A simple method for the preparation of glycosyl isothiocyanates

Article abstract of DOI:10.1055/s-2006-926359

Glycosyl isothiocyanates became accessible from the corresponding peracetylated sugars in one step, by application of trimethylsilyl isothiocyanate and a Lewis acid in dichloromethane at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926359

SHORT PAPER
949
A Simple Method for the Preparation of Glycosyl Isothiocyanates
G
lycosyl
I
sothiocyana
a
rt
c
edSugar
s
o Kühne,a Zoltán Györgydeák,b Thisbe K. Lindhorst*a
a
b
Received 26 August 2005; revised 6 October 2005
best promotor. The reaction is carried out at room temper-
ature and the product is obtained after an easy standard
workup. The scope of this method was tested with eight
different peracetylated sugars (Table 1).
Abstract: Glycosyl isothiocyanates became accessible from the
corresponding peracetylated sugars in one step, by application of
trimethylsilyl isothiocyanate and a Lewis acid in dichloromethane
at room temperature.
Key words: carbohydrates, isothiocyanates, disaccharides, ano-
meric purity, glycomimetics
OAc
O
OAc
O
SnCl4, TMSSCN
CH2Cl2, r.t.
AcO
AcO
AcO
AcO
NCS
OAc
OAc
OAc
Isothiocyanates are versatile reagents in organic chemis-
try since they easily undergo many important reactions,
such as cycloaddition and nucleophilic addition reac-
tions.1 Glycosyl isothiocyanates2 are used for the prepara-
tion of a variety of carbohydrate derivatives of synthetic,
biological and pharmaceutical interest.3 For example, they
serve as glycosidase inhibitors4 and for the synthesis of
glycosyl thiourea derivatives,5 glycosylamino heterocy-
cles,6 nucleoside analogues,7,8 N-glycopeptides,9 or glyco-
dendrimers.10
Scheme 1
The procedure was applicable to standard hexoses, deoxy
sugars, pentoses as well as disaccharides, showing that the
interglycosidic bond is not sensitive to the applied reac-
tion conditions. In Table 1, the results obtained with this
new method starting from the peracetylated sugars, are
compared to those obtained with the melting method,
which starts with the acetyl-protected glycosyl bro-
mides.16 Using the TMSSCN method, yields for the most
part higher than those reported earlier16 were obtained,
ranging from 41% to 86%, while one step less is required
for the new synthetic pathway. Significant NMR data
(H-1, C-1, NCS) are compared to those reported. The
stereochemical outcome of the SnCl4-promoted reaction
is mostly in agreement with the results obtained under
melting conditions, which clearly provide thermodynamic
control of the reaction. However, in the case of D-arabi-
nose (entry 6) a 2:3-anomeric a,b-mixture was obtained
with TMSSCN, whereas melting the respective arabinosyl
bromide surprisingly led to the a-isothiocyanate as the
only product.16 Moreover, in the case of L-fucose (entry 4)
mainly the a-configured product was obtained, starting
from fucose peracetate, while the melting reaction gave
the b-fucosyl isthiocyanate. The two fucosyl anomers can
be distinguished without any problems by their anomeric
coupling constants J1,2. It can be assumed that the two re-
actions, which are compared in Table 1, proceed via dif-
ferent mechanisms, which remain to be investigated.
Nevertheless, it may be considered as advantageous to use
either one or the other approach for the stereoselective
preparation of either a- or b-fucosyl isothiocyanates, re-
spectively.
Almost a century ago, E. Fischer reported the synthesis of
O-acetylated glycosyl isothiocyanates from the corre-
sponding glycosyl bromides using silver thiocyanate.11
However, due to the ambident character of the thiocyanate
anion, the isomeric glycosyl thiocyanates are often ob-
tained as side products of the reaction,12 causing a severe
purification problem. Therefore, a variety of alternative
methods for the preparation of glycosyl isothiocyanates
has been published over the years, such as treatment of
glycosylamines with thiophosgene,13 the reaction of gly-
cals with isothiocyanate derivatives,14 and the reaction of
glycosyl halides with less expensive thiocyanate salts
such as lead thiocyanate8 or potassium thiocyanate under
phase-transfer catalysis,15 or melting KSCN with the per-
acetylated glycosyl bromides.16
In the course of our studies on the synthesis of oligosac-
charide mimetics, we developed a simple method for the
preparation of O-protected lactosyl isothiocyanate, start-
ing from the corresponding peracetylated sugar.17 Herein
we describe the broad applicability of this short synthesis,
which delivers various glycosyl isothiocyanates from the
acetylated precursors by application of trimethylsilyl
isothiocyanate (TMSSCN) under Lewis acid catalysis in
dichloromethane (Scheme 1). From all Lewis acids inves-
tigated for this reaction, tin tetrachloride proved to be the
In conclusion, a mild one-step procedure for the synthesis
of a variety of glycosyl isothiocyanates is reported, which
might be also sufficient for oligosaccharides and sugar de-
rivatives with a sophisticated protecting-group pattern,
thus facilitating the synthesis of spacer-modified glyco-
mimetics.
SYNTHESIS 2006, No. 6, pp 0949–0951
x
x
.
x
x
.2
0
0
6
Advanced online publication: 27.02.2006
DOI: 10.1055/s-2006-926359; Art ID: T11505SS
© Georg Thieme Verlag Stuttgart · New York

