Ruthenium Catalyzed Stereo/Chemo/Regioselective One-Pot Synthesis of C(2)-C(3) Unsaturated and α-d-Mannopyranosyl Sulfones

Article abstract of DOI:10.1021/acs.joc.5b00975

An efficient and divergent approach to C(2)-C(3) unsaturated glycosyl and α-d-mannopyranosyl sulfones has been developed via ruthenium-promoted direct glycosylation, oxidation, and dihydroxylation from glycal in one-pot. The presence of stoichiometric amounts of NaIO₄ and in situ generation of RuO₄ from a RuCl₃-NaIO₄ reagent system were crucial for chemoselective oxidation of sulfide in the presence of an olefin moiety. The dual-role of ruthenium in sequential glycosylation-oxidation-dihydroxylation is amenable to a wide range of thio acceptors to access α-d-mannopyranosyl sulfones in good yields with high regioselectivity.

Full text of DOI:10.1021/acs.joc.5b00975

Article
pubs.acs.org/joc
Ruthenium Catalyzed Stereo/Chemo/Regioselective One-Pot
Synthesis of C(2)−C(3) Unsaturated and α‑D‑Mannopyranosyl
Sulfones
Sravanthi Chittela, Thurpu Raghavender Reddy, Palakodety Radha Krishna, and Sudhir Kashyap*
D-207, Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad-500 007, India
S
* Supporting Information
ABSTRACT: An efficient and divergent approach to C(2)−C(3) unsaturated glycosyl and α-D-mannopyranosyl sulfones has
been developed via ruthenium-promoted direct glycosylation, oxidation, and dihydroxylation from glycal in one-pot. The
presence of stoichiometric amounts of NaIO4 and in situ generation of RuO4 from a RuCl3−NaIO4 reagent system were crucial
for chemoselective oxidation of sulfide in the presence of an olefin moiety. The dual-role of ruthenium in sequential
glycosylation−oxidation−dihydroxylation is amenable to a wide range of thio acceptors to access α-D-mannopyranosyl sulfones
in good yields with high regioselectivity.
In addition, the glycosyl sulfones, the higher oxidized form of
thioglycosides have been extensively utilized as versatile chiral
synthons in assembling various functionalized saccharides,
involving (1) chemical glycosylation under a MgBr2·Et2O
reagent system;10 (2) Sm(OTf)3 catalyzed glycosylation;11 (3)
C-glycosylation via lithiated anion coupling reaction with a
carbonyl group;12 (4) Ramberg-Backlund and hydrogenation
reaction sequence for C-linked glycoconjugates;13 (5) stereo-
controlled C-glycosylation via glycosyl samarium intermedi-
ates;14 and (6) Umpolung approach to glycals via an anomeric
radical and sugar-chromium(III) complex.15
Owing to their promising therapeutic activities, the stereo-
selective preparation of sugar sulfones employing less toxic and
environmentally benign reagents, involving a simple reaction
operation and being compatible with other sensitive groups
would be highly desirable. Over the decades, several oxidative
reagent systems14b,c,16 have been created to overcome the
disadvantages of the most frequently used m-CPBA, as low
solubility in dichloromethane and unconventional reaction
operations at low temperature, compatibility in the presence of
other functionalities, and the purification of the desired
compound from byproducts remain unsolved issues.
INTRODUCTION
■
The efficient and stereoselective functionalization of glycosyl
mimetics has become an interesting area of research due to their
involvement in a vast array of biological processes1 and due to the
synthetic challenges associated with stereoselective construction
of glycosidic linkages.2 The sugar derivatives bearing C-1 thio-
linkages have unique importance in glycochemistry, particularly,
as versatile and stable glycosyl donors in chemical glycosylation
for assembling complex sugar scaffolds.3 Owing to their lower
susceptibility and stronger chemical stability toward hydrolysis,
the S-linked saccharides and glycoconjugates have been
recognized as potential chemical probes in glycobiology for
studying enzymatic inhibition.4
The glycosyl mimics bearing a sulfonyl moiety at the anomeric
center (Sugar-SO2R), an achiral, nonionic, and isoelectronic to
phosphate diester5 have been widely studied as convenient
glycosyltransferase inhibitors6 and potential antitumor agents7
(Figure 1). In recent years, several glycoconjugates appended
with S-linkages at C-1 have emerged as potent inhibitors against
human carbonic anhydrases (hCA): isozymes I and II and tumor-
associated isozymes IX and XII.8 Some of them showed selective
inhibition when compared to that of clinically approved drugs
such as acetazolamide (AZA), brinzolamide (BRZ), and
dorzolamide (DRZ) and therefore serve as important chemical
tools to probe such enzymatic studies (Figure 1). Recently, Kona
and co-workers demonstrated the utility of S-linked α-D-
mannopyranosyl as novel and selective inhibitors of human
Golgi α-mannosidase II (hGM), an interesting pharmaceutical
target linked to cancer chemotherapy.9
Although considerable efforts have been made in technical
improvement, the chemoselective oxidation of sulfide in a
molecule containing a double bond such as C(2)−C(3)-
unsaturated S-glycoside is quite elusive and particularly
interesting since the double bond present in the pyran ring
Received: April 30, 2015
© XXXX American Chemical Society
A
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Figure 1. Glycosyl sulfones and structure of some related drugs linked to cancer.
offers further synthetic utility to access chiral sugar derivatives.17
Scheme 1. Ru-Catalyzed Chemoselective Oxidation of 2,3-
Moreover, the regioselective dihydroxylation of C(2)−C(3)
olefin in one-pot by employing alternative equivalents of the
same reagent is a relatively scarce yet challenging transformation.
The exceptional versatility and efficiency of ruthenium
catalysis in various transformations18 have fueled our interest
with the expectation of finding ruthenium-based alternative
approaches in carbohydrate chemistry. In this context, recently
we demonstrated the sequential one-pot method for the
synthesis of mannosylated peptide and disaccharide glycoconju-
gates using ruthenium-catalysis.19a We envisioned that the
inherent ability of ruthenium(III) trichloride to generate
ruthenium (VIII) oxide in situ with a combination of co-oxidant
such as sodium metaperiodate would provide the promising and
highly efficient conditions for the chemoselective and
regioselective transformations.
In continuation of our research in glycochemistry exploring
Ru-catalysis,19 herein, we report our findings on the development
of a rapid and modular approach for the divergent synthesis of
C(2)−C(3)-unsaturated glycosyl sulfones and mannosyl
sulfones involving a sequential Ru-catalyzed stereoselective
glycosylation, chemoselective oxidation, and regioselective
dihydroxylation in one-pot. The directed glycosylation−
oxidation−dihydroxylation sequential transformations are ame-
nable to a wide range of acceptors to generate α-D-
mannopyranosyl sulfones from glycal in a single step.
Unsaturated α-Thioglucoside (3)
C(2)−C(3) olefinic protons were observed between δ 6.28−
6.30 ppm, while evidence of an anomeric proton at δ 5.13 (d, J1−2
= 1.7 Hz) and chemical shifts of other sugar protons at δ 5.28 (dd,
J = 9.3, 2.3 Hz, H-4), 4.67 (dt, J = 9.0, 4.3 Hz, H-5) confirmed the
product. Furthermore, the proton-decoupled carbon spectrum of
4a ambiguously proved the presence of anomeric carbon at δ
88.0, whereas resolved resonances for C(2)−C(6) were
observed at δ 129.2, 129.1 (C-2, C-3), 70.3, 63.7, and 62.8
ppm besides acetyl groups at δ 20.9 and 20.7 ppm. The ESI-
HRMS spectrum indicated the base peak corresponding to [4a +
NH4]+ of m/z 372.1100 calcd. for C16H22O7NS+ of 372.1111
further supported the assigned structure.
Other transition metal oxidative reagent systems, isoelectronic
to RuO4 such as toxic OsO4/NMO16b,21a or KMnO4/CuSO4·
5H2O16c,d for the chemoselective oxidation, were also studied,
and the results are summarized in Table 1. Notably, the reaction
was very slow and sluggish in the presence of OsO4 (5−10 mol
%) and co-oxidant N-mehtylmorpholine-N-oxide at room
temperature. Further increasing the amount of oxidizing reagent
resulted in decomposition or, for instance, mixtures of
uncharacterized compounds. Moreover, the KMnO4/CuSO4·
5H2O reagent system in CH3CN/H2O (5:1) afforded the
corresponding sulfone diol 5 as a result of oxidation−
dihydroxylation of sulfide and olefin, thus confirming the need
of ruthenium catalysis for chemoselective oxidation.
