Solvent participation in a one-pot glycosylation strategy (SPOG)

Article abstract of DOI:10.1002/adsc.201000888

Solvent participation in a one-pot glycosylation strategy (SPOG) was developed on the basis of the low concentration β-selective glycosylation method. This strategy enables the production of a β-glycosidic bond in a one-pot oligosaccharide synthesis without or with minimal use of any C-2 participating function.

Full text of DOI:10.1002/adsc.201000888

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DOI: 10.1002/adsc.201000888
Solvent Participation in a One-Pot Glycosylation Strategy
(SPOG)
Chin-Sheng Chao,a Yu-Fang Yen,a Wei-Cheng Hung,a
and Kwok-Kong Tony Monga,*
a
Department of Applied Chemistry, National Chiao Tung University, 1001, Ta Hsueh Road, Hsinchu, Taiwan, ROC 300
Fax : (+886)-3572-3764; e-mail: tmong@mail.nctu.edu.tw
Received: November 25, 2010; Revised: January 31, 2011; Published online: April 12, 2011
This paper is dedicated to Prof. Henry N.-C. Wong (CUHK) on occasion of his 60th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000888.
Abstract: Solvent participation in a one-pot glyco-
sylation strategy (SPOG) was developed on the
basis of the low concentration b-selective glycosyla-
tion method. This strategy enables the production
of a b-glycosidic bond in a one-pot oligosaccharide
synthesis without or with minimal use of any C-2
participating function.
construct the 1,2-trans b-glycosidic bond without reli-
ance on any C-2 participating function. A search in
the literature revealed that the solvent effect on reac-
tivity of glycosyl donors has been explored for one-
pot oligosaccharide synthesis, but the participation
effect of an alkyl nitrile solvent on one-pot glycosyla-
tion has not been investigated.[12,13] This lack of infor-
mation motivated us to develop a new one-pot glyco-
sylation strategy on the basis of the LCG method. As
the participation effect of an alkyl nitrile solvent is
explored, we coin this approach as a solvent participa-
tion in one-pot glycosylation (SPOG) strategy.
Keywords: low concentration glycosylation; nitriles;
one-pot process; reactivity-based reaction; solvent
participation
According to the order of solvent addition, two
SPOG procedures were studied (Figure 1). In the first
procedure, all glycosylation steps are performed
Oligosaccharide synthesis involves the coupling of under LCG conditions. As such, oligosaccharides with
carbohydrate units in a regio- and stereospecific 1,2-trans b-glycosidic bonds are prepared (Fig-
manner.[1,2] This process can be accelerated by a one- ure 1a).[10] In the second procedure, CH2Cl2 and a
pot glycosylation strategy[3] and automated solid- conventional substrate concentration are employed
phase synthesis.[4] One-pot glycosylation refers to cas- for the first glycosylation step. Upon completion of
cade coupling of three or more carbohydrate units in this reaction, calculated amounts of CH3CN and
one shot.[5] A key element in these reactions is the EtCN are added to the mixture providing the LCG
stereochemical control of glycosidic bond formation, conditions for the next glycosylation reaction (Fig-
which often relies on traditional methods. A point in ure 1b). The merit of the second procedure is to
case is the use of neighbouring group participation for allow adjustment of the solvent mixture for the con-
the construction of a 1,2-trans b-glycosidic bond.[6] struction of a- and b-glycosidic bonds.
