Efficient isomerization of methyl arabinofuranosides into corresponding arabinopyranosides in presence of pyridine

Article abstract of DOI:10.1016/j.carres.2016.07.014

Fisher glycosylation, the oldest but efficient reaction towards alkyl glycosides, suffers nonetheless from lack of selectivity, especially when dealing with pentoses. In this case, a mixture of the four isomers, namely the furanosides and the pyranosides, is formed. According to previous studies, the rate and selectivity of the reaction depend greatly on the reaction time and the temperature. In this report, another factor was evaluated, the introduction of a weak nucleophilic base. Interestingly, addition of pyridine few hours after the reaction has started allowed rapid isomerization of the methyl pentofuranosides into its pyranoside counterparts. The reaction proceeds with great diastereoselectivity using arabinose, ribose, xylose and lyxose as starting pentoses. Corresponding methyl pyranosides were obtained as the sole isomers with yields ranging from 65% to 75%.

Full text of DOI:10.1016/j.carres.2016.07.014

Accepted Manuscript
Efficient isomerization of methyl arabinofuranosides into corresponding
arabinopyranosides in presence of pyridine
Sunchu Prabhakar, Loïc Lemiègre, Thierry Benvegnu, Srinivas Hotha, Vincent
Ferrières, Laurent Legentil
PII:
S0008-6215(16)30245-2
10.1016/j.carres.2016.07.014
CAR 7234
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 6 June 2016
Revised Date: 8 July 2016
Accepted Date: 9 July 2016
Please cite this article as: S. Prabhakar, L. Lemiègre, T. Benvegnu, S. Hotha, V. Ferrières, L. Legentil,
Efficient isomerization of methyl arabinofuranosides into corresponding arabinopyranosides in presence
of pyridine, Carbohydrate Research (2016), doi: 10.1016/j.carres.2016.07.014.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Efficient isomerization of methyl arabinofuranosides into corresponding
arabinopyranosides in presence of pyridine.
Sunchu Prabhakar,a Loïc Lemiègre,a Thierry Benvegnu,a Srinivas Hotha,b Vincent
Ferrières,a and Laurent Legentila,*
(a) Ecole Nationale Supérieure de Chimie de Rennes, CNRS, UMR 6226, 11 Allée de
Beaulieu, CS 50837, 35708 Rennes Cedex 7, France
(b) Department of Chemistry, Indian Institute of Science Education and Research, Pune
411 008, India
Abstract: Fisher glycosylation, the oldest but efficient reaction towards alkyl glycosides,
suffers nonetheless from lack of selectivity, especially when dealing with pentoses. In this
case, a mixture of the four isomers, namely the furanosides and the pyranosides, is formed.
According to previous studies, the rate and selectivity of the reaction depend greatly on the
reaction time and the temperature. In this report, another factor was evaluated, the
introduction of a weak nucleophilic base. Interestingly, addition of pyridine few hours after
the reaction has started allowed rapid isomerization of the methyl pentofuranosides into its
pyranoside counterparts. The reaction proceeds with great diastereoselectivity using
arabinose, ribose, xylose and lyxose as starting pentoses. Corresponding methyl pyranosides
were obtained as the sole isomers with yields ranging from 65% to 75%.
