One-pot, highly stereoselective synthesis of dithioacetal-α,α-diglycosides

Article abstract of DOI:10.3390/molecules23040914

A one-step access to dithioacetal-α,α-diglycosides is reported. The synthetic strategy is based on the thioacetalization of aldehydes or ketones via highly stereoselective ring-opening of 1,6 anhydrosugars with bis(trimethylsilyl)sulfide.

Full text of DOI:10.3390/molecules23040914

molecules
Communication
One-Pot, Highly Stereoselective Synthesis of
Dithioacetal-α,α-Diglycosides
Maria F. Céspedes Dávila †, Jérémy P. Schneider †, Amélie Godard, Damien Hazelard and
ID
Philippe Compain *
Laboratoire d’Innovation Moléculaire et Applications (LIMA), Université de Strasbourg,
Université de Haute-Alsace, CNRS (UMR 7042), Equipe Synthèse Organique et Molécules Bioactives (SYBIO),
Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, 67000 Strasbourg, France;
mafercespedes@hotmail.com (M.F.C.D.); jeremy.schneider@live.fr (J.P.S.);
amelie.godard@etu.unistra.fr (A.G.); damien.hazelard@unistra.fr (D.H.)
* Correspondence: philippe.compain@unistra.fr; Tel.: +33-3-6885-2792
† These authors contributed equally to the work.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 28 March 2018; Accepted: 13 April 2018; Published: 15 April 2018
Abstract: A one-step access to dithioacetal-α,α-diglycosides is reported. The synthetic strategy is
based on the thioacetalization of aldehydes or ketones via highly stereoselective ring-opening of 1,6
anhydrosugars with bis(trimethylsilyl)sulfide.
Keywords: glycomimetics; thioglycosides; dithioacetals; 1,6-anhydrosugars; ring-opening
1. Introduction
Carbohydrates are a major class of inspiring structures for the design of biologically active
compounds. These densely functionalized chiral molecules represent also a prolific source of useful
building blocks and molecular tools for asymmetric synthesis. Moreover, their relative structural
complexity has been a fertile ground for accidental discoveries in organic synthesis [
we have recently reported a molecular Lego approach for the synthesis of functionalized cyclic and
acyclic neo-oligosaccharides [ ]. Our strategy was based on the linkage of bifunctional building blocks
by Cu(I)-catalyzed azide alkyne cycloaddition, the reducing end of the sugars being activated as a
glycosyl azide and masked as a 1,6-anhydro sugar [ ]. To explore the interest of thiol-click chemistry
for such modular strategies [ ], we needed to synthesize thioglycoside (Scheme 1). In a first attempt,
(TMS)2S ring-opening of 1,6-anhydro sugar mediated by TMSOTf following Zhu’s protocol [ ] did not
lead to the desired -glucosyl thiol (Scheme 1). Much to our surprise, dithioacetal- -diglucoside
was obtained as the major product in low yields and as a single diastereomer. We assumed that
the unexpected formation of dithioacetal was due to the accidental presence of traces of acetone
in the reaction mixture. Dithioacetal diglycosides have almost no precedent in the literature [ ].
These compounds may be viewed as analogues of trehalose ( ), a biologically relevant nonreducing
disaccharide found in microorganisms, bacteria, plants and invertebrates [ 11]. Examples of related
diglycoside acetals designed for asymmetric synthesis, molecular imaging or for their biological
interest have been described in the literature [12 13]. Chemistry wise, we were also attracted by the
1]. In this context,
2
−
2,3
4,
5
1
2
6
α
1
α
,α
3
3
7,8
4
9–
,
efficiency of this highly stereoselective process in which the formation of multiple C-S single bonds
generates an original thiodisaccharide analogue in one step. In this communication, we wish to report
our preliminary exploration of the synthetic scope of this TMSOTf-mediated one-pot reaction leading
to dithioacetal diglycosides via 1,6-anhydro sugar ring-opening.
Molecules 2018, 23, 914; doi:10.3390/molecules23040914
www.mdpi.com/journal/molecules

Molecules 2018, 23, 914
2 of 11
Scheme 1. (a) Unexpected formation of dithioacetal diglucoside 3. (b) Trehalose structure.
2. Results and Discussion
2.1. Optimization of the Reaction Conditions
Exploration of the synthetic scope of the one-pot process was first performed with
1,6-anhydro-D-glucose 5a [14] using benzaldehyde as the model carbonyl partner (Table 1). The choice
of benzaldehyde was guided by mechanistic considerations as we anticipated that this non-enolisable
carbonyl compound offered a good equilibrium between reactivity, stability and low volatility.
According to the tentative mechanism proposed in Figure 1, TMSOTf is expected to play a double
role in the formation of the dithioacetal product. In the first step, TMSOTf promotes the highly
diastereoselective (TMS)2S ring-opening of anhydrosugar
second step, addition of the resulting -thioglycoside to the TMSOTf-activated carbonyl compound
affords the stabilized -thio carbocation via thioacetal 15 18]. The subsequent interception of
-thioglycoside affords the dithioacetal- -diglycoside
A following a SN2-type mode [6]. In a
α
B
α
D
C [ –
this carbocation by a second molecule of
after aqueous work-up.
α
B
α
,α
E
Figure 1. Tentative mechanism for the TMSOTf-mediated formation of dithioacetal diglycosides.
According to Zhu’s optimized conditions [6], 1.4 equiv. of (TMS)2S were used in refluxing
dichloromethane and the quantity of TMSOTf was increased from 0.4 equiv. to stoichiometric quantity
to take into account the activation of the carbonyl compound according to our tentative mechanism
(Figure 1). The reaction was performed in hermetically sealed tubes to avoid solvent evaporation.
First attempts to obtain dithioacetal 6a by introducing benzaldehyde at the beginning of the reaction led
to unidentified degradation products. To avoid possible inhibition of the first step of the process, i.e.,
the formation of the key thioglycoside intermediate B, the carbonyl partner was added subsequently

Molecules 2018, 23, 914
3 of 11
after conversion of anhydrosugar 5a to the corresponding thioglycoside derivative. After several
assays performed in the absence of benzaldehyde, we found that a complete conversion of the starting
material into thioglycoside
7 could be achieved after 2 h when 1.1 equiv. of TMSOTf were used.
Various experimental parameters were then examined for the second step. In a first attempt made
at room temperature using 0.5 equiv. of benzaldehyde, the desired dithioacetal 6a was obtained in
13% yield, the major product being the unconverted thioglycoside
7 (entry 1, Table 1). To increase
the conversion of 5a to 6a, the amount of benzaldehyde was doubled and the temperature reduced
to avoid possible degradation. Following these conditi◦ons, the yield of the one-pot process could be
◦
doubled to 27% at
−
15 C and increased to 45% at
−
30 C (entries 2–3, Table 1). The yield was further
improved to 60% by adding 4Å molecular sieves [18] in the reaction mixture to avoid any possible
inhibition of the thioacetalization reaction by traces of water in the reaction mixture (entry 4, Table 1).
