Organotin-catalyzed regioselective benzylation of carbohydrate trans-diols

Article abstract of DOI:10.1016/j.tetlet.2017.08.043

A convenient approach to regioselective benzylation of carbohydrate trans-diols was developed, where 0.1 equiv. of Bu₂SnCl₂ and 0.1 equiv. of TBABr were used as the catalysts and 2.0 equiv. of BnCl was used as the benzylation reagent. In most cases, similar or better benzylation regioselectivities and isolated yields were obtained by using catalytic amounts of Bu₂SnCl₂, rather than stoichiometric amounts of organotin reagents required.

Full text of DOI:10.1016/j.tetlet.2017.08.043

Accepted Manuscript
Organotin-Catalyzed Regioselective Benzylation of Carbohydrate trans-Diols
Hengfu Xu, Ying Zhang, Hai Dong, Yuchao Lu, Yuxin Pei, Zhichao Pei
PII:
S0040-4039(17)31050-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.043
TETL 49233
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
1 June 2017
1 August 2017
18 August 2017
Please cite this article as: Xu, H., Zhang, Y., Dong, H., Lu, Y., Pei, Y., Pei, Z., Organotin-Catalyzed Regioselective
Benzylation of Carbohydrate trans-Diols, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.08.043
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Graphical Abstract
Organotin-Catalyzed Regioselective
Benzylation of Carbohydrate trans-Diols
Hengfu Xua#, Ying Zhangb#, Hai Dongb, Yuchao Lua, Yuxin Peia and Zhichao Peia
a College of Chemistry and Pharmacy, Northwest A&F University, Yangling, 712100 Shaanxi, PR China.
bSchool of Chemistry & Chemical Engineering, Huazhong University of Science & Technology, Luoyu Road 1037, 430074 Wuhan, PR China.
A convenient approach to regioselective benzylation of carbohydrate trans-diols was developed, where 0.1 equiv. of
Bu2SnCl2 and 0.1 equiv. of TBABr were used as the catalysts and 2.0 equiv. of BnCl was used as the benzylation reagent.

1
Tetrahedron Letters
jo u r n a l h o m e p a g e : w w w . e ls e v i e r . c o m
Organotin-Catalyzed Regioselective Benzylation of Carbohydrate trans-Diols
Hengfu Xua#, Ying Zhangb#,, Hai Dongb, Yuchao Lua, Yuxin Peia and Zhichao Peia
a College of Chemistry and Pharmacy, Northwest A&F University, Yangling, 712100 Shaanxi, PR China
b School of Chemistry & Chemical Engineering, Huazhong University of Science & Technology, Luoyu Road 1037, 430074 Wuhan, PR China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convenient approach to regioselective benzylation of carbohydrate trans-diols was developed,
where 0.1 equiv. of Bu2SnCl2 and 0.1 equiv. of TBABr were used as the catalysts and 2.0 equiv.
of BnCl was used as the benzylation reagent. In most cases, similar or better benzylation
regioselectivities and isolated yields were obtained by using catalytic amounts of Bu2SnCl2,
rather than stoichiometric amounts of organotin reagents required.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Bu2SnCl2
Trans-diol
Catalysis
Regioselective benzylation
Green
———
 Zhichao Pei. Tel.: +86 29 87091196; Fax: +86 29 87092769; E-mail: peizc@nwafu.edu.cn
 Hai Dong. Tel.: +86 27 87793243; Fax: +86 27 87793242; Email: hdong@mail.hust.edu.cn
# These authors contributed equally to this work.

