1,2-trans-1-Dihydroxyboryl benzyl S-glycoside as glycosyl donor

Article abstract of DOI:10.1016/j.carres.2014.05.010

Activated by NBS, readily available 1,2-trans-1-dihydroxyboryl benzyl S-glycosides served as glycosyl donors and reacted with certain simple alcohol acceptors to produce pure 1,2-cis-O-glycosides in moderate yields. The boronic acid moiety was revealed es

Full text of DOI:10.1016/j.carres.2014.05.010

Accepted Manuscript
Note
1,2-trans-1-Dihydroxyboryl Benzyl S-Glycoside as Glycosyl Donor
Xiao Liu, Bingbing Zhang, Xiangying Gu, Guohua Chen, Lin Chen, Xin Wang,
Bing Xiong, Qi-Dong You, Yue-Lei Chen, Jingkang Shen
PII:
S0008-6215(14)00202-X
http://dx.doi.org/10.1016/j.carres.2014.05.010
CAR 6749
DOI:
Reference:
Carbohydrate Research
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 March 2014
8 May 2014
9 May 2014
Please cite this article as: Liu, X., Zhang, B., Gu, X., Chen, G., Chen, L., Wang, X., Xiong, B., You, Q-D., Chen,
Y-L., Shen, J., 1,2-trans-1-Dihydroxyboryl Benzyl S-Glycoside as Glycosyl Donor, Carbohydrate Research (2014),
doi: http://dx.doi.org/10.1016/j.carres.2014.05.010
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Xiao Liu[a,b], Bingbing Zhang[c], Xiangying Gu[a,b], Guohua Chen[a], Lin Chen[b], Xin Wang[b], Bing
Xiong[b], Qi-Dong You*[a], Yue-Lei Chen*[b], and Jingkang Shen*[b]
a School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, P. R. China. E-mail: Q. Y.: youqidong@gmail.com
b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China. E-mail: Y. -L. C.: chenyuelei@gmail.com, J. S.:
jkshen@simm.ac.cn
c Sinochem Jiangsu Co, Ltd. 22F Jincheng Dasha, 216 Longpan Zhonglu, Baixia Qu, Nanjing, 210002, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Activated by NBS, readily available 1,2-trans-1-dihydroxyboryl benzyl S-glycosides served as
glycosyl donors and reacted with certain simple alcohol acceptors to produce pure 1,2-cis-O-
glycosides in moderate yields. The boronic acid moiety was revealed essential in the
glycosylation for product formation and good anomeric ratio. The preliminary model reactions
suggested that glycosyl aryl boronic acids could be used for stereoselective glycosylation.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
stereoselective
glycosylation
boronic acid
ate complex
S-glycoside
the spatial proximity and orbital arrangement, one of the oxygen
nucleophiles on the boronate ester or ate complex might have the
opportunity to attack the C-1 center bearing the activated sulfide,
with a better control of stereochemistry. Ideally, the product could be
a valuable 1,2-cis-O-glycoside (Scheme 1, structure II).
One of the central topics in synthetic carbohydrate chemistry is
building the glycosyl bond stereoselectively. [1] Although there is no
general rule to predict the stereochemistry outcome for a given
[8]
37 reagent or condition, glycosylation reactions prefer to give 1,2-trans
38
products due to the steric and stereoelectronic effects. [1,2] While 1,2-
trans outcome can be further ensured by neighboring-group
participations, the syntheses of 1,2-cis glycosides remain a challenge
for carbohydrate chemists.
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Among various methods leading to the 1,2-cis glycosyl bond, the
conceptually intriguing intramolecular aglycon delivery is a unique
solution. [3] In this method, it is necessary to tether the donor and
acceptor, and the tethering strategies have been classified by R. R.
Schmidt into 3 types according to the tethered position and tether
nature: leaving group based, bifunctional group based, and non-
reacting center based. [3b] An interesting class of leaving group based
intramolecular aglycon delivery utilises non-covalent interaction
such as hydrogen bonding to organize the donor and the acceptor. [4]
Recently, R. R. Schmidt et al has developed several useful methods,
[5]
that employ hydrogen bonding or boron ate complex to organize
the supramolecular structure. These methods belong to the category
of leaving group based aglycon delivery (Scheme 1).