Indeed, treatment of 3 with excess of organic peracid such as
meta-chloroperbenzoic acid, most commonly used for oxidation
of sulfide, in chloroform as the solvent at −10 to 0 °C for 24 h
afforded 4a in 55% yield with no evidence of epoxidation of the
double bond. In contrast, use of oxone (potassium peroxomo-
nosulfate)14c,21b in aqueous methanol afforded methyl glucoside
7 as the identified byproduct in 23% yield with traces of sulfone
4a at some point of time as observed by TLC. Switching the
solvent system to acetone/water was found unsuccessful and
resulted in decomposition after prolonged reaction time,
probably due to the hydrolysis of starting material. Alternatively,
the hypofluorous acid, HOF·CH3CN complex generated from
RESULTS AND DISCUSSION
■
For this purpose, the necessary 2,3-unsaturated α-thioglucoside
(3) was prepared by a Ferrier glycosylation reaction of 3,4,6-tri-
O-acetyl D-glucal (1) and thiophenol (2a) using our previously
reported method.19b Initially, we attempted the Ru-catalyzed syn
dihydroxylation of the C(2)−C(3) double bond in 3 following
the method we developed for the one-pot synthesis of α-D-
mannopyranosides.19a An interesting result was obtained upon
the treatment of 3 with ruthenium trichloride (5 mol %) and
sodium metaperiodate (2.2 equiv) in EtOAc/CH3CN/H2O
(3:3:1), a biphasic solvent system at 0 °C to room temperature
for 30 min (Scheme 1). The experiment revealed the exclusive
formation of C-1 glycosyl sulfone 4a as a result of chemoselective
oxidation of thio-sugar rather than dihydroxylation of olefin
moiety in pyran ring. Despite the known susceptibility of double
20
bonds toward RuO4 that could lead to the formation of
mannosyl sulfone 5 or thiomannopyranoside 6, the reaction
proved to be highly chemoselective to generate 4a in quantitative
yields.
The spectral data of 4a were consistent and in conformity with
the assigned structure and correlated with literature.10a In the 1H
NMR spectrum of 4a, the characteristic resonances due to
B
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a
Table 1. Comparative Study and Screening of Various Oxidants for Chemoselective Oxidation
b
c
entry
1
oxidizing system
solvent(s)
reagents equiv
time
product (s)
4a (96%)
RuCl3/NaIO4
OsO4/NMO
OsO4/NMO
OsO4/NMO
KMnO4/CuSO4
m-CPBA
CH3CN/EtOAc/H2O (3:3:1)
acetone/H2O (3:1)
acetone/H2O (3:1)
acetone/H2O (3:1)
CH3CN/H2O (5:1)
CHCl3
5 mol %/2.2 equiv
5 mol %/3 equiv
10 mol %/3 equiv
1 equiv/3 equiv
3 equiv/2 equiv
2−3 equiv
30 min
72 h
72 h
24 h
2 h
d
2
3 (60%), 4a (10%)
3 (40%), 4a (10%)
traces
d
3
e
4
5
5 (50%)
f
6
24 h
12 h
12 h
4a (55%)
7
oxone
CH3OH/H2O (2:1)
2.5 equiv
7 (23%)
d
8
oxone
acetone/H2O (2:1)
2.5 equiv
traces
a
b
c
Reaction conditions: see Experimental Section. All of the reactions were performed with 3 (50 mg, 0.16 mmol, 1.0 equiv). The isolated yields are
d
e
based on starting material 3. Reactions did not complete, and a mixture of sulfide and sulfone was observed. Decomposition of starting material
and unknown mixtures were observed. Based on 55−75% peroxide content in water.
f
the F2/CH3CN/H2O system,16e and dimethyldioxirane
(DMDO)12 have been reported for the oxidation of various
functionalities including sulfide and alkene.22 However, the use
of such a reagent is limited due to unconventional reaction
operations and substrate compatibility.
Table 2. Ru-Catalyzed Stereo/Chemoselective
Glycosylation−Oxidation in One-Pot
a
In light of our recent report on one-pot glycosylation/
dihydroxylation,19a we investigated whether the glycosylation
and chemoselective oxidation sequence can be achieved without
isolation of the Ferrier product 3. In a representative example,
glycal 1 was coupled with thiophenol (2a) under Ru-mediated
thioglycosylation following our previously reported procedur-
e.19b After the completion of the glycosylation step as judged by
TLC, the reaction mixture was treated with EtOAc (2 mL), H2O
(650 μL), and NaIO4 (2.2 equiv) at 0 °C. To our delight, the
complete conversion of 3 was realized in at most 30 min to obtain
the corresponding sulfone 4a in a one-pot process (Table 2, entry
1). With no further optimization needed, 4a was isolated in 84%
yield as an α/β mixture (88:12) with high stereoselectivity in
favor of the α-anomer.23
Though oxidation of thioglycosides have been achieved with
the aid of several oxidants, the present method constitutes the
first report on the dual role of ruthenium catalyst for one-pot
preparation of allyl glycosyl sulfones, valuable synthetic and
chiral intermediates in carbohydrate chemistry.
To further probe the scope and generality of the sequential
method, we decided to synthesize various functionalized glycosyl
sulfones containing the C(2)−C(3) double bond in the pyran
ring (Table 2). Thus, a wide range of thio acceptors comprising
thio-phenols (2b−2d), thio-naphthol (2e), benzyl mercaptans
(2f−2h), alicyclic (2i,2j), and aliphatic (2k) were successfully
incorporated with glycal 1 under ruthenium-mediated glyco-
sylation−oxidation to obtain the desired C-1 glycosyl sulfones
4b−4k in good yields with high anomeric selectivity (Table 2,
entries 2−11). It is pertinent to mention that the combination of
RuCl3 and NaIO4 has negligible effect on the stereochemical
outcome in the oxidation step since the anomeric ratio observed
in this transformation is almost identical to that of Ferrier
products obtained in the preceding glycosylation reaction.19b
The resurgence of our interest in the glycosylation and
synthesis of glycoconjugates24 persuaded us to examine the
reactivity of 4a as a glycosyl donor in C-glycosylation.10a Thus,
the reaction of 4a with AlMe3 (2.0 M in hexane, 2.0 equiv) in
CH2Cl2 as the solvent proceeded smoothly to furnish the
corresponding C-1 methyl glycoside 8 in 78% yield with an 80:20
anomeric mixture (Scheme 2).24a
a
Reaction conditions: Glycal 1 (100 mg, 0.367 mmol, 1.0 equiv),
R1SH (1.2 equiv), RuCl3 (5.0 mol %), CH3CN (2 mL), then EtOAc
(2 mL), H2O (650 μL), NaIO4 (2.2 equiv), 0 °C-rt, 30 min. Isolated
and unoptimized yields. The anomeric ratios were examined by H
NMR spectroscopy.
b
c
1
In view of understanding the importance of mannosylated
constructs in nature and the recently reported bioactivity of α-D-
mannopyranosyl sulfones encouraged us to investigate a
straightforward and stereocontrolled method by employing an
easily accessible substrate under mild reagent conditions. During
C
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EtOAc, H2O, and NaIO4 (3.7 equiv) in sequence. Pleasingly, the
reaction was concluded in 40 min to afford the corresponding
diol sulfone 5. Following acetylation of crude diol using a
standard procedure resulted in the venerable α-D-mannopyr-
anosyl sulfone 9 as major product in 80% overall yields (Table 3,
entry 1).
Scheme 2. Ruthenium Promoted Dihydroxylation and Use of
Glycosyl Sulfone as Donor
a
Table 3. Synthesis of Mannopyranosyl Sulfones via Sequential
a
Reactions
a
Reagents and conditions: (a) 4a (0.17 mmol, 1.0 equiv), AlMe3 (2.0
equiv), CH2Cl2, 0 °C-rt, 2 h; (b) 4a (0.30 mmol, 1.0 equiv), RuCl3
(5.0 mol %), CH3CN/EtOAc/H2O (3:3:1), NaIO4 (1.5 equiv), 0 °C-
rt, 30 min; (c) RuCl3 (5.0 mol %), CH3CN/EtOAc/H2O (3:3:1),
NaIO4 (3.7 equiv), 0 °C-rt, 40 min; (d) Ac2O (5 equiv), CH2Cl2/
Pyridine (10:1), DMAP (cat.), 0 °C-rt, 12 h.
this, we anticipated that postglycosylation−dihydroxylation of
the double bond in 4a could be accomplished by using alternative
equivalence of co-oxidant NaIO4 in combination with catalytic
RuCl3.