It was anticipated that the presence of water may facilitate the in situ hydrolysis of the glucosyl silyl
sulfide intermediate
equivalents of benzaldehyde at
mixture as judged on TLC. However, no improvement of the reaction yields was observed (entries
5–7, Table 1).
B
to the corresponding less reactive thiol (Figure 1) [19]. The addition of more
78 ◦C in the presence of 4Å molecular sieves led to a clean reaction
−
Table 1. Optimization of the one-pot thioacetalization process.
◦
Entry 1
PhCHO (equiv.)
T ( C) 2
t (h) 3
Yield (%) 4
1
2
3
0.5
1
1
1
3
4
8
25
20
1.5
1.5
1.5
1.5
2
13
27
45
60
45
42
41
−15
−30
−30
−78
−78
−78
4 5
5 5
6 5
7 5
1.5
1
2
3
The reactions are performed in sealed tubes. T refers to the temperature of the second step. t refers to the
4
5
reaction time of the second step. Isolated yields. Reaction performed in the presence of 4Å molecular sieves.
2.2. Reaction Scope
We then tested the one-pot reaction on a series of aldehydes under the optimized conditions to
evaluate its synthetic scope (Table 2). The influence of electron-withdrawing and electron-donating
substituents on the aromatic aldehyde moiety was explored with benzaldehyde analogues.
The presence of a para-methoxy group did not improve the efficiency of the process whereas
substitution with a trifluoromethyl group was found to strongly decrease the yield of the
reaction (entries 2–3). We were pleased to see that the one-pot synthesis of dithioacetal glycosides
could be performed with enolizable aliphatic aldehydes, however in lower yields compared to
benzaldehyde (entries 4–5). Not surprisingly, the modest yields obtained with pivaladehyde
compared to linear aldehydes suggested that the thioacetalization process was sensitive to steric
hindrance (entry 6). The experimental conditions were found to be compatible with allyl protecting
groups (entry 7).
The one-pot synthesis of dithioketal-
ketones (Scheme 2). The expected lowest reactivity of ketones compared to aldehydes resulted in
lower yields. Application of optimal conditions for the synthesis of afforded acceptable yields only for
α,α-diglycosides were explored with cyclic and acyclic
6

Molecules 2018, 23, 914
4 of 11
cyclobutanone giving 8b in 31% yield. Under these conditions, no desired products or poor conversions
were obtained with cyclohexanone and 3-pentanone. After extensive optimization with cyclohexanone
we founded that large excess of TMS2S (2.5 equiv.) is required and that the cyclohexanone have to be
present from the beginning of the reaction. With these conditions we are delighted to obtain compound
8a with 45% yield. The application of these conditions with 3-pentanone afforded 8c in poor yield
showing the less reactivity of acyclic ketone for this one-pot process.
Table 2. Scope of aldehydes in the one-pot formation of dithioacetal-α,α-diglycosides.
Entry
PG
RCHO
Product
Yield (%) 1
1
2
3
4
5
6
7
Bn
Bn
Bn
Bn
Bn
PhCHO
4-CF3-PhCHO
4-MeO-PhCHO
n-C3H7CHO
n-C5H11CHO
t-BuCHO
6a
6b
6c
6d
6e
6f
60
16
45
30
33
25
50
Bn
allyl
PhCHO
6g
1
Isolated yields.
Scheme 2. Scope of ketones in the one-pot formation of dithioketal-α,α-diglycosides.
1
It is noteworthy that the H NMR spectra of dithioketal glycosides
8
obtained from ketones
, the two sugars moieties are
magnetically equivalent. One signal is thus observed for the two anomeric protons which appear as a
are much simpler than those generated from aldehydes. In
8

Molecules 2018, 23, 914
5 of 11
doublet with a vicinal coupling constant of ~5 to 6 Hz. In contrast, two distinct doublets are observed
for the anomeric protons in (J ~5 to 6 Hz). In the case of compounds , the two pyranose moieties are
6
6
not magnetically equivalent. Tietze et al. have reported a similar observation for related diglycosides
acetals [12].
3. Materials and Methods
3.1. Preparation of Anhydroglucoses 2 and 5
1,6-Anhydro-2,3,4-tri-O-(triisopropylsilylpropargyl)-β-D-glucopyranose (2). To a solution of 1,6-Anhydro-
◦
2,3,4-tri-O-propargyl-
β
-D-glucopyranose [
3
] (1 equiv., 675 mg, 2.44 mmol) in THF (60.9 mL) at
−
70 C
was added LiHMDS (4 equiv., 1 M, 9.77 mL, 9.77 mmol) dropwise. Then after 20 min TIPSCl (4 equiv.,
1.94 g, 2.16 mL, 9.77 mmol) was added dropwise. The reaction mixture was stirred for 2 h. The reaction
was quenched with MeOH and the mixture was evaporated. Then saturated aqueous solution of
NH4Cl (40 mL) and Et2O (40 mL) were added. The aqueous layer was extracted with Et2O (2
×
40 mL).
The combined organic extracts were washed with brine (40 mL), dried with Na2SO4, filtered and
concentrated. The crude was purified by flash chromatography (Petroleum Ether/EtOAc 100/0 to
70/30), to afford
sharp) cm−1 1H NMR (400 MHz, CDCl3)
4,47–4.25 (m, 6H, OCH2C CTIPS), 3.97 (dd, J = 7.2, 0.8 Hz, 1H, H-6), 3.83 (m, 1H, H-3), 3.74–3.67
(m, 2H, H-4, H-6), 3.60 (s, 1H, H-2), 1.01–1.10 (m, 63H, TIPS). 13C NMR (100 MHz, CDCl3)
(ppm)
103.0, 102.9, 102.8 (3xC-10), 100.4 (C-1), 88.8, 88.6 (3xC-11), 75.1, 74.7, 74.3, 74.1 (4xCH-O), 65.4 (C-6),
58.0, 57.8, 57.5 (3xOCH2C CTIPS), 18.7 ( H3-CH-Si), 11.3 (CH3-
H-Si). HRMS (ESI) m/z [M + Na]+
calculated for [C42H76O5Si3Na]+: 767.489; found 767.487.
2
(1.15 g, 63%) as a yellow solid. [α]2D0
−
30 (c 1, EtOH). IR 2172 (C
≡
C, weak,
.
δ (ppm) 5.51 (s, 1H, H-1), 4,67 (d, J = 5.0 Hz, 1H, H-5,)
≡
δ
≡
C
C
1,6-Anhydro-2,3,4-tri-O-benzyl-
β
-D-glucopyranose (5a). To a solution of levoglucosan (1 equiv., 5 g,
◦
30.5 mmol) in DMF (200 mL) at 0 C was added benzyl bromide (3.5 equiv., 18.3 g, 12.8 mL, 106 mmol).
