β-Selective Glycosylation by Using O-Aryl-Protected Glycosyl Donors

Article abstract of DOI:10.1002/asia.201900700

New glycosyl donors have been developed that contained several para-substituted O-aryl protecting groups and their stereoselectivity for the glycosylation reaction was evaluated. A highly β-selective glycosylation reaction was achieved by using thioglycosides that were protected by 4-nitrophenyl (NP) groups, which were introduced by using the corresponding diaryliodonium triflate. Analysis of the stereoselectivities of several glycosyl donors indicated that the β-glycosides were obtained through an S_N2-type displacement from the corresponding α-glycosyl triflate. The NP group could be removed by reduction of the nitro group and acylation, followed by oxidation with ceric ammonium nitrate (CAN).

Full text of DOI:10.1002/asia.201900700

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Accepted Article
Title: β-Selective glycosylation using O-aryl protected glycosyl donors
Authors: Yuji Otsuka, Toshihiro Yamamoto, and Koichi Fukase
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10.1002/asia.201900700
Chemistry - An Asian Journal
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-Selective glycosylation using O-aryl protected glycosyl donors
Yuji Otsuka, [a, b] Toshihiro Yamamoto, [a, b] and Koichi Fukase*[a]
Abstract: Novel glycosyl donors possessing several para-substituted
O-aryl protecting groups that are introduced using diaryliodonium
triflate have been developed, and their glycosylation stereoselectivity
was evaluated. -Selective glycosylation was achieved using
thioglycosides protected by 4-nitrophenyl (NP) groups. Analysis of the
stereoselectivity of several glycosyl donors indicated that -glycosides
are obtained through an SN2-like displacement from the
corresponding -glycosyl triflate. The NP group can be removed by
reduction of the nitro group and acylation, followed by ammonium
hexanitratocerate (IV) (CAN) oxidation.
Introduction
Figure 1. Structure of O-arylated glycosyl donors.
Stereoselective O-glycosylation has attracted great attention
for the efficient synthesis of oligosaccharides.[1] The most widely
Results and Discussion
used method for stereoselective glycosylation is based on the
neighboring group participation of the 2-O-acyl functionality.
However, this protection is unpredictably accompanied by various
To investigate the effect of the presence of para-substituents in
side reactions, such as the formation of glycosyl orthoesters and
the aryl groups on the stereoselectivity of glycosylation, we
migration of the acyl group to both the anomeric center and the
synthesized four different glycosyl donors (Scheme 1). Tetra-O-
glycosyl acceptor. To overcome this issue, various methodologies
4-chlorophenylated thioglycoside
compound 5 by using bis(4-chlorophenyl)iodonium triflate and
Cs2CO3.[7] Tetra-O-4-nitrophenylated thioglycoside
was
prepared using 4-nitrophenylphenyliodonium triflate and tBuOK,
and tetra-O-4-acetamidophenylated thioglycoside 3a and tetra-O-
4-pivaloylaminophenylated thioglycoside 3b were obtained from
2 by reduction of the nitro group and subsequent acylation.
Pivaloylaminophenylated derivative 3b was soluble in
dichloromethane, whereas acetamidophenylated donor 3a was
not soluble in dichloromethane and, therefore, could not be used
1 was synthesized from
have been developed for the efficient and stereocontrolled
synthesis of oligosaccharides using different 2-O-protecting
groups. 2-O-ortho-cyanobenzyl,[2] 2-O-ortho-nitrobenzyl,[3] and 2-
O-picolyl groups[4] have been used for 1,2-trans glycosylation,
and several sulfide auxiliaries[5] as well as intramolecular aglycon
delivery (IAD)[6] are applicable to 1,2-cis glycosylation reactions.
The use of O-aryl groups for hydroxy protection has rarely been
explored because of the lack of suitable protection methods
(Figure 1). Recently, several synthetic methods for the O-arylation
of carbohydrates have been reported, which provides access to
the obtained arylated carbohydrates as unprecedented
derivatives of biomolecules and glycosyl donors.[7-10] Herein, we
describe the first use of O-aryl groups as stereodirecting
substituents for the formation of the 1,2-transglycosidic linkage.