To test this hypothesis, a preformed solution of 4a (106 mg,
0.30 mmol) in an acetonitrile/ethyl acetate/water (3:3:1) mixed
solvent system was treated with an aqueous solution of RuCl3 (15
μL of 0.1 M solution; 0.0015 mmol) and NaIO4 (107 mg, 0.45
mmol, 1.5 equiv) at 0 °C (Scheme 2). Remarkably, the
completion of the reaction was observed in 30 min to afford
the desired diol 5, which upon treatment with acetic anhydride in
the presence of catalytic DMAP in pyridine and dichloromethane
afforded the corresponding per-acetylated mannosyl sulfone 9 in
92% yields over two steps. In contrast, the catalytic OsO4 with
NMO as co-oxidant failed to give the desired diol,25 further
confirming the versatile synthetic utility of the ruthenium
method for such a type of substrate.
Given the success of these studies, we wondered whether it
would be possible to achieve the oxidation of sulfide and
dihydroxylation of the C(2)−C(3) olefin moiety in compound 3
in a single step by employing catalytic RuCl3 with excess of
NaIO4 (∼3.7 equiv) since oxidation of sulfide and dihydrox-
ylation of olefin required 2.2 and 1.5 equiv of NaIO4, respectively.
Presumably, the reaction of 3 with 5 mol % of RuCl3 and 3.7
equiv of NaIO4 in the CH3CN/EtOAc/H2O solvent system
afforded the desired 2,3-syn-diol sulfone 5, which was directed to
acetylation without further purification to obtain the mannosyl
sulfone 9 in 86% yield (Scheme 2).
Encouraged by these results, we attempted to investigate the
sequential glycosylation−oxidation−dihydroxylation reactions
in one-pot to access the mannose sulfones directly from
commercially available glycal 1 (Figure 2).
Accordingly, a preformed solution of 1 and 2a (1.2 equiv) in
anhydrous acetonitrile was treated with 5 mol % of RuCl3 under
an atmosphere of nitrogen. After the completion of the reaction,
the subsequent in situ oxidation−dihydroxylation of resultant
2,3-unsaturated thioglucoside (3) was performed by introducing
a
Reaction conditions: (i) Glycal 1 (100 mg, 0.367 mmol, 1.0 equiv),
R1SH (1.2 equiv), RuCl3 (5.0 mol %), CH3CN (2 mL), 40 °C, 1−8 h;
(ii) EtOAc (2 mL), H2O (650 μL), NaIO4 (3.7 equiv), 0 °C-rt, 40
min; (iii) Ac2O (5 equiv), CH2Cl2/Pyridine (10:1), DMAP (cat.), 0
°C-rt, 12 h. Isolated yields after purification by silica-gel column
chromatography (both isomers). Diastereomeric ratios were
b
c
1
determined by H NMR analysis of a crude reaction mixture.
Figure 2. One-pot sequential glycosylatiom/oxidation/dihydroxylation approach.
D
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Following the initial success of the sequential one-pot
approach, the scope was further expanded to construct different
sulfonyl moieties at anomeric positions of mannose (Table 3).
Generally, the one-pot method is efficient and mild enough to
generate various α-D-mannopyranosyl sulfones (10−16) from
glycal in good yields and high stereoselectivity (entries 2−8).
We further highlight the advantage of our method by
comparing with the traditional method. To this end, thiomanno-
side 18 was synthesized from readily prepared per-O-acetylated
mannose 17 using a literature procedure.16e Oxidation of
anomeric sulfide was then accomplished by using a combination
of KMnO4/CuSO4·5H2O16c in a CH3CN/H2O (5:1) mixed
solvent system to obtain the corresponding mannosyl sulfone 9
in 92% yield as anomeric mixture of α/β ratio 78:22 (Scheme 3).
Notably, the better results, in terms of yields and stereo-
chemistry, were accomplished under the one-pot method as
compared to stepwise reactions, which is otherwise time-
consuming and involves excessive use of reagents.
Subsequently, the complete dihydroxylation of 19 to 20 was
achieved by adding extra 1.5 equivalence of NaIO4 (106 mg, 0.35
mmol) in the same pot. Following simple workup and successive
acetylation of the crude diol 20 afforded the corresponding per-
acetylated α-menthyl mannoside 21 in 82% yield.19a
The next experiment was carried out to compare the reactivity
of allylic thio-sugar 3 with anomeric thio-sugar 18. Interestingly,
the allyl sulfide moiety undergoes selective oxidation under
similar reaction conditions to afford the corresponding
unsaturated glycosyl sulfone 4a in quantitative yields, whereas
only a small amount (<5%) of manosyl sulfone 9 was identified.
Nevertheless, exclusive formation of the sulfone product is
consistent with our studies and established the ability of RuO4 to
oxidize the sulfide moiety efficiently and chemoselectively.
CONCLUSIONS
■
In conclusion, the ruthenium tetraoxide generated in situ from
RuCl3 in combination with a stoichiometric amount of co-
oxidant is recognized as a powerful and efficient catalyst for
chemoselective oxidation. The Ru-mediated strategy is attractive
and enables the synthesis of unsaturated glycosyl and mannosyl
sulfones in one-pot from readily available starting materials:
glycal. The use of environmental friendly reagents and the
convenience of the reaction operation to generate valuable
mannosyl sulfones in a stereocontrolled manner are the key
advantages. Notably, this represents a valuable alternative to toxic
OsO4 in postglycosylation chemoselective and regioselective
reactions. Further studies include exploration of the synthetic
utility of glycosyl sulfone and application of Ru-catalysis for the
synthesis of other sugar scaffolds are currently underway.
a
Scheme 3. Synthesis of Mannosyl Sulfone
a
Reagents and conditions: (a) 17 (1.0 equiv), thiophenol (2.0 equiv),
BF3·Et2O (6.0 equiv), CH2Cl2, 0 °C-rt, 18 h; Method A. 18 (1.0
equiv), KMnO4 (1.5 equiv), CuSO4·5H2O (1.0 equiv), CH3CN/H2O
(5:1), room temperature, 2 h; Method B. 18 (1.0 equiv), RuCl3 (5.0
mol %), CH3CN/EtOAc/H2O (3:3:1), NaIO4 (2.2 equiv), 0 °C-rt, 20
min.
EXPERIMENTAL SECTION
■
We next set out to conduct control experiments to understand
the behavior of RuO4 in chemoselective oxidation (Scheme 4).
Thus, an equimolar mixture of thiomannoside 18 (100 mg, 0.23
mmol) and menthyl glycoside 19 (85 mg, 0.23 mmol) in an
acetonitrile/ethyl acetate/water (3:3:1) solvent system was
treated with an aqueous solution of RuCl3 (∼12 μL of 0.1 M
solution; 0.00115 mmol) and NaIO4 (176 mg, 0.50 mmol, 2.2
equiv) at 0 °C, and the reaction mixture was stirred for 20 min.
The reaction proceeded well to afford sulfone 9 of the
corresponding thiomannoside in excellent yields along with
traces of diol adduct 20 corresponding to menthyl glycoside.
General Synthesis Information. Unless otherwise noted,
materials were obtained from commercial suppliers and used without
purification. Anhydrous solvents were purchased for the reactions and
used without further desiccation. All reactions were performed in flame-
dried round-bottom flasks, fitted with rubber septa or glass gas adapters,
under a positive pressure of nitrogen or argon. Analytical thin-layer
chromatography (TLC) was performed using aluminum backed UV
F254 precoated silica gel flexible plates. Removal of solvent under
reduced pressure refers to distillation with a rotary evaporator attached
to a vacuum pump (∼3 mmHg). Melting points were obtained in open
capillary tubes using a micromelting point apparatus and were
uncorrected. Optical rotations were recorded with a digital polarimeter
at 589 nm (sodium D-line). NMR were recorded on 300, 400, or 500
MHz nuclear magnetic resonance spectrometers. The proton
resonances are annotated as chemical shifts (δ) relative to
tetramethylsilane (δ 0.0) using the residual solvent signal as an internal
standard or tetramethylsilane itself: chloroform-d (δ 7.26, singlet);
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad); coupling constant (J, Hz); and the number of protons for a given
resonance is indicated by nH. The chemical shifts of 13C NMR are
reported in ppm relative to the central line of the triplet at 77.0 ppm for
CDCl3. IR spectra were recorded on an FT-IR spectrometer, and wave
numbers of maximum absorption peaks are presented in cm−1. High
resolution mass analyses (HRMS) were performed on a mass
spectrometer using ESI-TOF techniques.
Scheme 4. Chemoselective Oxidation of Thioglycoside in
a
Control Experiments
General Procedure for RuO4 Oxidation (A). To a solution of 3
(50 mg, 0.16 mmol) in an acetonitrile/ethyl acetate/water (3:3:1)
mixed solvent system, RuCl3 (5 mol %, 0.1 M aqueous solution) and
NaIO4 (75 mg, 0.35 mmol, 2.2 equiv) were added at 0 °C for 30 min.