Sodium hydride (60% in oil, 5 equiv., 6.11 g, 152 mmol) was added portionwise. The ice bath was
removed, and the reaction was stirred overnight at r.t. Methanol (60 mL) was added, and 15 min
later water was added (120 mL). The aqueous layer was extracted with EtOAc (3
×
200 mL), and the
combined organic extracts were washed with brine (1 200 mL). The organic solution was dried over
×
sodium sulfate, filtered, concentrated to an oil that was purified by flash chromatography (Petroleum
Ether/EtOAc 8/2 to 6/4), to afford a solid that was then recrystallized from ethanol to afford 5a
1
(11.34 g, 26.23 mmol) as white crystals in 86% yield. H NMR (300 MHz, CDCl3)
δ
(ppm) 7.35–7.22 (m,
15H, Ph), 5.46 (s, 1H, H-1), 4.64–4.51 (m, 5H, H-5, O-C
H
2-Ph), 4.45 (d, J = 12.1 Hz, 1H, O-C 2-Ph) 4.41
H
(d, J = 12.1 Hz, 1H, O-CH2-Ph), 3.91 (d, J = 7.2 Hz, 1H, H-6), 3.68 (t, J = 6.5 Hz, 1H, H-6), 3.59 (m, 1H,
H-3), 3.35 (m, 2H, H-2, H-4). MS (ESI): m/z [M + K]+ calculated for [C27H28O5K]+: 471.16, found 471.16.
The analyses are in good agreement with the experimental data reported in literature [20].
1,6-Anhydro-2,3,4-tri-O-allyl-
6.11 mmol) in DMF (45 mL) at
β
-D-glucopyranose (5b). To a solution of levoglucosan (1 equiv., 1 g,
◦
−
20 C was added sodium hydride (60% in oil, 4 equiv., 0.98 g,
24.4 mmol) portionwise. The cooling bath was allowed to reach 0 ◦C within 1 h, then it was cooled
again to
20 ◦C and allyl bromide (4.5 equiv., 2.4 mL, 27.6 mmol) was added under vigorous stirring.
The reaction mixture was stirred overnight at r.t. The mixture was diluted with water and extracted
with diethyl ether (3 100 mL). The organic phases are combined and washed 5 times with water,
−
×
dried with Na2SO4, filtered, and concentrated to afford a yellow oil which was purified by flash
chromatography (Petroleum Ether/EtOAc, 9/1 to 1/1), to give 5b (1.63 g, 5.77 mmol) as a yellow oil in
1
95% yield. H NMR (400 MHz, CDCl3)
δ
(ppm) 5.92–5.79 (m, 3H, OCH2C
HCH2), 5.37 (s, 1H, H-1),
5.26–5.12 (m, 6H, OCH2CHC
H
2), 4.51 (m, 1H, H-5), 4.08–4.02 (m, 6H, OC 2CHCH2), 3.85 (dd, J = 7.1,
H
0.8 Hz, 1H, H-6), 3.64 (dd, J = 6.8, 6.0 Hz, 1H, H-6), 3.45 (m, 1H, H-3), 3.24 (m, 1H, H-4), 3.21 (m, 1H,
H-2). The analyses are in good agreement with the experimental data reported in literature [21].

Molecules 2018, 23, 914
6 of 11
3.2. General Procedure for the Synthesis of Diglycoside Thioacetals 6
Molecular sieves 4Å (80 mg) were added to a tube. A solution of anhydroglucose
5
(1 equiv.,
0.233 mmol) in CH2Cl2 (1 mL) was added via cannula to the flask. Bis (trimethylsilyl) sulfide (1.4 equiv.,
58.3 mg, 0.0613 mL, 0.327 mmol) followed by trimethylsilyl trifluoromethane sulfonate (1.1 equiv.,
57 mg, 0.0466 mL, 0.257 mmol) were added to the mixture. The tube was sealed and the medium was
stirred at 60 ◦C. After 2 h of reaction, a solution of the corresponding aldehyde (1 equiv., 0.233 mmol)
in 0.3 mL of CH2Cl2 was added at
warmed up to r.t. and washed with saturated aqueous NaHCO3 (50 mL). The aqueous layer was
extracted with CH2Cl2 (3 50 mL). The organic layers were combined and washed with brine (50 mL),
−
30 ◦C. The reaction was stirred for 1 h 30 min. The mixture was
×
dried over sodium sulfate and concentrated under reduced pressure. The crude obtained was purified
by flash column chromatography (Petroleum Ether/EtOAc) to afford compounds 6.
Dithioacetal 6a. According to the general procedure for the synthesis of diglycoside thioketals 6,
compound 6a was obtained as a solid in 60% yield after flash column chromatography (Petroleum
Ether/EtOAc, 8/2 to 4/6). [α]2D0 + 177 (c 0.7, CHCl3). IR 3431 cm-1 (broad O-H). 1H NMR (400 MHz,
0
CDCl3)
(m, 2H, O-C
δ
(ppm) 7.44–7.22 (m, 35H, Ph), 5.95 (d, J = 5.5 Hz, 1H, H-1 or H-1 ), 5.02 (s, 1H, H-7), 5.00–4.97
0
H
2-Ph, H-1 or H-1 ), 4.91–4.77 (m, 5H, O-C
H
2-Ph), 4.71 (d, J = 10.8 Hz, 1H, O-C
H
2-Ph), 4.62
(d, J = 11.4 Hz, 1H, O-CH2-Ph), 4.57 (d, J = 5.9 Hz, 1H, O-CH2-Ph), 4.54 (d, J = 5.7 Hz, 1H, O-CH2-Ph),
4.38 (d, J = 11.5 Hz, 1H, O-CH2-Ph), 4.32 (d, J = 11.5 Hz, 1H, O-CH2-Ph), 4.21 (m, 1H, H-5 or H-50),
4.14 (m, 1H, H-5 or H-50), 3.98–3.80 (m, 5H, H-2 or H-20, H-6, H-60, H3, H30), 3.67 (dd, J = 9.5; 5.6 Hz,
1H, H-2 or H-20), 3.63–3.55 (m, 2H, H-6, H60), 3.37 (dd, J = 10.0; 8.8 Hz, 1H, H-4 or H-40), 3.28 (dd,
J = 9.9; 8.8 Hz, 1H, H-4 or H-40). 13C NMR (100 MHz, CDCl3)
138.55 (Cq-Ar), 138.1 (Cq-Ar), 137.8 (Cq-Ar), 137.7 (Cq-Ar), 137.3 (Cq-Ar), 128.9–127.8 (35
82.8 (CH) 82.7 (CH), 82.6 (CH), 81.9 (C-1 or C-10), 79.4 (CH), 78.8 (CH), 77.8 (C-4 or C-40), 78.4 (C-4
or C-40), 75.9 (O- H2-Ph), 72.8 (C5 or C-50), 72.6 (C-5 or C50),
H2-Ph), 75.6 (O- H2-Ph), 75.2 (O-
72.3 (O-
δ
(ppm) 139.4 (Cq-Ar), 138.6 (Cq-Ar),
CHAr)
×
C
C
C
C
H2-Ph), 71.9 (O-C
H2-Ph), 63.0 (C-6 or C-60), 62.2 (C-6 or C-60), 46.2 (C-7). HRMS (ESI) m/z
[M + K]+ calculated for [C61H64O10S2K]+: 1059.357, found: 1059.366.
