) -113.91(CF), -117.23 (CF) ; HRMS
(ESI) (M + Na)+ m/z calculated for C21H22O11F2Na: 511.1022,
found 511.1028.
[α]D = - 3.0 (c, 1.00 in CHCl3); IR (neat, cm-1) 3467, 3359,
1
2959, 1757, 1610, 1360, 1201, 1060, 1034; H NMR (300
MHz, CDCl3) δ (ppm) 8.28 (s, 2H), 5.89 (d, J = 7.4 Hz, 1H),
5.34 – 5.26 (m, 1H), 5.22 – 5.10 (m, 2H), 4.31 (dd, J = 12.5,
4.3 Hz, 1H), 4.12 (ddd, J = 12.5, 1.2, 0.6 Hz, 1H), 3.91 (ddd, J
= 6.3, 3.8, 1.5 Hz, 1H), 2.08 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H),
1.99 (s, 3H), no NH2 protons observed; 13C{1H} NMR (75
MHz, CDCl3) δ (ppm) 170.7 (Cq), 170.2 (Cq), 169.5 (Cq),
169.4 (Cq), 169.1 (Cq), 161.9 (Cq), 150.7 (2 x Cq), 141.7 (2 x
CH), 120.4 (Cq), 92.3 (CH), 72.8 (CH), 72.7 (CH), 70.3 (CH),
67.9 (CH), 61.6 (CH2), 20.8 (CH3), 20.7 (3 x CH3); HRMS
(ESI) (M + Na)+ m/z calculated for C21H23I2NO11Na 741.9258,
found 741.9264.
β-D-Glucopyranose, 2,3,4,6-tetraacetate 1-(2-nitrobenzoate)
[7p]
Compound 7p was prepared by using the general procedure
(B) (reaction time: 1h), with commercial 2-nitrobenzoic acid
5p (32.1 mg, 0.19 mmol, 1.0 equiv.) and 1a (104.9 mg, 0.29
mmol, 1.5 equiv.), which afforded the product as a white solid
(55.0 mg, 58% yield after column chromatography
EtOAc/Cyclohexane
3:7);
TLC
Rf
=
0.36
β-D-Glucopyranose, 2,3,4,6-tetraacetate 1-acrylate [7s]
20
(EtOAc/Cyclohexane, 1:1, SiO2); mp: 74.9 – 75.6 °C ; [α]D
Compound 7s was prepared by using the general procedure
(B) (reaction time: 1h), with commercial acrylic acid 5s (13.8
mg, 0.19 mmol, 1.0 equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5
equiv.), which afforded the product as a white solid (60.2 mg,
78% yield after column chromatography EtOAc/Cyclohexane
3:7); TLC Rf = 0.56 (EtOAc/Cyclohexane, 1:1, SiO2); mp:
107.9 – 109.4 °C ; [α]D20 = - 2.7 (c, 1.00 in CHCl3); IR (neat,
= - 8.5 (c, 1.00 in CHCl3); IR (neat, cm-1) 2954, 2929, 1757,
1
1536, 1367, 1351, 1242, 1063, 1035; H NMR (300 MHz,
CDCl3) δ (ppm) 7.96 (d, J = 7.4 Hz, 1H), 7.78 – 7.61 (m, 3H),
5.93 (d, J = 8.2 Hz, 1H), 5.32 (t, J = 9.4 Hz, 1H), 5.16 (dd, J =
20.6, 9.1 Hz, 2H), 4.33 (dd, J = 12.5, 4.4 Hz, 1H), 4.15 (dd, J
= 12.0, 1.8 Hz, 1H), 4.02 – 3.82 (m, 1H), 2.11 (s, 3H), 2.08 (s,
3H), 2.04 (s, 3H), 2.01 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ (ppm) 170.7 (Cq), 170.2 (Cq), 169.7 (Cq), 169.5
(Cq), 163.9 (Cq), 147.8 (Cq), 133.4 (CH), 132.5 (CH), 130.2
(CH), 126.5 (Cq), 124.3 (CH), 93.1 (CH), 73.0 (CH), 72.8
(CH), 69.9 (CH), 67.8 (CH), 61.5 (CH2), 20.8 (2 x CH3), 20.7
(2 x CH3); HRMS (ESI) (M + Na)+ m/z calculated for
C21H23NO13Na 520.1067, found 520.1066.
1
cm-1) 3457, 2949, 1746, 1368, 1229, 1219, 1079, 1037 ; H
NMR (300 MHz, CDCl3) δ (ppm) 6.50 (d, J = 17.0 Hz, 1H),
6.11 (dd, J = 17.1, 10.5 Hz, 1H), 5.96 (d, J = 10.5 Hz, 1H),
5.78 (d, J = 8.0 Hz, 1H), 5.36 – 5.03 (m, 3H), 4.30 (dd, J =
12.5, 4.5 Hz, 1H), 4.11 (dd, J = 12.4, 2.3 Hz, 1H), 3.87 (ddd, J
= 10.1, 4.6, 2.3 Hz, 1H), 2.08 (s, 3H), 2.03 (s, 3H), 2.02 (s,
3H), 2.01 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ (ppm)
170.7 (Cq), 170.2 (Cq), 169.5 (Cq), 169.4 (Cq), 163.9 (Cq),
133.7 (CH2), 127.2 (CH), 92.1 (CH), 72.9 (CH), 72.8 (CH),
70.3 (CH), 68.0 (CH), 61.6 (CH2), 20.8 (CH3), 20.7 (3 x CH3);
HRMS (ESI) (M + Na)+ m/z calculated for C17H22O11Na
425.1060, found 425.1058.
β-D-Glucopyranose, 2,3,4,6-tetraacetate 1-(2-amino, 3,5-
dibromo, 6-chlorobenzoate) [7q]
Compound 7q was prepared by using the general procedure
(A) (reaction time: 15 min), with commercial 2-amino-3,5-
dibromo-6-chlorobenzoic acid 5q (63.24 mg, 0.19 mmol, 1.0
equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.), which af-
forded the product as a white solid (0.09 mmol, 47% yield
after column chromatography EtOAc/Cyclohexane 4:6); Rf
β-D-Glucopyranose,
butenoate) [7t]
2,3,4,6-tetraacetate
1-(3-methyl-2-
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Compound 7t was prepared by using the general procedure MHz, CDCl3) δ (ppm) 170.7 (Cq), 170.2 (Cq), 169.5 (Cq),
1
2
3
4
5
6
7
8
(B) (reaction time: 1h), with commercial 3,3-dimethylacrylic
acid 5t (19.2 mg, 0.19 mmol, 1.0 equiv.) and 1a (104.9 mg,
0.29 mmol, 1.5 equiv.), which afforded the product as an
amorphous solid (64.3 mg, 78% yield after column chroma-
169.4 (Cq), 163.6 (Cq), 150.3 (Cq), 150.1 (CH), 139.8 (CH),
132.7 (CH), 129.7 (CH), 129.5 (CH), 127.9 (CH), 126.8 (Cq),
121.4 (Cq), 92.7 (CH), 73.0 (CH), 72.7 (CH), 70.3 (CH), 67.9
(CH), 61.6 (CH2), 20.8 (CH3), 20.7 (3 x CH3); HRMS (ESI)
(M + Na)+ m/z calculated for C24H25NO11Na 526.1320, found
526.1328.
tography EtOAc/Cyclohexane 3:7); TLC Rf
=
0.46
20
(EtOAc/Cyclohexane, 1:1, SiO2); [α]D = - 4.9 (c, 1.00 in
CHCl3); IR (neat, cm-1) 3487, 2964, 1757, 1646, 1434, 1367,
1212, 1081, 1035 ; 1H NMR (300 MHz, CDCl3) δ (ppm) 5.74
(d, J = 8.3 Hz, 1H), 5.67 (s, 1H), 5.32 – 5.21 (m, 1H), 5.14 (dt,
J = 9.5, 6.8 Hz, 2H), 4.28 (dd, J = 12.5, 4.4 Hz, 1H), 4.10 (dd,
J = 12.5, 2.2 Hz, 1H), 3.84 (ddd, J = 10.0, 4.6, 2.1 Hz, 1H),
2.17 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 2.00 (s, 6H), 1.91 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 170.7 (Cq),
170.2 (Cq), 169.5 (Cq), 169.4 (Cq), 164.1 (Cq), 161.4 (Cq),
114.7 (CH), 91.3 (CH), 73.0 (CH), 72.7 (CH), 70.4 (CH), 68.0
(CH), 61.6 (CH2), 27.8 (CH3), 20.8 (CH3), 20.7 (4 x CH3);
HRMS (ESI) (M + Na)+ m/z calculated for C19H26O11Na
453.1373, found 453.1378.
