Solvent-free bismuth oxycarbonate-mediated mechanochemical glycosylation: A simple greener alternative to access O-/S-glycosides efficiently

Article abstract of DOI:10.1016/j.carres.2016.09.004

Preparation of a variety of per-O-acylated O- and S-glycosides of a set of commonly encountered mono- and disaccharides has been achieved effectively by solvent-free grinding of the corresponding acetylated/benzoylated glycosyl bromide and the desired acceptor alcohol/thiol in the presence of bismuth carbonate in a planetary ball mill. The method is simple, requires short reaction time periods and is practical allowing it to be performed at a milligram-to multi-gram scale as required. In the cases where the product is crystalline, it was often obtained in practically pure form by crystallization (and without the need for chromatographic isolation).

Full text of DOI:10.1016/j.carres.2016.09.004

Accepted Manuscript
Solvent-free bismuth oxycarbonate-mediated mechanochemical glycosylation: A
simple greener alternative to access O-/S-glycosides efficiently
Kashmir Prasad Sethi, K.P. Ravindranathan Kartha
PII:
S0008-6215(16)30362-7
10.1016/j.carres.2016.09.004
CAR 7254
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 20 July 2016
Revised Date: 3 September 2016
Accepted Date: 6 September 2016
Please cite this article as: K.P. Sethi, K.P.R. Kartha, Solvent-free bismuth oxycarbonate-mediated
mechanochemical glycosylation: A simple greener alternative to access O-/S-glycosides efficiently,
Carbohydrate Research (2016), doi: 10.1016/j.carres.2016.09.004.
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ACCEPTED MANUSCRIPT
Solvent-free bismuth oxycarbonate-mediated mechanochemical
glycosylation: A simple greener alternative to access O-/S-glycosides
efficiently
Kashmir Prasad Sethi and K. P. Ravindranathan Kartha*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research
Sector 67, S.A.S. Nagar, Punjab, 160062, India,
*rkartha@niper.ac.in
Graphical abstract
Abstract
Preparation of a variety of per-O-acylated O- and S-glycosides of a set of commonly
encountered mono- and disaccharides has been achieved effectively by solvent-free grinding
of the appropriate acetylated/benzoylated glycosyl bromide and the desired acceptor
alcohol/thiol in the presence of bismuth carbonate in a planetary ball mill. The method is
simple, requires short reaction time periods and is practical allowing it to be performed at a
milligram- to multi-gram scale as required. In the cases where the product is crystalline, it
was often obtained in practically pure form by crystallization (without the need for
chromatographic isolation).
Key words: Solvent-free glycosylation; Mechanochemical glycosylation; Bismuth
oxycarbonate catalyst; Ball milling
Highlights
•
•
•
•
A new bismuth carbonate-promoted mechanochemical glycosylation is reported
The method is simple, efficient, solvent-free and environmentally benign
The method is practical and is amenable to scale-up
It is suitable for the synthesis of both O- and S-alkyl/aryl glycosides
1

ACCEPTED MANUSCRIPT
Solvent-free bismuth oxycarbonate-mediated mechanochemical
glycosylation: A simple greener alternative to access O-/S-glycosides
efficiently
Kashmir Prasad Sethi and K. P. Ravindranathan Kartha*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research
Sector 67, S.A.S. Nagar, Punjab, 160062, India,
*rkartha@niper.ac.in
Abstract
Preparation of a variety of per-O-acylated O- and S-glycosides of a set of commonly
encountered mono- and disaccharides has been achieved effectively by solvent-free grinding
of the corresponding acetylated/benzoylated glycosyl bromide and the desired acceptor
alcohol/thiol in the presence of bismuth carbonate in a planetary ball mill. The method is
simple, requires short reaction time periods and is practical allowing it to be performed at a
milligram- to multi-gram scale as required. In the cases where the product is crystalline, it
was often obtained in practically pure form by crystallization (and without the need for
chromatographic isolation).
1. Introduction
In synthetic carbohydrate chemistry simple alkyl/aryl (or substituted alkyl/aryl) O- and S-
glycosides serve as important starting materials/building blocks for multi-step synthetic
operations. They are therefore very often required in substantial quantities. At the same time,
the preparation, and the use of these compounds in synthesis, very often accompany
deployment of toxic and hazardous solvents and reagents, besides the need to address some
of the other aspects such as their sensitivity to light, moisture, etc associated with the use of
these reagents and chemicals. In view of these and in view of the fact that eliminating the use
of solvents in chemical reactions, thus bringing down substantially on the toxic effluents-
burden, can contribute to achieving the goals of green chemistry well,1-2 we had recently
reported on some highly efficient solvent-free mechanochemical methods for the synthesis of
alkyl- and aryl ) O- and S-glycosides.3-4 In general, while the metal carbonates of the d-Block
elements were found suitable for the synthesis of the alkyl glycosides4, those of the alkali
metals were found as effective promoters in the synthesis of aryl glycosides.3
2