2
Tetrahedron
1. Introduction
Regioselective protection strategy plays a very important role
in carbohydrate chemistry due to the modification to specific
hydroxyl groups of carbohydrates and the construction of suitable
building blocks for the synthesis of oligosaccharides.[1-17]
Organotin reagents have been widely used in regioselective
protection strategies due to the relatively straightforward
manipulation and high regioselectivity and reliability.[18,19] The
methods have a broad substrate scope, including 1,2-diols, 1,3-
diols, cis-diols, trans-diols and polyols. Though the
regioselectivities for trans-diols are moderate in many cases, the
methods are certainly useful to avoid the wasteful formation of
di-benzylation side products.
A
cyclic dioxolane-type
intermediate formed by organotin with two adjacent hydroxyl
groups plays a key role for selectivities in the reaction, due to
stereo and stereoelectronic effects of the dioxolane
intermediate.[20-22] However, stoichiometric amounts of organotin
reagents had to be used in these methods (Figure 1a), which are
not environmental-friendly due to the inherent potential toxicity
of organotin reagents.[23,24] Therefore, several methods in which
nontoxic alternatives to organotin or reduced amount of
organotin species are used have been developed.[25-38] However,
these methods usually only lead to good regioselectivities for
substrates containing 1,2-diols, 1,3-diols, and cis-diols. Thus,
there is an urgent requirement to develop a selective protection
method for substrates containing trans-diol in which the use of
stoichiometric amounts of organotin can be avoided. In the
present study, an efficient method for selective benzylation of
carbohydrate trans-diols was developed (Figure 1b), where 0.1
equiv. of Bu2SnCl2 was used instead of stoichiometric amounts of
organotin. In most cases, similar or better benzylation
regioselectivities were obtained compared to using stoichiometric
amounts of organotins.
Figure 2 Proposed benzylation process: a) comparison of direct benzylation
with the benzylation using organotin reagents; b) inefficient catalytic process by
organotin with BnBr as the benzylation reagent due to the preferential direct
benzylation over the regeneration of the dibutylstannylene acetal intermediate; c)
efficient catalytic process by organotin with BnCl as the benzylation reagent.
2. Results and discussion
We have previously developed an organotin-catalyzed
regioselective benzylation method for cis-diols where 0.1 equiv.
of dibutyltin oxide was used as the catalyst and 1.5 equiv. of
BnBr was used as the benzylation reagent.[32] In this study, in
order to explore why that method led to poor selectivities for the
benzylation of carbohydrate trans-diols, trans-diol methyl 4,6-O-
benzylidene-α-D-glucopyranoside 1 was chosen to be benzylated
through the use of various amounts of dibutyltin oxide. The
experimental results showed that the ratio of 2-OBn product 2a
and 3-OBn product 2b increased from 1:0.9 to 1:0.3 by
increasing the amount of dibutyltin oxide from 0.1 equivalents to
1.1 equivalents.
In comparison with direct benzylation of trans-diol 1 leading
to no selectivity (Figure 2a), when stoichiometric amounts of
Table1 Comparison of results by variation from “standard” conditions.
Entry
Conditions
Standard conditionsa
No Bu2SnCl2
NMR Ratio (2a:2b)
1
2
2:1 (65:30)b
1:1
3
No TBABr
1:1
4
No K2CO3
No reaction
1.6:1
5
Me2SnCl2 instead of Bu2SnCl2
Ph2SnCl2 instead of Bu2SnCl2
BnBr instead of BnCl
PMBCl instead of BnCl
DMF instead of MeCN
PhMe instead of MeCN
6
1.8:1
7
1.2:1
8
1.4:1
9
Low reactivity
1:1
10
Figure 1 Comparison of the present method with previous reported
Reaction conditions: a substrate 1 (70 mg), Bu2SnCl2 (0.1 equiv.), TBABr (0.1
equiv.), K2CO3 (1.5 equiv.), BnCl (2 equiv.), acetonitrile (2 mL), 80 oC, 24 h.
b Isolated yield.
methods.