β-D-Glucopyranose,
2,3,4,6-tetraacetate
1-(3-
9
benzofurancarboxylate) [7w]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 7w was prepared by using the general procedure A
(reaction time: 15 min), with commercial benzofuran-3-
carboxylic acid 5w (31.1 mg, 0.19 mmol, 1.0 equiv.) and 1a
(104.9 mg, 0.29 mmol, 1.5 equiv.), which afforded the product
as a white solid (0.114 mmol, 60% yield after column chroma-
tography
EtOAc/Cyclohexane
4:6);
Rf
(40%
EtOAc/Cyclohexane) = 0.8 ; mp 122 - 128 °C ; [α]D25= −58.33
(c 0,006 CH2Cl2); IR (neat, cm-1) 2923, 2361, 1738, 1260,
1221, 1072, 1035, 797; H NMR (300 MHz, CDCl3) δ (ppm)
1
β-D-Glucopyranose,
thiophenecarboxylate) [7u]
2,3,4,6-tetraacetate
1-(2-
8.30 (s, 1H), 8.07 – 8.00 (m, J = 6.0, 3.1 Hz, 1H), 7.56 – 7.52
(m, J = 6.1, 3.1 Hz, 1H), 7.40 – 7.35 (m, J = 6.0, 3.2 Hz, 2H),
5.95 (dd, J = 5.8, 2.3 Hz, 1H), 5.35 (dd, J = 5.9, 2.8 Hz, 2H),
5.25 – 5.16 (m, J = 9.6, 6.5, 3.0 Hz, 1H), 4.34 (dd, J = 12.5,
4.4 Hz, 1H), 4.14 (dd, J = 12.5, 2.0 Hz, 1H), 4.00 – 3.92 (m,
1H), 2.07 (s, 3H), 2.04 (d, J = 2.2 Hz, 6H), 1.99 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ(ppm) 170.59(Cq),
170.06(Cq), 169.41(Cq), 169.36(Cq), 160.94(Cq), 155.63(Cq),
Compound 7u was prepared by using both general proce-
dures (A) (reaction time: 15 min) with commercial
2-thiophenecarboxylic acid 5u (24.6 mg, 0.19 mmol, 1.0
equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.), which af-
forded the product as a white solid (with Cu-catalyst 0.156
mmol, 82% yield, with Co-catalyst 0.157 mmol, 83% yield)
after column chromatography EtOAc/Cyclohexane 3:7); TLC
Rf = 0.50 (EtOAc/Cyclohexane, 1:1, SiO2); mp: 115.5 – 116.7
152.57(CH),
125.68(CH),
124.58(CH),
124.07(Cq),
121.84(CH), 113.01(Cq), 111.80(CH), 91.85(CH), 72.77(CH),
72.62(CH), 70.11(CH), 67.87(CH), 61.44(CH2), 20.69(CH3),
20.58 (3 x CH3); HRMS (ESI) (M + Na)+ m/z calculated for
C23H24O12Na: 515.1165, found 515.1167.
20
°C ; [α]D = - 20.8 (c, 1.00 in CHCl3); IR (neat, cm-1) 2959,
1
1758, 1524, 1416, 1364, 1221, 1065, 1037; H NMR (300
MHz, CDCl3) δ (ppm) 7.85 (d, J = 4.1 Hz, 1H), 7.64 (d, J =
4.8 Hz, 1H), 7.18 – 7.04 (m, 1H), 5.92 – 5.81 (m, 1H), 5.36 –
5.27 (m, 2H), 5.25 – 5.11 (m, 1H), 4.32 (dd, J = 12.5, 4.6 Hz,
1H), 4.13 (dd, J = 12.6, 2.3 Hz, 1H), 3.93 (ddd, J = 9.8, 4.5,
2.3 Hz, 1H), 2.07 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.00 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 170.8 (Cq),
170.2 (Cq), 169.6 (Cq), 169.4 (Cq), 160.1 (Cq), 135.3 (CH),
134.4 (CH), 131.9 (Cq), 128.3 (CH), 92.5 (CH), 72.9 (CH),
72.7 (CH), 70.2 (CH), 68.0 (CH), 61.6 (CH2), 20.8 (CH3), 20.7
(3 x CH3); HRMS (ESI) (M + Na)+ m/z calculated for
C19H22O11SNa 481.0781, found 481.0783.
β-D-Glucopyranose,
tridecancarboxylate) [7x]
2,3,4,6-tetraacetate
1-
Compound 7x was prepared by using both general proce-
dures (A) (reaction time: 15 min), and (B) (reaction time: 1h),
with commercial tridecanoic acid 5x (41.2 mg, 0.19 mmol, 1.0
equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.), which af-
forded the product as a transparent oil (with Cu-catalyst 0.114
mmol, 65% yield, with Co-catalyst 0.15 mmol, 79% yield)
after column chromatography EtOAc/Cyclohexane 3:7); TLC
20
Rf = 0.46 (EtOAc/Cyclohexane, 1:1, SiO2); [α]D = - 3.5 (c,
1.00 in CHCl3); IR (neat, cm-1) 2924, 2854, 1758, 1468, 1366,
1208, 1164, 1082, 1068 ; 1H NMR (300 MHz, CDCl3) δ
(ppm) 5.72 (d, J = 8.3 Hz, 1H), 5.23 (d, J = 9.3 Hz, 1H), 5.20
– 5.04 (m, 2H), 4.29 (dd, J = 12.5, 4.4 Hz, 1H), 4.09 (dd, J =
12.5, 2.2 Hz, 1H), 3.83 (ddd, J = 9.9, 4.6, 2.1 Hz, 1H), 2.34 (t,
J = 7.5 Hz, 2H), 2.07 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 2.00
(s, 3H), 1.66 – 1.51 (m, 2H), 1.30 (d, J = 7.0 Hz, 2H), 1.27 (s,
2H), 1.24 (s, 14H), 0.86 (t, J = 6.7 Hz, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ (ppm) 171.9 (Cq), 170.7 (Cq), 170.2 (Cq),
169.5 (Cq), 169.3 (Cq), 91.7 (CH), 72.9 (CH), 72.8 (CH), 70.3
(CH), 67.9 (CH), 61.6 (CH2), 34.2 (CH2), 32.0 (CH2), 29.7 (3
x CH2), 29.5 (2 x CH2), 29.3 (CH2), 29.1 (CH2), 24.7 (CH2),
22.8 (CH2), 20.8 (CH3), 20.7 (3 x CH3), 14.2 (CH3); HRMS
(ESI) (M + Na)+ m/z calculated for C27H44O11Na 567.2781,
found 567.2797.
