Full text of DOI:10.1007/s11172-016-1654-y

Russian Chemical Bulletin, International Edition, Vol. 65, No. 11, pp. 2776—2778, November, 2016
2776
Glycosylation of dibutyl phosphate anion with arabinofuranosyl bromide:
unusual influence of concentration of the reagents on the ratio
of anomeric glycosyl phosphates formed*
D. A. Ahiadorme,a,b N.M. Podvalnyy,a A. V. Orlova,a A. O. Chizhov,a and L. O. Kononova
аN. D. Zelinsky Institute of Organic Chemistry of Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: (499) 135 5328. Eꢀmail: kononov@ioc.ac.ru, leonid.kononov@gmail.com
bM. V. Lomonosov Moscow State University, Chemistry Department,
Build. 3, 1 Leninsky Gory, 119991 Moscow, Russian Federation
Glycosyl phosphates are widely used building blocks in
of glycosyl bromide 1 (while keeping the molar ratio beꢀ
tween all reagents constant) leads to an increase in the
reaction stereoselectivity in favor of the αꢀanomer 2a.
A more detailed study of the concentration dependence
of the stereoselectivity in a wide range of concentrations of
glycosyl bromide 1 (0.001—0.2 mol L–1) revealed that the
anomeric ratio of glycosyl phosphates 2 depends on conꢀ
centration of the reaction mixture in a complex manner
(Table 1, Fig. 1). While in the most concentrated solution
(с = 0.2 mol L–1) the glycosylation proceeds unselectively
(α/β = 1.5 : 1), upon transition to more diluted solutions
the share of αꢀanomer 2a increases, reaching a high value
(α/β = 20 : 1) at с = 0.01 mol L–1. Upon a further deꢀ
crease of concentration of glycosyl bromide 1 the stereoꢀ
selectivity increases sharply (Table 1, Fig. 1) and the reacꢀ
tion becomes virtually stereospecific (α/β > 50 : 1).
the synthesis of various natural products, for example,
nucleoside diphosphates,1—3 proteophosphoglycans,4 and
Сꢀ and Оꢀalkyl(aryl) glycosides5,6. Strategies of oligoꢀ
saccharide synthesis using glycosyl phosphates as glycosyl
donors7,8 were developed for various sugars (for example,
derivatives of mannose,9 sialic acids10 and arabinofuraꢀ
nose11).
Several known methods for the synthesis of the glycoꢀ
syl phosphates are based on glysosylation reaction as the
key step.3,12,13 During the synthesis (Scheme 1) of dibutyl
(2,3,5ꢀtriꢀOꢀbenzoylꢀDꢀarabinofuranosyl) phosphate (2) by
glycosylation of dibutyl phosphoric acid ((BuO)2P(O)OH)
with 2,3,5ꢀtriꢀOꢀbenzoylꢀαꢀDꢀarabinofuranosyl bromide
(1)14 in MeCN in the presence of Pri2NEt15 we found that
concentration of the reagents influences the anomeric ratio
of glycosyl phosphates 2. A decrease of concentration (c)
A considerable influence of concentration of reagents
on the outcome of glycosylation has been reported in sevꢀ
eral cases,16—20 both the product yield16c,e,f,17,18 and
stereoselectivity16e,f,17—20 as well as the reactivity16e,f,17 of
the glycosyl donor being affected by dilution of the reacꢀ
Scheme 1
α/β
200
150
100
50
Reagents and conditions: (BuO)2P(O)OH, Pri2NEt, MeCN, 2 h,
20 °C.
0
0
0.05
0.10
0.15
c/mol L–1
* Dedicated to Academician of the Russian Academy of Sciences
O. M. Nefedov on occasion of his 85th birthday.
Fig. 1. Dependence of the anomeric ratio (α/β) of glycosyl phosꢀ
phates 2 on the concentration (c) of glycosyl bromide 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2776—2778, November, 2016.
1066ꢀ5285/16/6511ꢀ2776 © 2016 Springer Science+Business Media, Inc.

