Regioselectivity of tin-mediated benzylation of glycoside

Article abstract of DOI:10.14233/ajchem.2013.13921

Regioselectivity of methyl α-D-glucopyranoside benzylation using dibutyltin dimethoxide (DBDM) as stannylating agent was probed, general factors affecting regioselectivity have been examined. The results show the O-2 position of glucoside has advantage of

Full text of DOI:10.14233/ajchem.2013.13921

Benzylation of methyl α-D-glucopyr-anoside: Methyl
Asian Journal of Chemistry; Vol. 25, No. 4 (2013), 2281-2283
http://dx.doi.org/10.14233/ajchem.2013.13921
Regioselectivity of Tin-Mediated Benzylation of Glycoside
XIN LOU
Material and Chemical Engineering College, Chuzhou Uniersity, Chuzhou 23900, P.R. China
Corresponding author: Fax: +86 550 3515035; Tel: +86 550 3511052; E-mail: franklinee@hotmail.com
(Received: 17 April 2012;
Accepted: 22 October 2012)
AJC-12331
Regioselectivity of methyl α-D-glucopyranoside benzylation using dibutyltin dimethoxide (DBDM) as stannylating agent was probed,
general factors affecting regioselectivity have been examined. The results show the O-2 position of glucoside has advantage of being
benzylated over the O-6 position. The major isomers of benzyl ether were separated by preparative HPLC method and characterized.
Key Words: Benzylation, Stannylene acetal, Regioselectivity.
or KBr discs, as specified. Melting points were measured on a
STUART melting point apparatus. Elemental analysis was
performed on an Exeter analytical CE 440 elemental analyzer.
Low and high resolution mass spectra were measured on
electrospray mass spectrometry in ES negative mode unless
otherwise indicated. TLC was performed on aluminium sheets
precoated with Silica Gel 60 (HF254, E. Merck) and spots visu-
alized by UV and charring with H2SO4-EtOH (1:20).
INTRODUCTION
Benzyl ethers are commonly used for the protection of
hydroxyl groups in carbohydrate chemistry since they are
stable with respect to both acids and bases and yet are easily
removable under mild hydrogenating conditions1-4. Conse-
quently, benzylated sugars find wide synthetic application as
glycosylating reagents, chiral synthons and pharmaceutical-
intermediate5,6. Carbohydrate stannylene acetals have proven
to be useful intermediates in the regioselective synthesis of
carbohydrate derivatives7-10, 1,6-dibutylstannylene acetals are
reactive intermediates that have been treated with acylating and
alkylating agents to provide mono-substituented derivatives of
diols or polyols with high regioselectivity11,12. However for
regioselective substitution of methyl α-D-glucoside, the substi-
tution position on pyranoside cycle often varied with detailed
condition. For instance, thiophosgene reaction takes place at
the 2 and 3 position of glucoside13; where allidenation of
glucopyranoside occurs across the 4 and 6 positions to give
4,6-O-allylidene-α-D- glucopyranoside14; while trimethyl-
silylation of glucopyrano-side gives only substitution on the 6
position15. In this work regioselectivity of glucoside benzylation
was probed, dibutyltin dimethoxide was used as the stannylating
reagent and benzyl bromide was used as alkylating agent.
α-D-glucopyranoside (0.97 g, 5 mmol) was dissolved in the
reaction solvent (40 mL) and dibutyltin dimethoxide (1.47 mL,
5.5 mmol) was added to the solution, causing effervescence.
The reaction mixture was kept at the required temperature and
a solution of benzyl bromide in solvent (10 mL) was added
dropwise over 1 h. The reaction was monitored using TLC
and terminated after at least 24 h. The mixture was evaporated
under vacuum to give a syrup. This was fractionated by flash
chromatography using a solvent mixture of chloroform:methanol
(8: 1) to give benzyl ether.
HPLC method development for analysis and separation
of isomers of methyl α-D-glucopyranoside benzyl ethers:
The determination of absorption spectrum of methyl α-D-
glucopyranoside benzyl ether based on UV studies was found
to be 258 nm.
Selection of suitable mobile phase: A series of mobile
phases which comprized two or three solvents were investi-
gated. The solution methanol:water (50: 50) was found to be
an appropriate solvent system for analysis of benzyl ethers of
methyl α-D-glucopyranoside. Fig. 1 is a HPLC chromatograph
of the reaction mixture from benzylation of methyl α-D-
glucopyranoside in dioxane, heated at reflux.
EXPERIMENTAL
1H and 13C spectra were recorded with Varian Inova 300,
500 NMR spectrometers. 1H chemical shifts in CD3OD were
referenced to CHD2OD (3.30 ppm); 13C chemical shifts in
CD3OD were referenced to CHD2OD (49.0 ppm). FTIR spectra
were recorded with a Nicolet FTIR 3000 using either thin film