β-D-Glucopyranose,
2,3,4,6-tetraacetate
1-(3-
quinolinecarboxylate) [7v]
Compound 7v was prepared by using the general procedure
(B) (reaction time: 1h), with commercial
3-quinolinecarboxylic acid 5v (33.3 mg, 0.19 mmol, 1.0
equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.), which af-
forded the product as a white solid (48.2 mg, 50% yield after
column chromatography EtOAc/Cyclohexane 3:7); TLC Rf =
0.27 (EtOAc/Cyclohexane, 1:1, SiO2); mp: 190.0 – 192.2 °C ;
[α]D20 = - 23.9 (c, 1.00 in CHCl3); IR (neat, cm-1) 3492, 2959,
1
1757, 1621, 1367, 1213, 1077, 1034; H NMR (300 MHz,
CDCl3) δ (ppm) 9.42 (d, J = 2.3 Hz, 1H), 8.84 (d, J = 2.4 Hz,
1H), 8.16 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.92 –
7.81 (m, 1H), 7.64 (t, J = 7.5 Hz, 1H), 6.01 (dd, J = 5.3, 2.6
Hz, 1H), 5.44 – 5.31 (m, 2H), 5.22 (ddd, J = 9.3, 6.2, 2.9 Hz,
1H), 4.34 (dd, J = 12.6, 4.5 Hz, 1H), 4.15 (dd, J = 12.5, 2.4
Hz, 1H), 3.98 (ddd, J = 10.1, 4.6, 2.3 Hz, 1H), 2.07 (s, 3H),
2.05 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H); 13C{1H} NMR (75
β-D-Glucopyranose,
phenylcyclopropanecarboxylate) [7y]
2,3,4,6-tetraacetate
1-(1-
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Compound 7y was prepared by using the general procedure A
(reaction time: 15 min), with commercial 1-
phenylcyclopropane-1-carboxylic acid 5y (31.2 mg, 0.19
mmol, 1.0 equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5 equiv.),
which afforded the product as a white solid (52 mg, 55% yield
0.29 mmol, 1.5 equiv.), which afforded the product as a white
1
2
3
4
5
6
7
8
solid (79 mg, 60% yield after column chromatography
EtOAc/Cyclohexane 4:6); Rf (50% EtOAc/Cyclohexane) =
0.28 ; mp 155 - 162 °C; [α]D25= −90.00 (c 0,002 CH2Cl2); IR
1
(neat, cm-1) 1742, 1704, 1365, 1258, 1227, 1149, 1032; H
after column chromatography EtOAc/Cyclohexane 4:6); Rf
NMR (300 MHz, CDCl3) δ (ppm) 5.69 (d, J = 8.2 Hz, 1H),
5.25 (d, J = 9.4 Hz, 1H), 5.16 – 5.04 (m, J = 15.3, 8.9 Hz, 4H),
4.91 (t, J = 9.6 Hz, 1H), 4.30 – 4.19 (m, 2H), 4.11 – 4.06 (m, J
= 7.8, 3.5 Hz, 1H), 3.96 – 3.88 (m, 1H), 3.87 – 3.81 (m, J =
9.0, 3.1 Hz, 1H), 3.74 – 3.70 (m, 1H), 3.70 – 3.66 (m, 1H),
3.64 – 3.59 (m, J = 10.1 Hz, 1H), 3.49 – 3.45 (m, J = 8.1, 5.3
Hz, 1H), 2.07 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 2.02 (d, J =
3.4 Hz, 9H), 2.01 (s, 3H), 1.99 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ (ppm) 170.51(Cq), 170.23(Cq), 170.03(Cq),
169.41(Cq), 169.34(Cq), 167.95(Cq), 91.91(CH), 75.95(CH),
73.96(CH), 73.83(CH), 72.81(CH), 72.53(CH), 71.50(CH),
71.27(Cq), 70.50(Cq), 70.17(Cq), 70.00(CH), 68.25(CH),
67.71(CH), 61.89(CH2), 61.35(CH2), 37.17(CH2), 20.67(3 x
CH3), 20.54(5 x CH3); HRMS (ESI) (M + Na)+ m/z calculated
for C30H40O20Na: 743.2011, found 743.1990.
25
(40% EtOAc/Cyclohexane) = 0.54 ; mp 154-162 °C; [α]D
=
−13.33 (c 0,006 CH2Cl2); IR (neat, cm-1) 3250, 1754, 1742,
1629, 1252, 1231, 1082; 1H NMR (300 MHz, CDCl3) δ
(ppm) 7.29 (s, 5H), 5.61 (d, J = 8.1 Hz, 1H), 5.17 (d, J = 9.2
Hz, 1H), 5.07 (t, J = 9.6 Hz, 1H), 4.98 (t, J = 8.7 Hz, 1H), 4.26
(dd, J = 12.5, 4.4 Hz, 1H), 4.12 – 4.04 (m, J = 17.0, 4.5 Hz,
1H), 3.83 – 3.77 (m, 1H), 2.07 (s, 3H), 2.00 (s, 3H), 1.98 (s,
3H), 1.96 (s, 3H), 1.77 – 1.69 (m, 1H), 1.60 – 1.52 (m, 1H),
1.26 (d, J = 7.1 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3)
δ(ppm) 172.60(Cq), 170.60(Cq), 170.06(Cq), 169.33(Cq),
168.82(Cq), 138.23(Cq), 130.4 (2 x CH), 128.24(2 x CH),
127.54(CH), 92.12(CH), 72.67(CH), 72.62(CH), 69.96(CH),
67.77(CH), 61.45(CH2), 28.94(Cq), 20.72(CH3), 20.54(2 x
CH3), 20.46(CH3), 17.00(CH2), 16.96(CH2); HRMS (ESI) (M
+ Na)+ m/z calculated for C24H28O11Na: 515.1524, found
515.1523.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2.1 Late stage functionalization of pharmaceutical carbox-
ylates
Procedure for the synthesis of β-D-Glucopyranose, 2,3,4,6-
β-D-Glucopyranose,
tetrahydro-1-naphthalenecarboxylate] [7z]
Compound 7z was prepared by using the general procedure
(B) (reaction time: 1h), with commercial
2,3,4,6-tetraacetate
1-(1,2,3,4-
tetraacetate
1-[3-(aminosulfonyl)-5-(butylamino)-4-
phenoxybenzoate] [7ab] and its characterization data
1,2,3,4-tetrahydronaphthalene-1-carboxylic acid 5z (33.8 mg,
0.19 mmol, 1.0 equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5
equiv.), which afforded the product as a white solid (65.7 mg,
68% yield after column chromatography EtOAc/Cyclohexane
3:7); diastereomeric mixture mostly visible on 13C NMR spec-
tra; TLC Rf = 0.53 (EtOAc/Cyclohexane, 1:1, SiO2); mp:
101.0 – 102.4 °C ; [α]D20 = - 9.1 (c, 1.00 in CHCl3); IR (neat,
Compound 7ab was prepared by using the general procedure
(reaction time: 2h), with commercial Bumetanide (70.0 mg,
0.19 mmol, 1.0 equiv.) and 1a (104.9 mg, 0.29 mmol, 1.5
equiv.), which afforded the product as a white solid (44.1 mg,
33% yield after column chromatography EtOAc/Cyclohexane
2:8 -> 3:7); TLC Rf = 0.35 (EtOAc/Cyclohexane, 1:1, SiO2);
20
mp: 103.4 – 104.5 °C ; [α]D = - 15.1 (c, 1.00 in CHCl3); IR
cm-1) 2944, 1757, 1455, 1366, 1209, 1073, 1033; H NMR
(neat, cm-1) 3418, 3270, 2959, 2924, 1745, 1436, 1367, 1213,
1
1
(300 MHz, CDCl3) δ (ppm) 7.21 – 7.01 (m, 4H), 5.73 (dd, J =
7.5, 5.2 Hz, 1H), 5.30 – 5.02 (m, 3H), 4.36 – 4.22 (m, 1H),
4.11 (dd, J = 12.6, 1.3 Hz, 1H), 3.95 – 3.69 (m, 2H), 2.91 –
2.61 (m, 2H), 2.24 – 2.12 (m, 1H), 2.08 (s, 3H), 2.02 (s, 3H),
2.00 (d, J = 1.5 Hz, 3H), 1.96 – 1.88 (m, 1H), 1.86 (d, J = 3.9
Hz, 3H), 1.83 – 1.68 (m, 2H); 13C{1H} NMR (75 MHz,
CDCl3) δ (ppm) 173.0 (Cq), 172.7 (Cq), 170.7 (Cq), 170.2
(Cq), 169.5 (Cq, which is splited into 169.3), 137.6 (Cq, which
is splited into 137.4), 132.13 (Cq), 129.6 (2 x CH, which is
splited into 129.5 and 129.4), 127.25 (CH), 126.0 (CH, which
is splited into 125.9), 92.0 (CH, which is splited into 91.8),
72.9 (2 x CH, which is splited into 73.0 and 72.8), 70.2 (CH,
which is splited into 70.1), 68.0 (CH, which is splited into
67.9), 61.6 (CH2), 44.8 (CH, which is splited into 43.9), 29.1
(CH2, which is splited into 29.0), 26.5 (CH2, which is splited
into 25.8), 20.9 (CH3, which is splited into 20.4), 20.7 (3 x
CH3), 20.2 (CH2); HRMS (ESI) (M + Na)+ m/z calculated for
C25H30O11Na 529.1680, found 529.1682.
1034; H NMR (300 MHz, CDCl3) δ (ppm) 7.95 (d, J = 1.8
Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.39 – 7.23 (m, 2H), 7.10 (t,
J = 7.3 Hz, 1H), 6.91 (dd, J = 8.6, 2.9 Hz, 2H), 5.96 – 5.84 (m,
1H), 5.39 – 5.27 (m, 2H), 5.27 – 5.12 (m, 1H), 5.06 (s, 2H),
4.32 (dd, J = 12.5, 4.5 Hz, 1H), 4.14 (dd, J = 12.4, 2.5 Hz,
1H), 3.95 (ddd, J = 12.8, 7.6, 3.9 Hz, 2H), 3.10 (dd, J = 12.5,
6.8 Hz, 2H), 2.07 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 2.02 (s,
3H), 1.73 – 1.56 (m, 1H), 1.41 – 1.27 (m, 1H), 1.22 – 1.07 (m,
2H), 0.82 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ (ppm) 170.8 (Cq), 170.2 (Cq), 169.6 (Cq), 169.5
(Cq), 163.5 (Cq), 155.7 (Cq), 142.5 (Cq), 140.7 (Cq), 136.6 (Cq),
130.2 (2 x CH), 126.4 (Cq), 124.0 (CH), 117.1 (CH), 116.8
(CH), 115.5 (2 x CH), 92.8 (CH), 72.9 (CH), 72.6 (CH), 70.3
(CH), 68.0 (CH), 61.6 (CH2), 43.1 (CH2), 31.0 (CH2), 20.8
(CH3), 20.7 (3 x CH3), 19.9 (CH2), 13.8 (CH3); HRMS (ESI)
(M + Na)+ m/z calculated for C31H38N2O14SNa 717.1936,
found 717.1982.