Anomeric ratio of arabinofuranosyl phosphates
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 11, November, 2016 2777
Table 1. Influence of concentration of glycosyl bromide 1 on the
outcome of glycosylation
culated for C34H39NaO11P+: 677.2122. 1H NMR (300 MHz,
CDCl3), δ: 0.84—0.98 (m, 6 H, Bun); 1.32—1.49 (m, 4 H, Bun);
1.55—1.76 (m, 4 H, Bun); 4.15 (qd, 4 H, BunO, J = 6.7 Hz,
J = 3.8 Hz); 4.72 (dd, 1 H, H(5a), J = 13.0 Hz, J = 6.5 Hz);
4.78—4.86 (m, 2 H, H(4), H(5b)); 5.61 (d, 2 H, H(3), J = 3.9 Hz);
5.69 (s, 2 H, H(2)); 6.09 (d, 1 H, H(1), J = 5.0 Hz); 7.25—7.34
(m, 2 H, Ph); 7.37—7.55 (m, 5 H, Ph); 7.56—7.65 (m, 2 H, Ph);
7.98—8.06 (m, 4 H, Ph); 8.06—8.13 (m, 1 H, Ph). 13C NMR
(75 MHz, CDCl3), δ: 13.5, 18.6, 32.1, 32.2 (Bun); 63.4 (C(5)); 67.8
(d, BunO (1), J = 5.5 Hz); 67.9 (d, BunO (2), J = 5.5 Hz); 77.2
(C(3)); 82.0 (d, C(2), J = 11.1 Hz); 83.2 (C(4)); 102.8 (d, C(1),
J = 5.3 Hz); 128.3, 128.5, 128.5, 129.7, 129.9, 133.1, 133.6 (Ph);
165.0, 165.6, 166.0 (CO). 31P NMR (121 MHz, CDCl3), δ: –3.2.
Dibutyl (2,3,5ꢀtriꢀOꢀbenzoylꢀβꢀDꢀarabinofuranosyl) phosꢀ
phate (2b), Rf 0.21 (EtOAc—toluene, 1 : 5.7 (v/v)). 1H NMR
(300 MHz, CDCl3), δ (selected signals): 5.99—6.06 (m, 1 H,
H(2)); 6.26 (dd∼t, 1 H, H(1), J = 5.0 Hz). 13C NMR (75 MHz,
CDCl3), δ: 65.3 (С(5)); 75.0 (С(3)); 79.7 (С(4)); 97.7 (d, С(1),
J = 4.8 Hz). 31P NMR (121 MHz, CDCl3), δ: –2.4.
[1]/(mol L–1 a
)
2a/2b (α/β)b
Yield 2 (%)
0.001
0.002
0.005
0.01
0.02
0.05
0.1
232c
154c
55c
20
11.8
6.7
76
75
78
75
75
77
82
85
2.5
1.5
0.2
a In all experiments the same amount of glycosyl bromide 1
(50 mg, 95 μmol) was used. Concentration of the other reagents
was proportional to the concentration of 1 (molar ratio
1 : Pri2NEt : (BuO)2P(O)OH = 1 : 4 : 4). b Anomeric ratio of the
glycosyl phosphate 2 (α/β) was calculated by integration of the
signals of αꢀ and βꢀanomers of glycosyl phosphates 2 in 31P NMR
spectra of the reaction mixtures after work up. c In the low conꢀ
centration range (0.001—0.005 mol L–1), integration of the sigꢀ
nal of βꢀanomer 2b was not precise due to a low signalꢀtoꢀnoise
ratio. At the same time, in the 31P NMR spectra, the intensity of
the signal of βꢀanomer 2b significantly decreases upon dilution
of the reaction mixture.
This work was supported by the Russian Science Founꢀ
dation (Project No. 16ꢀ13ꢀ10244).
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ararbinofuranosyl bromide 1 can be related to a change in
the glycosylation mechanism15,21 or a change in the strucꢀ
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To a solution of 2,3,5ꢀtriꢀOꢀbenzoylꢀαꢀDꢀarabinofuranosyl
bromide (1) (50 mg, 0.095 mmol) in anhydrous MeCN (half of
the volume, required to obtain the desired concentration (see
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77 μL) and Pri2NEt (0.38 mmol, 66 μL) in the second half of the
required volume of anhydrous MeCN was added. The reaction
mixture was stirred at ∼20 °С for 2 h. Then saturated aqueous
NaHCO3 (15 mL) was added and the resulting mixture was exꢀ
tracted with toluene (3×20 mL). The combined organic layer
was washed with saturated aqueous NaHCO3 (20 mL) and filꢀ
tered through a layer of Na2SO4 (∼10 mm). The filtrate was
concentrated in vacuo on a waterꢀaspirator pump, the residue was
dried in vacuo on an oil pump. The obtained mixture of the αꢀ and
βꢀglycosyl phosphates 2a and 2b was analyzed by NMR and
TLC on silica gel; yields and anomeric ratios are listed in Table 1.
Dibutyl (2,3,5ꢀtriꢀOꢀbenzoylꢀαꢀDꢀarabinofuranosyl) phosꢀ
phate (2a), Rf 0.32 (EtOAc—toluene, 1 : 5.7 (v/v)), [α]D21 –14.4
(c 1.0, CHCl3). Massꢀspectrum: m/z 677.2118 [M + Na]+. Calꢀ

2778
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Received September 21, 2016;
in revised form October 4, 2016