Dithioacetal 6b. According to the general procedure for the synthesis of diglycoside thioketals 6,
compound 6b was obtained in 16% yield after flash column chromatography (Petroleum Ether/EtOAc,
8/2 to 0/1). [α]2D0 + 152 (c 0.9, CHCl3). IR 3428 cm (broad O-H). 1H NMR (400 MHz, CDCl3)
δ (ppm)
−1
7.69 (J = 8.2 Hz, 2H, H-10), 7.62 (J = 8.1 Hz, 2H, H-9), 7.45–7.09 (m, 30H, Ph), 5.93 (d, J = 5.5 Hz, 1H,
0
H-1 or H-1 ), 5.06 (s, 1H, H-7), 4.99 (d, J = 10.9 Hz, 1H, O-C
H2-Ph), 4.91–4.78 (m, 6H, O-C
H2-Ph, H-1 or
H-10), 4.71 (d, J = 10.9 Hz, 1H, O-CH2-Ph), 4.63 (d, J = 11.2 Hz, 1H, O-CH2-Ph), 4.55 (d, J = 10.5 Hz,
2H, O-CH2-Ph), 4.43 (d, J = 11.8 Hz, 1H, O-CH2-Ph), 4.39 (d, J = 11.7 Hz, 1H, O-CH2-Ph), 4.17 (ddd,
J = 9.9, 7.4, 2.0 Hz, 1H, H-5 or H-50), 4.09 (ddd, J = 9.7, 6.9, 2.8 Hz, 1H, H-5 or H-50), 3.97–3.76 (m, 5H,
H-6, H-60, H-3, H-30, H-2 or H-20) 3.68 (dd, J = 9.4, 5.6 Hz, 1H, H-2 or H-20), 3.64–3.54 (m, 2H, H-6,
H-60) 3.35 (dd, J = 10.0; 8.9 Hz, 1H, H-4 or H-40), 3.28 (dd, J = 10.0; 8.8 Hz, 1H, H-4 or H-40). 13C NMR
(100 MHz, CDCl3)
δ (ppm) 143.7 (C-8), 138.55 (Cq-Ar), 138.5 (Cq-Ar), 138.0 (Cq-Ar), 137.7 (Cq-Ar),
137.5 (Cq-Ar), 137.2 (Cq-Ar), 128.8-127.8 (34
82.55 (CH), 82.0 (CH, C-1 or C-1 ), 79.4 (CH), 79.0 (C-2 or C-2 ), 78.4 (C-4 or C-4 ), 77.7 (C-4 or C-4 ), 75.9
×
CHAr), 125.9 (C9, q, J C-F = 4 Hz), 82.65 (CH) 82.6 (CH),
0
0
0
0
0
0
(O-
72.4 (O-
66.5 (3F, s, CF3). HRMS (ESI) m/z [M + K]+ calculated for [C62H63F1O10S2K]+: 1127.345, found:
1127.332.
C
H2-Ph), 75.6 (O-
C
H2-Ph), 75.2 (O-
C
H2-Ph), 72.85 (C-5 or C-5 ), 72.8 (C-5 or C-5 ), 72.5 (O-
CH2-Ph),
C
H2-Ph), 63.1 (C-6 or C-6), 62.1 (C-6 or C-60), 45.2 (C-7). 19F NMR (376 MHz, CDCl3)
δ (ppm)
−
Dithioacetal 6c. According to the general procedure for the synthesis of diglycoside thioketals
6,
compound 6c was obtained in 45% yield after flash column chromatography (Petroleum Ether/EtOAc,
8/2 to 0/1). [α]2D0 + 151 (c 1.1, CHCl3). IR 3437 cm (broad O-H). 1H NMR (400 MHz, CDCl3)
7.49 (d, J = 8.8 Hz, 2H, H-10), 7.44–7.37 (m, 2H, Ph), 7.37–7.19 (m, 26H, Ph), 7.18–7.11 (m, 2H, Ph),
δ
(ppm)
−1

Molecules 2018, 23, 914
7 of 11
6.88 (J = 8.8 Hz, 2H, H-9), 5.93 (d, J = 5.4 Hz, 1H, H-1 or H-10), 5.01–4.95 (m, 3H, H-7, H-1 or H-10,
O-CH2-Ph), 4.90–4.63 (m, 3H, O-CH2-Ph), 4.81 (d, J = 5.0 Hz, 2H, O-CH2-Ph), 4.78 (d, J = 4.9 Hz,
1H, O-CH2-Ph), 4.69 (d, J = 10.8 Hz, 1H, O-CH2-Ph), 4.60 (d, J = 11.4 Hz, 1H, O-CH2-Ph), 4.55 (d,
J = 5.4 Hz, 1H, O-CH2-Ph), 4.53 (d, J = 5.1 Hz, 1H, O-CH2-Ph), 4.39 (d, J = 11.5 Hz, 1H, O-CH2-Ph),
4.32 (d, J = 11.6 Hz, 1H, O-CH
2-Ph), 4.20 (ddd, J = 10.1, 7.4, 2.5 Hz, 1H, H-5 or H-50), 4.13 (ddd, J = 9.7,
6.9, 2.8 Hz, 1H, H-5 or H-50), 3.96–3.79 (m, 5H, H-6, H-60, H-3, H-30, H-2 or H-20), 3.80 (s, 3H, OCH3),
3.67 (dd, J = 9.5; 5.6 Hz, 1H, H-2 or H-20), 3.64-3.54 (m, 2H, H-6, H-60) 3.35 (dd, J = 9.8; 8.9 Hz, 1H,
H-4 or H-40), 3.27 (dd, J = 10.0; 8.9 Hz, 1H, H-4 or H-40) 13C NMR (100 MHz, CDCl3)
δ (ppm) 159.7
(C-11), 138.65 (Cq-Ar), 138.6 (Cq-Ar), 138.1 (Cq-Ar), 137.8 (Cq-Ar), 137.7 (Cq-Ar), 137.4 (Cq-Ar), 131.3
(C-8), 129.5 (C10), 128.7–127.7 (34 x CHAr), 114.2 (C-9), 82.75 (CH) 82.7 (CH), 82.6 (CH), 81.9 (C-1
or C-10), 79.4 (CH), 78.9 (C-2 or C-20), 78.4 (C-4 or C-40), 77.8 (C-4 or C-40), 75.9 (O-
C
H2-Ph), 75.6
(O-
C
H2-Ph), 75.1 (O-
C
H2-Ph), 72.7 (C-5 or C-50), 72.5 (C-5 or C-50), 72.2 (O-
C
H2-Ph), 71.9 (O- H2-Ph),
C
63.0 (C-6 or C-60), 62.1 (C-6 or C-60), 55.5 (OCH3), 45.7 (C-7). HRMS (ESI) m/z [M + K]+ calculated for
[C62H66O11S2K]+: 1089.368, found: 1089.367.