Procedure for the synthesis of β-D-Glucopyranose, 2,3,4,6-
tetraacetate 1-[4-[(dipropylamino)sulfonyl]benzoate] [7ac]
and its characterization data
D-glycero-D-gulo-Octonic acid, 3,7-anhydro-2-deoxy-, 2,3,4,
6-tetra-O-acetyl-β-D-glucopyranosyl
tetraacetate [7aa]
ester,
4,5,6,8-
Prepared according to the general procedure C, thiosugar 1a
(96 mg, 0.262 mmol), 4-(N,N-dipropylsulfamoyl)benzoic acid
(Probenecid) (50 mg, 0.175 mmol), Cu(acac)2 (4.5mg, 5%,
0.009mmol) and Ag2CO3 (145 mg, 0.525 mmol). The mixture
was stirred at 130 °C for 15mn in microwaves. The crude
product was purified by silica gel chromatography (50%
Compound 7aa was prepared by using the general procedure
A (reaction time: 15 min), with 2-((2S,3S,4R,5R,6R)-3,4,5-
triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)acetic
acid 5aa (75 mg, 0.19 mmol, 1.0 equiv.) and 1a (104.9 mg,
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The Journal of Organic Chemistry
Page 14 of 20
1-(3,5-
EtOAc/Pentane), and the product was isolated as a white oil
(57.15 mg, 53%).
β-D-Mannopyranose,
dichlorobenzoate) [8c]
2,3,4,6-tetraacetate
1
2
3
4
5
6
7
8
25
Rf (50% EtOAc/Pentane) = 0.62 ; [α]D = -20.1(c 0.0016
CH2Cl2) ; IR (neat, cm-1) 1760, 1367, 1243, 1085, 1069 ; 1H
NMR (300 MHz, CDCl3) δ (ppm) 8.14 (d, J = 8.3 Hz, 2H),
7.88 (d, J = 8.3 Hz, 2H), 5.94 – 5.89 (m, 1H), 5.36 – 5.32 (m,
2H), 5.22 – 5.14 (m, 1H), 4.31 (dd, J = 12.5, 4.5 Hz, 1H), 4.13
(dd, J = 12.5, 1.8 Hz, 1H), 4.00 – 3.90 (m, 1H), 3.13 – 3.05
(m, 4H), 2.04 (t, 9H), 1.99 (s, 3H), 1.61 – 1.46 (m, J = 14.8,
7.4 Hz, 4H), 0.86 (t, J = 7.4 Hz, 6H) ; 13C{1H} NMR (75
MHz, DMSO) δ(ppm) 170.45(Cq), 169.95(Cq), 169.34(Cq),
Compound 8c was prepared by using the general procedure
(reaction time: 1h), with commercial 3,5-dichlorobenzoic acid
5m (36.7 mg, 0.19 mmol, 1.0 equiv.) and 1c (104.9 mg, 0.29
mmol, 1.5 equiv.), which afforded the product as a white solid
(42.8 mg, 43% yield after column chromatography
EtOAc/Cyclohexane
3:7);
TLC
Rf
=
0.58
20
(EtOAc/Cyclohexane, 1:1, SiO2); mp: 80.0 – 81.5 °C ; [α]D
= + 26.3 (c, 1.00 in CHCl3); IR (neat, cm-1) 3087, 2959, 1750,
1572, 1369, 1271, 1095, 1051; 1H NMR (300 MHz, CDCl3) δ
(ppm) 7.91 (d, J = 1.7 Hz, 2H), 7.67 – 7.56 (m, 1H), 6.31 (s,
1H), 5.49 – 5.35 (m, 3H), 4.32 (dd, J = 12.6, 5.3 Hz, 1H), 4.12
(dd, J = 9.3, 3.4 Hz, 2H), 2.21 (s, 3H), 2.09 (s, 6H), 2.04 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 170.7 (Cq),
170.1 (Cq), 169.8 (Cq), 169.6 (Cq), 161.8 (Cq), 135.9 (2 x Cq),
134.0 (CH), 131.6 (Cq), 128.4 (2 x CH), 92.2 (CH), 71.4 (CH),
68.9 (CH), 68.3 (CH), 65.4 (CH), 62.1 (CH2), 20.9 (CH3), 20.8
(3 x CH3); HRMS (ESI) (M + Na)+ m/z calculated for
C21H22Cl2O11Na 543.0437, found 543.0444.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
169.27(Cq),
130.74(2xCH), 127.17(2xCH), 92.70(CH), 72.89(CH),
72.48(CH), 70.13(CH), 67.85(CH), 61.40(CH2),
163.23(Cq),
145.36(Cq),
131.66(Cq),
49.90(2xCH2), 21.89(2xCH2), 20.61(CH3), 20.51(3xCH3),
11.09(2xCH3); HRMS (ESI) (M + H)+ m/z calculated for
C27H38NO13S: 616.2058, found 616.2061.
β-D-Galactopyranose,
dimethoxybenzoate) [8a]
2,3,4,6-tetraacetate
1-(2,6-
Compound 8a was prepared by using the general procedure A
(reaction time: 15 min), with commercial 3,5-dichlorobenzoic
acid 5c (36.7 mg, 0.19 mmol, 1.0 equiv.) and 1b] (104.9 mg,
0.29 mmol, 1.5 equiv.), which afforded the product as a white
solid (70.7 mg, 71% yield after column chromatography
β-D-Fucopyranose, 2,3,4,6-tetraacetate 1-(2,6-dimethoxy
benzoate) [8d]
Compound 8d was prepared by using the general procedure
(reaction time: 15 min), with commercial 2,6-
dimethoxybenzoic acid 5c (27.75 mg, 0.152 mmol, 1.0 equiv.)
and 1d (70.0 mg, 0.228 mmol, 1.5 equiv.), which afforded the
product as a white oil (50 mg, 72 % yield after column chro-
EtOAc/Cyclohexane
3:7);
TLC
Rf
=
(30%
EtOAc/Cyclohexane) = 0.91; [α]D25= −29.00 (c 0,0031
CH2Cl2); IR (neat, cm-1) 2844, 1746, 1598, 1478,1369, 1232,
1
1113, 1053; H NMR (300 MHz, CDCl3) δ (ppm) 7.22 (d, J
matography (1% MeOH/DCM); TLC Rf
=
(50%
= 8.0 Hz, 1H), 6.48 (d, J = 8.5 Hz, 2H), 6.00 (d, J = 8.3 Hz,
1H), 5.41 – 5.30 (m, 2H), 5.08 (dd, J = 10.4, 3.4 Hz, 1H), 4.12
(d, J = 5.9 Hz, 1H), 4.06 (dd, J = 7.4, 2.0 Hz, 2H), 3.74 (s,
6H), 2.07 (s, 3H), 2.01 (s, 3H), 1.98 (d, J = 3.9 Hz, 3H), 1.94
EtOAc/Cyclohexane) = 0.63 ; [α]D25= -16.68 (c 0.0016
CH2Cl2); IR (neat, cm-1) 1575, 1598 ,1257 ,1056 ,726 ; H
1
NMR (300 MHz, CDCl3) δ (ppm) 7.29 (t, J = 8.4 Hz, 1H),
6.54 (d, J = 8.5 Hz, 2H), 6.05 (d, J = 8.3 Hz, 1H), 5.45 – 5.33
(m, 1H), 5.29 (d, J = 3.3 Hz, 1H), 5.15 (dd, 1H), 4.16 – 4.07
(m, 1H), 3.80 (s, 6H), 2.16 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H),
1.31 – 1.24 (m, J = 6.5, 1.9 Hz, 3H) ; 13C{1H} NMR (75
MHz, CDCl3) δ (ppm) 13C NMR (75 MHz, CDCl3) δ (ppm)
170.55(Cq), 170.04(Cq), 169.30(Cq), 164.43(Cq), 157.69(2 x
Cq), 131.67(CH), 111.59(2 x CH), 103.95(CH), 92.50(CH),
71.59(CH), 70.50(CH), 70.10(CH), 68.24(CH), 55.99(2 x
CH3), 20.66(CH3), 20.61(CH3), 20.57(CH3), 15.98(CH3);
HRMS (ESI) (M + H)+ m/z calculated for C21H27O11:
455.15479, found 455.1542.
