Glycosylation of acid sensitive acceptors. Synthesis of (2,3-epoxy-1-propyl) glycosides

Article abstract of DOI:10.1016/j.carres.2005.07.010

Treatment of O-benzylated derivatives of glycosyl N-allyl thiocarbamate with racemic or enantiomerically pure glycidol and bromine provides the 1,2-cis-glycidyl glycosides. This protocol was mild, highly stereoselective and efficient.

Full text of DOI:10.1016/j.carres.2005.07.010

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 2443–2446
Note
Glycosylation of acid sensitive acceptors. Synthesis of
(2,3-epoxy-1-propyl) glycosides
Anna Kasprzycka,a,* Wiesław Szejaa and Grzegorz Grynkiewiczb
aSilesian Technical University, Department of Chemistry, Krzywoustego 4, 44-100 Gliwice, Poland
bPharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland
Received 15 April 2005; received in revised form 11 July 2005; accepted 19 July 2005
Available online 18 August 2005
Abstract—Treatment of O-benzylated derivatives of glycosyl N-allyl thiocarbamate with racemic or enantiomerically pure glycidol
and bromine provides the 1,2-cis-glycidyl glycosides. This protocol was mild, highly stereoselective and efficient.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: Glycidyl glycosides; Glycosides; Glycosylation; N-Allyl thiocarbamates
It is now generally accepted that sugars, being informa-
tion-rich molecules, are well suited for exploratory syn-
theses leading to new types of constructs with expected
biological activity, including new drugs.1 While glyco-
sides are plentiful among secondary metabolites and
many of them are exploited as medicinal compounds,
synthetic drugs having complex glycosidic structure are
relatively few.2–4 This is at least in part due to intrinsic
difficulties experienced by researchers seeking control
over the anomeric centre chemistry, in terms of synthetic
efficiency and desirable stereoselection.5 Considering
various possibilities of chemical glycoconjugation as a
way to improve bioavailability and pharmacokinetics
of poorly soluble active substances,6 we have turned
our attention to glycidyl (2,3-epoxy-1-propyl) glycosides
of the general formula depicted in Figure 1.
Glycidyl glycosides combine desirable features of
chemical reactivity in their structure. Both the glyceryl
and glycosyl moieties of the molecule may act as
substrate for selected enzymes, like lipases, glycosylases,
kinases, etc., offering various pathways for bioprocess-
ing, including targeting and biodegradation. Despite
predicted high reactivity of the glycidyl glycosides, con-
siderable degree of selectivity can be expected in reac-
tions under both chemical and biological conditions.
Indeed, it has been recently demonstrated that such
compounds, named glycidol-carbohydrate hybrids, are
capable of alkylating DNA selectively at the N-7 site
of guanine residues.7
There are several approaches to the synthesis of
(2,3-epoxy-1-propyl) glycosides. Epoxidation of allyl
glycosides is efficient and operationally simple, but its
diastereoselectivity is somewhat difficult to control.8
We have observed that the alkylation of 1-OH sugars
with glycidol derivatives containing a good leaving
group usually leads to anomeric mixtures. Recent
synthesis of glycidol-carbohydrate hybrids7,9 involved
glycerol derivative, rather than glycidol glycosylation.
The glycosylation of epoxide is not a trivial task. This
reaction is usually performed using strong acids (e.g.,
derivatives of trifluoromethanesulfonic acid, perchloric
acid, trifluoroborate–etherate complex).10 Due to the
sensitive nature of oxiranes in acidic media, a complex
O
O
OR
CH2 CH CH2
O
R: C6H5CH2, H
Figure 1.