Scheme 1. Several examples of leaving group based aglycon delivery and the
[6]
On the basis of our study on glycosyl aryl boronic acids,
we
design of a boronic acid directed glycosylation.
speculated if these compounds could be used for leaving group based
aglycon delivery (Scheme 1). As the starting material, boronic acid-
containing 1,2-trans-S- or O-Glycosides (Scheme 1, structure I) are
readily prepared. When these boronic acids were treated with the
acceptor alcohol, boronate ester or ate complex should be expected.
Next, if the sulfide were activated [7] by an oxidating reagent, due to
Following this design, o-dihydroxyboryl substituted phenyl and
benzyl S-glucosides (compound 6 and 7) and galactoside (compound
13) were prepared. O-Bn Protections were used to minimize the
unwanted interruption in the later glycosylation experiments. The
syntheses were demonstrated in Scheme 2. From acetobromoglucose
1

1 and per-O-acetyl galactosyl bromide 10, standard S-glycosylation
method was used to prepare per-O-Ac glycosides 2, 3, and 11. The
O-Ac protections on 2, 3, and 11 were then removed and the O-Bn
protections were installed to yield compounds 4, 5, and 12. Bromine
containing glycosides 4, 5, and 12 were treated with t-BuLi and
B(OMe)3 successively to produce the desired boronic acids 6, 7, and
13 in good yields. Lithiated 4, 5, and 12 were also directly quenched
with MeOH to give compounds 8, 9, and 14, which were used as
control in the following study.
1
2
3
4
5
6
7
8
9
Entry
Donor
S-activator
Yield (alpha:beta) [b]
8
1
2
3
4
5
6
NBS
NBS
40% (2.1:1)
55% (4.3:1)
91% (1:2.6)
44% (2.8:1)
58% (4.8:1)
89% (1:1.5)
6
6
9
7
7
NBS, TfOH
NBS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
NBS
NBS, TfOH
[a] Reaction conditions and reagents: 3.0 equiv of 3-methylbenzyl alcohol, 2.2
equiv of activator, 3 Å MS, DCM, -40 oC to RT, overnight. [b] Yields and
anomeric ratios were determined by HPLC analysis using the pure anomers as
[9]
control.
Encouraged by the preliminary findings, we performed extensive
optimization to improve the stereochemistry outcome of the
glycosylation reaction. In table 1, the results from benzyl glycoside 7
and phenyl glycoside 6 were similar. We considered that the benzyl
glycoside might enjoy more conformational flexibility which should
benefit an efficient delivery of larger acceptors; therefore we used
only benzyl glycoside 7 for further optimization. Firstly, different S-
Scheme 2. Preparation of glucosyl donors (6, 7, 8, and 9) and galactosyl donors
(13 and 14). Reaction conditions and reagents: a) For compound 2: 2-
bromothiophenol, TBAHS, 1.5 M aq. Na2CO3, ethyl acetate, RT, 2h. For
compound 3 and 11: 2-bromobenzyl mercaptan, TBAHS, 1.5 M aq. Na2CO3, ethyl
acetate, RT, 2h. b) NaOMe, MeOH, rt, 2h. c) NaH, TBAI, BnBr, 1,4-dioxane, 60
oC, overnight. d) t-BuLi, B(OMe)3, Ether, -78 oC to RT. e) t-BuLi, CH3OH, Ether,
-78 oC to RT.