(s, 3H); 13C{1H} NMR (75 MHz, CDCl3)
δ (ppm)
170.30(Cq), 170.16(Cq), 170.01(Cq), 169.20(Cq), 164.29(Cq),
157.67(2 x Cq), 131.82(CH), 103.96 (2 x CH), 92.46(CH),
71.85(CH), 71.14(CH), 68.07(CH), 66.79(CH), 60.90(CH2),
56.01(2 x CH3), 29.70(CH3), 20.63(3 x CH3), 20.56(CH3);
HRMS (ESI) (M + Na)+ m/z calculated for C23H28O13Na:
535.1428, found 535.1428.
(β-D-Galactopyranose,
dichlorobenzoate)[8b]
2,3,4,6-tetraacetate
1-(3,5-
Compound 8b was prepared by using the general procedure
(reaction time: 1h), with commercial 3,5-dichlorobenzoic acid
5m (36.7 mg, 0.19 mmol, 1.0 equiv.) and 1b (104.9 mg, 0.29
mmol, 1.5 equiv.), which afforded the product as a white solid
(70.7 mg, 71% yield after column chromatography
β-D-Glucopyranose,
2,3,4,6-benzoate
1-(3,5-
dichlorobenzoate) [8e]
Compound 8e was prepared by using the general procedure
(reaction time: 1h), with commercial 3,5-dichlorobenzoic acid
5m (36.7 mg, 0.19 mmol, 1.0 equiv.) and 1e (176.3 mg, 0.29
mmol, 1.5 equiv.), which afforded the product as a white solid
(75.1 mg, 51% yield after column chromatography
EtOAc/Cyclohexane
3:7);
TLC
Rf
=
0.58
20
(EtOAc/Cyclohexane, 1:1, SiO2); mp: 67.6 – 69.5 °C ; [α]D
= - 10.4 (c, 1.00 in CHCl3); IR (neat, cm-1) 3087, 1739, 1572,
1368, 1208, 1081, 1030; 1H NMR (300 MHz, CDCl3) δ
(ppm) 7.92 (s, 2H), 7.58 (s, 1H), 5.89 (d, J = 8.3 Hz, 1H), 5.57
– 5.37 (m, 2H), 5.16 (dd, J = 10.4, 3.5 Hz, 1H), 4.23 – 3.99
(m, 3H), 2.19 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 170.5 (Cq), 170.2
(Cq), 170.1 (Cq), 169.5 (Cq), 162.5 (Cq), 135.7 (2 x Cq), 133.9
(CH), 131.4 (Cq), 128.6 (2 x CH), 93.4 (CH), 72.0 (CH), 70.7
(CH), 67.8 (CH), 66.9 (CH), 61.1 (CH2), 20.8 (3 x CH3), 20.7
EtOAc/Cyclohexane
3:7);
TLC
Rf
=
0.84
(EtOAc/Cyclohexane, 1:1, SiO2); mp: 100.9 – 101.5 °C ;
20
[α]D = + 8.9 (c, 1.00 in CHCl3); IR (neat, cm-1) 3067, 2969,
1
1722, 1602, 1452, 1316, 1091, 1086, 1026; H NMR (300
MHz, CDCl3) δ (ppm) 8.05 (d, J = 7.3 Hz, 2H), 7.94 (dd, J =
7.5, 4.1 Hz, 4H), 7.90 (s, 1H), 7.89 (s, 2H), 7.87 (s, 1H), 7.56
(d, J = 7.3 Hz, 1H), 7.54 – 7.51 (m, 2H), 7.51 – 7.47 (m, 1H),
7.44 (dd, J = 7.3, 2.8 Hz, 2H), 7.37 (d, J = 7.3 Hz, 3H), 7.32
(d, J = 7.8 Hz, 3H), 7.28 (s, 1H), 6.27 (d, J = 7.9 Hz, 1H), 6.06
(t, J = 9.4 Hz, 1H), 5.84 (dd, J = 13.5, 5.8 Hz, 2H), 4.69 (dd, J
= 12.3, 2.7 Hz, 1H), 4.52 (dd, J = 12.3, 4.7 Hz, 1H), 4.47 –
4.36 (m, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ (ppm)
(CH3); HRMS (ESI) (M
C21H22Cl2O11Na 543.0437, found 543.0433.
+
Na)+ m/z calculated for
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The Journal of Organic Chemistry
(m, 2H, ), 3.24 (d, J = 4.1 Hz, 0.7H, OH), 2.82 (d, J = 2.7 Hz,
166.2 (Cq), 165.8 (Cq), 165.2 (2 x Cq), 162.6 (Cq), 135.6 (3 x
1
2
3
4
5
6
7
8
Cq), 133.8 (2 x CH), 133.7 (2 x CH), 133.5 (CH), 133.3 (CH),
131.5 (Cq), 130.0 (4 x CH), 129.9 (4 x CH), 129.6 (Cq), 128.7
(2 x Cq), 128.6 (5 x CH), 128.5 (4 x CH), 93.4 (CH), 73.5
(CH), 72.7 (CH), 71.0 (CH), 69.0 (CH), 62.7 (CH2); HRMS
(ESI) (M + Na)+ m/z calculated for C41H30Cl2O11Na 791.1063,
found 791.1062.
0.3H, OH), 0.98 (s, 3H, CH3), 0.89 (dd, J = 4.4, 2.3 Hz, 21H,
7XCH3), 0.82 (s, 3H, CH3), 0.21 (d, J = 15.0 Hz, 3H, CH3),
0.18 – 0.14 (m, 6H , 2XCH3), 0.12 (d, J = 2.0 Hz, 3H, CH3),
0.09 (d, J = 4.5 Hz, 3H, CH3), 0.05 (s, 3H, CH3). 13C{1H}
NMR (75 MHz, CDCl3) δ (ppm) 164.23 (C=O), 132.25 ( Ph),
129.02 (Ph), 128.83 (C1), 128.76 (Ph), 127.46 (Ph),
127.25(Ph), 93.57 (C1'), 91.77 (C1'), 74.85, 74.66, 74.00,
71.98, 71.65, 71.50, 70.58, 63.35 (C6'), 63.19 (C6'), 25.18
(SiC(CH3)3), 24.97 (SiC(CH3)3), 24.77 (SiC(CH3)3), 17.40
(SiC(CH3)3), 17.23 (SiC(CH3)3), 16.93 (SiC(CH3)3), -5.03
(SiCH3), -5.08 (SiCH3), -5.18 (SiCH3), -5.30 (SiCH3), -5.42
(SiCH3), -6.46 (SiCH3). HRMS (ESI) (M + Na)+ m/z calculat-
ed for C31H62NO7Si3+ 644.3832, found 644.3834.