*
Corresponding author. Fax: +48 32 237 20 94; e-mail:
akasprzycka@interia.pl
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.07.010

2444
A. Kasprzycka et al. / Carbohydrate Research 340 (2005) 2443–2446
S
Br
2
+
R
O
C
HOCH CH CH
R
O CH CH CH
2 2
2
2
DBU
NH CH CH CH
2
2
O
O
2 R,S
3 R
2a, 2b, 2c
3a, 4a
1a-c
4 S
R=
OBn
O
OBn
OBn
O
OBn
OBn
BnO
O
OBn OBn
BnO
BnO
OBn
OBn
a
b
c
Scheme 1.
products mixture is usually formed. To our knowledge,
no general procedure has been reported so far for glyco-
sylation of compounds bearing an epoxide group.
Our experience with anomeric N-allyl thiocarba-
mates, which are storable, easily activated, efficient gly-
cosylating reagents for various unstable substrates,
encouraged us to try them as glycosyl donors for gly-
cidols, which are acid and base sensitive acceptors.11
We have found that glycosyl N-allyl thiocarbamates
react with glycidol in the presence of non-nucleophilic
bases and halogens, pseudohalogens or some thiophilic
metal salts as activators, with formation of the
expected glycidyl glycosides. The reaction is highly ste-
reoselective and leads practically exclusively to a-glyco-
sides. The stereochemical integrity of chiral glycidols is
preserved under the applied conditions, affording pure
single diastereoisomers as the reaction products
(Scheme 1).
1. Experimental
1.1. General methods
Optical rotations were measured with a Perkin Elmer
141 polarimeter using a sodium lamp (589 nm) at room
temperature. 1H NMR spectra were recorded with a
Varian 300 MHz spectrometer for solutions in CDCl3
(internal TMS). TLC was performed on precoated
plates of Silica Gel 60F254 (E. Merck), using 3:1 hex-
ane–EtOAc or 2:1 toluene–EtOAc and the spots were
visualized by spraying with H2SO4, followed by heat-
ing plates at 150 ꢁC. Chromatographic purification
was performed on Silica Gel 60 (E. Merck) 0.063–
0.2 mm. All solns were concentrated under diminished
pressure at 40 ꢁC. Organic solns were dried over anhyd
MgSO4.
We have observed that introduction of lithium fluor-
ide into the reaction mixtures improved the efficiency
of these glycosylations. It seems likely that the fluoride
ion, being strong and hard base, forms in the reaction
mixture a complex with the hydroxyl group of the accep-
tor, letting it more nucleophilic12 and thus facilitating
the anomeric exchange.13 The obtained glycidyl glyco-
pyranosides are compounds designed for chemical con-
jugation, involving oxirane ring opening, primarily by
a nucleophilic group of chosen pharmacophoric sub-
strate, suitable also for parallel synthesis followed by
high throughput screening.
1.2. Starting materials
(R,S) Glycidol 97% (GC), (R) glycidol 97% (98% ee/
GLC) and (S) glycidol 97% (98% ee/GLC) are commer-
cially available (Aldrich). 2,3,4,6-Tetra-O-benzyl-1-O-
[N-allylthiocarbamoyl]-b-D-glucopyranose (1a), 2,3,4,6-
tetra-O-benzyl-1-O-[N-allylthiocarbamoyl]-b-D-galacto-
pyranose (1b) and 2,3,4,6-tetra-O-benzyl-1-O-[N-allyl-
thiocarbamoyl]-b-D-mannopyranose (1c) were prepared
from 2,3,4,6-tetra-O-benzylated hexopyranose (0.2 g,
0.77 mmol) according to Ref. 14. Sugar was dissolved
in a mixture of toluene/HMPA (3 mLn0.3 mL) contai-
˚
The obtained products and their selected physico-
chemical data are collected in Table 1.
ning micronized molecular sieves of 4 A (0.05 g). Then,
K2CO3 (0.10 g, 0.77 mmol), DBU (0.008 mL, 0.077
mmol) were added, the reaction mixture was stirred vigo-
rously and N-allyl isothiocyanate (0.140 mL, 1.54 mmol)
was added. The reaction was completed (TLC) in 4 h.