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Among the former class of compounds investigated in this context, CdCO3 was found to be
the most effective and promising metal carbonate. But in view of the reports on the
hazard/toxicity associated with the use of Cd compounds5-13, we continued our search for a
friendlier/greener choice of the metal carbonate suitable for use with the per-O-acylated
glycosyl halides for their conversion to their corresponding alkyl/aryl glycosides. And indeed
we are in a position to report now that bismuth oxycarbonate [bismuth carbonate, (BiO)2CO3]
is an effective alternative to CdCO3 in this regard. It is also commercially available at
14
approximately the same price as that of CdCO3 ; it is less basic compared to many of the
other metal carbonates and, owing to its excellent stability can be stored at room temperature
without difficulty. (BiO)2CO3 is reported to possess very low solubility in blood/blood plasma
and, in case ingested, gets easily cleared through urine; no carcinogenic/teratogenic effects on
the human body have been found reported so far; and bismuth compounds are more
environmentally benign compared to many of the other heavy metal salts.15-16
2. Results and discussion
In our work on the synthesis of oligosaccharides corresponding to the type II group B
Streptococcus capsular polysaccharide antigen we needed a stock of 2-(trimethylsilyl)ethyl
2,3,6,2',3',4',6'-hepta-O-acetyl-β-D-lactoside (2) in multi-gram quantities. The conventional
Koenigs–Knorr reaction of the corresponding lactosyl bromide (1) and 2-
(trimethylsilyl)ethanol (TMSE-OH) promoted by Ag2CO3-AgClO4 combination in anhydrous
CH2Cl2 led to a yield of only 55% of the desired 2 in our hands.18 Considering the relatively
high cost of AgClO4 as well as TMSE-OH used in the reaction, a method that could provide a
significantly improved yield was therefore desired. The mechanochemical method that made
use of the relatively inexpensive CdCO3 that we had recently developed4 when applied for
this reaction led to an improved yield of 65%. In addition to attempting to achieve any
possible further improvements in this reaction along with finding a possible greener
alternative to CdCO3 thus became issues that were considered subsequently in this context.
Thus, taking cue from the work on the development of the CdCO3-mediated glycosylation
mentioned above, choosing acetobromolactose (1) as a model substrate, its reaction with
TMSE-OH (2 mol equiv) was explored in the presence of (BiO)2CO3 (2 mol equiv) by
subjecting them to homogenization in a planetary ball mill at 500 rpm for 5 h (see entry 1,
Table 1 and the reaction depicted thereunder). Analysis of the reaction mixture at this point
revealed a complete disappearance of the bromide 1 (TLC, EtOAc:Hex, 2:3) which had been
accompanied by the formation of the desired product as confirmed by a comparison of its Rf
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value with the authentic sample along with hepta-O-acetyl lactose as the by-product.
Importantly, no orthoester formation was observed. The identity of the product obtained as
that of the desired 2 was indeed further confirmed by spectroscopic analysis (1H and 13C
NMR, see the electronic SI) and the agreement observed in its optical rotation on comparison
with authentic sample.17 The hepta-O-acetylated 2-(trimethylsilyl)ethyl lactoside 2 was
obtained in an isolated yield of 75% (entry 1, Table 1). The percentage of the hemiacetal
isolated was to an extent of 15%. In an effort to eliminate/reduce the formation of the by-
product, powdered molecular sieves was also incorporated in the reaction mixture for
grinding. Indeed, it was found that this led to the exclusive formation of the glycoside 2 and
an isolated yield of 81% of 2 was achieved.
Table 1 Optimization of conditions for (BiO)2CO3-mediated solvent-free glycosylation by
ball millinga
Entry TMSE-OH (BiO)2CO3 Reaction
Product
Remarks
(mol equiv) (mol equiv) time (h) (Yield, %)
75
1
2
No Molecular sieves used
Complete reaction; no by-
products observed
Incomplete reaction; 1
(30%) recovered
Incomplete reaction; 1
(20%) recovered
2
2
5
8
8
8
81
50
62
70
3
4
5
1
1
1.2
1.5
1.2
1.5
Incomplete reaction; 1
(15%) recovered
a The reactions were carried out using 1 mmol (0.7 g) of the bromide (1) in SS cup (50 mL
capacity) using SS balls (10, 10 mm diameter)
Encouraged by these results, the conditions required for the best achievable yield was
optimized subsequently (entries 3-5, Table 1). Use of lower quantities of TMSE-OH and
(BiO)2CO3 led to incomplete reactions and consequently poorer yields in all cases. Thus a
ratio of 1:TMSE-OH: (BiO)2CO3 = 1:2:2 was found optimum for this reaction. For studying
4