α-D-Glucopyranose,
2,3,4,6-tetra-O-methyl
1-(2,6-
dimethoxybenzoate) [α–8f]
Compounds α–8f and β–8f were prepared by using the proce-
dure (A) (reaction time: 15 min) with commercial
2,6-dimethoxybenzoic acid 5c (91.46 mg, 0.502 mmol, 1.0
equiv.) and 1f (190.0 mg, 0.753 mmol, 1.5 equiv.), which
afforded the product as a yellow oil in a mixture of α:β (1:1
ratio) (184 mg, 91%). After purification through column
chromatography EtOAc/Cyclohexane 5:5), both anomers were
isolated and characterized:
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
β-D-Cellobiose,
2,2',3,3',4',6,6'-heptaacetate
1-(2,6-
Anomer α–8f: 45% yield, TLC Rf
=
(50%
dimethoxybenzoate) [8h]
EtOAc/Cyclohexane) = 0.4 ; [α]D25= 123.07 (c 0.0016
CH2Cl2); IR (neat, cm-1) 1752, 1597, 1476, 1257, 1091, 730;
1H NMR (300 MHz, CDCl3) δ (ppm) 7.28 (t, J = 8.4 Hz,
1H), 6.54 (d, J = 8.4 Hz, 2H), 5.72 (d, J = 7.8 Hz, 1H), 3.77
(d, J = 15.4 Hz, 6H), 3.68 – 3.67 (m, J = 1.9 Hz, 1H), 3.65 (s,
3H), 3.63 (d, J = 3.8 Hz, 1H), 3.57 (s, 3H), 3.55 (s, 3H), 3.50 –
3.45 (m, 1H), 3.41 (s, 3H), 3.29 (dd, J = 10.5, 6.1 Hz, 2H),
3.25 – 3.18 (m, 1H) ; 13C{1H} NMR (75 MHz, CDCl3) δ
(ppm) 164.90(Cq), 157.40(Cq), 131.28(CH), 112.52(Cq),
Compound 8h was prepared by using the general procedure A
(reaction time: 15 min), with commercial 2,6-
dimethoxybenzoic acid 5c ( (18.58 mg, 0.102mmol, 1.0
equiv.) and 1h (99.85 mg, 0.153 mmol, 1.5 equiv.), which
afforded the product as a yellow oil (43.3 mg, 53% yield after
column chromatography 2% MeOH/DCM); TLC Rf = (50%
MeOH/DCM) = 0.29; [α]D25= −43.75 (c 0,0032 CH2Cl2); IR
(neat, cm-1) 3400, 1759, 1738, 1364, 1212, 1114, 1042 ; 1H
NMR (300 MHz, CDCl3) δ (ppm) 7.22 (d, J = 6.5 Hz, 1H),
6.47 (d, J = 8.4 Hz, 2H), 5.96 (d, J = 8.1 Hz, 1H), 5.26 – 5.18
(m, J = 8.9 Hz, 1H), 5.14 – 5.03 (m, 2H), 4.99 (d, J = 9.6 Hz,
1H), 4.87 (t, J = 8.4 Hz, 1H), 4.51 – 4.43 (m, 2H), 4.30 (dd, J
= 12.4, 4.5 Hz, 1H), 4.13 (dd, J = 12.2, 4.5 Hz, 1H), 4.03 –
3.97 (m, J = 12.6 Hz, 1H), 3.86 – 3.80 (m, J = 6.7 Hz, 1H),
3.79 – 3.75 (m, 1H), 3.73 (s, 6H), 3.64 – 3.57 (m, J = 9.8 Hz,
1H), 2.06 (s, 3H), 2.04 (s, 3H), 1.98 (s, 6H), 1.97 (s, 3H), 1.95
(s, 3H), 1.93 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
(ppm) 169.52(Cq), 169.27(Cq), 169.22(Cq), 168.71(Cq),
168.46(Cq), 168.29(Cq), 168.01(Cq), 163.08(Cq), 156.73(2 x
Cq), 130.85(CH), 110.30(Cq), 102.97(2 x CH), 99.61(CH),
90.96(CH), 74.93(CH), 72.74(CH), 71.92(CH), 71.61(CH),
70.99(CH), 70.60(CH), 69.81(CH), 66.85(CH), 60.69(CH2),
60.59(CH2), 54.99(2 x CH3), 19.81(CH3), 19.63(CH3), 19.53(5
x CH3); HRMS (ESI) (M + Na)+ m/z calculated for
C35H44O21Na: 823.2273, found 823.2275.
103.83(2
x
CH), 94.65(CH), 86.42(CH), 82.65(CH),
78.78(CH), 75.73(CH), 70.75(Cq), 60.81(CH3), 60.29(CH3),
60.15(CH3), 59.30(CH3), 55.85(2 x CH), 29.63(CH2); HRMS
(ESI) (M + H)+ m/z calculated for C19H29O9: 401.1806, found
401.1766.
β-D-Glucopyranose,
2,3,4,6-tetra-O-methyl
1-(2,6-
dimethoxybenzoate) [β–8f]
Anomer
β
–8f: 45% yield, TLC Rf
=
(50%
EtOAc/Cyclohexane) = 0.52 ; [α]D25= 235.72 (c 0.0016
CH2Cl2); IR (neat, cm-1) 1745, 1596, 1476, 1257, 1097, 990;
1H NMR (300 MHz, CDCl3) δ (ppm) 7.28 (s, 1H), 6.54 (d, J
= 8.4 Hz, 2H), 6.49 (d, J = 3.5 Hz, 1H), 3.95 – 3.86 (m, J =
12.9, 5.4 Hz, 1H), 3.80 (s, 6H), 3.62 (s, 2H), 3.61 (s, 3H), 3.55
(s, 3H), 3.49 (s, 3H), 3.40 (s, 3H), 3.39 (d, J = 3.5 Hz, 1H),
3.36 (d, J = 3.6 Hz, 1H), 3.32 – 3.26 (m, J = 9.5 Hz, 1H;
13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 164.78(Cq),
157.81(Cq), 131.38(CH), 112.44(Cq), 104.02(2
x
CH),
β-D-Cellobiose,
2,2',3,3',4',6,6'-heptaacetate
1-(3,5-
89.96(CH), 83.05(CH), 80.52, (CH) 78.82(CH), 72.41(CH),
70.67(Cq), 60.73(CH3), 60.45(CH3), 59.14(CH3), 58.24(CH3),
55.91(2 x CH), 29.65(CH2); HRMS (ESI) (M + H)+ m/z
calculated for C19H29O9: 401.1806, found 401.1766.
dichlorobenzoate) [8i]
Compound 8i was prepared by using the general procedure B
(reaction time: 1h), with commercial 3,5-dichlorobenzoic acid
5m (36.7 mg, 0.19 mmol, 1.0 equiv.) and 1h (187.8 mg, 0.29
mmol, 1.5 equiv.), which afforded the product as a white solid
(69.1 mg, 45% yield after column chromatography
D-Glucopyranose, 2,4,6-tri-O-[tert-butyldimethylsilyl] 1-
benzoate [8g]
EtOAc/Cyclohexane
3:7);
TLC
Rf
=
0.41
(EtOAc/Cyclohexane, 1:1, SiO2); mp: 162.2 – 164.0 °C ;
Compound 8g was prepared by using the general procedure A
(reaction time: 15 min), with commercial benzoic acid 5a (1.0
equiv.) and 1g (1.2 equiv.), which afforded the product as a
colourless oil in a mixture of two isomers 2:1 ratio (36 mg,
70% yield after column chromatography EtOAc/Cyclohexane
[α]D20 = - 10.7 (c, 1.00 in CHCl3); IR (neat, cm-1) 2949, 1757,
1
1745, 1368, 1230, 1215, 1168, 1037; H NMR (300 MHz,
CDCl3) δ (ppm) 7.87 (d, J = 2.2 Hz, 2H), 7.58 (t, J = 2.2 Hz,
1H), 5.87 (d, J = 7.8 Hz, 1H), 5.34 – 5.21 (m, 2H), 5.11 (dt, J
= 18.9, 9.7 Hz, 2H), 4.98 – 4.90 (m, 1H), 4.56 – 4.46 (m, 2H),
4.37 (dd, J = 12.5, 4.5 Hz, 1H), 4.13 (dd, J = 12.2, 4.2 Hz,
1H), 4.06 (dd, J = 12.5, 2.4 Hz, 1H), 3.93 – 3.79 (m, 2H), 3.68
(ddd, J = 9.7, 4.6, 2.3 Hz, 1H), 2.11 (s, 3H), 2.10 (s, 3H), 2.06
(s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 170.6 (Cq), 170.4
1
3:7); TLC Rf = 0.33 (EtOAc/Cyclohexane, 95:5, SiO2); H
NMR (300 MHz, CDCl3) δ (ppm) 8.08 (m, 2H, H-2, H-6),
7.59 (m, 1H, H-4), 7.47 (dt, J = 15.1, 7.6 Hz, 2H, H-3, H-5),
6.33 (d, J = 3.4 Hz, 0.3H, H-1'), 6.09 – 5.99 (m, 0.7H, H-1'),
4.08 – 3.93 (m, 2H, ), 3.85 (d, J = 2.7 Hz, 2H, ), 3.81 – 3.58
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(2 x Cq), 169.7 (Cq), 169.6 (Cq), 169.5 (Cq), 169.2 (Cq), 162.4
13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 170.8 (2 x Cq),
1
2
3
4
5
6
7
8
(Cq), 135.7 (2 x Cq), 133.9 (CH), 131.5 (Cq), 128.6 (2x CH),
100.9 (CH), 92.8 (CH), 76.0 (CH), 73.8 (CH), 73.0 (CH), 72.3
(CH), 72.2 (CH), 71.7 (CH), 70.4 (CH), 67.9 (CH), 61.8
(CH2), 61.7 (CH2), 21.0 (CH3), 20.8 (CH3), 20.7 (5 x CH3);
HRMS (ESI) (M + Na)+ m/z calculated for C33H38Cl2O19Na
831.1277, found 831.1299.