The mixture was filtered, washed with 10% aq NaCl
(3 · 5 mL), water (3 · 5 mL), dried (anhyd MgSO4), fil-
tered and concentrated. Column chromatography of the
residue (8:1, 5:1, 3:1 hexane–EtOAc) gave the anomeric
mixture of thiocarbamate. 1H NMR in CDCl3 showed a
ratio of a:b = 3:1.
Table 1. Formation of glycidyl glycosides 2a–c, 3a and 4a
20
Entry Glycosides Acceptor ½aꢀD
Yield (%)
1
2
3
4
5
2a
2b
2c
3a
4a
2
2
2
3
4
4.7 (c 0.8, CHCl3) 94
4.9 (c 0.9, CHCl3) 88
4.8 (c 0.9, CHCl3) 85
ꢁ10.0 (c 1.0, CHCl3) 93
9.8 (c 1.0, CHCl3) 91

A. Kasprzycka et al. / Carbohydrate Research 340 (2005) 2443–2446
2445
1.3. Synthesis of (2,3-epoxy-1-propyl) glycosides 2-4:
general procedure
2H, CH epoxide (R,S)), 3.70–4.10 (m, 16H), 4.50–5.00
(m, 16H), 4.83 (d, 1H, J1,2 1.60 Hz, H-1), 5.00 (d, 1H,
J1,2 1.59 Hz, H-1), 7.15–7.38 (m, 40H, Ph). 13C NMR
(CDCl3): d 44.65 (C-epoxide), 44.76 (C-epoxide), 50.24
(C-epoxide), 50.53 (C-epoxide), 97.51 (C-1), 97.71 (C-
1). Anal. Calcd for C37H40O7: C, 74.47; H, 6.75. Found:
C, 74.43; H, 6.73.
To the corresponding sugar thiocarbamate 1a–c
(1 mmol) in CH2Cl2 (3.0 mL), dry molecular sieves of
˚
4 A (100 mg), potassium fluoride (1 mmol) and anhyd
sodium carbonate (1 mmol) were added and the magnet-
ically stirred suspension was cooled in an external bath
to ꢁ25 ꢁC. Next, a soln of bromine (1 mmol in 1 mL
of CH2Cl2) was added, followed immediately after dis-
colouration of the mixture, by a soln of the correspond-
ing glycidols 2, 3, 4 (2 mmol) and DBU (2 mmol) in
CH2Cl2 (1.0 mL). Glycosidation reactions were moni-
tored by TLC. The glycosyl donor disappeared com-
pletely in ca. 10 min, as evidenced by TLC of the
reaction mixture. After 30 min, the reaction mixture
was diluted with CH2Cl2 (50 mL), washed with water,
aq sodium thiosulfate and water again. The organic
layer was dried with anhyd MgSO4, filtered and evapo-
rated under diminished pressure. The oily residue was
flash-chromatographed through a short silica gel col-
umn and eluted with 8:1 hexane–EtOAc. Pooled frac-
tions containing benzylated epoxypropyl glycosides
were evaporated under diminished pressure.
1.3.4. (R) (2,3 Epoxy-1-propyl) 2,3,4,6-tetra-O-benzyl-a-
D-glucopyranoside (3a). From 1a (0.05 g), (syrup,
20
0.043 g, 93%), ½aꢀD ꢁ10 (c 1, CHCl3), 1H NMR
(CDCl3): d 2.60–2.65 (m, 1H, CH2 epoxide), 2.70–2.80
(m, 1H, CH2 epoxide), 3.10–3.22 (m, 1H, CH epoxide),
3.42–4.15 (m, 9H), 4.40–5.00 (m, 9H), 4.89 (d, 1H, J1,2
3.60 Hz, H-1), 7.10–7.40 (m, 20H, Ph). 13C NMR
(CDCl3):
d 44.75 (C-epoxide), 50.23 (C-epoxide),
68.62, 68.94, 70.33, 73.26, 73.50, 75.00, 75.70, 77.70,
80.02, 81.75, 97.31 (C-1), 127.62-128.51 (20C, PhCH2),
138.25, 138.58, 138.70, 138.85 (4C, C-1 Ph). Anal. Calcd
for C37H40O7: C, 74.47; H, 6.75. Found: C, 74.46; H,
6.74.