After the completion of the reaction, the reaction was quenched with
saturated NaHCO3 (10 mL), diluted with EtOAc (10 mL), and
extracted with EtOAc (30 mL × 3). The combined organic layers were
washed with brine solution, dried over anhydrous Na2SO4, concentrated
in vacuo, and purified by silica gel column chromatography (hexanes−
a
Reagents and conditions: (a) RuCl3 (5.0 mol %), CH3CN/EtOAc/
H2O (3:3:1), NaIO4 (2.2 equiv), 0 °C-rt, 20 min; (b) NaIO4 (1.5
equiv), 0 °C-rt, 30 min; (c) Ac2O (5 equiv), CH2Cl2/pyridine (10:1),
DMAP (cat.), 0 °C-rt, 12 h.
E
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EtOAc 2:1) to afford the corresponding sulfone 4a (54 mg, 96% yield)
as a white solid.
Phenyl 4,6-Di-O-acetyl-2,3-dideoxy-1-sulfonyl-α-D-erythro-hex-2-
enopyranoside (4a). Following general procedure F using thiophenol
(2a) in the glycosylation step and purification by silica gel column
chromatography afforded the title compound as a white solid (109 mg,
84%). Rf 0.5 (1:1, hexane−EtOAc); Mp. 148−150 °C; [α]2D5 +113.33 (c
1.5, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.99 (d, J = 7.2 Hz, 2H),
7.72 (t, J = 7.6 Hz, 1H), 7.60 (t, J = 7.4 Hz, 2H), 6.30 (s, 2H), 5.28 (dd, J
= 9.3, 2.3 Hz, 1H), 5.13 (d, J = 1.7 Hz, 1H), 4.67 (dt, J = 9.0, 4.3 Hz, 1H),
4.17 (d, J = 4.0 Hz, 2H), 2.11 (s, 3H), 2.10 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 170.5, 170.1, 137.1, 134.3, 133.2, 129.2, 129.1, 119.1,
88.0, 70.3, 63.7, 62.8, 20.9, 20.7. IR (CHCl3, cm−1): 3019, 2926, 2854,
1740, 1550, 1464, 1372, 1215, 1042, 928, 770, 745, 667, 601. HRMS
(ESI): m/z [M + NH4]+ calcd. for C16H22O7NS+: 372.11115; found,
372.11004.
General Procedure for OsO4 Reaction (B). In a representative
experiment, to a preformed solution of compound 3 (50 mg, 0.16
mmol) and NMO (30 μL, 0.48 mmol) in acetone/water (3:1 v/v, 0.5
mL) was added 78 μL of 0.1 M aqueous OsO4 solution (0.0078 mmol, 5
mol %). The reaction was allowed to stir at room temperature for 2−3
days. The reaction mixture was quenched by the addition of saturated
aqueous sodium bisulfite (5 mL) and extracted with EtOAc (30 mL ×
3). The combined organic layers were washed successively with 2 × 10
mL of 1 N aqueous sodium bisulfate and 10 mL of brine. The organic
layer was dried over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure to provide a crude product.
General Procedure for KMnO4 Reaction (C). To a solution of
compound 3 (50 mg, 0.16 mmol) in CH3CN−H2O (5:1 v/v; 2 mL) was
added a finely ground mixture of solid KMnO4 (75 mg, 0.48 mmol, 3.0
equiv) and CuSO4·5H2O (80 mg, 0.32 mmol, 2.0 equiv) and stirred at
room temperature until the completion of the reaction. The reaction was
extracted with EtOAc (30 mL × 3). The combined organic layers were
washed with brine solution, dried over anhydrous Na2SO4, and
concentrated in vacuo to provide crude diol-sulfone 5. Following
acetylation of diol-sulfone 5 in CH2Cl2 (5 mL), pyridine (0.5 mL) and
acetic anhydride (5 equiv) in the presence of a catalytic amount of
DMAP gave the corresponding per acetylated glycoside. Following the
usual workup and purification by chromatography (silica gel, hexanes−
EtOAc 2:1) afforded mannosyl sulfone 9 (37 mg, 50% yield over 2 steps)
as a colorless oily liquid.
General Procedure for m-Chloroperbenzoic Acid Reaction
(D). To a preformed solution of m-CPBA (55−75% peroxide content in
H2O, 100 mg, 0.57 mmol) in chloroform (3 mL) at −10 °C was added a
solution of 3 (50 mg, 0.16 mmol) in chloroform (800 μL). The reaction
was allowed to warm at 0 °C for 1 h and then stirred at room
temperature for 24 h. The reaction mixture was quenched with saturated
aqueous sodium hydrogen carbonate (10 mL) and extracted with
chloroform (50 mL × 3). The combined organic layers were washed
with water and brine, dried over Na2SO4, and concentrated in vacuo to
provide crude product. The crude mixture was purified by silica gel
column chromatography (hexane−EtOAc 2:1) to provide compound
4a (30 mg, 55% yield) as a white solid.
General Procedure for the Oxone Reaction (E). To a solution of
compound 3 (50 mg, 0.16 mmol) in methanol (2 mL) was added a
solution of oxone (72 mg, 0.40 mmol) in water (1 mL) at 0 °C. The
resulting cloudy slurry was stirred vigorously for 2 h at room
temperature. The reaction mixture was extracted with chloroform (50
mL × 3). The organic extracts were combined and washed with water,
brine, dried over Na2SO4, and concentrated under reduced pressure.
The crude product was purified by silica gel column chromatography
(hexane−EtOAc 2:1) to afford methyl glycoside 7 (20 mg, 23% yield) as
a colorless liquid.
General Procedure for the One-Pot Glycosylation−Oxidation
Reaction (F). To a stirred solution of 3,4,6-tri-O-acetyl-D-glucal 1 (100
mg, 0.36 mmol) and a thio acceptor (0.42 mmol, 1.2 equiv) in
anhydrous acetonitrile (2 mL) under an atmosphere of argon was added
RuCl3 (5 mol %) at room temperature. The reaction mixture was stirred
at 40 °C until the complete consumption of the starting material
(glycal), adjudged by TLC. The reaction mixture was cooled at 0 °C and
diluted with EtOAc (2 mL). An aqueous solution of NaIO4 (0.79 mmol,
2.2 equiv) in H2O (650 μL) was added to the above-mentioned reaction
and stirred vigorously. The reaction deemed complete by TLC in at
most 30 min to provide the corresponding sulfone, which generally
moves slowly on TLC as compared to the sulfide. The reaction was
quenched with saturated NaHCO3 (10 mL), diluted with EtOAc (10
mL), and extracted with EtOAc (30 mL × 3). The combined organic
layers were washed with brine solution, dried over anhydrous Na2SO4,
concentrated in vacuo, and purified by silica gel column chromatography
(hexane−EtOAc 2:1) to afford the 2,3-unsaturated glycosyl sulfones in
good yields. All of the products were confirmed by 1H NMR, 13C NMR,
and MS/HRMS spectroscopy, and the α:β ratios were determined by
relative integration of anomeric or separable proton in 1H NMR spectra.
4′-Chlorophenyl 4,6-Di-O-acetyl-2,3-dideoxy-1-sulfonyl-α-D-er-
ythro-hex-2-enopyranoside (4b). Following general procedure F
using 4-chlorothiophenol (2b) in the glycosylation step and purification
by silica gel column chromatography afforded the title compound as a
white solid (127 mg, 90%). Rf 0.5 (3:2, hexane−EtOAc); Mp. 130−132
°C; [α]2D5 +173.33 (c 1.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.92
(d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 6.31 (dt, J = 10.5, 1.7 Hz,
2H), 6.27 (dt, J = 10.4, 1.9 Hz, 2H), 5.28 (dq, J = 9.0, 2.0 Hz, 1H), 5.11
(q, J = 2.3 Hz, 1H), 4.65 (ddd, J = 8.4, 5.5, 2.4 Hz, 1H), 4.19 (dd, J = 12.4,
2.4 Hz, 1H), 4.15 (dd, J = 12.5, 5.7 Hz, 1H), 2.11 (s, 3H), 2.11 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 170.2, 169.9, 140.9, 135.3, 133.2, 130.5,
129.3, 118.7, 87.8, 70.3, 63.5, 62.6, 29.5, 20.7, 20.6. IR (CHCl3, cm−1):
3019, 2925, 2854, 1741, 1463, 1322, 1215, 1046, 928, 745, 667, 623.