2
for
the
glycosylation
reaction.
Finally,
was synthesized from
1 by Pd catalyzed Buchwald methoxylation
tetra-O-4-
methoxyphenylated thioglycoside
thioglycoside
method.[11]
4
The stereoselectivity of the glycosylation was then investigated
using benzyl alcohol 8 as a glycosyl acceptor under several
conditions (Table 1). In procedure A, a mixture containing a
glycosyl donor and the glycosyl acceptor was reacted with N-
iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH)
at –20 °C. In procedure B, a similar mixture was treated with
Me2S2-Tf2O reagent at –40 °C. [12] In procedure C, the glycosyl
donor was first pre-activated with diphenylsulfoxide (Ph2SO) and
trifluoromethanesulfonic anhydride (Tf2O) in the presence of tri-
tert-butylpyrimidine (TTBP) at –60 °C and then the glycosyl
acceptor was added to the mixture.[13]
[a]
[b]
Prof. K. Fukase
Department of Chemistry, Graduate School of Science
Osaka University
Machikaneyama 1-1, Toyonaka
Osaka 560-0043 (Japan)
FAX: (+81)6-6850-5419
E-mail : koichi@chem.sci.osaka-u.ac.jp
Dr. Y. Otsuka, Dr. T. Yamamoto
Peptide Institute, Inc.
Saito-Asagi 7-2-9, Ibaraki
Osaka 567-0085 (Japan)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Scheme 1. Syntheses of tetra-O-arylated thioglycosides.
Table 1. Glycosylation of O-aryl protected thioglycosides.
Glycosylation of 4-chlorophenyl (4-ClPhe) protected glycosyl
donor 1 by procedures A and B afforded benzyl glycoside 9 with
low stereoselectivity (Entries 1 and 2). On the contrary, the
glycosylation by procedure C furnished the desired product in
good yield with high -selectivity (Entry 3). 4-Methoxyphenyl (MP)
protected thioglycoside 4 was smoothly activated by procedure A
to give benzyl glycoside 10 in good yield (Entry 4). However, when
using procedure B and C, the presence of a powerful electrophilic
reagent resulted in the modification of the MP moiety in 4 without
getting desired compound 10 (Entries 5 and 6). The glycosylation
of 4-pivaloylaminophenyl (PAP) protected thioglycoside 3b gave
the desired product 11 with low stereoselectivity by procedure A
(Entry 7) and with high -selectivity by procedure B (Entry 8),
whereas procedure C caused decomposition of 3b due to the
activation of the amide moiety in the PAP group (Entry 9). 4-
Nitrophenyl (NP) protected thioglycoside 2 showed high -
selectivity in procedure A (Entry 10) and the use of procedure B
led to an improvement of the -selectivity (Entry 11). Moreover,
the glycosylation of 2 by procedure C afforded the desired product
12 in good yield with exceptionally high -selectivity (Entry 12). In
general, the -selectivity was found to increase as the
temperature decreased, which suggests that the glycosylation
proceeds most likely via an SN2-like reaction of the -glycosyl
triflate intermediates. It was also apparent that the electron-
withdrawing character of the phenyl groups affected the selectivity
of glycosylation.
Entry
Donor
Method
Products
Isolated
yield
/
Ratio
1
2
3
A[a]
B[b]
C[c]
9
9
9
65%
64%
83%
1 : 1.2
1 : 1.4
1 : 7.5
R =
R =
1
4
4
5
A
B
C
A
B
C
A
B
C
10
10
10
11
11
11
12
12
12
86%
0%
1 : 1.2
-
6
0%
-
7
55%
57%
0%
1 : 1.5
1 : 7.3
-
R =
8
3b
9
10
11
12
70%
72%
87%
1 : 5.7
1 : 9.3
1 : 27
R =
2
[a] Procedure A : NIS, TfOH, –20 °C. [b] Procedure B : Me2S2-Tf2O, –40 °C.
[c] Procedure C : Ph2SO, Tf2O, TTBP, –60 °C.