[12]
activators including NIS, NBS, NCS, interhalogens,
bromine,
MeI and DMTSF (dimethyl-(methylthio)-sulfonium tetrafluoroborate)
[4c] were tested (Table 2, entries 1-8). NBS and bromine both showed
better stereochemistry outcome (Table 2, entries 2 and 6), and the
reaction with NBS looked cleaner by TLC. In addition, one
unexpected finding was that IBr gave reversed anomeric ratio in
contrast to all other activators (Table 2, entry 4). Next, we kept NBS
as the activator and investigated solvent effect in the glycosylation
(Table 2, entries 9-12). In ether and toluene, the anomeric ratio was
improved. Equally interesting observation was from acetonitrile,
with which the anomeric ratio was again reversed in favor of the
beta-amomer. Therefore, ether was used as the solvent for the third
round of screening. In Table 2, entries 13-17, the equivalence of
NBS and 3-methylbenzyl alcohol was further optimized. It was
found that 5 equiv of NBS and 3 equiv of alcohol acceptor (both to
the donor) gave the best anomeric ratio and yield. Decreasing the
equivalence of acceptor to 2.0 equiv or 1.0 equiv gave less or no
product 15, and this could be regarded as another evidence
supporting that the ate-complex mechanism was involved in the
glycosylation. Eventually, the temperature effect was probed. The
Glucose derivatives 6 and 7, along with NBS as a common S-
activator, were used for the preliminary screening. We chose m-
methyl benzyl alcohol as glycosyl acceptor, since the glycoside
product 15 showed on proton NMR distinct methyl peaks depending
on the anomeric configuration. To ensure the reaction between
boronic acid and acceptor alcohol, 3.0 equiv of alcohol was stirred
with the sugar donor in DCM at RT for 1 h, in the presence of
activated 3 Å molecular sieves. The mixture was then cooled to -
40 ℃, treated with NBS, and warmed to RT overnight. The resulting
mixture was subjected to aqueous workup and HPLC inspection
using the purified 15 [9] as control. The results were encouraging: for
the phenyl-S-glycoside series (Table 1, entry 1 and 2), the alpha:beta
ratio from boronic acid derivative 6 was 2 times higher than that
from 8. For the benzyl-S-glycosides 9 and 7 (Table 1, entry 4 and 5),
the results were also in favour of 7. According to these results, it is
reasonable to speculate that the boronic acid plays certain role in the
o
results in Table 2, entries 18 and 19 suggested that -20 C was an
optimal temperature for both stereoselectivity and yield. A major
side product from this glycosylation was compound 16. As a
representative example, 25% of compound 16 was isolated from
Table 2, entry 14. Compound 16 might come from hydrolysis
(during workup procedure) of the S-activated intermediate.
delivery of the aglycon moiety. In other experiments (Table 1, entry
[7, 10]
50 3 and 6), TfOH
51 boronic acid derivatives 6 or 7, and significant change of the
was added to the reaction mixture of the
[11]
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anomeric ratio was observed for both cases.
In addition, when
Table 2. Optimization of the reaction condition using glucosyl donor 7.
thiophilic AgOTf was used, deboronation on the starting material 6
and 7 were observed. Therefore we did not use acid or heavy metal
reagents in further experiments.
Table 1. Initial screening demonstrated the importance of boronic acid for the
glycosylation step.
S-acti-
Equiv of
alcohol
Yield of 15 [c]
(alpha:beta)
Entry
1
Solv.
DCM
Temp.
-20 °C
vator [b]
NIS
3.0
43% (1.0:1)
2

2
3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeCN
Et2O
THF
-20 °C
-20 °C
-20 °C
-20 °C
-20 °C
-20 °C
-20 °C
-20 °C
-20 °C
-20 °C
-20 °C
-20 °C
NBS
NCS
IBr
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
49% (3.6:1)
No reaction
65% (1:10)
36% (2.0:1)
37% (4.4:1)
No reaction
48% (1.2:1)
57% (1:4.0)
51% (7.2:1)
58% (4.0:1)
62% (5.5:1)
42% (5.3:1)
EtOH: i-PrOH =
17:18 = 2:1, 40% in total (alpha
3
4
7
7
2:1[c]
only for both) [d]
t-BuOH
19, 41% (alpha only)
20, 42% (6.7:1)
4
1
2
3
4
5
6
7
8
9
5
ICl
5
6
7
7
6
Br2
7
MeI
21, 35% (8.5:1)
23, 49% (9.8:1)
8
DMSTF
NBS
NBS
NBS
NBS
NBS[d]
9
10
11
12
13
7
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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32
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34
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40
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42
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50
MePh
Et2O
13
13
8
9
i-PrOH
24, 34% (alpha only)
25, 45% (5.1:1)
71% (9.4:1),
with 25% of
compound 16
22
14
Et2O
-20 °C
NBS[e]
3.0
[a] Reaction conditions and reagents: 3 equiv Of acceptor, 5 equiv of NBS, 3 Å
MS, ether, -40 oC to -20 oC, overnight. [b] Yields after separation and NMR ratio.