Dithioacetal 6d. According to the general procedure for the synthesis of diglycoside thioketals 6,
compound 6d was obtained in 30% yield after flash column chromatography (Petroleum Ether/EtOAc,
8/2 to 4/6). [α]2D0 + 136 (c 1, CHCl3). IR 3440 cm−1 (bro0ad O-H). 1H NMR (400 MHz, CDCl3)
δ (ppm)
0
7.35–7.26 (m, 30H, Ph), 5.85 (d, J = 4.5 Hz, 1H, H-1 or H-1 ), 5.37 (d, J = 5.4 Hz, 1H, H-1 or H-1 ), 5.01–4.95
(m, 2H, O-CH2-Ph), 4.93 (s, 1H, O-CH2-Ph), 4.90–4.85 (m, 2H, O-CH2-Ph), 4.84 (s, 1H, O-CH2-Ph), 4.79
(t, J = 11.1 Hz, 2H, O-CH2-Ph), 4.74 (m, 1H, O-CH2-Ph), 4.71–4.70 (m, 2H, O-CH2-Ph), 4.63–4.55 (m,
5H, O-CH2-Ph), 4.16–4.09 (m, 1H, H5 or H-50), 4.05–3.95 (m, 2H, H-7, H-4 or H50), 3.91–3.75 (m, 6H,
H-6, H-60, H-3, H-30, H-2, H20), 3.68–3.5 (m, 2H, H-6, H60), 3.47–3.41 (m, 1H, H-4 or H-40), 3.36 (dd,
J = 10.1; 8.4 Hz, 1H, H-4 or H-40), 1.93–1.87 (m, 2H, H-8), 1.76–1.64 (m, 1H, H-9), 1.50–1.39 (m, 1H,
H-9), 0.96–0.92 (m, 3H, H-10). 13C NMR (100 MHz, CDCl3)
(Cq-Ar), 137.8 (Cq-Ar), 137.7 (Cq-Ar), 137.65 (Cq-Ar),128.7-128.0 (30
δ (ppm) 138.8 (Cq-Ar), 138.6 (Cq-Ar), 138.1
×
CHAr), 82.8 (CH), 82.52 (CH),
0
0
0
82.5 (CH), 81.3 (C-1 or C-1 ), 79.6 (CH), 79.3 (CH), 78.4 (C-4 or C4 ), 77.4 (C4 or C-4 ), 75.9 (CO-
C
H2-Ph),
75.8 (O-
C
H2-Ph), 75.6 (O-
C
H2-Ph), 75.4 (O-
C
H2-Ph), 72.9 (C5 or C50), 72.5 (O-
CH2-Ph), 72.3 (C5 or
C50), 72.2 (O-
C
H2-Ph), 62.8 (C-6 or C60), 61.9 (C6 or C-60), 45.0 (C-7), 38.5 (C-8), 20.5 (C-9), 13.9 (C-10).
HRMS (ESI) m/z [M + K]+ calculated for [C59H68O10S2Na]+: 1023.415, found: 1023.420.
Dithioacetal 6e. According to the general procedure for the synthesis of diglycoside thioketals 6,
compound 6e was obtained in 33% yield after flash column chromatography (Petroleum Ether/EtOAc,
8/2 to 0/1). [α]2D0 + 173 (c 0.95, CHCl3). IR 3452 cm-1 (broad O-H). H NMR (400 MHz, CDCl3)0δ
1
0
(ppm) 7.45–7.17 (m, 30H, Ph), 5.85 (d, J = 4.3 Hz, 1H, H-1 or H-1 ), 5.38 (d, J = 5.3 Hz, 1H, H-1 or H-1 ),
5.02–4.54 (m, 12H, O-CH2-Ph), 4.11 (ddd, J = 10.1, 6.8, 2.5 Hz, 1H, H-5 or H-50), 4.05–3.93 (m, 2H, H-5
or H-50, H-7), 3.91–3.75 (m, 6H, H-6, H-60, H-3, H-30, H-2, H20), 3.66 (dd, J = 12.6; 5.8 Hz, 1H, H-6 or
0
0
0
H-6 ), 3.59 (dd, J = 11.6, 6.6 Hz, 1H, H-6 or H-6 ), 3.48–3.42 (m, 1H, H-4 or H-4 ), 3.36 (dd, J = 9.9; 8.6 Hz,
1H, H-4 or H-40), 1.96–1.88 (m, 2H, H-8), 1.76–1.61 (m, 1H, H-9), 1.46–1.36 (m, 1H, H-9), 1.36–1.25 (m,
4H, H-10, H11), 0.97–0.85 (m, 3H, H-12). 13C NMR (100 MHz, CDCl3)
δ
(ppm) 138.8 (Cq-Ar), 138.6
(Cq-Ar), 138.1 (Cq-Ar), 137.8 (Cq-Ar), 137.7 (Cq-Ar), 137.6 (Cq-Ar), 128.7-127.7 (30 CHAr), 82.8 (CH),
82.55 (CH), 82.5 (CH), 81.4 (C-1 or C-10), 79.5 (CH), 79.3 (CH), 78.4 (C4 or C-40), 77.4 (C-4 or C40), 75.9
(O- H2-Ph), 75.8 (O- H2-Ph), 75.6 (O- H2-Ph), 75.4 (O- H2-Ph), 72.8 (O-
H2-Ph), 72.5 (C-5 or C-50),
72.3 (C-5 or C-50), 72.25 (O-
×
C
C
C
C
C
C
H2-Ph), 62.8 (C-6 or C-60), 61.9 (C-6 or C-60), 45.4 (C-7), 36.3 (C-8), 31.7
(C-10 or C-11), 26.7 (C-9), 22.7 (C-10 or C-11), 14.2 (C-12). HRMS (ESI) m/z [M + K]+ calculated for
[C60H70O10S2K]+: 1053.404, found: 1053.391.