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Since the electronic environment of the anomeric position can
be assessed by the chemical shift of the anomeric proton
observed in the H-NMR spectra, the stereoselectivity outcomes
Table 2. Glycosylation of NP protected thioglycosides.
1
were plotted against the chemical shift values of the 1-proton of
thioglycosides 1, 2, 3b, and 4 (Figure S1). From this result, it can
be extracted that the chemical shifts of the 1-proton were
downfield shifted as the electron-withdrawing effect of the
protecting group increased; thus, the 1-proton of the compound
bearing NP appeared at 4.98 ppm, that with PAP at 4.87 ppm,
with 4-ClPhe at 4.85 ppm, and with MP at 4.85 ppm. The -
selectivity was found to increase linearly as the chemical shifts
increased.
Wong et al. reported the correlation between the chemical shifts
of the anomeric protons and the reactivity of the glycosyl
donors.[14] For example, glycosyl donors possessing upfield-
shifted anomeric protons showed high reactivity. On the other
hand, the relationship between the stereoselectivity and the
chemical shift of the proton has been rarely reported. Jensen et
al. reported the effect of para-substituted benzyl-type protecting
groups on the reactivity of thioglycoside glycosyl donors; glycosyl
donors having electron-donating substituents showed higher
reactivity than those having electron-withdrawing substituents,
whereas the β-selectivity decreased by protection with substituted
benzyl groups having electron-withdrawing groups.[15] Notably,
our results regarding the stereoselectivity reveal the opposite
tendency, and the glycosyl donor having NP groups exhibited the
highest β-selectivity.
Entry
Acceptor
Products
Isolated
yield
/
Ratio
1
2
3
4
benzyl alcohol 8
methanol 13
R = Bn 12
87%
80%
77%
62%
1 : 27
1 : 30<
1 : 30<
1 : 30<
R = Me 25
1-butanol 14
R = Bu 26
R =
15
27
28
5
6
7
Cyclohexanol 16
R =
R =
R =
80%
77%
91%
1 : 30<
1 : 30<
1 : 13
1-Adamantanol 17
29
18
19
20
The scope and limitations of the glycosylation using the NP
protected glycosyl donor 2 were then investigated by using
methanol 13, 1-butanol 14, glycerol derivative 15, cyclohexanol
16, 1-adamantanol 17, galactopyranose 18, glucopyranoside 19,
another glucopyranoside 20, fucopyranoside 21, serine derivative
22, glucofuranose 23, and 2,2,2-trifluoroethanol (TFE) 24 as
glycosyl acceptors (Table 2). The glycosylation of 13, 14, and 15,
which have a primary hydroxy group, afforded the desired
products 25, 26, and 27 in high yields with high -selectivities
(Entries 2-4). The glycosylation of acceptors 16 and 17 having
secondary and tertiary hydroxy groups also proceeded smoothly
to give compound 28 and 29 with high -selectivities in good
yields (Entries 5, 6). The glycosylation of several sugars 18, 19,
20, and 21, and serine 22 gave the desired disaccharides 30-33
and sugar amino acid 34, respectively, in moderate yields with
high -selectivities (Entries 7-11). Conversely, the glycosylation
of glucofuranose 23 and TFE 24 showed -selectivities probably
owing to the low nucleophilicity of acceptors (Entries 12, 13).[16]
To elucidate the mechanism of this -selective reaction, we
examined the glycosylation with several glycosyl donors (Table 3).
The glycosylation with benzyl protected thioglycoside 37 as a
reference in procedure C, was carried out to afford product 43 with
low stereoselectivity (Entry 1). The glycosylation reactions using
partially NP protected glycosyl donors were then examined
(Entries 2-4). It was found that the glycosylation of mono-O-NP
protected thioglycoside 38 and di-O-NP protected thioglycoside 7
proceeded with low and moderate -selectivity, respectively. In
contrast, with tri-O-NP protected thioglycoside 39 afforded 46 with
high -selectivity.