[c] 2 equiv of EtOH was mixed with 7. The mixture was stirred at RT for 1 h,
15
16
17
18
19
Et2O
Et2O
Et2O
Et2O
Et2O
-20 °C
-20 °C
-20 °C
-78 °C
0 °C
NBS[e]
NBS
2.0
1.0
5.0
3.0
3.0
31% (2.4:1)
Trace
o
o
cooled to -40 C, treated with 1 equiv of i-PrOH, stirred at -40 C for 10 min, and
then activated by NBS. See supporting information for details. [d] Compounds 17
and 18 were collected as a mixture and analyzed by quantitative 13C-NMR.
NBS
64% (8.2:1)
30% (3.3:1)
70% (7.8:1)
NBS[e]
NBS[e]
Although various results in table 1 and 2 suggested that the
glycosylation was related to the boronate ester or boron ate complex
intermediate, further control experiments were still desirable. Thus,
glycosyl donors 5, 9, 12 and 14, bearing no boronic acid on the
phenyl ring, were tested with the optimized glycosyation condition.
Except for donor 9, which gave low yield (11%) of product 15,
essentially no reaction could be observed with donors 5, 12, and 14.
These results further indicated that the boron-glycosyl acceptor
complex was involved in the aglycon delivery process. It should be
noted, however, that at this stage, a detailed mechanistic picture is
not clear and different possibilities remain. More studies on related
reactions are ongoing.
[a] Reaction conditions and reagents: 3-methylbenzyl alcohol, indicated activator,
3 Å MS, DCM, indicated reaction temperature, overnight. [b] 2.2 equiv of
activator was used unless otherwise mentioned. [c] Yields after separation and
NMR ratio. [d] 1.0 equiv of NBS was used. [e] 5.0 equiv of NBS was used.
Using the optimized condition described in Table 2, entry 14, we
took some simple glycosyl acceptors to study the stereochemistry
outcome on donor 7. Aliphatic alcohols gave moderate yields which
seemed not to be affected by the steric hindrance. The
stereoselectivity was quite reliable with pure 1,2-cis outcomes (Table
3, entries 1-2). To further study the glycosylation, donor 7 was first
reacted with 2 equiv. of EtOH at RT and then 1 equiv. i-PrOH at -40
oC. At the end, corresponding alpha-ethyl and alpha-isopropyl
glucosides were obtained with 2:1 ratio. Cyclic aliphatic alcohols, as
well as the sugar alcohol 22, gave low to moderate yields, too.
Although the anomeric ratio was still good, the erosion of anomeric
stereochemistry control indicated that the glycosylation mechanism
already changed in these cases (Table 3, entries 4-6). The same
reaction condition was applied to galactosyl donor 13 as well and the
yields were again moderate (Table 3, entries 7-8). Concerning the
stereochemistry, isopropanol consistently gave perfect result, while
the sugar alcohol 22 provided lower anomeric ratio. Although the
formation of 1-OH pyranoses again significantly diminished yields
in all cases in Table 3, the good to perfect 1,2-cis glycosylation
outcome suggested that glycosyl aryl boronic acid could be a useful
glycosyl donor.
Table 4. Further experiments showed that the boronic acid is crucial for the
glycosylation.
Entry
Donor
Product, yield (alpha:beta) [b]
5
1
2
3
4
No reaction
15, 11% (6.2:1)
No reaction
9
12
14
No reaction
51 Table 3. Screening the cceptors using glucosyl donor 7 and galactosyl donor 13.
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54
55
56
57
58
59
60
61
62
63
64
65
[a] Reaction conditions and reagents: a) 3.0 equiv of 3-methylbenzyl alcohol, 5.0
equiv of NBS, 3 Å MS, ether, -40 oC to -20 oC, overnight. [b] Yields after
separation and NMR ratio.