3
organotin are used, all trans-diol 1 firstly turns to cyclic
dioxolane-type intermediates 1M which further react with BnBr
to form major 2Ma and minor 2Mb, thus leading to good
selectivity. Based on this, if a catalytic amounts of organotin
were used, the regeneration of the cyclic dioxolane-type
intermediate 1M would be vital to the efficient catalytic process.
Therefore, the inefficient catalytic process[32] for benzylation of
trans-diol 1 must be due to the preferential direct benzylation
over the regeneration of 1M via the transformation of organotin
species from intermediates 2Ma and 2Mb to trans-diol 1 (Figure
2b). In other words, the efficient catalytic process for benzylation
of trans-diol 1 would proceed if the regeneration of 1M were
preferential over the direct benzylation. This inspired us to use
BnCl as the benzylation reagent instead of BnBr in the catalytic
process (Figure 2c). Since the reactivity of BnCl is much less
than that of BnBr in the substitution reaction, we hypothesized
that the direct benzylation of trans-diol 1 with BnCl would be
less favored than the regeneration of the intermediate 1M,
leading to good selectivity of 2-OBn product 2a.
5
6
89
14: 86
16: 67
7
8
9
80
75
81
24a:24b
43:40
10
The hypothesis was further supported by the selective
benzylation of trans-diol 1 where 0.1 equiv. of Bu2SnCl2 and 0.1
equiv. of TBABr were used as the catalysts and 2.0 equiv. of
BnCl was used as the benzylation reagent (Table 1). Under the
standard conditions, trans-diol 1 (70 mg) was allowed to react
with 2.0 equiv. of BnCl in the presence of 0.1 equiv. of Bu2SnCl2,
0.1 equiv. of TBABr and 1.5 equiv. of K2CO3 in acetonitrile at 80
oC for 24 h. The NMR ratio of products 2a and 2b appeared 2:1
and the ratio of the corresponding isolated yields was 65:30
(Entry 1 in Table 1). Without Bu2SnCl2 or TBABr, the NMR
ratio dramatically decreased to 1:1 (Entries 2 and 3 in Table 1),
whereas, without K2CO3 no reaction occurred (entry 4 in Table 1).
With Me2SnCl2 or Ph2SnCl2 instead of Bu2SnCl2, the NMR ratio
of 2a and 2b decreased to 1.6:1 and 1.8:1 respectively (Entries 5
and 6 in Table 1), which might reflect the steric effect of alkyl
groups in organotins. Using BnBr or PMBCl instead of BnCl, the
NMR ratio decreased to 1.2:1 and 1.4:1 respectively (Entries 7
and 8 in Table 1), which reflect the reactivities of the benzylation
reagents. The more direct benzylation of 1 by benzylation
reagents with higher reactivity led to poorer regioselectivity
(Figure 2b). DMF as the solvent led to low reactivity (Entry 9,
Table 1), and toluene as the solvent led to no selectivity (Entry
10, Table 1).
26a:26b
56:34
11
12
13
90
85d
Reaction conditions：a substrates (70 mg), Bu2SnCl2 (0.1 equiv.), K2CO3 (1.5
o
b
equiv.), TBABr (0.1 equiv.), BnCl (2.0 equiv.), MeCN (2 mL), 80 C, 24 h.
use of BnBr instead of BnCl. c NMR ratio. d Large scale.
The method was further tested with methyl 4,6-O-
benzylidene glycoside trans-diols 3, 5 and 7 (Entries 1-3 in Table
2). The ratio of benzylation products 4a/4b, 6a/6b and 8a/8b
were 66/19, 30/70 (NMR ratio) and 21/70 respectively. In
comparison with these results, the ratio of 4a/4b, 6a/6b and
8a/8b were 48/32, 43/57 (NMR ratio) and 38/46 respectively
when BnBr was used instead of BnCl as the benzylation reagent
in the method. It has been summarized that only trans-diols
where one adjacent substituent is equatorial and one is axial
exhibit good selectivities on the hydroxyl groups adjacent to the
axial substituent in the benzylation using stoichiometric amounts
of organotins.[18] For example, trans-diols 1 and 7 usually
exhibited good selectivities[39] and trans-diols 3 and 5 usually
exhibited poor selectivities[40,41] when using stoichiometric
amounts of organotin reagents. The resulted regioselectivities has
been proposed to be caused by stereo and stereoelectronic
effects.[21] Interestingly, all these four diols (1, 3, 5 and 7)
exhibited good selectivities in the organotin-catalyzed method.
Furthermore, azido 4,6-O-benzylidene glycoside trans-diols 9
and 11 exhibited higher selectivities with this method. It can be
seen that products 10, where the 2-position is selective
benzylated, and 12, where the 3-position is selective benzylated,
were isolated in 87% and 89% yields, respectively (Entries 4 and
5 in Table 2). The tests with glycoside trans-diols 13, 15, 17, and
19, where the 3,4-hydroxyl groups are free, also gave satisfied
results. The selective benzylation products 14, 16, 18, and 20
were isolated in 86%, 67%, 80% and 75% respectively (Entries
6-8 in Table 2). Application of the method in the construction of
thioglycoside building blocks was extremely important since
thioglycoside, as glycosylation donors, are widely used in
Table2 Regioselective benzylation of carbohydrate trans-diola.
Isolated Yields
Entry
Substrate
Product
(%)
4a/4b
66/19
1
(48/32)b
6a/6bc
2
30/70
(43/57)b
8a/8b
3
4
21/70
(38/46)b
87