Keywords: Fisher glycosylation, methyl pentosides, isomerization
*
Corresponding author: Tel.: +33 223 238 140; Fax: +33 223 238 046. E-mail address: laurent.legentil@ensc-
rennes.fr
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1. Introduction
Arabinose is an abundant carbohydrate from biomass found either as
L
- or D- series. The first
one is particularly present in plants1 while the second one constitutes a crucial component of
the cell membrane of mycobacteria.2 Interestingly the corresponding alkyl arabinosides
constitute key intermediates for the development of new detergents that can advantageously
replace ionic surfactants.3,4 Such glycoconjugates can be accessed easily from readily
available arabinose thanks to Fisher glycosylation. This is a very simple procedure, involving
just the free sugar and an aliphatic alcohol in the presence of an acid.5,6 However, such
protocol necessitates long reaction times and leads to a mixture of the four different isomers
namely, the alkyl α/β-arabinofuranosides (Araf) and -pyranosides (Arap) with low to
moderate yields. For example, methyl arabinoside can be obtained using concentrated
HCl/MeOH (reflux, 1h, 81%, methyl β-
-Arap only),8 2,4,6-trichloro-1,3,5-triazine/DMSO/MeOH (RT, 24h, 98%,
Arap:Araf 4:2)9 or 0.18N HCl/MeOH (RT, 5h, 79%, methyl
D
-Arap only),7 Amberlite IR120/MeOH (reflux, 12h,
30%, methyl β-
D
D-Araf only as mixture of
anomers).10 Other protocols were also described to synthesize other alkyl arabinosides but
always as a mixture.11-13
Owing to the growing demand of pure manufactured products obtained in a straightforward
and inexpensive manner, it becomes crucial to optimize such protocol in term of reaction time
and selectivity. In this report we show that the introduction of pyridine increases both the
selectivity and the rate of the glycosylation of methanol with arabinose. Different bases and
nucleophiles were then screened to confirm the hypothesized mechanism of the reaction.
Finally, the methodology was extended to other pentoses.
2. Results and discussion
The mechanism of Fisher glycosylation was deciphered in the late 1950’s. According to it, the
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methyl arabinofuranosides are formed first as they are kinetically favored but quickly
isomerized into the thermodynamically stable pyranosides through arabinose dimethylacetal
intermediate (Scheme 1).14 But unlike hexoses, it is rather cumbersome to pull the reaction
towards only one isomer. In order to tune the reactivity of the glycosylation of methanol with
arabinose towards methyl arabinopyranoside, one can introduce a good leaving group on the
acetal intermediate. It will thus speed the ring expansion toward the thermodynamic product.
Pyridine is known as good nucleophilic base that increases the rate of esterification through
the formation of acyl pyridinium intermediates.15 We envisioned that a similar acetal
pyridinium intermediate can be formed if pyridine was introduced during the course of Fisher
glycosylation.
Scheme 1. Mechanism of Fisher glycosylation of methanol by D-arabinose
The reaction was performed first on D-arabinose in methanol in the presence of an equimolar
amount of hydrochloric acid (generated in situ by action of acetyl chloride on methanol at
0 °C). After 12h of reaction at room temperature, different amount of pyridine were added to
the solution (Table 1, entries 1-4). While an excess of pyridine quenched the reaction to give
predominantly the methyl arabinofuranosides 1b (Entry 1), sub-stoechiometric amount of the
base allowed to drive the reaction quickly towards the pyranoside counterparts 1a (Entries 2-
4). Best result was obtained using one equivalent of pyridine (Entry 2). Under these
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conditions, a precipitate corresponding to methyl β-D-arabinopyranoside 1aβ formed after 3h.
The overall yield after filtration reached 75%. The resulting compound was unambiguously
1
characterized by H and 13C NMR with the anomeric carbon at 101 ppm and the
corresponding proton as a doublet at 4.67 ppm with a coupling constant of 3 Hz, typical of a
1
1,2-cis linkage. NMR data are also in accordance with a C4 conformation in solution (See
Supporting Information).
Table 1. Action of pyridine on the rate of glycosylation
HO
1. AcCl
MeOH
OMe
OH
OH
O
O
OMe
+
DꢀAra
OH
OH
2. Pyridine
OH
Methyl ꢀAraf
D
Methyl DꢀArap
1b
1a
Amount of
Yield (%) of
ratio α/β of
Entry
1
1a/1b
1a1
pyridine (equiv.)
8
1
70
1:9
N.D.2
2
3
4
1
75
53
40
1:0
7:3
9:1
0:1
3:7
2:8
0.5
0.1
1 As determined by 1H NMR; 2 Not Determined
Under the optimized conditions (Entry 2, Table 1), the kinetic of the reaction was then
monitored with 1H NMR (See Supporting Information) and 13C NMR in deuterated methanol
(Figure 1). One hour after the addition of hydrochloric acid, the two arabinofuranosidic
anomers (δ 1-Cβf: 104 ppm and 1-Cαf: 110 ppm) were already present with no arabinose
remaining. After 4h, the other isomers, namely the methyl β- and α-pyranosides, started to
appear. Before the addition of pyridine, the four isomers were found with the 5-membered
rings as the major compounds. These observations are in accordance with the admitted
mechanism. This ratio however shifted quickly towards the methyl β-
D-Arap 1aβ just 3 hours
after addition of deuterated pyridine. This means that the nucleophilic base increases greatly
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the kinetics of the reaction toward the thermodynamic product.
