"One-pot" access to α-d-mannopyranosides from glycals employing ruthenium catalysis

Article abstract of DOI:10.1039/c4ra08241a

Ru-catalyzed synthesis of α-d-mannopyranosides from glucal is described via one-pot glycosylation-dihydroxylation reaction. This method is amenable to a variety of acceptors, including carbohydrate-derived and amino-acid containing alcohols to obtain mannosylated peptides and disaccharides.

Full text of DOI:10.1039/c4ra08241a

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“One-pot” access to a-D-mannopyranosides from
glycals employing ruthenium catalysis†
Cite this: RSC Adv., 2014, 4, 46327
Sravanthi Chittela, Thurpu Raghavender Reddy, Palakodety Radha Krishna
*
and Sudhir Kashyap
Received 6th August 2014
Accepted 2nd September 2014
DOI: 10.1039/c4ra08241a
www.rsc.org/advances
Ru-catalyzed synthesis of a-D-mannopyranosides from glucal is
described via one-pot glycosylation–dihydroxylation reaction. This
method is amenable to a variety of acceptors, including carbohydrate-
derived and amino-acid containing alcohols to obtain mannosylated
peptides and disaccharides.
Fig. 1 Mannosylation by using glycosyl donor.
In view of the critical role played by carbohydrates in diverse
sets of biological processes,1 the development of stereoselective
and efficient methods for assembling potent sugar molecules
continues to serve as important chemical tools in glyco-science
as well as in chemical biology. However, our understanding of
these dynamic biosynthetic processes remains incomplete as
Nature seldom provides sufficient amounts of pure and well
dened saccharides for biological studies, hence, access to
signicant quantities of target homogeneous glycoconjugates
oen relies on chemical synthesis.2 Unlike polypeptide and
polynucleotide syntheses, incorporating glycosidic linkages in a
regio and stereocontrolled manner is notoriously difficult and
remains a challenging forefront in the area of complex oligo-
saccharides syntheses.3
Owing to the unique importance of b-mannans4a and a-
linked oligomannosides4b in biological system and synthetic
challenges associated with mannosylation, designing of new
glycosylation strategies for constructing selective glycosidic
linkages in mannopyranosides remains a venerable task for
carbohydrate researchers. As evident, a plethora of glycosylation
reagent systems have been investigated for the activation of
glycosyl donor, functionalized with a leaving group at anomeric
carbon such as anomeric halides, anomeric oxygen or sulphur-
derived latent moiety (Fig. 1).5 Despite the signicant advances
in the chemical glycosylation, extensive studies of functional
group manipulation and anomeric activation in diverse reac-
tion conditions such as temperature, solvents, etc., have
remained quite elusive. In parallel, the transition-metal medi-
ated glycosylation as an alternative equivalents approach has
become increasingly popular in recent years.6
In addition to the well appreciated role played by glycals as
versatile and chiral synthons in the synthesis of several complex
oligosaccharides and glycoconjugates,7 the exceptional
synthetic potential of enol–ether functionality in glycals has
been also highlighted for the preparation a-D-mannopyrano-
sides.8 Since the traditional glycal assembly approach repre-
sents the most efficient and reliable method for this conversion
otherwise time consuming and involves multi-steps wherein the
epoxidation of glycal substrate to generate 1,2-anhydropyrano-
sides following epoxide ring-opening and subsequent inversion
of C-2 stereocenter led to desired mannoside.8a Alternatively,
the oxidative mannosylation in one-pot via epoxidation–glyco-
sylation from glucal utilizing stiochiometric amount of
D-207, Discovery Laboratory, Organic and Biomolecular Chemistry Division,
CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India. E-mail:
skashyap@iict.res.in; Fax: +91-402-2716-0387; Tel: +91-402-2716-1649
† Electronic supplementary information (ESI) available: General synthesis
information and 1H NMR, 13C NMR spectra, IR spectra and MS/HRMS data of
all the products are provided. See DOI: 10.1039/c4ra08241a
Fig. 2 Synthesis of mannopyranosides from glycal.