Methyl 2-O-benzyl-α-D-glucopyranoside: yield 47.4 %;
Methyl 6-O-benzyl-α-D-glucopyranoside:Yield 15.8 %;
methyl α-D-glucopyranoside: The reaction temperature was
2282 Lou
Asian J. Chem.
Table-2 showed that the increasing temperature leads to
an increased yield of monoether, however there is reduced
regioselectivity. Possibly the various stannylene acetals of
methyl α-D-glucopyranoside migrate more easily between
different vicinal diol systems at higher temperatures and so a
mixture of isomers is given.
45.00
40.00
35.00
30.00
25.00
20.00
15.00
10.00
5.00
TABLE-2
EFFECT OF TEMPERATURE ON REGIOSELECTIVITY OF
TIN-MEDIATED BENZYLATION REACTION
0.00
Ratio of isomers*
Overall yield of
monoethers (%)
Temperature (°C)
5.00
10.00
15.00
20.00
25.00
30.00
min
Heated at reflux
80 °C
20 : 11 : 6:1
10: 4 : 1
2.6 : 1
85
72
61
3
Fig. 1. HPLC-UV chromatograph of benzylation of methyl α-D-
glucopyranoside using methanol: water = 50: 50 as the mobile phase;
R1 = 14.94, R2 = 18.71, R3 = 24.45, R4 = 28.86 min; A1: A2: A3: A4
= 6: 20: 1.6: 11 (R-retention time; A-area of peaks)
60 °C
N/A
40°C
Ratio of isomers was detected by HPLC using method G (mobile
phase: methanol: water = 50: 50, flow rate = 1.0 mL/min, UV detector),
Reaction conditions: methyl α-D-glucopyranoside: DBDM: benzyl
bromide = 1: 1.1: 4, solvent: dioxane. Peaks are in the order of
decreasing composition, Rts for these peaks are 19.11, 28.86, 15.44,
24.45 min
It can be seen from Fig. 1 that four isomers were well
separated and the retention times of Rt1 = 14.94, Rt2 = 18.71,
Rt3 = 24.45, Rt4 = 28.86 min corresponded with the 3-O iso-
mer, 2-O isomer, 4-O isomer, 6-O isomer respectively.
RESULTS AND DISCUSSION
Following optimization of the reaction conditions (tempe-
rature: 60 ºC; solvent: dioxane), we found the reaction gave a
mixture of 2-O and 6-O isomers in a ratio of 2.6: 1. 13C NMR
was used to elucidate the structure of the mixture of methyl
α-D-glucopyranoside benzyl ether isomers, comparison of
these data with the NMR data for esterification indicates
benzylation has a much greater effect on 13C shift of the
substituted carbons (+7.5-8.2 ppm) than esterification (2-3
ppm). It is worthy of mention that the H-2 of the O-2 isomer
and H-6 of the 6-O isomer is nearly unchanged, which is not
the case for esterification, where we found that the H-2 had a
shift of 1.1-1.2 ppm for all the methyl 2-O-acyl-α-D-gluco-
pyranosides12.
The initial finding showed that benzylation of methyl α-
D-glucopyranoside using dibutyltin dimethoxide differs from
esterification in that it has to be carried out at higher temperatures,
with an excess amount of benzyl bromide (4-6 equiv.).A series
of factors were investigated that influence the regioselectivity
to probe this reaction.
Effect of solvent on regioselectivity of benzylation of
maintained at 80 ºC and various solvents were investigated to
probe the effect on regioselectivity. The effect of addition of a
base was also investigated for dioxane and toluene.