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the general applicability of the reaction to the preparation of other frequently required
glycosides, the above optimised condition was applied to the corresponding sets of the
glycosyl halides
Table 2. (BiO)2CO3-Mediated solvent-free mechanochemical glycosylation using a ball milla
Donor:Acceptor:
Glycosyl halide
substrate
Reaction
time (h)
Yield
(%)
Acceptor alcohol
(BiO)2CO3 (by
mol equiv)
1:2:2
Product
TMSE-OH
Propargyl-OH
Ph-SH
p-H(O)C-Ph-OH
ROCH2CH2-OH
(R = H)
3
1
1
2.5
2
418
519
620
721
85
92
90
90
85
1:1.5:1.5
1:1.2:1.5
1:1.5:1.5
1:2:2
822
(R = H)
Propargyl-OH
1
1023
90
1:1.5:1.5
1224
12
85
85
92
88
1:2:2
TMSE-OH
3
3
1.5
2
TMSE-OHb
Propargyl-OH
p-Me-Ph-SH
1:1.5:1.5
1:1.5:1.5
1:1.2:1.5
1325
1426
217
2
81
81
91
89
1:2:2
TMSE-OH
5.5
5
5
TMSE-OHb
Propargyl-OH
p-Me-Ph-SH
1:1.5:1.5
1:1.5:1.5
1:1.2:1.5
Acetobromolactose
1527
1626
(1)
4
a
A mixture of the glycosyl bromide (2 g), the desired acceptor (1.2-2 mol equiv) and bismuth carbonate (1.5-2
mol equiv) was homogenized in a planetary ball mill using a SS cup (50 mL capacity) and SS balls (10x10 mm
diameter) for the specified time periods. The yield reported is that of the isolated pure product; b These reactions
were carried out at 25 g scale of the glycosyl bromide and in these cases only 1.5 mol equiv each of TMSE-OH
and (BiO)2CO3 were used.
and the acceptor alcohols. The results are summarized in Table 2. Thus, the mono- and
disaccharide-derived aceto-/benzobromo derivatives 1, 3, 9 and 11 reacted smoothly with
5