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Table 1 Screening of ruthenium-catalyzed glycosylation–dihydroxyl-
sulfoxide reagent and triic anhydride has encountered several
drawbacks.8b Regardless of the stereochemical outcome, use of
unconventional and toxic reagent system, excessive loading of
nucleophiles and complicated reaction operation, low yield and
limited substrate scope have long been recognized as unsolved
issues (Fig. 2).
ation in one-pota
In this context, search of new protocol for the synthesis of
structurally diverse sugar molecules from readily available
starting materials by using mild reagent system is always
appreciated. To pursue our interest in glycoconjugate syntheses
and developing new glycosylation methods,9 herein, we present
an alternative process applicable for efficient and convenient
synthesis of a-D-mannopyranosides via one pot glycosylation–
dihydroxylation of glycals exploiting ruthenium catalysis.
Recent demonstration on the efficiency of ruthenium(III) chlo-
ride as Lewis acid in glycosylation9g and its ability to generate
ruthenium(VIII) oxide, a well known oxidant for stereoselective
cis-dihydroxylation of olens,10 encouraged us to relate this
strategy to readily prepare mannopyranoside from glycals in
one-pot. We anticipated that in situ generation of RuO4 from a
combination of reagent system RuCl3/NaIO4 would promote
oxidative dihydroxylation of C(2)–C(3) olen, which in turn
could be obtained by RuCl3-catalyzed glycosylation of corre-
sponding glycal in preceding step.
Entry R1OH
Timeb (1,2) Yieldc (%) a-manno/b-allosed
1
BnOH 2a
10, 10 min 92
>89 : 11
2
30, 10 min 88
>96
2b
Mannopyranosides
To test this hypothesis, the glycosylation reaction of 3,4,6-tri-
O-acetyl glucal (1) with benzyl alcohol (2a) was performed in the
presence of 5 mol% RuCl3 in acetonitrile at room temperature.
To our delight, the reaction proceeded smoothly and complete
conversion was realized within 10 min to afford corresponding
2,3-unsaturated glucoside with high stereoselectivity in favour
of a-anomer. Subsequently, the crucial in situ dihydroxylation of
resultant C(2)–C(3) olen in pyran ring was achieved by intro-
ducing aqueous solution of NaIO4 as secondary oxidant in the
ꢀ
a
presence of catalytic amount of CeCl3$7H2O at 0 C. Although,
Reaction conditions:
(5.0 mol%), CH3CN (2 mL), EtOAc (2 mL), NaIO4 (1.5 equiv.), H2O
(1 mL), CeCl3$7H2O (5.0 mol%). Time required for glycosylation
1 (1.0 equiv.), R1OH (1.2 equiv.), RuCl3
complete conversion of glycal (1) to 2,3-syn-diol (3a0) was
observed in 10 min,11 the in situ dihydroxylation of anomeric
mixture of 2,3-unsaturated glucosides afforded a-D-mannopyr-
anosides (3a0) as major product in 92% yield along with trace
amount of epimeric b-allopyranoside (4a0) as another product
(Table 1, entry 1).
b
c
(1)–dihydroxylation (2).
Isolated and un-optimized yields over
2 steps. d The ratios were analyzed by H NMR spectrum.
1
Noteworthy, anomeric activation of glycal donor in glyco- the dihydroxylation of 2,3-unsaturated benzyl a-glucoside with
sylation step would have a signicant inuence on the stereo- catalytic OsO4,10f,g,13a isoelectronic to RuO4 and relatively more
chemical outcome in the dihydroxylation reaction. For instance, toxic, usually takes 2 days to afford corresponding cis-diol (3a0)
the glycosylation reaction of 1 with a secondary alcohol such as in moderate yield.14 Acetylation of 2,3-syn-diols with acetic
L-menthol (2b) and subsequent in situ dihydroxylation resulted anhydride in the presence of pyridine and catalytic amount of
menthyl-a-D-mannopyranoside (3b0) as a major product (dr, DMAP in dichloromethane as the solvent afforded the corre-
>96) in 88% yields over 2 steps. (Table 1, entry 2). The 1H NMR sponding per-acetylated glycosides (3a–3j) in quantitative
spectrum of 3a0 reveals the presence of characteristic resonance yields. The spectroscopic analyses indicate that dihydroxylation
due to anomeric proton of a-D-mannopyranoside at d 4.98 (s, occurred in highly stereocontrolled manner depending on
1H), whilst resonance of benzylic protons of were observed at d anomeric conguration of the Ferrier product.