However, such an approach requires the selective in-
Before exploiting the SPOG procedures, it was cru-
troduction of a C-2 participating function and it occa- cial to know if the LCG method would apply to non-
sionally suffers from side reactions that decreases the thioglycoside donors. Thus, perbenzyl thioglucoside 1,
yield of glycosylations.[7,8] Although alternative meth- glucosyl chloride 2, glucosyl trichloroacetimide 3, and
ods are available, only few of them are adapted to glucopyranosyl diphenyl phosphate 4 were prepared
one-pot oligosaccharide synthesis.[9,10]
and were used for glycosylation of the galactosyl ac-
Recently, a low concentration b-selective glycosyla- ceptor 5 (Scheme 1, see Table 1S in the Supporting
tion (LCG) method was developed.[11] This method Information).[14] In brief, glycosylation of 5 with glyco-
makes use of: (i) a CH2Cl2/CH3CN/EtCN solvent syl donor 1, 3 or 4 furnished the desired disaccharide
system; (ii) low substrate concentrations (10–15 mM); 6 in high yield with excellent b-selectivity (a/b 1:>19
and (iii) low reaction temperature (ꢀ70 to ꢀ608C) to based on the anomeric 1H NMR signal at ca.
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Figure 1. Solvent-participation in one pot glycosylation (SPOG) procedures.
5.50 ppm). However, no desired product was detected vent mixture, selected glycosylations were repeated in
for the glycosylation with glycosyl chloride 2. The pure CH2Cl2 (Table 1, entries 5 and 8). Under LCG
configuration of the newly formed glycosidic bond in conditions, glycosylations with the glycosyl phosphate
6 was supported by the 13C NMR chemical shift at donor (4 or 7) furnished the corresponding disacchar-
104.3 ppm and JCH coupling constant of 160 Hz.[11,15] ides in satisfactory 47–77% yields with high to excel-
Based on the results of the investigations, glycosyl lent b-selectivity in the glcyosylation. The a/b anomer
donors 3 and 4 were carried forward for subsequent ratios of the glycosylating products varied from 1:10
studies.
to 1:>19 (Table 1, entries 3, 4, 6, 7 and 9). The config-
In subsequent studies, glucosyl trichloroacetimide 3, uration of the glycosidic bond of the desired b-anom-
glucosyl diphenyl phosphate 4, and galactosyl diphen- ers 12–16 was evidenced by the chemical shift of the
yl phosphate 7 were used as donors for glycosylations anomeric carbons, which lies between 101.6 and
of the thioglycosides 8–11 under LCG conditions 104.2 ppm.[15,17] However, glycosylation of the secon-
(Table 1).[16] To compare the effect of the nitrile sol- dary acceptor 10 with glucosyl trichloroacetimide 3
was not productive and a substantial amount of amide
rearrangement product was formed (Table 1,
entry 2).[17] A concern in the glycosylation of thiogly-
coside is the transfer of a thioacetal function from the
acceptor to the donor.[18,19] Such a transfer reaction
occurred in glycosylations of thioglycosides 9 and 11
when CHCl3 was used as the reaction solvent
(Table 1, entries 5 and 8); nevertheless, this transfer
reaction was greatly reduced under LCG conditions
(Table 1, entries 4 and 7). We attributed this reduction
to the shielding of the oxocarbenium ion by the par-
ticipating nitrile solvent. Encouraged by the results of
the above studies, we carried on to develop the
SPOG strategy for oligosaccharide synthesis. To sim-
plify the investigation, subsequent studies focused on
Scheme 1. Glycosylations of 5 with glucosyl donors 1–4
under LCG conditions.
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Solvent Participation in a One-Pot Glycosylation Strategy (SPOG)
Table 1. Results orthogonal glycosylations of thioglycosyl acceptors 8–11 with glycosyl donors 3, 4 and 7.
Entry
Donor/acceptor
A or B[a]
Product (%, a/b)[b]
Product
17
1
2
3
4
5
6
7
8
9
3/8
3/10
4/8
4/9
4/9
4/10
4/11
4/11
7/8
A
A
A
A
B
A
A
B
12 (77, 1:>19)
14 (30, 1:9)
7
–
6
5
55
8
7
40
–
12 (77, 1:>19)
13 (73, 1:>19)
13 (25, 1:1)
14 (47, 1:10)[c]
15 (74, 1:>19)
not isolable
A
16 (70, 1:>19)
[a]
A refers to the LCG method and B refers to the conventional glycosylation method in CH2Cl2.