HRMS (ESI): m/z [M + NH4]+ calcd. for C16H21ClO7NS+, 406.07218;
found, 406.07068.
p-Tolyl 4,6-di-O-acetyl-2,3-dideoxy-1-sulfonyl-α-D-erythro-hex-2-
enopyranoside (4c). Following general procedure F using p-
toluenethiol (2c) in the glycosylation step and purification by silica
gel column chromatography afforded the title compound as a white solid
(110 mg, 82%). Rf 0.6 (1:1, hexane−EtOAc); Mp. 176−178 °C; [α]D25
+50.00 (c 1.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.86 (d, J = 8.1
Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 6.29 (s, 2H), 5.28 (dd, J = 9.1, 2.1 Hz,
1H), 5.09 (d, J = 1.9 Hz, 1H), 4.66 (dt, J = 8.8, 4.2 Hz, 1H), 4.18−4.14
(m, 2H), 2.47 (s, 3H), 2.11 (s, 3H), 2.10 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 170.5, 170.1, 145.4, 134.0, 133.0, 129.8, 129.2, 119.3, 88.0,
70.2, 63.7, 62.8, 21.7, 20.9, 20.7. IR (CHCl3, cm−1): 3020, 2957, 2926,
2854, 1741, 1645, 1464, 1371, 1215, 1143, 1080, 745, 667. HRMS
(ESI): m/z [M + NH4]+ calcd. for C17H24O7NS+, 386.12680; found,
386.12580.
4′-Trifuoromethylphenyl 4,6-Di-O-acetyl-2,3-dideoxy-1-sulfonyl-
α-D-erythro-hex-2-enopyranoside (4d). Following general procedure
F using 4-(trifluoromethyl)thiophenol (2d) in the glycosylation step
and purification by silica gel column chromatography afforded the title
compound as a white solid (124 mg, 80%). Rf 0.4 (2:1, hexane−EtOAc);
Mp. 145−147 °C; [α]2D5 +73.33 (c 1.5, CHCl3); 1H NMR (500 MHz,
CDCl3): δ 8.13 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 6.34 (dd, J =
10.5, 0.9 Hz,, 1H), 6.31−6.26 (m, 1H), 5.31−5.27 (m, 1H), 5.15 (q, J =
2.3 Hz, 1H), 4.68 (ddd, J = 8.2, 5.5, 2.3 Hz, 1H), 4.20 (dd, J = 11.5, 12.4
Hz, 1H), 4.16 (dd, J = 12.4, 5.7 Hz, 1H), 2.12 (s, 3H), 2.10 (s, 3H). 13C
NMR (125 MHz, CDCl3): δ 170.3, 170.0, 140.7, 133.8, 129.8, 126.2,
118.4, 88.0, 70.5, 63.6, 62.7, 20.8, 20.7. IR (CHCl3, cm−1): 3020, 2957,
2926, 2854, 1741, 1645, 1464, 1371, 1215, 1143, 1080, 745, 667. HRMS
(ESI): m/z [M + Na]+ calcd. for C17H17O7F3SNa+, 445.05393; found,
445.05355.
Naphthyl 4,6-Di-O-acetyl-2,3-dideoxy-1-sulfonyl-α-D-erythro-
hex-2-enopyranoside (4e). Following general procedure F using 2-
napthalenethiol (2e) in the glycosylation step and purification by silica
gel column chromatography afforded the title compound as a white solid
(115 mg, 78%). Rf 0.4 (1:1, hexane−EtOAc); Mp. 138−140 °C; [α]D25
+200.00 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.46 (s, 1H),
8.02−8.00 (m, 2H), 7.95 (d, J = 7.9 Hz, 1H), 7.85 (dd, J = 8.5, 1.7 Hz,
1H), 7.70 (d, J = 7.0 Hz, 1H), 7.66 (d, J = 7.0 Hz, 1H), 6.62 (d, J = 5.6
Hz, 1H), 5.21 (dd, J = 10.8, 5.8 Hz, 1H), 4.96 (ddd, J = 10.7, 3.4, 2.3 Hz,
1H), 4.45 (t, J = 5.8 Hz, 1H), 4.40 (dd, J = 12.2, 5.8 Hz, 1H), 4.39 (d, J =
3.7 Hz, 1H), 4.35 (dd, J = 12.4, 2.0 Hz, 1H), 2.06 (s, 3H), 1.80 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 170.6, 170.0, 148.4, 136.4, 135.3, 132.0,
F
DOI: 10.1021/acs.joc.5b00975
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The Journal of Organic Chemistry
Article
130.7, 129.5, 129.4, 129.3, 128.0, 127.9, 123.4, 90.7, 70.4, 65.8, 61.7,
57.8, 20.7, 20.5. IR (CHCl3, cm−1): 3021, 2926, 2854, 1740, 1645, 1456,
1370, 1348, 1314, 1214, 1144, 1126, 1068, 817, 743, 666. HRMS (ESI):
m/z [M + NH4]+ calcd. for C20 H24O7SN+, 422.12680; found,
422.12752.
yellow crystalline solid (94 mg, 74%). Rf 0.4 (3:2, hexane−EtOAc); Mp.
82−84 °C; [α]2D5 −1.28 (c 1.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ
6.27 (dt, J = 10.5, 2.3 Hz, 1H), 6.15 (ddd, J = 10.7, 2.3, 1.9 Hz, 1H), 5.34
(dq, J = 9.1, 1.8 Hz, 1H), 5.19 (q, J = 2.4 Hz, 1H), 4.57 (ddd, J = 8.5, 4.8,
2.5 Hz, 1H), 4.26 (dd, J = 12.4, 2.0 Hz, 1H), 4.22 (dd, J = 12.4, 4.9 Hz,
1H), 3.70 (quint, J = 8.1 Hz, 1H), 2.25−2.18 (m, 1H), 2.15−2.01 (m,
2H), 2.10 (s, 3H), 2.09 (s, 3H), 1.87−1.81 (m, 1H), 1.73−1.64 (m, 2H),
1.41−1.21 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 170.5, 170.1,
133.0, 118.8, 85.2, 70.2, 63.5, 62.3, 59.3, 27.6, 25.9, 25.8, 25.7, 20.9, 20.7.
IR (CHCl3, cm−1): 3020, 2927, 2854, 1741, 1530, 1450, 1370, 1216,
1099, 1045, 975, 743, 667. HRMS (ESI): m/z [M + NH4]+ calcd. for
C15H26O7NS+, 364.14245; found, 364.14386.
n-Butyl 4,6-Di-O-acetyl-2,3-dideoxy-1-sulfonyl-α-D-erythro-hex-2-
enopyranoside (4k). Following general procedure F using n-
butanethiol (2k) in the glycosylation step and purification by silica gel
column chromatography afforded the title compound as pale yellow
solid (100 mg, 82%). Rf 0.5 (3:2, hexane−EtOAc); Mp. 96−98 °C; [α]D25
−53.33 (c 1.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ 6.29 (dt, J =
10.7, 1.9 Hz, 1H), 6.15 (ddd, J = 10.7, 2.6, 1.8 Hz, 1H), 5.33 (dq, J = 10.9,
1.9 Hz, 1H), 5.16 (q, J = 2.3 Hz, 1H), 4.57 (ddd, J = 7.7, 4.7, 2.6 Hz, 1H),
4.29−4.18 (m, 2H), 3.15 (t, J = 7.9 Hz, 2H), 2.11 (s, 3H), 2.10 (s, 3H),
1.94−1.81 (m, 2H), 1.50 (quint., J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz,
3H). 13C NMR (125 MHz, CDCl3): δ 170.5, 170.1, 133.3, 118.4, 85.6,
70.4, 63.6, 62.4, 50.4, 23.5, 21.9, 20.9, 20.7, 13.5. IR (CHCl3, cm−1):
3020, 2957, 2926, 2854, 1742, 1549, 1515, 1465, 1216, 1099, 1046, 926,
972, 771, 667, 604. HRMS (ESI): m/z [M + Na]+ calcd. for
C14H22O7NaS+, 357.09784; found, 357.09739.