170.7 (Cq), 170.6 (Cq), 170.5 (Cq), 170.0 (2 x Cq), 169.8 (Cq),
169.7 (Cq), 169.6 (Cq), 162.4 (Cq), 135.7 (2 x Cq), 133.9 (CH),
131.5 (Cq), 128.6 (2 x CH), 96.2 (CH), 95.8 (CH), 92.4 (CH),
74.9 (CH), 73.6 (CH), 73.2 (CH), 72.6 (CH), 71.8 (CH), 70.9
(CH), 70.6 (CH), 70.2 (CH), 69.5 (CH), 69.3 (CH), 68.7 (CH),
68.0 (CH), 62.7 (CH2), 62.4 (CH2), 61.5 (CH2), 21.1 (3 x
CH3), 20.8 (7 x CH3); HRMS (ESI) (M + Na)+ m/z calculated
for C45H54Cl2O27Na 1119.2127, found 1119.2125.
β-D-Glucopyranose, O-2,3,4,6-tetra-O-acetyl-α-D-
glucopyranosyl-(1→4)-O-2,3,6-tri-O-acetyl-α-D-
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glucopyranosyl-(1→4)-,
dimethoxybenzoate) [8j]
2,3,6-triacetate
1-(2,6-
Compound 8j was prepared by using the general procedure A
(reaction time: 15 min), with commercial 2,6-
dimethoxybenzoic acid 5c (10.2 mg, 0.056 mmol, 1.0 equiv.)
and 1i[25] (79.0 mg, 0.084 mmol, 1.5 equiv.), which afforded
the product as a white solid (25.6 mg, 42% yield after column
chromatography (1% MeOH/DCM); TLC Rf = Rf (50%
EtOAc/Cyclohexane) = 0.17; mp: 92-101 °C ; [α]D25= +28.88
(c 0,0045 CH2Cl2); IR (neat, cm-1) 3260,2978, 1757, 1641,
1369, 1297, 1115, 1044; 1H NMR (300 MHz, CDCl3) δ
(ppm) 7.22 (d, J = 6.6 Hz, 1H), 6.47 (d, J = 8.5 Hz, 1H), 6.03
(d, J = 7.9 Hz, 1H), 5.37 – 5.33 (m, J = 4.0 Hz, 2H), 5.29 (d, J
= 4.4 Hz, 2H), 5.25 (dd, J = 6.9, 3.5 Hz, 2H), 5.02 – 4.95 (m, J
= 9.0, 4.4 Hz, 2H), 4.80 (dd, J = 10.5, 3.9 Hz, 1H), 4.69 (dd, J
= 10.3, 4.0 Hz, 1H), 4.43 – 4.38 (m, 2H), 4.32 (dd, J = 12.1,
4.0 Hz, 1H), 4.19 (dd, J = 12.5, 3.4 Hz, 1H), 4.08 (d, J = 7.1
Hz, 1H), 4.03 – 3.99 (m, J = 7.4 Hz, 1H), 3.92 – 3.85 (m, J =
8.5 Hz, 4H), 3.73 (s, 6H), 2.09 (d, J = 3.9 Hz, 6H), 2.04 (s,
3H), 2.01 (s, 3H), 1.97 (s, 9H), 1.96 – 1.93 (m, 9H); 13C{1H}
NMR (75 MHz, CDCl3) δ (ppm) 170.79(2 x Cq), 170.64(2 x
Cq), 170.50(Cq), 170.19(Cq), 169.93(Cq), 169.78(2 x Cq,
169.60(2 x Cq), 164.14(Cq), 157.91(Cq), 132.00(CH), 104.12(2
β-D-Glucopyranose, 2,3,4,6-tetraacetate 1-[4-[[3,4,6-tri-O-
acetyl-2-(acetylamino)-2-deoxy-β-D-glucopyranosyl]thio]
benzoate] [9a]
According to A. Bruneau et al. procedure[31], a sealed tube is
charged with Xantphos Pd-G3 precatalyst (2 mol%), N-acetyl-
1-thio-β-D-aminoglucopyranose 1j (27.2 mg, 0.075 mmol, 1.0
equiv.),
(2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((4-
iodobenzoyl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate 7l
(43.4 mg, 0.075 mmol, 1 equiv.). After Argon flushing, diox-
ane (0.3 mL, 0.25M) is added. Upon stirring the reaction mix-
ture, NEt3 (0.01 mL, 0.075 mmol, 1 equiv.) is added to the
medium. The reaction mixture was stirred at room temperature
under Argon during 2h, which afforded the product 9a as a
white solid (54.9 mg, 90% yield after column chromatography
EtOAc/Cyclohexane 5:5 -> 8:2); TLC Rf
=
0.07
(EtOAc/Cyclohexane, 1:1, SiO2); mp: 248.9 – 249.4 °C ;
19
[α]D = - 8.5 (c, 1.00 in CHCl3); IR (neat, cm-1) 2939, 1740,
1
1595, 1434, 1367, 1213, 1084, 1043; H NMR (300 MHz,
CDCl3) δ (ppm) 7.92 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz,
2H), 5.89 (d, J = 7.9 Hz, 1H), 5.73 (d, J = 9.2 Hz, 1H), 5.36 –
5.30 (m, 2H), 5.30 – 5.13 (m, 2H), 5.13 – 4.99 (m, 2H), 4.32
(dd, J = 12.6, 4.4 Hz, 1H), 4.23 – 4.09 (m, 3H), 3.93 (ddd, J =
9.7, 4.5, 2.2 Hz, 1H), 3.81 (ddd, J = 10.0, 5.6, 2.6 Hz, 1H),
2.10 (s, 3H), 2.07 (s, 3H), 2.04 (s, 6H), 2.03 (s, 6H), 1.98 (s,
3H), 1.95 (s, 3H), no NH proton observed; 13C{1H} NMR (75
MHz, CDCl3) δ (ppm) 171.2 (Cq), 170.7 (2 x Cq), 170.3 (Cq),
170.2 (Cq), 169.6 (Cq), 169.5 (Cq), 169.4 (Cq), 164.1 (Cq),
141.9 (Cq), 130.6 (2 x CH), 129.6 (2 x CH), 126.9 (Cq), 92.5
(CH), 85.6 (CH), 76.1 (CH), 73.5 (CH), 72.9 (CH), 72.7 (CH),
70.2 (CH), 68.4 (CH), 68.0 (CH), 62.5 (CH2), 61.6 (CH2), 53.4
(CH), 23.4 (CH3), 20.9 (CH3), 20.8 (2 x CH3), 20.7 (4 x CH3);
HRMS (ESI) (M + Na)+ m/z calculated for C35H43NO19SNa
836.2048, found 836.2033.
x
CH), 96.00(CH), 95.84(CH), 91.84(CH), 75.60(CH),
73.63(CH), 73.30(CH), 72.70(CH), 71.89(CH), 71.58(CH),
70.59(CH), 70.22(CH), 69.54(CH), 69.14(CH), 68.67(CH),
68.09(CH), 63.00(CH2), 62.47(CH2), 61.57(CH2), 56.15(2 x
CH3),29,85(Cq), 21.00(CH3), 20.81(CH3), 20.73(8 x CH3);
HRMS (ESI) (M + Na)+ m/z calculated for C47H60O29Na:
1111.3118, found 1111.3125.
β-D-Glucopyranose, O-2,3,4,6-tetra-O-acetyl-α-D-
glucopyranosyl-(1→4)-O-2,3,6-tri-O-acetyl-α-D-
glucopyranosyl-(1→4)-,
dichlorobenzoate) [8k]
2,3,6-triacetate
1-(3,5-
Compound 8k was prepared by using the general procedure B
(reaction time: 1h), with commercial 3,5-dichlorobenzoic acid
5m (36.7 mg, 0.19 mmol, 1.0 equiv.) and 1i (270.8 mg, 0.29
mmol, 1.5 equiv.), which afforded the product as a white solid
(80.6 mg, 38% yield after column chromatography
L-Cysteine, N-acetyl-S-[4-[[(2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosyl)oxy]carbonyl]phenyl]- [9b]
According to A. Bruneau et al. procedure[31], a sealed tube is
charged with Xantphos Pd-G3 precatalyst (4 mol%), N-Acetyl-
L-Cysteine (17 mg, 0.10 mmol, 1.0 equiv.), (2R,3R,4S,5R,6S)-
2-(acetoxymethyl)-6-((4-iodobenzoyl)oxy)tetrahydro-2H-
pyran-3,4,5-triyl triacetate 7l (50 mg, 0.086 mmol, 1 equiv.).