Dithioacetal 6f. According to the general procedure for the synthesis of diglycoside thioketals 6,
compound 6f was obtained as a solid in 25% yield after flash column chromatography (Petroleum
Ether/EtOAc, 8/2 to 4/6. [α]2D0 + 128 (c 1.3, CHCl3). IR 3445 cm−1 (broad O-H). 1H NMR (400 MHz,
CDCl3) δ
(ppm) 7.39–7.29 (m, 30H, Ph), 5.76 (d, J = 4.8 Hz, 1H, H-1 or H-10), 5.38 (d, J = 5.4 Hz, 1H,

Molecules 2018, 23, 914
8 of 11
H-1 or H-10), 5.01–4.66 (m, 9H, O-CH2-Ph), 4.61 (m, 2H, O-CH2-Ph), 4.63–4.56 (m, 1H, O-CH2-Ph),
4.10–4.05 (m, 1H, H-5 or H-50), 4.03–3.98 (m, 1H, H-5 or0H-50), 3.90–3.77 (m, 6H, H-7, H-3, H-30, H6,
0
0
0
H6 , H-2 or H-2 ), 3.76 (dd, J = 9.5; 5.4 Hz, 1H, H-2 or H-2 ), 3.66 (dd, J = 12.3; 5.9 Hz, 1H, H-6 or H-6 ),
3.59 (dd, J 0= 11.6, 6.2 Hz, 1H, H-6 or H-60), 3.44 (t, J = 9.3 Hz, 1H, H-4 or H-40), 3.36 (t, J = 9.2 Hz, 1H,
H-4 or H-4 ), 1.19 (s, 9H, H-9). 13C NMR (100 MHz, CDCl3)
(Cq-Ar), 137.9 (Cq-Ar), 137.6 (Cq-Ar), 137.5 (Cq-Ar), 128.7-127.7, (30xCHAr), 86.0 (CH, C-1 ), 83.0 (CH),
δ
(ppm) 138.9 (Cq-Ar), 138.5 (Cq-Ar), 138.0
0
0
0
82.0 (CH), 81.3 (CH, C-1), 79.8 (C2 ), 79.0 (CH), 78.4 (C4), 77.7 (C4 ) 75.8 (O-CH2-Ph), 75.6 (O-CH2-Ph),
75.4 (O-CH2-Ph), 73.8 (O-CH2-Ph), 73.0 (C-5), 72.2 (O-C
H2-Ph), 72.1 (C-5) 62.8 (C-60), 62.2 (C-6), 59.6
(C-7), 38.6 (C-8), 28.3 (C-9). HRMS (ESI) m/z [M + Na]+ calculated for [C58H66O10S2Na]+: 1009.399,
found: 1009.404.
Dithioacetal 6g. According to the general procedure for the synthesis of diglycoside thioketals 6,
compound 6g was obtained in 50% yield after flash column chromatography (Petroleum Ether/EtOAc,
9/1 to 1/9). [α]2D0 + 388 (c 0.51, CHCl3). IR 3425 cm−1 (broad O-H). 1H NMR (400 MHz, CDCl3)
δ
(ppm)
0
7.53–7.51 (m, 2H, Ph), 7.34–7.26 (m, 3H, Ph), 5.98–5.82 (m, 6H, 5x OCH2C
(m, 1H, OCH2C
4.38–4.04 (m, 13H, 6
H
=CH2, H1 or H-1 ), 5.70–5.61
H
=CH2), 5.38–5.06 (m, 12H, 6xOCH2CH=CH2), 5.02–4.96 (m, 3H, H10, H7, 1 CH-O),
×
OCH2CHCH2), 3.98 (dd, J = 11.4, 2.7 Hz 1H, H-6 or H-60), 3.88 (dd, J = 11.7,
0
0
0
2.7 Hz, 1H, H-6 or H-6 ), 3.78–3.47 (m, 8H, H6, H6 , 6H CH-O), 3.19 (dd, J = 9.7, 9.6 Hz, 1H, H-4 or H-4 ),
3.10 (dd, J = 9.5, 9.6 Hz, 1H, H-4 or H-40). 13C NMR (100 MHz, CDCl3)
135.2, 134.7, 134.5, 134.4, 134.3, (6x OCH2 H=CH2), 128.7 (2 CHAr), 128.4, (CHAr), 128.3, (2
118.0, 117.8, 117.7, 117.2, 116.9, 116.8 (6 OCH2CH=
H2), 82.8 (C-1 or C-10), 82.2, 82.1, 81.9, 79.05,
79.0 (5xCH), 78.3 (C-4 or C-40), 77.7 (C4 or C40), 74.5 (2
δ
(ppm) 139.3 (Cq-Ar) 135.3,
CHAr),
C
×
×
×
C
×
O
CH2CH=CH2), 74.4 (O
C
H2CH=CH2), 74.0
0
(OC
H2CH=CH2), 72.6 (CH), 72.5 (CH), 71.3 (O
62.2 (C-6 or C-60), 46.1 (C-7). HRMS (ESI) m/z [M + Na]+ calculalted for [C37H52NaO10S2]+: 743.290,
C
H2CH=CH2), 71.1 (O
C
H2CH=CH2), 63.2 (C-6 or C-6 ),
found 743.290.
3.3. Synthesis of Dithioketal-α,α-Diglycosides 8 and Characterization of Compound 3
Diglycoside thioketal 8a. In a tube, to a solution of cyclohexanone (1 equiv., 13.2 mg, 0.014 mL,
0.134 mmol) and anhydroglucose 5a (2 equiv., 116 mg, 0.269 mmol) in CH2Cl2 (0.6 mL) was added
(TMS)2S (5 equiv., 0.126 mL, 0.672 mmol) and TMSOTf (2 equiv., 0.0488 mL, 0.269 mmol). The tube was
◦
sealed and the mixture was heated at 60 C for 18 h. The mixture was washed with saturated aqueous
NaHCO3 (40 mL) and extracted with CH2Cl2 (3
×
50 mL). The organics layers were combined and
washed with brine (40 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude
obtained was purified by flash column chromatography (Petroleum Ether/EtOAc, 8/2 to 1/1) to
afford compound 8a (61 mg) in 45% yield. [α]2D0 + 114 (c 1, CH2Cl2). IR 3463 (O-H, weak, broad), 2928
1
(C-H) cm-1. H NMR (400 MHz, CDCl3)
δ
(ppm) 7.31–7.13 (m, 30H, H-Ar), 5.79 (d, J = 5.4 Hz, 2H, H-1),
2-O), 4.06 (dt, J = 10.1, 3.1 Hz, 2H, H-5), 3.73 (t, J = 9.5 Hz, 2H, H-3), 3.69 (m,
4H, H-6), 3.60 (dd, J = 9.8, 5.6 Hz, 2H, H-2), 3.46 (t, J = 9.3 Hz, 2H, H-4), 1.96 (t, J = 5.6 Hz, 4H, H-8), 1.54
(m, 4H, H-9), 1.31 (m, 2H, H-10). 13C NMR (100 MHz, CDCl3)
(ppm) 138.5 (Cq-Ar,) 138.2 (Cq-Ar,),
138.1 (Cq-Ar) 128.64, 128.60, 128.54, 128.51, 128.18, 128.14, 128.09, 128.05, 127.84, 127.77, 127.67 ( H Ar),
H2-O), 72.7
4.84–4.48 (m, 12H, Ph-C
H
δ
C
83.4 (C-3), 82.6 (C-1), 79.6 (C-2), 77.4 (C-4), 75.7 (Ph-CH2-O), 75.3 (Ph-CH2-O), 73.0 (Ph-C
(C-5), 64.1 (C-7), 62.0 (C-6), 39.9 (C-8), 25.3 (C-10), 23.1 (C-9). HRMS (ESI) m/z [M + Na]+ calculated for
[C60H68O10S2Na]+: 1035.415; found 1035.416.