Benzyl 4,6-Di-O-acetyl-2,3-dideoxy-1-sulfonyl-α-D-erythro-hex-2-
enopyranoside (4f). Following general procedure F using benzyl
mercaptan (2f) in the glycosylation step and purification by silica gel
column chromatography afforded the title compound as pale yellow
semi solid (105 mg, 78%). Rf 0.4 (3:2, hexane−EtOAc); [α]2D5 +42.40 (c
1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.46−7.40 (m, 5H), 6.26
(dt, J = 10.5, 2.0 Hz, 1H), 6.01 (ddd, J = 10.5, 2.9, 2.3 Hz, 1H), 5.32 (dq, J
= 9.3, 2.1 Hz, 1H), 5.01 (q, J = 2.4 Hz, 1H), 4.65 (ddd, J = 8.5, 5.8, 2.3
Hz, 1H), 4.59 (d, J = 14.0 Hz, 1H), 4.35 (dd, J = 12.4, 2.3 Hz, 1H), 4.25
(d, J = 9.6 Hz, 1H), 4.23 (dd, J = 12.4, 5.7 Hz, 1H), 2.15 (s, 3H), 2.11 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 170.6, 170.1, 133.7, 130.8, 129.2,
129.1, 127.5, 118.1, 83.0, 70.4, 63.7, 62.6, 56.9, 20.9, 20.8. IR (CHCl3,
cm−1): 3019, 2956, 2925, 2853, 1743, 1461, 1370, 1316, 1217, 1101,
1044, 970, 913, 771, 698, 668, 621. HRMS (ESI): m/z [M + Na]+ calcd.
for C17H20O7NaS+, 391.08219; found, 391.08133.
4′-Chlorobenzyl 4,6-Di-O-acetyl-2,3-dideoxy-1-sulfonyl-α-D-er-
ythro-hex-2-enopyranoside (4g). Following general procedure F
using 4-chlorobenzyl mercaptan (2g) in the glycosylation step and
purification by silica gel column chromatography afforded the title
compound as a white solid (117 mg, 80%). Rf 0.4 (2:1, hexane−EtOAc);
Mp. 130−132 °C; [α]2D5 +93.33 (c 1.5, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 7.39 (br s, 4H), 6.27 (dt, J = 10.6, 1.9 Hz, 2H), 6.02 (ddd, J =
10.6, 2.8, 2.3 Hz, 1H), 5.32 (dq, J = 9.3, 2.1 Hz, 1H), 4.99 (q, J = 2.5 Hz,
1H), 4.62 (ddd, J = 8.1, 5.5, 2.1 Hz, 1H), 4.55 (d, J = 14.2 Hz, 1H), 4.37
(dd, J = 12.5, 2.3 Hz, 1H), 4.23 (d, J = 14.2 Hz, 1H), 4.21 (dd, J = 12.5,
5.7 Hz, 1H), 2.14 (s, 3H), 2.12 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
170.5, 170.1, 135.5, 133.9, 132.1, 129.4, 125.9, 117.81, 83.2, 70.5, 63.6,
62.4, 56.1, 20.9, 20.8. IR (CHCl3, cm−1): 3021, 2926, 2854, 1742, 1492,
1371, 1319, 1215, 1098, 1044, 880, 743, 666, 599. HRMS (ESI): m/z [M
+ Na]+ calcd. for C17H19O7ClNaS+, 425.04322; found, 425.04379.
4′-tert-Butylbenzyl 4,6-Di-O-acetyl-2,3-dideoxy-1-sulfonyl-α-D-er-
ythro-hex-2-enopyranoside (4h). Following general procedure F using
4-tert-butylbenzyl mercaptan (2h) in the glycosylation step and
purification by silica gel column chromatography afforded the title
compound as oily liquid (131 mg, 85%). Rf 0.5 (3:2, hexane−EtOAc);
[α]2D5 +28.45 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.43 (d, J
= 8.3 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 6.26 (dt, J = 10.2, 1.1 Hz, 1H),
6.02 (ddd, J = 10.6, 2.8, 2.3 Hz, 1H), 5.32 (dq, J = 9.1, 1.5 Hz, 1H), 5.03
(q, J = 1.9 Hz, 1H), 4.65 (ddd, J = 8.3, 5.7, 1.5 Hz, 1H), 4.57 (d, J = 14.4
Hz, 1H), 4.33 (dd, J = 12.1, 1.9 Hz, 1H), 4.23 (d, J = 14.2 Hz, 1H), 4.21
(dd, J = 12.1, 5.7 Hz, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 1.34 (s, 9H). 13C
NMR (125 MHz, CDCl3): δ 170.6, 170.1, 152.4, 133.6, 130.4, 126.1,
124.4, 118.2, 82.9, 70.4, 63.7, 62.6, 56.5, 34.7, 31.2, 20.9, 20.8. IR
(CHCl3, cm−1): 3022, 2959, 2925, 2854, 1743, 1511, 1461, 1369, 1344,
1315, 1217, 1124, 1101, 1044, 978, 840, 746, 667, 605. HRMS (ESI): m/
z [M + NH4]+ calcd. for C21H32O7NS+, 442.18940; found, 442.19019.
Cyclohexyl 4,6-Di-O-acetyl-2,3-dideoxy-1-sulfonyl-α-D-erythro-
hex-2-enopyranoside (4i). Following general procedure F using
cyclohexanethiol (2i) in the glycosylation step and purification by silica
gel column chromatography afforded the title compound as a white solid
(102 mg, 78%). Rf 0.5 (3:2, hexane−EtOAc); Mp. 96−98 °C; [α]D25
+0.72 (c 1.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ 6.28 (dt, J = 10.6,
1.7 Hz, 1H), 6.15 (ddd, J = 12.5, 2.8, 1.9 Hz, 1H), 5.35−5.27 (m, 2H),
4.59 (ddd, J = 7.9, 4.9, 2.6 Hz, 1H), 4.28−4.17 (m, 2H), 3.22 (tt, J = 12.1,
3.4 Hz, 1H), 2.34−2.26 (m, 1H), 2.15−2.10 (m, 1H), 2.10 (s, 6H),
2.01−1.92 (m, 2H), 1.78−1.56 (m, 3H), 1.41−1.23 (m, 3H). 13C NMR
(125 MHz, CDCl3): δ 170.5, 170.1, 133.2, 118.9, 83.5, 70.2, 63.6, 62.6,
59.6, 26.1, 25.3, 25.2, 25.0, 23.7, 20.9, 20.7. IR (CHCl3, cm−1): 3022,
2929, 2857, 1740, 1549, 1451, 1370, 1218, 1097, 1044, 852, 771, 666,
614. HRMS (ESI): m/z [M + Na]+ calcd. for C16H24O7NaS+,
383.11349; found, 383.11335.
C-Methyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyr-
anoside (8). A preformed solution of compound 4a (60 mg, 0.17 mmol)
in CH2Cl2 (1 mL) was treated with a solution of trimethylaluminum
(170 μL, 2.0 M in hexanes, 0.17 mmol, 2.0 equiv) at 0 οC. The reaction
mixture was stirred vigorously for 10−15 min at ice-cold temperature
and then allowed to warm at room temperature and stirred for 2 h. The
reaction was quenched with saturated NaHCO3 (5 mL), diluted with
EtOAc (10 mL), and extracted with EtOAc (30 mL × 3). The combined
organic layers were washed with brine solution, dried over anhydrous
Na2SO4, concentrated in vacuo, and purified by silica gel column
chromatography to obtain the desired C-methyl glycosides 8 (30 mg,
78% yield) as a pale yellow liquid. Rf 0.4 (2:1, hexane−EtOAc); [α]D25
+124.46 (c 1.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ 5.89 (ddd, J =
10.4, 2.6, 1.7 Hz, 1H), 5.77 (ddd, J = 10.3, 2.9, 2.1 Hz, 1H), 5.12 (m,
1H), 4.45−4.39 (m, 1H), 4.26 (dd, J = 11.9, 6.2 Hz, 1H), 4.16 (dd, J =
10.5, 3.7 Hz, 1H), 3.96 (dt, J = 6.3, 3.6 Hz, 1H), 2.10 (s, 3H), 2.09 (s,
3H), 1.31 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 170.8,
170.4, 134.5, 122.7, 69.5, 67.8, 64.8, 62.7, 21.0, 20.7, 19.0. IR (CHCl3,
cm−1): 3019, 1737, 1371, 1214, 1047, 742, 667. HRMS (ESI): m/z [M -
+
H]+ calcd. for C11H15O5 , 227.0914; found, 227.9060.
General Procedure for One-Pot Glycosylation−Oxidation−
Dihydroxylation Reaction (G). Glycosylation coupling reaction
between glycal 1 and a thio acceptor was performed following procedure
F. The solution was then cooled at 0 °C, and EtOAc (2 mL) and an
aqueous solution of NaIO4 (1.36 mmol, 3.7 equiv) in H2O (650 μL)
were successively added, and the reaction mixture was stirred vigorously
for 30−40 min. The reaction was quenched with saturated NaHCO3 (10
mL), diluted with EtOAc (10 mL), and extracted with EtOAc (30 mL ×
3). The combined organic layers were washed with brine solution, dried
over anhydrous Na2SO4, and evaporated under reduced pressure to
provide crude product. Following the acetylation of crude diol in
CH2Cl2 (5 mL), pyridine (0.5 mL), and acetic anhydride (5 equiv) in
the presence of a catalytic amount of DMAP gave the corresponding
per-acetylated glycoside. Following the usual workup and purification by
chromatography (silica gel, hexanes−EtOAc) afforded the desired α-D-
mannopyranosides (9-16) as major products in good yields.