950
M. Kühne et al.
SHORT PAPER
Table 1 Glycosyl Isothiocyanates 1–8a
Entry
1
Glycosyl isothiocyanates
Anomeric
ratiob
Yield
(%)
1H NMR data
H-1 [ppm] (J1,2[Hz])
13C NMR data
dC-1, dNCS [ppm]
d
OAc
found:
only b
only b
51
60
5.03 (8.3) (b)
5.02 (8.2) (b)
83.43, 144.18 (b)
83.47, 144.22 (b)
O
AcO
reported:
AcO
NCS
OAc
OAc
2
3
found:
only a
only a
70
57
5.57 (2.0) (a)
5.55 (2.0) (a)
82.77, 144.20 (a)
OAc
O
AcO
reported:
82.81, 144.17 (a)
(JC-1,H-1 172.6 Hz)c
AcO
NCS
found:
a/b (1:8)
a/b (1:9)
a/b (8:1)
69
57
65
5.00 (8.8) (b)
5.91 (3.8) (a)
83.93, 143.73 (b)
83.65, 144.27 (a)
OAc
AcO
O
AcO
NCS
reported:
found:
4.98 (8.6) (b)
5.90 (4.0) (a)
83.96, 143.70 (b)
82.72, 144.26 (a)
OAc
4
5
6
7
8
5.85 (4.2) (a)
4.97 (8.8) (b)
82.93, 143.21 (a)
83.98, 143.21 (b)
NCS
OAc
O
OAc
OAc
reported:
found:
only b
only a
only a
51
86
41
4.97 (8.6) (b)
5.47 (1.2) (a)
5.47 (1.5) (a)
84.02, 143.21 (b)
82.78, 143.11 (a)
NCS
O
reported:
82.96, 143.33 (a)
(JC-1,H-1 175.1 Hzb)
AcO
AcO
O
OAc
found:
a/b (1:1.6)
68
5.86 (1.5) (b)
5.01 (6.0) (a)
82.95, 142.31 (b)
83.23, 143.71 (a)
NCS
OAc
OAc
OAc
reported:
found:
only a
only b
only b
74
41
53
5.01 (6.1) (a)
4.97 (8.7) (b)
4.97 (8.7) (b)
82.90, 141.17 (a)
83.33, 144.08 (b)
83.36, 144.08 (b)
OAc
O
OAc
O
AcO
reported:
O
AcO
NCS
AcO
OAc
OAc
OAc
found:
only b
only b
49
41
4.99 (8.4) (b)
4.98 (8.1) (b)
83.35, 144.15 (b)
83.29, 144.01 (b)
OAc
AcO
AcO
O
reported:
O
O
NCS
AcO
OAc
OAc
a Reported values are from reference 16.
b Anomers could be separated by flash chromatography.
c Obtained from the gated decoupled NMR spectrum.
1
The H and 13C NMR data were recorded in CDCl3 on a Bruker
spectrometer ARX 300 or on a Bruker DRX 500. As internal stan-
dard TMS was used. TLC was performed on Merck silica gel plates
GF 245 with detection under UV light. Flash column chromatogra-
phy was performed on silica gel 60 (ICN, 0.032–0.063 mm).
Acknowledgment
We acknowledge support of our work by the Fonds of the German
Chemical Industry (FCI) and the Alexander von Humboldt Found-
ation.
Glycosyl Isothiocyanates; General Procedure
References
The fully acetylated sugar (0.5 mmol) and SnCl4 (0.5 mL, 1 M soln
in anhyd CH2Cl2) were dissolved in anhyd CH2Cl2 (3 mL). After 5
min TMSSCN (0.55 mmol) was added and the reaction mixture was
stirred at r.t. for 2 d. Then, sat. aq NaHCO3 soln was added and the
aqueous phase was extracted with CH2Cl2. The combined organic
phases were washed with H2O (10 mL), dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel with cyclohexane–
EtOAc–CH2Cl2 (1:1:1) as the eluent in all the cases reported here.
(1) Mukerjee, A. K.; Ashare, R. Chem. Rev. 1991, 91, 1.
(2) (a) Witczak, Z. J. Adv. Carbohydr. Chem. Biochem. 1986,
44, 91. (b) García Fernández, J. M.; Ortiz Mellet, C. Adv.
Carbohydr. Chem. Biochem. 1999, 55, 35.
(3) (a) Reitz, A. B.; Tuman, R. W.; Marchione, C. S.; Jordan, A.
D. Jr.; Bowden, C. R.; Maryanoff, B. E. J. Med. Chem. 1989,
32, 2110. (b) Parrot-Lopez, H.; Galon, H.; Coleman, A. W.;
Mahnteau, J.; Miocque, M. Tetrahedron Lett. 1992, 33, 209.
(4) Shulman, M. L.; Shigan, S. D.; Korlin, A. Y. Biochim.
Biophys. Acta 1976, 445, 169.
(5) Goodman, I. Adv. Carbohydr. Chem. 1958, 13, 215.
Synthesis 2006, No. 6, 949–951 © Thieme Stuttgart · New York