30
8
R =
R =
R =
R =
R =
65%
68%
57%
46%
48%
1 : 30<
1 : 25
31
9
32
10
11
12
1 : 7.8
1 : 30<
3.6 : 1
21
33
22
34
23
24
35
13
R =
83%
2.5 : 1
36
The anomer ratio was determined by HPLC (UV350 nm).
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The proposed reaction mechanism is described in Scheme 2,
according to which the electron-withdrawing NP groups
destabilize the oxocarbenium ion and promote the formation of an
-glycosyl triflate. The glycosylation proceeds via SN2-like
displacement of the -glycosyl triflate, affording high β-selectivity.
On the other hand, electron-donating groups such as MP stabilize
the oxocarbenium ion and promote the SN1 pathway, resulting in
low selectivity. Therefore, it can be concluded that the
stereoselectivity of the glycosylation can be controlled by the
substituents on the aryl protecting groups.
Table 3. Glycosylation of several glycosyl donors.
Entry
1[a]
Donor
Products
Isolated
yield
/
Ratio
85%
65%
77%
58%
88%
1 : 1.9
1 : 1.2
1 : 4.0
1 : 16
1 : 1.2
37
38
7
43
44
45
46
2[a]
3[a]
4[a]
5[a]
Scheme 2. Proposed reaction mechanism.
Finally, we investigated the removal of the NP group from
compound 31 (Scheme 3). Thus, reduction of the nitro moiety of
31 with zinc afforded aminophenyl derivative 49.[18] Next, we
tested the oxidative cleavage of the aminophenyl group by using
39
ammonium
hexanitratocerate
(IV)
(CAN),
however,
decomposition of the electron-rich aminophenyl group occurred.
Then we examined the acetamidophenyl group as deprotection
substrate. Acetamidophenyl derivative 51 was obtained from
compound 31 in good yield by reduction of the nitro groups
followed by acetylation. Cleavage of the acetamidophenyl group
by CAN and subsequent acetylation of the hydroxy groups
proceeded smoothly to give the desired compound 52 in good
yield.
40
41
42
47
48
12
6[a]
92%
51%
1.3 : 1
7[b]
1 : 6.0
[a] Ph2SO, Tf2O, TTBP, –60 ºC. [b] BF3·OEt2, –60 ºC.
On the other hand, NP protected galactosyl donor 40 or
mannosyl donor 41 afforded the desired products with low
stereoselectivities following procedure C, due to the steric effects
of axial hydroxy groups (Entries 5, 6). For 2,2,2-trifluoro-N-phenyl
acetimidate donor[17] 42, the glycosylation was carried out in the
presence of a non-triflate based Lewis acid (Entry 7). The
moderate -selectivity was obtained through activation with
BF3·OEt2 via SN2-like displacement of -glycosyl imidate.
These results indicated that the β-selectivity increased with the
number of NP groups. Furthermore, a linear correlation was
observed between -selectivity and the chemical shifts of the
anomeric protons of thioglysides 2, 37, 38, and 39, but not of 7,
40, 41 having different steric environments (Figure S2).
Scheme 3. Removal of NP group.
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2011, 50, 11872-11923; c) J. Guo, X-S. Ye, Molecules 2010, 15, 7235-
7265.
Conclusions
[2]
a) K. L. M. Hoang, X-W. Liu, Nat. Commun. 2014, 5, 5051; b) S. Buda,
M. Nawꢀj, P. Gołębiowska, K. Dyduch, A. Michalak, J. Mlynarski, J. Org.
Chem. 2015, 80, 770-780.
In summary, we have developed several O-aryl-protected
glycosyl donors and investigated their stereoselectivity in the
glycosylation reaction. In particular, NP protected thioglycoside
showed high -selectivity at low temperature, which indicates that
the reaction probably proceeds via an SN2-type reaction that
involves an -glycosyl triflate. Finally, the NP group can be
removed by reduction of the nitro group and acylation, followed
by CAN oxidation. Further studies on the reactivity of O-arylated
glycosyl donors and their application are currently in progress in
our laboratory.
[3]
[4]
[5]
[6]
S. Buda, P. Gołębiowska, J. Mlynarski, Eur. J. Org. Chem. 2013, 3988-
3991.