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acceptor alcohols such as TMSE-OH, propargyl alcohol, 4-hydroxy-benzaldehyde,
thiophenol and p-thiocresol giving the respective O-/S-glycosides (4 - 8, 10, 12 - 16) as
desired in excellent yields. Similarly, the 2-hydroxyethyl glucoside 8 was also synthesized in
very good yields by the mono-substitution reaction of ethylene glycol with
acetobromoglucose (3) without difficulty. The general observations that could be made on the
requirement of the halide donor to the alcohol acceptor ratio (by mol equiv) in the course of
the preparation of the O- and the S-glycosides mentioned above are: (i) a ratio of 1:1.5 was
satisfactory for all acceptor alcohols except TMSE-OH; (ii) in the case of TMSE-OH as
acceptor, while a ratio of 1:1.5 was sufficient in multi-gram scale reactions, a ratio of 1:2 was
required in small scale reactions; (iii) Owing to the better nucleophilicity of the thiols,
however, in the case of thiol acceptors ratio of 1:1.2 has been found to be sufficient for good
results; and (iv) In the case of ethylene glycol a ratio of 1:2 was used in obtaining maximum
mono-O-glycosylated product.
In conclusion, (BiO)2CO3 has been found to be an excellent promoter for the glycosylation
reaction of common acceptor alcohols, phenols and thiophenols with aceto-/benzohalosugars
under solvent-free mechanochemical conditions using a planetary ball mill. The method is
simple, easy to perform and affords the desired glycosides in relatively short reaction periods
in excellent yields. The reactions could be scaled up to multi-gram quantities with
equal/higher efficiency.
3. Experimental
3.1. General
All the reagents were used as purchased without further purification. Solvents used for the
reactions were dried according to standard methods. Reactions were monitored by thin layer
chromatography, which were performed with 0.2 mm Merck pre-coated silica gel 60 F254
aluminium sheets. Compounds were detected by dipping the TLC plates in an ethanolic
solution of sulphuric acid (10%v/v) and thereafter heating them. The detection of compounds
were also carried out by UV lamp, iodine vapour and KMnO4 spray as developing agents.
Chromatographic separations were performed by column chromatography using silica gel
(60-120, 100-200 mesh). Melting points were determined on a Buchi melting point apparatus.
1
13
The H and C NMR spectra were recorded at 400/100 MHz on a DRX-Bruker advanceIII
spectrometer, using TMS as an internal standard (chemical shifts in ). Specific rotations
δ
were obtained on Rudolph Research Autopol IV polarimeter at 20 °C. The mass spectra were
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recorded on MALDI (Bruker Daltronics, Ultraflex TOF/TOF) spectrometer and high
resolution mass spectra (HRMS) on Bruker Maxis spectrometer.
3.2. General procedure for glycoside synthesis by planetary ball mill
The glycosyl bromide (1 mmol), thiophenol/2-(trimethylsilyl)ethyl alcohol or another desired
alcohol (1.5-2 mmol), (BiO)2CO3 (1.5-2 mmol) and 4Å MS were allowed to mix in a
stainless steel (SS) jar (capacity, 50 mL) containing 10 SS balls (10 mm diameter) for the
requisite time (depending upon the glycosyl bromide as substrate) in a planetary ball mill
(Retsch PM-100, Retsch GmbH & amp; Co. KG, Germany) at 500 rpm. For larger scale
reactions (15 g or more of the glycosyl halide) 1.2 mol equiv of the alcohol were mixed in the
presence of 1.5-2 mol equiv. (BiO)2CO3 in the SS jar (125 ml capacity) using 6 SS balls (20
mm diameter.) at 500 rpm. After completion of the reaction EtOAc was added followed by
water to dissolve the sticky mass of reaction mixture. The organic layer was separated via
filtration and washed successively with aq. Na2CO3 solution (10%, w/v) and water and was
dried over Na2SO4 and concentrated under reduce pressure to afford the respective crude
glycoside. The crude residue was either crystallized from Et2O-n-Hex or by chromatography
(EtOAc:n-hex 1:4 v/v ) to obtain the analytically pure product.
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