In conclusion, we prepared a new type of glycosyl donor and
attempted a 1,2-cis glycosylation method. From readily available
glycosyl bromides, through S-glycosylation, protection manipulation,
and lithiation, 1-dihydroxyboryl phenyl and benzyl beta-S-glucosides
as well as 1-dihydroxyboryl benzyl beta-S-galactosides were
efficiently prepared in good yields as starting materials. Activated by
Entry
Donor
ROH
EtOH
Product, yield (alpha:beta) [b]
17, 47% (alpha only)
1
2
7
7
i-PrOH
18, 42% (alpha only)
3

Kimura, M. Sekine, D. Takahashi, K. Toshima, Angew. Chem. Int. Ed. 2013,
52, 12131-12134.
NBS, 1-dihydroxyboryl benzyl S-glucosides served as glycosyl
donors for O-glycosylation. It was found that the boronic acid moiety
was essential in the glycosylation for product formation and good
anomeric ratio. After optimization of the glycosylation step, some
simple 1,2-cis-O-glycosides could be prepared with good to perfect
anomeric ratio. Although there is room to improve the glycosylation
yield and broaden the substrate scope, the preliminary model
reactions suggested that glycosyl aryl boronic acids could be used for
stereoselective glycosylation.
[6]
[7]
(a) G. Chen, X. Gu, L. Chen, X. Wang, Y.-L. Chen, J. Shen, W. Zeng,
Protein and Peptide Letters, accepted for publication; (b) Y.-L. Chen et al,
unpublished results.
1
2
3
4
5
6
7
8
9
Frequently, such activation is not good enough for the generation of a
C-1 leaving group at low temperature, even in the presence of
intracyclic oxygen. With NBS, glycosylation with 1-PhS glycosides
o
proceeds at 25 C. See: (a) K. C. Nicolaou, S. P. Seitz, D. P. Papahatjis, J.
Am. Chem. Soc. 1983, 105, 2430-2434; and this reaction was very slow at
low temperature according to our experiments. Also, the stereochemistry
outcome is not satisfying for most of the examples. The activation of S-
glycosides with NBS is more often associated with an acid, see for
example: (b) Z.-H. Qin, H. Li, M.-S. Cai, Z.-J. Li, Carbohydr. Res. 2002,
337, 31-36; (c) M. Sasaki, K. Tachibana, H. Nakanishi, Tetrahedron Lett.
1991, 32, 6873-6876.
Acknowledgments
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This work was supported by the National Natural Science
[8]
An ate complex may enhance the nucleophilicity of the oxygen: see for
example: (a) S. E. Denmark, G. L. Beutner, Angew. Chem. Int. Ed. 2008, 47,
1560-1638. In carbohydrate chemistry, particular boronates and borinates
were also found to enhance the reactivity of glycosyl acceptors. This was
largely demonstrated by Aoyama et al: (b) K. Oshima, T. Yamauchi, M.
Shimomura, S. Miyauchi, Y. Aoyama, Bull. Chem. Soc. Jpn. 2002, 75,
1319-1324; (c) K. Oshima, Y. Aoyama, J. Am. Chem. Soc. 1999, 121,
2315-2316; (d) K. Oshima, E.-i. Kitazono, Y. Aoyama, Tetrahedron Lett.
1997, 38, 5001-5004; and by Taylor et al: (e) C. A. McClary, M. S. Taylor,
Carbohydr. Res. 2013, 381, 112-122; (f) E. Dimitrijevic, M. S. Taylor,
Chem. Sci. 2013, 4, 3298-3303; (g) D. Lee, C. L. Williamson, L. Chan, M.
S. Taylor, J. Am. Chem. Soc. 2012, 134, 8260-8267; (h) D. Lee, M. S.
Taylor, J. Am. Chem. Soc. 2011, 133, 3724-3727; (i) C. Gouliaras, D. Lee,
L. Chan, M. S. Taylor, J. Am. Chem. Soc. 2011, 133, 13926-13929; (j) L.
Chan, M. S. Taylor, Org. Lett. 2011, 13, 3090-3093; and by Madsen et al:
(k) T. H. Fenger, R. Madsen, Eur. J. Org. Chem. 2013, 26, 5923-5933.