[b]
a/b ratios were referred to integral ratios of the tolyl CH3 protons of the a/b anomers at around 2.30 ppm, and a 1:>19
a/b ratio was given when no corresponding signal of the a-anomer was observed.
[c]
1
The H NMR spectrum of a-anomer of 14 is given in the Supporting Information.
the yield and anomeric purity of the glycosylation Accordingly, target 21 was obtained in 55% yield as a
products.
single anomer after chromatographic purification and
Initially, the first SPOG procedure was examined no undesired isomers were detected (Scheme 2).[21]
for synthesis of oligosaccharides 21 and 22. The trisac- The tetrasaccharide 22 was prepared from thiolacto-
charide 21 was prepared from glucosyl diphenyl phos- side 19, thioglucoside 20 and galactosyl acceptor 5 by
phate 4, 2-azido-2-deoxy thioglucoside 18 and galacto- the known reactivity-based one-pot glycosylation.[22,23]
syl acceptor 5 by one-pot orthogonal glycosylation,[20] To effect the reactivity-based glycosylation, the armed
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Chin-Sheng Chao et al.
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Scheme 3. One-pot synthesis of b
by the first SPOG procedure.
G
Scheme 2. One-pot synthesis of oligosaccharides 21 and 22
using the first SPOG procedure.
thiolactoside 19 and disarmed thioglucoside 20 were
designed and they were coupled smoothly under LCG
conditions to give a trisaccharide intermediate.[24] Fur-
ther reaction of the intermediate with 5 furnished the
desired tetrasaccharide 22 (Scheme 2).[25]
As the aforementioned SPOG procedure worked
well for the one-pot three-components system, a one-
pot four-components glycosylation was employed for
synthesis of bACHTUNGTRENNUNG
24 was prepared from glucosyl phosphate 4, armed
thioglucoside 8, disarmed thioglucoside 20, and chlor-
ohexanol 23 by a combined use of the orthogonal and
reactivity-based glycosylation methods (Scheme 3).[24]
To our delight, the desired b
G
tained as a single anomer in 48% yield.[28] Notably, a
previous one-pot synthesis of a similar target fur-
nished a a/b-anomeric mixture with moderate selec-
tivity of glycosylation.[10]
Scheme 4. One pot synthesis of oligosaccharides 28 and 32
by the second SPOG procedure.
After examining the first SPOG procedure, the
second SPOG procedure was explored. Thus, trisac-
charide 28 and tetrasaccharide 32 were selected as the
synthetic targets. The trisaccharide 28 contains an a-
glycosidic bond; therefore, a one-pot cis-trans glycosy- thiofucoside 25 to furnish a disaccharide intermediate
lation is required. The tetrasaccharide 32 is known as (Scheme 4).[30] Being a deoxy sugar, the thiofucoside
lacto-N-neo-tetrose that constitutes the structural unit 25 is far more reactive than thioglucoside 26; as a
in the cell wall of some bacteria species.[29] For the result, it is activated preferentially in the presence of
synthesis of 28, 2-azido-2-deoxy thioglucoside 26 in 25.[22a,b] Upon completion of the glycosylation of 26,
CH2Cl2 solution (40 mM) was firstly glycosylated with CH3CN and EtCN were added to the mixture to pro-
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Solvent Participation in a One-Pot Glycosylation Strategy (SPOG)
J=1 Hz, 1H), 1.77–1.69 (m, 4H, CH2 ꢁ2), 1.46–1.44 (m, 4H,
CH2 ꢁ2), 0.72 (d, J=6 Hz, CH3 ꢁ2); 13C NMR (75 MHz,
CDCl3, 258C): d=166.5 (C=O), 166.3 (C=O), 139.3, 139.0,
138.8, 138.6, 138.5, 137.6, 133.8, 133.5, 130.2, 130.1, 130.02,
130.00, 129.1, 129.0, 128.87, 128.85, 128.77, 128.76, 128.65,
128.59, 128.55, 128.37, 128.26, 128.25, 128.12, 128.09, 127,98,
127.7, 104.5 (C-1’), 103.7 (C-1), 97.1 (C-1’’), 81.4, 79.5, 79.2,
78.1, 76.19, 76.13, 75.8, 75.5, 75.3, 75.2, 74.9, 74.0, 73.7, 73,6,
72.4, 70.2, 67.7, 66.9, 63.7, 63.1, 45.5 (CH2Cl), 32.9, 30.0,
27.1, 26.0, 16.5; HR-MS (ESI): m/z=1402.4464, calcd. for
C80H86ClN3NaO16 [M+Na]+: 1402.5589.