4
Tetrahedron
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substituent, which is the same as the method using stoichiometric 2014, 30, 774-777.
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amounts of organotins. Furthermore, the benzylation of trans- 13. Liang, X. Y.; Bin, H. C.; Yang, J. S. Org. Lett. 2013, 15, 2834–2837.
diols where the adjacent substituents are either both equatorial (3, 14. Dong, H.; Rahm, M.; Thota, N.; Deng, L.; Brinck, T.; Ramstrom, O. Org.
9, 13, 15, 23, 25) or both axial (5) also gave good selectivities in
Biomol. Chem. 2013, 11, 648-653.
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3. Conclusions
In conclusion, a method for regioselective benzylation of
carbohydrate trans-diols has been developed through the use of
0.1 equiv. of Bu2SnCl2 as the catalyst and the use of BnCl as the
benzylation reagent. In most cases, similar or better
regioselectivities and isolated yields were obtained using
catalytic amounts of organotin reagents than stoichiometric
amounts of organotin reagents traditionally required (Table S1).
Furthermore, this method has also been successfully applied in
the efficient construction of thioglycoside building blocks
through the selective benzylation of thioglycoside trans-diols.
18. Grindley, T. B. Adv. Carbohydr. Chem. Biochem. 1998, 53, 17-142.
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4. Experimental Section
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953.
General procedure for selective benzylation of trans-diols:
Carbohydrate trans-diols (70 mg) were allowed to react with 2.0
equiv. of BnCl in the presence of 0.1 equiv. of Bu2SnCl2, 0.1
equiv. of TBABr and 1.5 equiv. of K2CO3 in acetonitrile. The
reaction proceeds at 80 C for 24 h. After the removal of the
solvents, the residue was purified by column chromatography to
26. Xu, H. F.; Ren, B.; Zhao, W.; Xin, X. T.; Lu, Y. C.; Pei, Y. X.; Dong, H.;
Pei, Z. C. Tetrahedron 2016, 72, 3490-3499.
o
27. Ren, B.; Ramstrom, O.; Zhang, Q.; Ge, J. T.; Dong, H. Chem. Eur. J. 2016,
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give desired products.
28. Zhang, X. L.; Ren, B.; Ge, J. T.; Pei, Z. C.; Dong, H. Tetrahedron 2016,
72, 1005-1010.
Large scale: Compound 30 (500 mg, 1.4 mmol) were allowed
to react with 2.0 equiv. of BnCl (323 uL, 2.8 mmol) in the
presence of 0.1 equiv. of Bu2SnCl2 (35 mg, 0.14 mmol), 0.1
equiv. of TBABr (45 mg, 0.14 mmol) and 1.5 equiv. of K2CO3
(290 mg, 2.1 mmol) in acetonitrile (2 mL). The reaction proceeds
29. Saikam, V.; Dara, S.; Yadav, M.; Singh, P.; Vishwakarma, R. A. J. Org.
Chem. 2015, 80, 11916-11925.
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o
31. Giordano, M.; Iadonisi, A. J. Org. Chem. 2014, 79, 213-222.
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C. Adv. Synth. Catal. 2014, 356, 1735-1740.
at 80 C for 24 h. After the removal of the solvents, the residue
was directly purified by flash column chromatography to afford
the pure product 30 (555 mg, 88% yield).
33. Ren, B.; Rahm, M.; Zhang, X. L.; Zhou, Y. X.; Dong, H. J. Org. Chem.
2014, 79, 8134-8142.
5. Acknowledgments
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This study was supported by the National Nature Science
Foundation of China (Nos. 21272083 and 21572181).
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5

6
Tetrahedron
Highlights
An approach to regioselective benzylation of
carbohydrate trans-diols was developed.
The benzylation uses 0.1 equiv. of Bu2SnCl2 and
0.1 equiv. of TBABr as the catalysts.
The key in the benzylation is to use BnCl as the
benzylation reagent.