4.72 and 4.54 (each d, J ¼ 11.8 Hz, each 1H, –CH2Ph), however,
The stereochemistry of newly formed stereocenters in
corresponding chemical shis for minor epimer 4a0 were compound 3a was precisely correlated by spectroscopic analysis
identied at 4.78 and 4.62 (each d, J ¼ 7.8 and 11.8 Hz, each and compared with literature data.13b In the 1H NMR spectrum
0.12H, –CH2Ph).12 Furthermore, the 13C spectrum ambiguously of 3a, presence of resonance due to anomeric proton at d 4.89 (d,
proved the presence of anomeric carbon at d 98.8 whereas J1–2 ¼ 1.2 Hz) and chemical shis of other sugar protons at d
minor peak at d 99.4 further conrmed the product with high 5.38 (dd, J3–4 ¼ 10.1 Hz, H-3), 5.30 (dd, J4–5 ¼ 10.2 Hz, H-4), 5.29
selectivity in favour of a-mannopyranoside. On the other hand, (dd, J2–3 ¼ 3.5 Hz, H-2) with distinctive coupling constant
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veried the trans-diaxial, trans-diequatorial or cis-(e,a) rela-
To probe the scope of above-mentioned method, a range of
tionship between adjacent protons. In the proton-decoupled acceptors comprising alicyclic (2c, 2d), 2-ethoxyethanol (2e),
carbon spectrum of 3a, the anomeric carbon was observed at and 9-uorenemethanol (9FM, 2f), were successfully coupled
96.7 ppm whilst resolved signals for C(2)–C(6) were identied in with glycal in one-pot method to obtain various functionalized
between 60 and 70 ppm. In addition, compound 3a gave satis- mannopyranosides in good yields (Table 1). In contrast,
factory MS/HRMS analysis [HRMS (ESI) m/z [M + NH4]+ calcd for hydroxylamine derivatives such as N-hydroxysuccinimide (2g)
C
21H20O10N+: 456.18842; found: 456.18803]. The overall spec- and N-hydroxyphthalimide (2h), underwent glycosylation in
troscopic data of benzyl 2,3,4,6-tetra-O-acetyl-a-D-mannopyr- highly stereoselective manner to generate corresponding a-O-
anoside (3a) consistent and with conformity that of observed in mannosylhydroxylamine derivatives (3g, 3h) in high yields with
later experiment.14
exclusive a-selectivity. A facile deprotection of phthalimide
Table 2 Direct access to a-D-mannopyranosides from glucala
Yieldc (%)
Entry
1
Acceptor
Product
Timeb
a-manno/b-allosed
70%
>90
60 min
74%
>89
2
3
4
45 min
80 min
40 min
66%
76%
>88
72%
>88
5
30 min
68%
>88
6
7
8
40 min
30 min
40 min
86%
>87
76%
>90
9
60 min
70%
a
Reaction conditions: see general experimental procedure. b Time required for glycosylation (1)–dihydroxylation (2). c Isolated and un-optimized
yields over 2 steps. d The ratios were based on relative integration of separable protons in H NMR spectrum.
1
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group would generate O-aminoxy-mannosyl, wherein the pres- anomeric effect and equilibrium between kinetic and thermo-
ence of aminoxy moiety at sugar anomeric center offers further dynamic oxocarbenium intermediate. Subsequent oxidation of
synthetic value in constructing neoglycoconjugates of biological Ru(III) to Ru(VIII) in the presence of IO4ꢁ followed by [3 + 2]-syn-
signicance.15
cycloaddition of RuO4 to the C(2)–C(3) olen from the less
Additionally, the glycosylation–dihydroxylation reaction of 1 sterically hindered face, then oxidation following hydrolytic
with 2-chloroethanol (2i) and 2-amino-alcohol (2j) proceeded dissociation of Ru-complex will provide desired a-D-mannose
smoothly to produce corresponding mannosides comprising 2- epimeric cis-diol as major product.
chloro/amino-ethyl linkers at anomeric center (3i, 3j). Notably,
In summary, we demonstrated an efficient and convenient
the glycosides containing spacers or linkers are oen utilized in ruthenium-catalyzed highly a-selective glycosylation and syn-
the chemical ligation of sugars to various biomolecules and dihydroxylation to obtain a-D-mannopyranosides in one-pot.