Phenyl 2,3,4,6-Tetra-O-acetyl-1-sulfonyl-α-D-mannopyranoside
(9). Following general procedure G using thiophenol (2a) in the
glycosylation step and purification by silica gel column chromatography
afforded the title compound as a white semisolid (138 mg, 80%). Rf 0.4
Cyclopentyl 4,6-Di-O-acetyl-2,3-dideoxy-1-sulfonyl-α-D-erythro-
hex-2-enopyranoside (4j). Following general procedure F using
cyclopentanethiol (2j) in the glycosylation step and purification by
silica gel column chromatography afforded the title compound as a
(1:1, hexane−EtOAc); [α]2D5 +11.27 (c 1.3, CHCl3). H NMR (500
1
MHz, CDCl3): δ 7.97 (d, J = 8.2 Hz, 2H), 7.73 (t, J = 7.5 Hz, 1H), 7.62
(t, J = 7.6 Hz, 2H), 6.03 (dd, J = 3.5, 2.1 Hz, 1H), 5.72 (dd, J = 9.3, 3.7
G
DOI: 10.1021/acs.joc.5b00975
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Article
Hz, 1H), 5.29 (t, J = 9.5 Hz, 1H), 4.84−4.9 (m, 2H), 4.23 (dd, J = 12.5,
6.0 Hz, 1H), 4.06 (dd, J = 12.5, 2.3 Hz, 1H), 2.13 (s, 3H), 2.09 (s, 3H),
2.06 (s, 3H), 2.03 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 170.3, 169.6,
169.4, 169.3, 136.2, 134.7, 129.4, 129.1, 90.3, 73.4, 68.8, 65.4, 65.2, 62.6,
20.7, 20.5. IR (CHCl3, cm−1): 3022, 2957, 2926, 2854, 1749, 1448, 1370,
1313, 1217, 1164, 1131, 1068, 1044, 981, 914, 733, 686, 667, 596, 580.
HRMS (ESI): m/z [M + NH4]+ calcd. for C20H28O11NS +, 490.13776;
found, 490.13827.
4′-Chlorophenyl 2,3,4,6-Tetra-O-acetyl-1-sulfonyl-α-D-manno-
pyranoside (10). Following general procedure G using 4-chlorothio-
phenol (2b) in the glycosylation step and purification by silica gel
column chromatography afforded the title compound as a pale yellow
solid (160 mg, 86%). Rf 0.5 (1:1, hexane−EtOAc); Mp. 128−130 °C;
[α]2D5 +15.00 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.90 (d, J
= 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 6.01 (dd, J = 3.4, 2.3 Hz, 1H),
5.67 (dd, J = 9.2, 3.5 Hz, 1H), 5.28 (t, J = 9.3 Hz, 1H), 4.81 (d, J = 2.0 Hz,
1H), 4.77 (ddd, J = 9.0, 6.1, 2.0 Hz, 1H), 4.23 (dd, J = 12.5, 6.0 Hz, 1H),
4.07 (dd, J = 12.5, 2.1 Hz, 1H), 2.14 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H),
2.04 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 170.2, 169.5, 169.3, 169.3,
141.6, 134.5, 130.6, 129.7, 90.1, 73.4, 68.6, 65.3, 65.0, 62.5, 20.6, 20.5. IR
(CHCl3, cm−1): 3020, 2926, 2854, 1752, 1465, 1371, 1325, 1215, 1047,
975, 928, 744, 667, 608. HRMS (ESI): m/z [M + NH4]+ calcd. for C20
H27O11NClS+, 524.09879; found, 524.09632.
4′-Chlorobenzyl 2,3,4,6-Tetra-O-acetyl-1-sulfonyl-α-D-mannopyr-
anoside (14). Following general procedure G using 4-chlorobenzyl
mercaptan (2g) in the glycosylation step and purification by silica gel
column chromatography afforded the title compound as a white solid
(143 mg, 75%). Rf 0.5 (3:2, hexane−EtOAc); Mp. 128−130 °C; [α]D25
+110.00 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.41−7.36 (m,
4H), 5.89 (dd, J = 3.7, 2.1 Hz, 1H), 5.58 (dd, J = 9.2, 3.66 Hz, 1H), 5.28
(t, J = 9.6 Hz, 1H), 4.71 (ddd, J = 9.6, 5.8, 2.3 Hz, 1H), 4.65 (d, J = 2.0
Hz, 1H), 4.50 (d, J = 14.2 Hz, 1H), 4.28 (dd, J = 12.5, 5.8 Hz, 1H), 4.23
(d, J = 14.2 Hz, 1H), 4.28 (dd, J = 12.5, 2.4 Hz, 1H), 2.14 (s, 3H), 2.12 (s,
3H), 2.07 (s, 3H), 2.00 (s, 3H). 13C NMR (125 MHz, CDCl3): δ170.3,
169.6, 169.2, 169.1, 135.7, 132.1, 129.5, 125.2, 86.1, 73.5, 68.8, 65.2,
64.3, 62.5, 56.2, 20.8, 20.6, 20.5. IR (CHCl3, cm−1): 3021, 2926, 2854,
1750, 1463, 1370, 1322, 1214, 1116, 1045, 980, 746, 666. HRMS (ESI):
m/z [M + NH4]+ calcd. for C21H29O11NClS+, 538.11444; found,
538.11563.
4′-tert-Butylbenzyl 2,3,4,6-Tetra-O-acetyl-1-sulfonyl-α-D-manno-
pyranoside (15). Following general procedure G using 4-tert-
butylbenzyl mercaptan (2h) in the glycosylation step and purification
by silica gel column chromatography afforded the title compound as a
white oily liquid (161 mg, 81%). Rf 0.5 (1:1, hexane−EtOAc); [α]D25
+63.33 (c 1.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.43 (d, J = 8.3
Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 5.91 (dd, J = 3.6, 1.7 Hz, 1H), 5.61
(dd, J = 9.4, 3.6 Hz, 1H), 5.29 (t, J = 9.6 Hz, 1H), 4.74 (ddd, J = 9.3, 5.6,
1.9 Hz, 1H), 4.71 (d, J = 1.3 Hz, 1H), 4.52 (d, J = 14.4 Hz, 1H), 4.29 (dd,
J = 12.5, 5.6 Hz, 1H), 4.23 (d, J = 14.4 Hz, 1H), 4.13 (dd, J = 12.5, 2.1 Hz,
1H), 2.14 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H), 1.99 (s, 3H), 1.32 (s, 9H).
13C NMR (125 MHz, CDCl3): δ 170.3, 169.6, 169.2, 169.1, 152.5, 130.4,
Tolyl 2,3,4,6-Tetra-O-acetyl-1-sulfonyl-α-D-mannopyranoside
(11). Following general procedure G using p-toluenethiol (2c) in the
glycosylation step and purification by silica gel column chromatography
afforded the title compound as a white solid (142 mg, 80%). Rf 0.5 (1:1,
hexane−EtOAc); Mp. 145−147 °C; [α]2D5 +10.00 (c 1.5, CHCl3). H
1
NMR (500 MHz, CDCl3): δ 7.84 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.1 Hz,
2H), 6.01 (dd, J = 3.5, 2.1 Hz, 1H), 5.72 (dd, J = 9.3, 3.5 Hz, 1H), 5.30 (t,
J = 9.6 Hz, 1H), 4.81 (ddd, J = 8.1, 5.8, 2.0 Hz, 1H), 4.78 (d, J = 1.8 Hz,
1H), 4.23 (dd, J = 12.5, 5.8 Hz, 1H), 4.07 (dd, J = 12.4, 2.0, Hz, 1H), 2.47
(s, 3H), 2.13 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 170.3, 169.6, 169.4, 146.0, 133.1, 130.0, 129.1,
90.3, 73.2, 68.8, 65.4, 65.3, 62.5, 21.7, 20.6, 20.5. IR (CHCl3, cm−1):
3021, 2948, 1730, 1465, 1445, 1373, 1244, 1217, 1045, 937, 847, 642,
667, 633, 607. HRMS (ESI): m/z [M + NH4]+ calcd. for C21H30O11NS+,
504.15341; found, 504.15391.