A.
C-1
B.
αf
βf
βp
C.
αf
β
f βp
αp
D.
βp
αf
αp
βf
E.
βp
13
Figure 1. C NMR follow-up. A.
D-Ara; B. 2h after addition of AcCl (1.04 equ.); C. 12h
after addition of AcCl; D. 1h after addition of pyridine (1.03 equ.); E. 3h after addition of
pyridine.
Interestingly, the substitution of pyridine with non-nucleophilic base like triethylamine, bulky
base like 2,6-lutidine or stronger base like 4-dimethylaminopyridine (DMAP) prevented the
acceleration of the glycosylation towards arabinopyranose (See Supporting Information)
whatever the amount of base that was added. First activation with a strong acid is also
compulsory as pyridinium chloride on its own was unable to catalyze the reaction. These
results confirm the possibility of a two-steps mechanism that starts with the acid catalyzed
formation of the methyl furanoside. Then pyridine probably acts as an activating group upon
attack on the oxonium intermediate 2 (Scheme 2). The resulting mixed acetal 3 should exhibit
enhanced reactivity thanks to the pyridinium leaving group and should quickly cyclize into
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1
the stable methyl Arap 1a. The anomeric effect would then favor the β-anomer in the C4
conformation as shown by NMR. DMAP and triethylamine are too strong bases and simply
might have stopped the glycosylation while bulky 2,6-lutidine would not be able to attack the
oxonium probably due to steric hindrance.
Scheme 2. Proposed mechanism on the action of pyridine on Fisher glycosylation of
D-
arabinose
With these improved conditions in hand, the protocol was further applied to other pentoses
(Table 2). In all cases, a shift from the 5-membered ring to the desired 6-membered ring was
observed. The isomerization went to completion for
L-arabinose (L-Ara, entry 1) and
D-
xylose ( -Xyl, entry 3). As for -lyxose ( -Lyx, entry 2) and
D
L
L
D-ribose (D
-Rib, entry 4), the
equilibrium was already in favor of the pyranoside forms before the addition of pyridine.
However, enhancement of the ratio was observed after action of the base. The anomeric effect
favored once again one anomer over the other one. This procedure constitutes an alternative to
those using hydrochloric acid in methanol as catalyst without base. For example, Toth and
coworkers16 obtained methyl β-
L
-arabinoside 4, and methyl
D
-xyloside 6 (α:β 1:2) with 37%
-lyxoside were both
and 36% yields respectively. Meanwhile methyl
D-riboside and methyl
D
obtained with quantitative yield but as a mixture of anomer (α:β 85:15). Other catalysts were
used recently, like montmorillonite17 or amberlyst,18 with excellent result. Nevertheless these
protocols still required high temperature.
We wanted also to monitor the action of pyridine on the glycosylation with
D-galactose (D-
Gal). As expected before addition of pyridine, all the isomers were present (ratio Galf:Galp
55:45). However the addition of an equimolar amount of pyridine did change neither the
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kinetic nor the ratio between each isomer (See Supporting Information). This is not surprising
as for hexoses, acid-catalyzed glycosylation already favors the 6-membered ring even for
Gal whose ratio furanose/pyranose is higher than for other monosaccharide.
D-
Table 2. Extension to pentoses
Ratio furanoside : pyranoside
Isolated yield
Entry Sugar
Compounds
before addition
of pyridine
7 : 3
after addition of
pyridine
0 : 1
(%)
1
2
3
4
L
-Ara
72 (β only)
68 (α only)
65 (α:β 6:4)
67 (β only)
4
5
6
7
L-Lyx
3 : 7
1 : 24
D
-Xyl
-Rib
7 : 3
0 : 1
D
1 : 4
2 : 23
To conclude, the introduction of a weak nucleophilic base like pyridine induces a dramatic
effect on the isomerization rate of methyl arabinofuranoside into methyl arabinopyranoside.