1.3.5. (S) (2,3 Epoxy-1-propyl) 2,3,4,6-tetra-O-benzyl-a-
D-glucopyranoside (4a). From 1a (0.05 g), (syrup,
20
0.042 g, 91%), ½aꢀD 9.8 (c 1, CHCl3), 1H NMR (CDCl3):
1.3.1. (R,S) (2,3 Epoxy-1-propyl) 2,3,4,6-tetra-O-benzyl-
a-D-glucopyranoside (2a). From 1a (0.05 g), (syrup,
d 2.50–2.61 (m, 1H, CH2 epoxide), 2.65–2.80 (m, 1H,
CH2 epoxide), 3.10–3.25 (m, 1H, CH epoxide), 3.40–
4.10 (m, 9H), 4.40–5.07 (m, 9H), 5.10 (d, 1H, J1,2
3.60 Hz, H-1), 7.10–7.40 (m, 20H, Ph). 13C NMR
20
0.044 g, 94%), ½aꢀD 4.7 (c 0.8, CHCl3), 1H NMR
(CDCl3): d 2.58–2.68 (m, 2H, CH2 epoxide (R,S)),
2.70–2.90 (m, 2H, CH2 epoxide (R,S)), 3.10–3.30 (m,
2H, CH epoxide (R,S)), 3.40–4.10 (m, 16H), 4.40–5.08
(m, 16H), 4.89 (d, 1H, J1,2 3.61 Hz, H-1), 5.10 (d, 1H,
J1,2 3.60 Hz, H-1), 7.10–7.40 (m, 40H, Ph). 13C NMR
(CDCl3): d 44.64 (C-epoxide), 44.75 (C-epoxide), 50.23
(C-epoxide), 50.53 (C-epoxide), 97.31 (C-1), 97.52 (C-
1). Anal. Calcd for C37H40O7: C, 74.47; H, 6.75. Found:
C, 74.45; H, 6.74.
(CDCl3):
d 44.64 (C-epoxide), 50.53 (C-epoxide),
68.60, 68.95, 70.32, 73.26, 73.50, 75.01, 75.70, 77.64,
80.01, 81.05, 97.29 (C-1), 127.63–128.52 (20C, PhCH2),
138.26, 138.60, 138.70, 138.90 (4C, C-1 Ph). Anal. Calcd
for C37H40O7: C, 74.47; H, 6.75. Found: C, 74.45; H,
6.73.
Acknowledgements
1.3.2. (R,S) (2,3 Epoxy-1-propyl) 2,3,4,6-tetra-O-benzyl-
a-D-galactopyranoside (2b). From 1b (0.05 g), (syrup,
This work was supported by KBN grant no. 4 T09A 075
23 and Polpharma Foundation grant no. 011/2002.
20
0.041 g, 88%), ½aꢀD 4.9 (c 0.9, CHCl3), 1H NMR
(CDCl3): d 2.55–2.65 (m, 2H, CH2 epoxide (R,S)),
2.60–2.80 (m, 2H, CH2 epoxide (R,S)), 3.00–3.22 (m,
2H, CH epoxide (R,S)), 3.70–4.20 (m, 16H), 4.41–4.82
(m, 16H), 4.85 (d, 1H, J1,2 3.40 Hz, H-1), 5.00 (d, 1H,
J1,2 3.42 Hz, H-1), 7.15–7.40 (m, 40H, Ph). 13C NMR
(CDCl3): d 44.64 (C-epoxide), 44.75 (C-epoxide), 50.23
(C-epoxide), 50.52 (C-epoxide), 98.21 (C-1), 98.42 (C-
1). Anal. Calcd for C37H40O7: C, 74.47; H, 6.75. Found:
C, 74.44; H, 6.73.
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