Naphthyl 2,3,4,6-Tetra-O-acetyl-1-sulfonyl-α-D-mannopyrano-
side (12). Following general procedure G using 2-napthalenethiol
(2e) in the glycosylation step and purification by silica gel column
chromatography afforded the title compound as a white solid (143 mg,
75%). Rf 0.5 (1:1, hexane−EtOAc); Mp. 141−143 °C; [α]2D5 +50.00 (c
1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.56 (s, 1H), 8.05 (d, J =
3.5 Hz, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.91 (dd, J
= 8.7, 1.7 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 6.09
(dd, J = 3.5, 2.1 Hz, 1H), 5.78 (dd, J = 9.2, 3.5 Hz, 1H), 5.30 (t, J = 9.5
Hz, 1H), 4.92 (d, J = 2.0 Hz, 1H), 4.86 (ddd, J = 8.9, 6.0, 2.3 Hz, 1H),
4.23 (dd, J = 12.5, 6.0 Hz, 1H), 4.04 (dd, J = 12.5, 2.3 Hz, 1H), 2.12 (s,
3H), 2.10 (s, 3H), 2.04 (s, 3H), 1.91 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 170.3, 169.6, 169.3, 135.7, 133.0, 131.4, 132.1, 131.4, 129.8,
129.6, 129.5, 128.0, 127.9, 123.1, 90.3, 73.3, 68.8, 65.5, 65.3, 62.6, 20.6,
20.5, 20.5. IR (CHCl3, cm−1): 3021, 2925, 2854, 1748, 1457, 1369, 1318,
1215, 1161, 1121, 1066, 746, 667, 568. HRMS (ESI): m/z [M + NH4]+
calcd. for C24 H30O11NS+, 540.15341; found, 540.15434.
Benzyl 2,3,4,6-Tetra-O-acetyl-1-sulfonyl-α-D-mannopyranoside
(13). Following general procedure G using benzyl mercaptan (2f) in
the glycosylation step and purification by silica gel column
chromatography afforded the title compound as a white solid (128
mg, 72%). Rf 0.4 (3:2, hexane−EtOAc); [α]2D5 +22.05 (c 1.3, CHCl3). 1H
NMR (500 MHz, CDCl3): δ 7.48−7.39 (m, 5H), 5.89 (dd, J = 3.7, 2.0
Hz, 1H), 5.60 (dd, J = 9.3, 3.7 Hz, 1H), 5.28 (t, J = 9.6 Hz, 1H), 4.73
(ddd, J = 8.2, 6.0, 2.3 Hz, 1H), 4.69 (d, J = 1.8 Hz, 1H),4.53 (d, J = 14.2
Hz, 1H), 4.28 (dd, J = 12.5, 6.0 Hz, 1H), 4.27 (d, J = 14.2 Hz, 1H), 4.15
(dd, J = 12.5, 2.3 Hz, 1H), 2.14 (s, 3H), 2.11 (s, 3H), 2.07 (s, 3H), 1.99
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 170.3, 169.6, 169.2, 169.0,
130.8, 129.3, 129.1, 126.8, 86.0, 73.3, 68.8, 65.2, 64.4, 62.5, 57.0, 20.7,
20.6, 20.4. IR (CHCl3, cm−1): 3021, 2925, 2854, 1748, 1457, 1369, 1318,
1215, 1161, 1121, 1066, 746, 667, 568. HRMS (ESI): m/z [M + NH4]+
calcd. for C21H30O11NS+, 504.15341; found, 504.15323.
126.2, 123.6, 86.1, 73.3, 68.8, 65.2, 64.5, 62.5, 56.6, 34.7, 31.2, 20.7, 20.6,
20.4. IR (CHCl3, cm−1): 3022, 2961, 2927, 2856, 1749, 1369, 1319,
1215, 1115, 1046, 746, 667. HRMS (ESI): m/z [M + NH4]+ calcd. for
C25H38O11NS +, 560.21601; found, 560.21714.
Cyclohexyl 2,3,4,6-Tetra-O-acetyl-1-sulfonyl-α-D-mannopyrano-
side (16). Following general procedure G using cyclohexanethiol (2i)
in the glycosylation step and purification by silica gel column
chromatography afforded the title compound as a white solid (131
mg, 75%). Rf 0.5 (1:1, hexane−EtOAc); Mp. 102−104 °C; [α]2D5 +40.00
(c 1.3, CHCl3). 1H NMR (500 MHz, CDCl3): δ 5.95 (dd, J = 3.5, 2.0 Hz,
1H), 5.63 (dd, J = 9.3, 3.7 Hz, 1H), 5.30 (t, J = 9.6 Hz, 1H), 4.96 (d, J =
1.8 Hz, 1H), 4.70 (ddd, J = 7.9, 5.6, 2.1 Hz, 1H), 4.26 (dd, J = 12.5, 5.8
Hz, 1H), 4.14 (dd, J = 12.5, 2.3 Hz, 1H), 3.15 (tt, J = 12.2, 3.4 Hz, 1H),
2.32−2.23 (m, 1H), 2.01−1.92 (m, 1H), 2.17 (s, 3H), 2.11 (s, 3H), 2.06
(s, 3H), 2.02 (s, 3H), 1.76−1.56 (m, 3H), 1.41−1.14 (m, 3H); 0.92−
0.83 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 170.3, 169.7, 169.3,
169.2, 85.8, 73.2, 68.8, 65.3, 65.3, 62.5, 59.9, 25.8, 25.2, 25.1, 24.9, 23.5,
20.7, 20.6, 20.5. IR (CHCl3, cm−1): 3022, 2928, 2856, 1748, 1452, 1370,
1311, 1214, 1157, 1113, 1047, 979, 745, 666, 600. HRMS (ESI): m/z [M
+ NH4]+ calcd. for C20H34O11NS+, 496.1847; found, 496.18539.
Menthyl 2,3,4,6-Tetra-O-acetyl-α-D-mannopyranoside (21). Rf0.5
1
(3:2, hexane−EtOAc); [α]D25 +103.78 (c 3.9, CHCl3). H NMR (500
MHz, CDCl3): δ 5.33 (dd, J = 10.1, 3.2 Hz, 1H), 5.29 (t, J = 9.9 Hz, 1H),
5.14 (dd, J = 3.1, 1.7 Hz, 1H), 5.02 (d, J = 1.2 Hz, 1H), 4.26 (dd, J = 12.4,
5.3 Hz, 1H), 4.09 (dd, J = 12.2, 2.1 Hz,1H), 4.04 (ddd, J = 9.5, 5.2, 2.1
Hz, 1H), 3.46 (td, J = 10.7, 4.1 Hz, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 2.06
(s, 3H), 2.00 (s, 3H), 2.22−2.17 (m, 1H), 2.05−2.01 (m, 1H), 1.70−
1.64 (m, 2H), 1.38−1.29 (m, 2H), 0.95 (d, J = 7.0 Hz, 3H), 0.98−0.84
(m, 3H), 0.92 (d, J = 6.7 Hz, 3H), 0.77 (d, J = 6.9 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 170.6, 170.1, 169.8, 169.7, 94.2, 76.8, 70.5, 69.1,
68.9, 66.0, 62.5, 47.4, 39.5, 34.1, 31.3, 25.3, 22.6, 22.1, 21.0, 20.9, 20.7,
20.6, 15.2. IR (CHCl3, cm−1): 3025, 2956, 2923, 1745, 1452, 1216, 1130,
1038, 977, 770, 754, 599. HRMS (ESI): m/z [M + NH4]+ calcd. for
C24H42NO10+, 504.28195; found, 504.28032.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra of all the products. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.5b00975.
H
DOI: 10.1021/acs.joc.5b00975
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(c) Griffin, F. K.; Murphy, P. V.; Paterson, D. E.; Taylor, R. J. K.
Tetrahedron Lett. 1998, 39, 8179−8182. (d) Murphy, P. V.; McDonnell,
C.; Hamig, L.; Paterson, D. E.; Taylor, R. J. K. Tetrahedron: Asymmetry
2003, 14, 79−85.
AUTHOR INFORMATION
Corresponding Author
*Tel: +91-402-716-1649. E-mail: skashyap@iict.res.in.
Notes
■
(15) Micskei, K.; Juhas
́ ́ ́
z, Z.; Ratkovic, Z. R.; Somsak, L. Tetrahedron
Lett. 2006, 47, 6117−6120.
The authors declare no competing financial interest.
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Tetrahedron 2008, 64, 7426−7431.
ACKNOWLEDGMENTS
■
S.K. is grateful for financial support from Department of Science
and Technology (GAP0397 & 0471), New Delhi. We are also
grateful to the Director CSIR-IICT for providing the necessary
infrastructure. S.C. acknowledges the CSIR, New Delhi for SRF.
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