Evidences suggest the activation of the anomeric carbon by formation of a strong electrophilic
center. The resulting methyl
D-arabinopyranoside constitutes in itself a valuable product as
surfactant precursor as well as a key platform for further derivatization. In addition, this
improved procedure could be applied to a range of pentoses with good yield and selectivity
and can compete with other reported protocols.
3. Experimental
3.1 General methods
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All reactions were carried out in oven-dried glassware. Dried MeOH and pyridine were
purchased sealed on molecular sieves. Optical rotations were measured at 20 °C on a Perkin-
Elmer 341 polarimeter. NMR spectra were recorded at 400 MHz for 1H and 100 MHz for 13C.
1
Chemical shifts are given in δ units (ppm) and referenced to CHD2OD (3.31 ppm, H) and
CD3OD (49.0 ppm, 13C). Coupling constants J were calculated in Hertz (Hz).
3.2. Typical procedure for preparation of methyl β-
Acetyl chloride (0.5 mL, 7 mmol) was treated with methanol (2 mL) at 0 °C for 30 min, and
to this solution was added a methanol (10 mL) solution of -arabinose (1.0 g, 6.7 mmol) at
D-arabinopyranoside (1a).
D
0 °C. The mixture was allowed to stir at room temperature for 12 h before the addition of
pyridine (0.56 mL, 6.9 mmol). The resulting solution was stirred for another 3 h at room
temperature. Methyl β-
D
-arabinopyranoside was isolated by filtration as a white solid (820
1
mg, 75%). [α]20D -244 (c 1.0; MeOH); H NMR (CD3OD, 400 MHz): δ 4.67 (d, 1H, J1,2 3.0
Hz, H-1), 3.85 (ddd, 1H, J4,3 3.4, J4,5a 2.3, J4,5b 1.7 Hz, H-4), 3.83-3.73 (m, 3H, H-2, H-3, H-
5a), 3.57 (dd, 1H, J5a,5b 12.3 Hz, H-5b), 3.39 (s, 3H, OCH3); 13C NMR (100 MHz, CD3OD) δ
102.0 (C-1), 70.8 (C-4), 70.7 (C-3), 70.3 (C-2), 63.9 (C-5), 55.8 (OCH3).
3.3. NMR follow-up protocol.
To a solution of D-arabinose (500 mg, 3.3 mmol) in deuterated methanol (5 mL) was added
acetyl chloride (250 µL, 3.6 mmol). The mixture was allowed to stir at room temperature for
12h before the addition of pyridine (275 µL, 3.5 mmol). Every hour, 400 µL of the reaction
media were sampled for 1H and 13C NMR recording.
3.4. General procedure for glycosylation of methanol with pentoses.
Acetyl chloride (52 µL, 0.73 mmol) was treated with methanol (200 µL) at 0 °C for 30 min,
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and to this solution was added a methanol (1 mL) solution of the desired pentose (100 mg, 0.67
mmol) at 0 °C. The mixture was allowed to stir at room temperature for 12 h before the
addition of pyridine (56 µL, 0.69 mmol). The resulting solution was stirred for another 3 h at
room temperature. After evaporation, the crude material was purified by column
chromatography on silica gel with dichloromethane:MeOH (9:1) as eluent.
3.4.1. Methyl β-
Methyl β- -arabinopyranoside (4) was obtained according to general procedure starting from
-arabinose. Column chromatography purification yielded 4 as a white solid (79 mg, 72 %).
L-arabinopyranoside (4).
L
L
1
[α]20 +245 (c 1.0; MeOH), lit.19 +245; H NMR (400 MHz, CD3OD) δ 4.67 (d, 1H, J1,2 3.0
D
Hz, H-1), 3.85 (ddd, 1H, J4,5a 2.4, J4,5b 2.0, J4,3 1.2 Hz, H-4), 3.82-3.71 (m, 3H, H-2, H-3, H-
5a), 3.57 (dd, 1H, J5b,5a 12.3 Hz, H-5b), 3.39 (s, 3H, OCH3); 13C NMR (100 MHz, CD3OD) δ
102.0 (C-1), 70.8 (C-4), 70.7 (C-3), 70.3 (C-2), 63.9 (C-5), 55.8 (OCH3).