J. T. Smoot, P. Pornsuriyasak, A. V. Demchenko, Angew. Chem. Int. Ed.
2005, 44, 7123-7126.
J-H. Kim, H. Yang, J. Park, G-J. Boons, J. Am. Chem. Soc. 2005, 127,
12090-12097.
a) F. Barresi, O. Hindsgaul, J Am Chem Soc. 1991, 113, 9376-9377; b)
G. Stork, G. Kim, J. Am. Chem. Soc. 1992, 114, 1087-1088; c) C. M. P.
Seward, I. Cumpstey, M. Aloui, S. C. Ennis, A. J. Redgrave, A. Fairbanks,
J. Chem. Commun. 2000, 1409-1410; d) Y. Ito, T. Ogawa, Angew. Chem.
Int. Ed. 1994, 33, 1765-1767; e) A. Ishiwata, Y. Munemura, Y. Ito, Eur J.
Org Chem. 2008, 4250-4263.
Experimental Section
[7]
[8]
[9]
G. L. Tolnai, U. J. Nilsson, B. Olofsson, Angew. Chem. Int. Ed. 2016, 55,
11226-11230.
The synthetic procedures and characterization of the compounds studied
herein can be found in the Supporting Information.
V. Dimakos, E. Graham, G. E. Garrett, M. S. Taylor, J. Am. Chem. Soc.
2017, 139, 15515-15521.
W. Shang, Z-D. Mou, H. Tang, X. Zhang, J. Liu, Z. Fu, D. Niu, Angew.
Chem. Int. Ed. 2018, 57, 314-318.
[10] Y. Otsuka, T. Yamamoto, K. Fukase, Synlett 2018, 29, 1510-1516.
[11] C. W. Cheung, S. L. Buchwald, Org. Lett. 2013, 15, 3998-4001.
[12] J. Tatai, P. Fügedi, Org. Lett. 2007, 9, 4647-4650.
[13] J. D. C. Codée, R. E. J. N. Litjens, R. den Heeten, H. S. Overkleeft, J. H.
van Boom, G. A. van der Marel, Org. Lett. 2003, 5, 1519-1522.
[14] Z. Zhang, I. R. Ollmann, X-S. Ye, R. Wischnat, T. Baasov, C-H. Wong,
J. Am. Chem. Soc. 1999, 121, 734-753.
Acknowledgements
We are grateful to Dr. Kazuya Kabayama, Dr. Atsushi
Shimoyama, and Dr. Yoshiyuki Manabe of Osaka University, for
their helpful discussions.
[15] M. Heuckendorff, L. T. Poulsen, H. H. Jensen, J. Org. Chem. 2016, 81,
4988-5006.
Keywords: Glycosylation • O-aryl protection • 4-nitrophenyl
[16] S. van der Vorm, T. Hansen, H. S. Overkleeft, G. A. van der Marel, J. D.
C. Codeé, Chem. Sci. 2017, 8, 1867-1875.
group
[17] B. Yu, H. Tao, Tetrahedron Lett. 2001, 42, 2405-2407.
[18] K. Fukase, T. Yasukochi, Y. Nakai, S. Kusumoto, Tetrahedron Lett. 1996,
37, 3343-3344.
[1]
a) X. Zhu, R. R. Schmidt, Angew. Chem. Int. Ed. 2009, 48, 1900-1934;
b) C-H. Hsu, S-C. Hung, C-Y. Wu, C-H. Wong, Angew. Chem. Int. Ed.
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10.1002/asia.201900700
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FULL PAPER
Glycosylation using O-aryl protected
glycosyl donors is described. Highly -
selective glycosylation was achieved
using 4-Nitrophenyl (NP) protected
thioglycosides. Because increasing the
electron-withdrawing property of the O-
aryl groups enhances -selectivity,
glycosylation probably proceeds via
SN2-like displacement from the
corresponding -glycosyl triflate.
Yuji Otsuka, Toshihiro Yamamoto,
Koichi Fukase*
Page No. – Page No.
-Selective glycosylation using O-aryl
protected glycosyl donors
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