After Argon flushing, dioxane (1 mL) is added. Upon stirring
the reaction mixture, NEt3 (0.129 mmol) is added to the medi-
um. The reaction mixture was stirred at 60 °C during 20 min,
which afforded the product 9b as a beige solid (35.5 mg, 67%
yield after column chromatography MeOH/DCM 1:9); Rf (5%
MeOH/DCM) = 0.29 ; mp: 152-160 °C; [α]D25= −50.00 (c
0,002 CH2Cl2); IR (neat, cm-1) 1752, 1738, 1595, 1235,
EtOAc/Cyclohexane
1:1);
TLC
Rf
=
0.25
(EtOAc/Cyclohexane, 1:1, SiO2); mp: 125.4 – 126.7 °C ;
[α]D20 = + 64.0 (c, 1.00 in CHCl3); IR (neat, cm-1) 2964, 2934,
1
1756, 1572, 1433, 1367, 1205, 1024; H NMR (300 MHz,
CDCl3) δ (ppm) 7.88 (s, 2H), 7.58 (s, 1H), 5.97 (d, J = 7.7
Hz, 1H), 5.44 – 5.35 (m, 4H), 5.33 (d, J = 4.4 Hz, 1H), 5.29
(d, J = 4.6 Hz, 1H), 5.17 – 5.09 (m, 1H), 5.05 (d, J = 9.9 Hz,
1H), 4.86 (dd, J = 10.3, 4.1 Hz, 1H), 4.75 (dd, J = 10.3, 3.9
Hz, 1H), 4.47 (d, J = 11.6 Hz, 2H), 4.28 (ddd, J = 20.8, 12.4,
3.6 Hz, 2H), 4.21 – 4.12 (m, 1H), 4.10 – 4.00 (m, 2H), 3.93
(dd, J = 11.1, 6.0 Hz, 3H), 2.15 (s, 6H), 2.10 (s, 3H), 2.06 (s,
3H), 2.04 (s, 6H), 2.03 (s, 3H), 2.01 (s, 3H), 1.99 (s, 6H);
1
1214, 1087, 1054, 1033 ; H NMR (300 MHz, DMSO) δ
(ppm) 7.77 (d, J = 8.3 Hz, 2H), 7.66 – 7.61 (m, 1H), 7.42 (d, J
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The Journal of Organic Chemistry
3.67 – 3.62 (m, 1H, H-3), 3.60 (dd, J = 6.8, 5.0 Hz, 1H, H-5),
= 8.4 Hz, 2H), 6.16 (d, J = 8.2 Hz, 1H), 5.53 (t, J = 9.6 Hz,
1
2
3
4
5
6
7
8
1H), 5.17 – 5.09 (m, 1H), 5.03 (t, J = 9.7 Hz, 1H), 4.33 – 4.25
(m, J = 9.2 Hz, 1H), 4.20 (dd, J = 12.2, 4.8 Hz, 1H), 4.02 (d, J
= 12.4 Hz, 1H), 3.59 – 3.50 (m, 1H), 3.36 – 3.21 (m, 2H), 2.08
(s, 3H), 2.00 (d, J = 1.2 Hz, 6H), 1.98 (s, 3H), 1.95 (s, 3H);
13C{1H} NMR (75 MHz, DMSO) δ(ppm) 172.88(Cq),
170.87(Cq), 170.31(2 x Cq), 170.09(2 x Cq), 164.14(Cq),
147.14(Cq), 130.25(2 x CH), 126.48( 2 x CH), 124.07(Cq),
3.11 (d, J = 4.7 Hz, 1H, OH), 2.42 (d, J = 8.5 Hz, 1H, SH),
0.94 (s, 6H, 2XCH3), 0.92 (s, 9H, 3XCH3), 0.90 (s, 12H,
4XCH3), 0.18 (s, 3H, CH3), 0.16 (s, 3H, CH3), 0.14 (d, J = 2.8
Hz, 6H, 2XCH3), 0.09 (s, 6H, 2XCH3); 13C{1H} NMR (101
MHz, CDCl3): δ 79.96 (C1), 78.32 (C3), 77.55 (C2), 77.22
(C4), 72.78 (C5), 65.21 (C6), 26.44 (SiC(CH3)3), 26.23
(SiC(CH3)3), 26.01 (SiC(CH3)3), 18.64 (SiC(CH3)3), 18.41
(SiC(CH3)3), 18.27 (SiC(CH3)3), -3.18 (SiCH3), -3.27 (SiCH3),
-3.47 (SiCH3), -3.57 (SiCH3), -5.20 (SiCH3), -5.23 (SiCH3).
92.06(CH), 72.02(2
x
CH), 70.48(CH), 68.06(CH),
61.71(CH2), 53.90(CH), 34.92(CH2), 22.97(CH3), 20.81(CH3),
20.69(CH3), 20.62(CH3), 20.54(CH3).; HRMS (ESI) (M +
Na)+ m/z calculated for C26H31NO14NaS: 636.1363, found
636.1370.
+
HRMS (ESI) (M + NH4)+ m/z calculated for C24H58NO5SSi3
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556.3338, found 556.3353.
3. Extension of the methodology for molecular diversity
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Full optimization table, NMR spectra of all synthesized com-
pounds and HPLC chromatograms.
3.1 Procedure for the synthesis of 2-acetamidoethyl 3,5-
dichlorobenzoate [10a] and its characterization data
Compound 10a was prepared by using the general procedure
(reaction time: 1h), with commercial 3,5-dichlorobenzoic acid
5m (36.7 mg, 0.19 mmol, 1.0 equiv.) and commercial
N-acetylcysteamine (34.3 mg, 0.29 mmol, 1.5 equiv.), which
afforded the product as a white solid (35.8 mg, 68% yield after
column chromatography EtOAc/Cyclohexane 1:1 -> 7:3);
TLC Rf = 0.13 (EtOAc/Cyclohexane, 1:1, SiO2); mp: 139.0 –
AUTHOR INFORMATION
Corresponding Author
* samir.messaoudi@u-psud.fr
20
139.5 °C ; [α]D = - 5.1 (c, 1.00 in CHCl3); IR (neat, cm-1)
Author Contributions
1
3293, 3078, 1728, 1642, 1570, 1432, 1385, 1362, 1274; H
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the manu-
script.
NMR (300 MHz, CDCl3) δ (ppm) 7.90 (d, J = 1.9 Hz, 2H),
7.56 (t, J = 2.0 Hz, 1H), 5.99 – 5.77 (m, 1H, NH proton), 4.43
(t, J = 5.3 Hz, 2H), 3.66 (dd, J = 10.9, 5.5 Hz, 2H), 2.03 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 170.7 (Cq),
164.5 (Cq), 135.6 (2 x Cq), 133.2 (CH), 132.7 (Cq), 128.2 (2 x
CH), 64.8 (CH2), 39.0 (CH2), 23.4 (CH3); HRMS (ESI) (M +
Na)+ m/z calculated for C11H11NO3Cl2Na 298.0014, found
298.0025.
Funding Sources
Any funds used to support the research of the manuscript should
be placed here (per journal style).
Notes
Any additional relevant notes should be placed here.
ABBREVIATIONS
Synthesis of the starting thiosugars 1g
β-D-Glucopyranose,
2,4,6-tris-O-[(1,1-dimethylethyl)
ACKNOWLEDGMENT
dimethylsilyl]-1-thio-1g
NaOMe (0.5 M sol. in MeOH, 6 ml, 1.5 eq) was added to a
solution thiosugar 1a (750 mg, 2 mmol) in MeOH (28 ml) and
stirred at RT for 30 min under Ar atmosphere. The solution
was neutralized using Dowex® 50WX8 100-200 (H), filtered,
concentrated and used without further purification.
Authors acknowledge support of this project by CNRS, University
Paris-Sud, ANR (ANR-15-CE29- 0002), and by la Ligue Contre
le Cancer through an Equipe Labellisée 2014 grant. We also thank
the Algerian Ministry of Education and Research for a fellowship
(Profas B+) to Nedjwa Bennai. Our laboratory is a member of the
Laboratory of Excellence LERMIT supported by a grant (ANR-
10-LABX-33)
To the polyhydroxy product in anhydrous DMF (14 ml),
TBDMSCl (3 g, 20 mmmol, 10 equiv.) and imidazole (3.3 g,
48 mmmol, 24 equiv.) were added and stirred at RT for over-
night under Ar atmosphere. TLC showed no more starting
material and also showed products with different number of
TBS protecting groups (three and four according to HRMS
(ESI+)). The reaction was quenched with MeOH (10ml) then
extracted with pentane (3x 15 ml). The pentane layers were
collected and dried over MgSO4, filtered, concentrated under
reduced pressure then purified by column chromatography
using (1-2% EtOAc in pentane). Out of all fractions, only one
pure fraction was obtained as colorless oil (72 mg) in 7%
yield.
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