Foundation of China (81102306) and National Science
&
Technology Major Project “Key New Drug Creation and
Manufacturing Program”, China (2012ZX09301001).
References and notes
[1]
[2]
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Molecules of Life, 2nd Edition, Elsevier, Oxford, 2009; (d) Handbook of
Chemical Glycosylation (Eds.: A. V. Demchenko), Wiley-VCH Verlag
GmbH & Co. KGaA, 2008; (e) G.-J. Boons, K. J. Hale, Organic Synthesis
with Carbohydrates, Sheffield Academic Press Ltd, 2008.
For recent discussions and works on this topic, see for example: (a) T. J.
Boltje, T. Buskas, G.-J. Boons, Nat. Chem 2009, 1, 611-622; (b) T. J. Boltje,
J.-H. Kim, J. Park, G.-J. Boons, Nat. Chem 2010, 2, 552-557. (c) T. Fang,
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(e) A.-H. A. Chu, S. H. Nguyen, J. A. Sisel, A. Minciunescu, C. S. Bennett,
Org. Lett. 2013, 15, 2566-2569.
[9]
Both anomers of 15 were prepared from compound 8 according to literature
procedures. For DMF assisted 1,2-cis-glycosylation, see S.-R. Lu, Y.-H. Lai,
J.-H. Chen, C.-Y. Liu, K.-K. T. Mong, Angew. Chem. Int. Ed. 2011, 50,
7315-7320; For experimental details, see supporting information.
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Barresi, O. Hindsgaul, Can. J. Chem. 1994, 72, 1447-1465.
[10] G. H. Veeneman, S. H. van Leeuwen, J. H. van Boom, Tetrahedron Lett.
1990, 31, 1331-1334.
[11] Addition of TfOH could facilitate the departure of the sulphide leaving
group, thus reduced the directing effect of boronic acid. Consequently, the
native reactivity of cyclic carbohydrate led to a 1,2-trans glycoside.
[12] (a) A. Meijer, U. Ellervik, J. Org. Chem. 2004, 69, 6249-6256; (b) A.
Meijer, U. Ellervik, J. Org. Chem. 2002, 67, 7407-7412; (c) K. P. R. Kartha,
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[4]
[5]
For related concepts: a) R. B. Woodward, E. Logusch, K. P. Nambiar, K.
Sakan, D. E. Ward, B. W. Au-Yeung, P. Balaram, L. J. Browne, P. J. Card,
C. H. Chen, et al, J. Am. Chem. Soc. 1981, 103, 3215-3217; b) S. Hanessian,
C. Bacquet, N. Lehong, Carbohydr. Res. 1980, 80, C17-C22; c) M. E.
Behrendt, R. R. Schmidt, Tetrahedron Lett. 1993, 34, 6733-6736; K. L. M.
Hoang, Y. Bai, X. Ge, X.-W. Liu, J. Org. Chem. 2013, 78, 5196-5204.
Supplementary Material
(a) Y. Geng, A. Kumar, H. M. Faidallah, H. A. Albar, I. A. Mhkalid, R. R.
Schmidt, Angew. Chem. Int. Ed. 2013, 52, 10089–10092; (b) A. Kumar, V.
Kumar, R. T. Dere, R. R. Schmidt, Org. Lett. 2011, 13, 3612-3615; c) T.
Experimental details and copies of NMR spectra.
4

Highlights:



1,2-trans-1-dihydroxyboryl benzyl S-glycosides were readily prepared.
From these compounds, glycosylation with simple alcohols gave pure 1,2-cis-O-glycoside outcome.
Boronic acid moiety was found essential for the reaction and the anomeric ratio.

1,2-trans-1-Dihydroxyboryl Benzyl S-Glycoside
as Glycosyl Donor
Xiao Liu, Bingbing Zhang, Xiangying Gu, Guohua Chen, Lin Chen, Xin Wang, Bing Xiong, Qi-Dong You*, Yue-
Lei Chen*, and Jingkang Shen*