Table-1 showed solvents did not obviously affect the
regioselectivity, giving 3 or 4 isomers in all cases, while the
addition of a base to toluene or dioxane either disimproved
regioselectivity or had little effect.
1H NMR (500 MHz, CD3OD): δ 7.38-7.22 (m, 5H, aromatic
H), 4.72 (d, 1H, J = 12.0 Hz, CHaPh), 4.64 (d, 1H, J1,2 = 3.6
Hz, H-1), 4.63 (d, 1H, J = 12.0 Hz, CHbPh), 3.79 (dd, 1H, J5,
Effect of temperature on regioselectivity of glucoside
benzylation: Dioxane was chosen as the solvent for the
benzylation reaction. The reaction was carried out at different
temperatures to investigate the effect on regioselectivity.
6a = 2.4 Hz, J6a,6b = 11.7 Hz, H-6a), 3.74 (apt t, 1H, J2,3 = J3,4
=
9.5 Hz, H-3), 3.65 (dd, 1H, J5,6b = 5.5 Hz, J6a,6b = 11.7 Hz, H-
6b), 3.49 (ddd, 1H, J5,6a = 2.4 Hz, J5,6b = 5.5 Hz, J4,5 = 9.5 Hz,
H-5), 3.33 (s, 3H, OCH3), 3.32 (dd, 1H, J1,2 = 3.6 Hz, J2,3 = 9.5
Hz, H-2), 3.30 (apt t, 1H, J3,4 = J4,5 = 9.5 Hz, H-4); 13C NMR
(500 MHz, CD3OD): δ 139.9, 129.4, 129.4, 129.3, 129.3, 128.9
(aromatic C), 99.4 (C-1), 81.1 (C-2), 74.4 (CH2Ph), 74.1 (C-
3), 73.4 (C-5), 71.9 (C-4), 62.7 (C-6), 55.4 (OCH3); CI-LRMS:
Found 284.1 required 284.1.
TABLE-1
EFFECT OF SOLVENT AND NUCLEOPHILE ADDITION ON
THE REGIOSELECTIVITY OF BENZYLATION OF METHYL
α-D-GLUCOPYRANOSIDE USING DBDM
Solvent
Base
Isomers
numbers
Ratio of
peaks*
Yield of
monoether
(%)
1H NMR (500 MHz, CD3OD): δ 7.38-7.22 (m, 5H, aromatic
H), 4.72 (d, 1H, J = 12.0 Hz, CHaPh), 4.66 (d, 1H, J1,2 = 3.7
Hz, H-1), 4.63 (d, 1H, J = 12.0 Hz, CHbPh), 3.80 (dd, 1H, J5,6a
= 2.5 Hz, J6a,6b = 11.8 Hz, H-6a), 3.67 (dd, 1H, J5,6b = 5.7 Hz,
J6a,6b = 11.9 Hz, H-6b), 3.61 (apt t, 1H, J2,3 = J3,4 = 9.2 Hz, H-
3), 3.52 (ddd, 1H, J5,6a = 2.4 Hz, J5,6b = 5.4 Hz, J4,5 = 9.9 Hz, H-
5), 3.4 (s, 3H, OCH3), 3.39 (dd, 1H, J1,2 = 3.7 Hz, J2,3 = 9.2
Hz, H-2), 3.37 (apt t, 1H, J3,4 = J4,5 = 9.2 Hz, H-4); 13C NMR
(500 MHz, CD3OD): δ 139.76, 129.39, 129.39, 128.85, 128.85,
128.68 (aromatic C), 101.38 (C-1), 75.23 (C-3), 74.56
DMF
4
4
6: 4: 2.4: 1
11: 6: 1.5:
1
78
Acetonitrile
65
Dioxane
Dioxane
DME
3
4
3
4
4
10: 4: 1
72
87
61
48
58
DMAP
TEA
2: 1.7: 1: 1
3: 1.5: 1
4: 3: 2: 1
2: 1.5: 1: 1
Toluene
Toluene
*Ratio of isomers was detected by HPLC using Method G, Reaction
conditions: Methyl α-D-glucopyranoside: DBDM: benzyl bromide
= 1: 1.1: 4, T: 80 °C, Peaks are in the order of decreasing
composition, Rts for these peaks are 19.11, 28.86, 15.44, 24.45 min

Vol. 25, No. 4 (2013)
Regioselectivity of Tin-Mediated Benzylation of Glycoside 2283
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ACKNOWLEDGEMENTS
This work was supported by Project of State Key Lab of
Chinese Pharmaceutical Process Technology SKL2010M0303,
Provincial-level University Research Projects in Anhui
Province KJ2011Z275 and Anhui Provincial-level Chemical
Engineering and Technology TeachingTeam 20101035 . Thanks
also due to Dr. Seamas Cassidy and Prof. Gary Henehan in
DIT, Ireland for their suggestions during this work.
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