Diglycoside thioketal 8b. In a tube, to a solution of anhydroglucose 5a (2 equiv., 100 mg, 0.231 mmol)
in CH2Cl2 (0.6 mL) was added (TMS)2S (2.8 equiv., 0.0608 mL, 0.324 mmol) and TMSOTf (2.2 equiv.,
0.0461 mL, 0.254 mmol). The tube was sealed and the mixture was heated at 50 ◦C for 2 h.
Then cyclobutanone (1 equiv., 8.1 mg, 0.00871 mL, 0.116 mmol) was added to the mixture at
and stirred 15 h. The mixture was washed with saturated aqueous NaHCO3 (40 mL) and extracted with
CH2Cl2 (3 50 mL). The organics layers were combined and washed with brine (40 mL), dried over
−
70 ◦C
×

Molecules 2018, 23, 914
9 of 11
Na2SO4 and concentrated under reduced pressure. The crude obtained was purified by flash column
chromatography (Petroleum Ether/EtOAc, 8/2 to 0/1) to afford compound 8b (35 mg) in 31% yield.
[α]2D0 + 87 (c 1, CH2Cl2). IR 3466 (O-H, weak, broad), 2925 (C-H) cm−1. H NMR (400 MHz, CDCl3)
1
δ
(ppm) 7.31–7.13 (m, 30H, H-Ar), 5.74 (d, J = 5.6 Hz, 2H, H-1), 4.79 (t, J = 10.9 Hz, 4H, O-CH2-Ph),
4.69 (d, J = 10.4 Hz, 2H, O-CH2-Ph) 4.57 (d, J = 10.9 Hz, 2H, O-CH2-Ph), 4.09 (dt, J = 9.7, 3.1 Hz, 2H,
H-5), 3.79–3.66 (m, 6H, H-3, H-6), 3.60 (dd, J = 9.9, 5.7 Hz, 2H, H-2), 3.47 (dd, J = 9.6, 9.0 Hz, 2H, H-4),
2.58–2.47 (m, 2H, H-8a), 2.40–2.31 (m, 2H, H-8b), 2.06 (q, J = 7.6 Hz, 2H, H-9). 13C NMR (100 MHz,
CDCl3)
127.3 (
(O-
δ
(ppm) 138.4, (Cq-Ar), 138.1 (Cq-Ar), 137.9 (Cq-Ar), 128.5, 128.4, 128.03, 127.97, 127.93, 127.7,
C
HAr), 83.8 (C-1), 83.2 (C-3), 79.4 (C-2), 77.3 (C-4), 75.6 (O-CH2-Ph), 75.1 (O- H2-Ph), 72.7
C
C
H2-Ph), 72.5 (C-5), 61.8 (C-6), 59.1 (C-7), 38.9 (C-8), 18.0 (C-9). HRMS (ESI) m/z [M + Na]+
calculated for [C58H64O10S2 Na]+: 1007.383; found 1007.382.
Diglycoside thioketal 8c. In a tube, to a solution of 3-pentanone (1 equiv., 9.96 mg, 0.0122 mL,
0.116 mmol) and anhydroglucose 5a (2 equiv., 100 mg, 0.231 mmol) in CH2Cl2 (0.6 mL) was added
(TMS)2S (5 equiv., 103 mg, 0.109 mL, 0.578 mmol) and TMSO◦Tf (2 equiv., 51.4 mg, 0.0419 mL,
0.231 mmol). The tube was sealed and the mixture was heated at 50 C for 2 h. The mixture was washed
with saturated aqueous NaHCO3 (40 mL) and extracted with CH2Cl2 (3
×
50 mL). The organics layers
were combined and washed with brine (40 mL), dried over Na2SO4 and concentrated under reduced
pressure. The crude obtained was purified by flash column chromatography (Petroleum Ether/EtOAc,
8/2 to 4/6) to afford compound 8c (13 mg) in 11% yield. [α]2D0 + 104 (c 1, CH2Cl2). IR 3465 (O-H,
1
weak, broad), 2875 (C-H) cm−1. H NMR (400 MHz, CDCl3)
δ (ppm) 7.40–7.15 (m, 30H, H-Ar), 5.83 (d,
J = 5.7 Hz, 2H, H-1), 4.87 (d, J = 6.3 Hz, 2H, O-CH2-Ph), 4.85 (d, J = 6.2 Hz, 2H, O-CH2-Ph), 4.76 (d,
J = 10.9 Hz, 2H, O-CH2-Ph), 4.66–4.56 (m, 6H, O-CH2-Ph), 4.10 (dt, J = 9.8, 3.2 Hz, 2H, H-5), 3.84–3.75
(m, 6H, H-3, H-6), 3.63 (dd, J = 9.9, 5.6 Hz, 2H, H-2), 3.52 (dd, J = 10.0, 8.9 Hz, 2H, H-4), 2.02–1.92 (m, 2H,
H-8a), 1.92–1.81 (m, 2H, H-8b), 0.99 (t, J = 7.3 Hz, 6H, H-9). 13C NMR (100 MHz, CDCl3)
δ
(ppm) 138.5
(Cq-Ar), 138.2 (Cq-Ar), 138.1 (Cq-Ar) 128.64, 128.53, 128.50, 128.17, 128.06, 127.82, 127.76, 127.5 ( H Ar),
H2-O), 72.8
C
83.3 (C-3), 83.9 (C-1), 79.6 (C-2), 77.4 (C-4), 75.7 (Ph-CH2-O), 75.3, (Ph-CH2-O), 73.1 (Ph-C
(C-5), 68.5 (C-7), 61.9 (C-6), 31.9 (C-8), 9.1 (C-9). HRMS (ESI) [M + K]+ calculated for [C59H68O10S2K]+:
1039.389; found 1039.394.
Diglycoside thioketal 3. [α]2D0 + 128 (c 1, CH2Cl2). IR 2174 (C
(400 MHz, CDCl3) (ppm) 5.56 (d, J = 5.7 Hz, 2H, H-1), 4.66–4.24 (m, 12H, H-9), 3.97 (dd, J = 9.9 and
≡
C, weak, sharp) cm−1 1H NMR
.
δ
5.7 Hz, 2H, H-2), 3.91–3.80 (m, 4H, H-5, H-6a), 3.73 (dd, J = 11.8, 5.2 Hz, 2H, H-6b), 3.63 (t, J = 9.2 Hz, 2H,
H-3), 3.43 (t, J = 9.4 Hz, 2H, H-4), 1.68 (s, 6H, H-8), 1.12–0.98 (m, 126H, H-TIPS). 13C NMR (100 MHz,
CDCl3)
δ
(ppm) 103.9, 103.7, 102.9 (3
×
C-10), 88.9, 87.8, 87.5 (3
C-9), 58.7 (C-7), 32.9 (C-8), 18.7 (
C
H-Si). HRMS (ESI) m/z [M + Na]+ calculated for [C87H160O10S2Si6Na]+: 1619.996; found
×
C-11), 83.6 (C-1), 82.7 (C-3), 77.2
(C-2), 76.7 (C-4), 73.1 (C-5), 62.5 (C-6), 61.0, 60.7, 59.1 (3
11.3 (CH3-
1619.989.