3.4.2. Methyl α-L-lyxopyranoside (5).
Methyl α- -lyxopyranoside (5) was obtained according to general procedure starting from
L
L-
lyxose. Column chromatography purification yielded 5 as a white solid (74 mg, 68 %). [α]20
D
1
-57 (c 1.0; MeOH), lit.19 -60; H NMR (400 MHz, CD3OD) δ 4.55 (d, 1H, J1,2 2.9 Hz, H-1),
3.82-3.72 (m, 2H, H-3, H-4), 3.69-3.61 (m, 2H, H-2, H-5a), 3.42 (dd, 1H, J5b,5a 11.0, J5b,4 9.1
Hz, H-5b), 3.37 (s, 3H, OCH3); 13C NMR (100 MHz, CD3OD) δ 103.1 (C-1), 72.7 (C-3), 71.
6 (C-2), 68.5 (C-4), 64.0 (C-5), 55.5 (OCH3).
3.4.2. Methyl
D-xylopyranoside (6).
Methyl -xylopyranoside (6) was obtained according to general procedure starting from
D
D-
xylose. Column chromatography purification yielded 6 as a white solid (71 mg, 65 %) and as
1
a mixture of isomers (α:β 6:4). H NMR (400 MHz, CD3OD) δ 4.72 (d, 1H, J1α,2α 3.7 Hz,
H1α), 4.21 (d, 1H, J1β,2β 7.6 Hz, H-1β), 3.96 (dd, 1H, J 11.4, 5.3 Hz, H-5a), 3.70-3.37 (m,
12H, H-3, H-4, H-5, 2xOCH3), 3.34-3.21 (m, 2H, H-5, H-2); 13C NMR (100 MHz, CD3OD) δ
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105.9 (C-1β), 101.3 (C-1α), 77.6 (C-3β), 75.1 (C-3α), 74.7 (C-2β), 73.4 (C-2α), 71.3 (C-4α),
71.0 (C-4β), 66.8 (C-5β), 62.7 (C-5α), 57.2, 55.6 (OCH3).
3.4.2. Methyl β-D-ribopyranoside (7).
Methyl β-
D
-ribopyranoside (7) was obtained according to general procedure starting from
D-
ribose. Column chromatography purification yielded 7 as a white solid (73 mg, 67 %). [α]20
D
-106 (c 1.0; MeOH) lit.19 -103; 1H NMR (400 MHz, CD3OD) δ 4.61 (d, 1H, J1,2 3.7 Hz, H-1),
3.81 (t, 1H, J3,2 = J3,4 3.1 Hz, H-3), 3.79-3.72 (m, 2H, H-4, H-5a), 3.67 (dd, 1H, J5b,5a 12.2,
J5b,4 5.1 Hz, H-5b), 3.59-3.53 (m, 1H, H-2), 3.40 (s, 3H, OCH3); 13C NMR (100 MHz,
CD3OD) δ 103.3 (C-1), 72.4 (C-2), 70.5 (C-3), 68.0 (C-4), 64.7 (C-5), 56.0 (OCH3).
Electronic Supporting Information
NMR follow-up of the glycosylation of methanol with
D-arabinose in presence of
triethylamine, 2,6-lutidine and DMAP, 1H and 13C NMR spectra of 1, 4-7.
Acknowledgements
We are grateful to CEFIPRA organization for a fellowship attributed to S. P. We also thank
the CNRS and the Ministère de l’Enseignement Supérieur et de la Recherche for financial
supports.
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Highlights
•
•
•
A new procedure to selectively synthesize methyl β-D-arabinopyranoside from arabinose is
described using pyridine as a promotor of Fisher glycosylation.
Kinetics of the reaction is described as well as a putative mechanism where pyridine act as a
nucleophile.
Extension to other pentoses, lyxose, xylose and ribose was performed with good yields and
selectivity.