SHORT PAPER
Glycosyl Isothiocyanates from Peracetylated Sugars
(13) (a) García Fernández, J. M.; Ortiz Mellet, C.; Jiménez
951
(6) Fuentes, J.; Moreda, W.; Ortiz Mellet, C.; Robina, I.; Welsh,
C. Tetrahedron 1992, 48, 6413.
(7) Yamamoto, I.; Fukui, K.-I.; Yamamoto, S.; Ohta, K.;
Matsuzaki, K. Synthesis 1985, 686.
(8) (a) Ogura, H.; Takahashi, H. Heterocycles 1982, 17, 87.
(b) Fuentes, J.; Angulo, M.; Pradera, M. A. J. Org. Chem.
2002, 67, 2577.
(9) (a) Khorlin, A. Y.; Zurabyan, S. E.; Macharadze, R. G.
Carbohydr. Res. 1980, 85, 201. (b) Garg, H. B.; Jeanloz, R.
W. Adv. Carbohydr. Chem. Biochem. 1985, 43, 135.
(10) Röckendorf, N.; Lindhorst, T. K. Topics Curr. Chem. 2001,
217, 201.
Blanco, J. L.; Fuentes Mota, J.; Gadelle, A.; Coste-Gargnet,
A.; Defaye, J. Carbohydr. Res. 1995, 268, 57. (b) López,
O.; Maya, I.; Fuentes, J.; Fernández-Bolanos, J. G.
Tetrahedron 2004, 60, 61.
(14) (a) Heyns, K.; Hohlweg, R. Chem. Ber. 1978, 111, 1632.
(b) Guthrie, R. D.; Irvine, R. H. Carbohydr. Res. 1980, 82,
207.
(15) Camarasa, M. J.; Fernández-Resa, P.; Garcia-López, M. T.;
De Las Heras, F. G.; Méndez-Castrillón, P. P.; San Felix, A.
Synthesis 1984, 509.
(16) Lindhorst, T. K.; Kieburg, C. Synthesis 1995, 1228.
(17) Patel, A.; Lindhorst, T. K. Eur. J. Org. Chem. 2002, 79.
(11) Fischer, E. Ber. Dtsch. Chem. Ges. 1914, 47, 1377.
(12) Müller, A.; Wilhelms, A. Ber. Dtsch. Chem. Ges. B 1941,
74, 698.
Synthesis 2006, No. 6, 949–951 © Thieme Stuttgart · New York