×
CH3-CH-Si),
4. Conclusions
In conclusion, we have reported
dithioacetal- -diglycosides, a class of disaccharide mimetics with almost no precedent. This highly
a
one-pot, highly stereoselective access to
α,α
convergent approach is based on the in situ formation of a thioglycoside intermediate via
1,6-anhydrosugars ring opening and its reaction with an aldehyde or a ketone. In this process, three
C-S bounds are generated successively and two primary hydroxyl groups, that may be orthogonally
protected or further functionalized, are released. The pseudo thiodisaccharides obtained could have
interesting applications in glycobiology or asymmetric synthesis. Further applications of this approach
to the synthesis of unprecedented disaccharide mimetics of biological interest are currently under
investigation in our laboratory.

Molecules 2018, 23, 914
10 of 11
Supplementary Materials: Supplementary materials are available online.
Acknowledgments: This work was supported by the CNRS and the University of Strasbourg. J.P.S. thanks the
French ministry of research for a fellowship
Author Contributions: P.C. conceived the project and designed the experiments with D.H.; P.C. wrote the paper;
MFCD, J.P.S. and A.G. performed the experiments under the supervision of D.H.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Compain, P. Searching for Glycomimetics That Target Protein Misfolding in Rare Diseases. Succesees,
Failures and Unexpected Progress Made in Organic Synthesis. Synlett 2014, 25, 1215–1240. [CrossRef]
Lepage, M.L.; Schneider, J.P.; Bodlenner, A.; Compain, P. Towards a Molecular Lego Approach for the
Diversity-oriented Synthesis of Cyclodextrin Analogues Designed as Scaffolds for Multivalent Systems.
J. Org. Chem. 2015, 80, 10719–10733. [CrossRef] [PubMed]
2.
3.
4.
5.
Lepage, M.L.; Bodlenner, A.; Compain, P. Stereoselective Synthesis of α-glycosyl azides by TMSOTf-mediated
Ring Opening of 1,6-Anhydrosugars. Eur. J. Org. Chem. 2013, 1963–1972. [CrossRef]
Lian, G.; Zhang, X.; Yu, B. Thioglycoside in Carbohydrate research. Carbohydr. Res. 2015, 403, 13–22.
[CrossRef] [PubMed]
Witczak, Z.J. Thio-Click Chemistry in Glycoscience: Overview and Perspective. In Click Chemistry in
Glycosciences. New Developments and Strategies; Witczak, Z.J., Bielski, R., Eds.; John Wiley & Sons, Inc:
Hoboken, NJ, USA, 2013; pp. 33–43, ISBN 9781118275337. [CrossRef]
6.
Zhu, X.; Dere, R.T.; Jiang, J.; Zhang, L.; Wang, X. Synthesis of α-Glycosyl Thiols by Stereospecific
Ring-Opening of 1,6-Anhydrosugars. J. Org. Chem. 2011, 76, 10187–10197. [CrossRef] [PubMed]
Durette, P.L.; Shen, T.Y. Synthesis of 1-thio-β-cellobiosides. Carbohydr. Res. 1978, 67, 484–490. [CrossRef]
7.
8.
ˇ
Staneˇk, J.; Šindlerová, M.; Cerny, M. Derivatives of D-thioxylopyranose and of some reducing
1-Deoxy-1-thiodisaccharides. Coll. Czech. Chem. Commun. 1965, 30, 297–303. [CrossRef]
Elbein, A.D.; Pan, Y.T.; Pastuszak, I.; Caroll, D. New insights on trehalose: A multifunctional molecule.
Glycobiol. 2003, 13, 17R–27R. [CrossRef] [PubMed]
9.
10. Ohtake, S.; Wang, Y.J. Trehalose: Current Use and Future Applications. J. Pharm. Sci. 2011, 100, 2020–2053.
[CrossRef] [PubMed]
11. Thanna, S.; Sucheck, S.J. Targeting the trehalose utilization pathways of Mycobacterium tuberculosis.
Med. Chem. Commun. 2016, 7, 69–85. [CrossRef] [PubMed]
12. Tietze, L.F.; Beller, M. Glycoside syntheses 19. stereoselective synthesis of acetal-β,β-diglucosides, a novel
class of glycosides and chiral acetals. Angew. Chem. Int. Ed. 1991, 30, 868–869. [CrossRef]
13. Storr, T.; Obata, M.; Fisher, C.L.; Bayly, S.R.; Green, D.E.; Brudzinska, I.; Mikata, Y.; Patrick, B.O.; Adam, M.J.;
Yano, S.; et al. Novel carbohydrate-appended metal complexes for potential use in molecular imaging.
Chem. Eur. J. 2005, 11, 195–203. [CrossRef] [PubMed]
14. Ruckel, E.R.; Schuerch, C. Preparation of High Polymers from 1,6-Anhydro-2,3,4-tri-O-Substituted
β-D-Glucopyranose. J. Org. Chem. 1966, 31, 2233–2239. [CrossRef]
15. Akagawa, K.; Kudo, K. Biomimetic iterative method for polyketide synthesis. Chem. Commun. 2017, 53,
8645–8648. [CrossRef] [PubMed]
16. Martel, A.; Chewchanwuttiwong, S.; Dujardin, G.; Brown, E. Low temperature syntheses of thioketals from
enol ethers and carbonyl compounds. Tetrahedron Lett. 2003, 44, 1491–1494. [CrossRef]
17. Noyori, R.; Murata, S.; Suzuki, M. Trimethylsilyl triflate in organic synthesis. Tetrahedron 1981, 37, 3899–3910.
[CrossRef]
18. Nicolaou, K.C.; Kiappes, J.L.; Tian, W.; Gondi, V.B.; Becker, J. Synthesis of the Carboline Disaccharide Domain
of Shishijimicin A. Org. Lett. 2011, 13, 3924–3927. [CrossRef] [PubMed]
19. Xin, G.; Zhu, X. A facile and highly stereoselective synthesis of 1-thiotrehalose. Tetrahedron Lett. 2012, 53,
4309–4312. [CrossRef]

Molecules 2018, 23, 914
11 of 11
20. McDevitt, J.P.; Lansbury, P.T. Glycosamino Acids: New Building Blocks for Combinatorial Synthesis. J. Am.
Chem. Soc. 1996, 118, 3818–3828. [CrossRef]
ˇ
21. Strašák, T.; Karban, J.; Št’astná, L.C.; Maixnerová, L.; Brˇezinová, A.; Bernard, M.; Fajgar, R. Synthesis of
substituted titanocene dichloride derivatives by hydrosilylation. J. Organomet. Chem. 2014, 768, 115–120.
[CrossRef]
Sample Availability: Samples of the compounds 6 are available from the authors.
©
2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).