serves as valuable building blocks of N-linked glycan core.16 Usefulness of this method has been highlighted in the glycosyl-
Therefore, this approach seems to be advantageous to obtain ation of diverse range acceptors comprising sugar and amino-acid
modied-carbohydrate scaffolds, generally known as glycomi- derived alcohols to incorporate mannose in disaccharides and
metics.17 Next, we focused on glycosylation of sugar-derived peptides. Considering the ready availability of starting materials
acceptors to access disaccharide containing mannose. Thus, and the exceptional versatility of glycals, this economical and eco-
various acceptors comprising glucose, mannose, galactose, friendly ruthenium reagent system should contribute signi-
ribose sugar (2k–p) were successfully glycosylated under present cantly in glyco-chemistry. The insights outcome of present
reagent system at ambient temperature to generate variety of a- protocol to access N-/C-linked glycosides constitutes exploiting
(1 / 6, 1 / 5, 1 / 4)-linked disaccharides containing Ru-catalysis is currently under investigation.
mannose (3k–p) in stereoselective manner (Table 2, entries 1–6).
The gaining impetus of mannosylated peptides constructs18
in Nature has motivated us to investigate glycosylation of serine
Acknowledgements
and threonine to incorporate mannose into peptide. Therefore, Financial support from Department of Science & Technology,
coupling of Fmoc-Ser-OMe (2q) and Fmoc-The-OMe (2r) with New Delhi is gratefully acknowledged. The authors are also
glucal 1 was accomplished under ruthenium promoted tandem grateful to the Director CSIR-IICT for providing necessary
glycosylation–dihydroxylation to obtain mannosylated peptides infrastructure. S.K. is thankful to Prof. S. Hotha for his
(3q, 3r) in good yields (Table 2, entry 7, 8). Encouraged by these encouragement. S.C. acknowledges a CSIR Fellowship.
results, we envisioned a robust and straightforward synthetic
route for Hyp-functionalized mannose. Thus, ruthenium medi-
ated glycosylation–dihydroxylation of glycal with N-a-uo-
Notes and references
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20 General experimental procedure for Ru-catalyzed one-pot
glycosylation–dihydroxylation method: (1) to
a stirred
solution of 3,4,6-tri-O-acetyl-D-glucal (1 equiv.) and
1
acceptor (1.2 equiv.) in anhydrous acetonitrile (2 mL
mmolꢁ1) under an atmosphere of argon was added RuCl3
(5 mol%) at room temperature. The reaction mixture was
stirred until the complete consumption of the starting
material (glycal), adjudged by TLC. (2) The reaction
ꢀ
mixture was cooled at 0 C and diluted with EtOAc (2 mL).
An aqueous solution of NaIO4 (1.5 equiv.) and CeCl3$7H2O
(5 mol%) in 1 mL H2O was added to above mentioned
reaction and stirred vigrously. The reaction deemed
complete by TLC in utmost 10 min to obtain
corresponding diols. The reaction was quenched with
saturated NaHCO3 (10 mL), diluted with EtOAc (10 mL),
and extracted with EtOAC (3 ꢂ 30 mL). The combined
organic layes were washed with brine solution, dried over
anhydrous Na2SO4, concentrated in vacuo and puried by
silica gel coloumn chromatography (Hexanes-EtOAc 2 : 1).
Following acetylation of diol in CH2Cl2 (5 mL), pyridine
(0.5 mL), and acetic anhydride (5 equiv.) in the presence of
catalytic amount of DMAP gave corresponding per-
acetylated glycoside. Following usual work-up and
purication by chromatography (silica gel, hexanes-EtOAc)
afforded desired a-D-mannopyranosides (3a–s) as major
product in good yields. All the compounds were conrmed
by 1H NMR, 13C NMR and MS/HRMS spectroscopy and
overall data were in complete agreement with the assigned
structures.
11 In contrast, the in situ dihydroxylation step without
CeCl3$7H2O usually takes 45 min, presumably a result of
slow hydrolytic dissociation of Ru-complex. However,
results were consistent with that of previous experiment in
terms of stereochemical outcome and chemical yields.
12 See ESI.†
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T. Saloranta and R. Leino, Eur. J. Org. Chem., 2009, 6, 870–
888.
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