vide LCG conditions for glycosylation of the subse-
quently added acceptor 27. As such, trisaccharide 28
was obtained in 48% yield in one shot.
Regarding the synthesis of 32, thiogalactoside 29,
thioglucoside 30 and lactoside 31 were required
(Scheme 4).[31] Thiogalactoside 29 was innately more
reactive than 30;[32] thus, glycosylation of 29 with 30
furnished a LacNAc intermediate.[22a,b] After the com-
pletion of the first glycosylation, subsequent addition
of the alkyl nitrile solvent mixture, lactoside 31 and
NIS promoter furnished the desired tetrasaccharide
32 in 50% yield after chromatographic purifica-
tion.[33,34]
To summarize, a convenient solvent participation in
one pot glycosylation (SPOG) strategy is reported,
which enables the one-pot synthesis of oligosacchar-
ides without or with minimal use of a C-2 participat-
ing function.
Acknowledgements
Thanks are due to the National Science Council of Taiwan
for financial support (Grant: 99-2113M-009-009) as well as
Prof. Y.-C. Chen (NCTU) and Prof. C.-H. Lin (Academia
Sinica) for mass spectroscopy.
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Typical Second SPOG Procedure for Synthesis of
Trisaccharide 28
A suspension of thiofucoside 25 (147 mg, 0.27 mmol), 2-
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Trisaccharide 28: [a]2D5: ꢀ35.7 (c 0.68 CHCl3); Rf 0.4
(hexane/CH2Cl2/EtOAc/toluene:
8/4/1/1);
1H NMR
(300 MHz, CDCl3): d=8.06 (d, J=9 Hz, 2H, ArH), 7.96 (d,
J=9 Hz, 2H, ArH), 7.61–7.54 (m, 2H, ArH), 7.48–7.20 (m,
32H, ArH), 7.11–7.08 (m, 2H, ArH), 5.76 (d, J=3.6 Hz,
1H, H-1’’), 5.05 (d, J=11 Hz, 1H), 4.99–4.93 (m, 3H), 4.90
(s, 2H), 4.87 (d, J=8 Hz, 1H), 4.82–4.78 (m, 3H), 4.72 (d,
J=11 Hz, 2H), 4.62–4.54 (m, 4H), 4.51–4.46 (m, 1H), 4.37
(d, J=75 Hz, 1H), 4.25 (dd, J=6, 11 Hz, 1H), 4.14 (dd, J=
4, 10 Hz, 1H), 4.00–3.90 (m, 4H), 3.87–3.97 (m, 3H), 3.72–
3.61 (m, 3H), 3.55 (m, 1H), 3.52 (t, J=7 Hz, 2H), 3.31 (d,
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[31] Preparations and references of 29–31 are given in the
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103.5 (C-1) ppm.
[23] Preparations of building blocks 18, 19 and 20 are given
in the Supporting Information.
[34] The yields of oligosaccharide 21, 22, 24, 28 and 32
ranged from 45 to 55%. From TLC examination, the
reactions were relatively clean except for 22 and 24,
wherein a disarmed building block 20 was used. Proba-
bly, building block 20 contains a C-2 benzoyl function
that might cause some side reactions. The formation of
truncated coupling products is possible as the first gly-
cosylation generates small amount of thio-transfer
product that can react with the acceptor. However, we
have not isolated these products as they were minor
components in reaction mixture.
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96.5 ppm (C-1).
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ppm.
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