Microwave-assisted glycosylation for the synthesis of glycopeptides

Article abstract of DOI:10.1016/j.carres.2004.12.014

An efficient one-step synthesis of O-linked glycosylamino acids is described. This methodology converts commercially available peracetylated mono- and disaccharides activated by cheap and environmentally safe FeCl₃ under microwave irradiation w

Full text of DOI:10.1016/j.carres.2004.12.014

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 507–511
Note
Microwave-assisted glycosylation for the synthesis of glycopeptides
Jurgen Seibel,* Lars Hillringhaus and Roxana Moraru
¨
Technical University of Braunschweig, Department for Carbohydrate Technology, Langer Kamp 5, D-38106 Braunschweig, Germany
Received 11 October 2004; received in revised form 30 November 2004; accepted 15 December 2004
Abstract—An efficient one-step synthesis of O-linked glycosylamino acids is described. This methodology converts commercially
available peracetylated mono- and disaccharides activated by cheap and environmentally safe FeCl3 under microwave irradiation
with Fmoc-Ser-OBn to the corresponding b-glycosides in short reaction times and moderate yields.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: Glycopeptides; Microwave activation; O-Glycosylation
Some functional glycoproteins are expressed on tumour
cell surfaces,1 for example, T–F (Thomson–Frieden-
reich),2 and sialyl-Tn.3 Vaccines containing these struc-
tures, usually as carbohydrate–protein conjugates,
have been shown to induce specific antitumour cell anti-
body responses in mice and patients.4 Thus, much efforts
have been devoted to establish easy and efficient meth-
ods for glycopeptide synthesis.5,6
For the synthesis of glycopeptides, very efficient gly-
cosylation procedures have been achieved.7 The com-
mon approach uses a glycosyl donor with a leaving
group at the anomeric centre, which is activated with a
promoter to yield an oxocarbenium ion susceptible to
nucleophilic attack by a glycosyl acceptor. Recently,
Carvalho et al. reported on the mercuric bromide-
promoted glycosylation of Fmoc-Ser-OBn with 2-acet-
amido-2-deoxy-3,4,6-tri-O-acetyl-a-D-glucopyranosyl
chloride.8 The glycosylation of Fmoc-Ser-OH with
b-glucose pentaacetate in dichloromethane under
BF3ÆOEt2 promotion has been reported previously in
yields from 30% to 37% and reaction times from 2 to
18 h.9 The glycosylation reactions described require
multi-step reactions for the synthesis of the glycosyl
donor and/or heavy-metal reagents such as AgOTf,
HgBr2 and HgCN2 for the activation. Long reaction
times are often required and low yields are observed.
Thus, we were interested in the efficient direct b-glyco-
sylation of Fmoc-Ser-OBn, which could be useful for
glycopeptide synthesis on solid supports.
FeCl3 has been reported to promote the b-glycosyl-
ation of alcohols with b peracetylated glycosides.10
Hence, FeCl3 was used as Lewis acid initially under
refluxconditions in toluene to activate galactose penta-
acetate 2 in the presence of Fmoc-Ser-OBn 1, which sub-
sequently formed the O-linked b-galactosyl-serine
derivate 311 (Scheme 1). Under these conditions, many
side products were observed. The optimal temperature
with respect to activation and side products was 45 ꢁC.
The initial in situ activation of the anomeric acetyl
OAc
O
RO
OAc
AcO
AcO
OH
OBn
FmocHN
1
O
°
FeCl3, 4 A MS
toluene
OAc
O
RO
AcO
O
AcO
OBn
FmocHN
O
*
Corresponding author. Tel.: +49 531 391 7262; fax: +49 531 391
7263; e-mail: j.seibel@tu-bs.de
Scheme 1.
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.12.014

508
J. Seibel et al. / Carbohydrate Research 340 (2005) 507–511
group with FeCl3 was observed by TLC, indicating that
the addition rather than activation was problematic.
After 15 h reaction time, no starting material of 2 was
left. We also observed that only the b-anomers of 2, 4,
6 and 8 reacted to the corresponding glycosylamino
acids 3,11 5,12 7 and 9,11 respectively.
the reaction scope (Table 1). These products were puri-
1
fied by silica gel column chromatography, and their H
NMR spectra confirmed the b-configuration of the newly
formed glycosidic linkage (i.e. maltose, H-1: d 4.45, J1,2
7.7 Hz). We were thus able to prepare N-9-fluorenyl-
methoxycarbonyl-O-[2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-
O-acetyl-b-D-galactopyranosyl)-b-D-glucopyranosyl]-L-
serine benzylester 9 from per-O-acetylated lactose in 54%
yield. Preparation of 9 has been compared to the litera-
ture method, which requires three steps and results in
an overall yield of 9%, including the synthesis of 3,6,20,
30,40,60-hexa-O-acetyl-1,2-O-(1-cyanoethylidene)-a-D-
lactose.11
We were unable to activate the a-anomers of galactose
2, glucose 4 and cellobiose peracetates under the same
conditions. In a mixture of a- and b-glucose peracetate
(1:1) 4, only the b-anomer of 4 reacted, the a-anomer
of 4 being re-isolated. A simple control experiment
showed the importance of microwave heating. When
an anomeric mixture of 4 in toluene was heated at
110 ꢁC for 15 h in an oil bath with FeCl3 and 1, only
20% conversion to the glycopeptide 5 was observed after
work up. In contrast the analogue microwave experi-
ment in an open vessel yielded 7 in 51% in 4 min with
a maximum temperature of 68 ꢁC. Lukasiewcz et al.
reported recently the microwave-assisted oxidation of
aromatic molecules into the corresponding aryl ketones,
However, increase in the amount of acetylated sugar
did not increase the glycopeptide formation neither
under refluxconditions, nor in the presence of additional
and different Lewis acid catalysts (AlMe3, TiCl4). Thus,
it appears that steric hindrance to the nucleophilic attack
of the serine derivative 1 caused the low yields and long
reaction times. Microwave-assisted synthesis has demon-
strated that steric problems could be overcome.13 This
approach has been shown to greatly increase yields in
many reactions, such as in the open vessel Diels–Alder
reaction. Encouraged by these previous studies, we used
microwave irradiation in the following experiments. The
glycosylation of Fmoc-Ser-OBn 1 in the presence of
FeCl3 (1.0 equiv), toluene or acetonitrile was successfully
carried out in open vessels under microwave conditions
in a microwave oven (200 W), which led to the disappear-
ance of the starting materials after 4 min and to the
generation of the corresponding glycosylated Fmoc-
Ser-OBn compounds as the major products. The per-
O-acetylated galactose 2, glucose 4, maltose 6 and lactose
8 derivatives were subjected to these conditions to study
Table 1. FeCl3-mediated glycosylation of Fmoc-Ser-OBn 1
Donor
Product
Microwave
Conventional
Time (min)
a/b (yield %)
Time (min)
a/b (yield %)
OAc
O
OAc
O
AcO
AcO
2
AcO
AcO
O
OAc
2b
2a
4
4
0:1 (52)
0:0 (0)
720
300
0:1 (31)
0:0 (0)
AcO
AcO
OBn
FmocHN
311
O
O
OAc
OAc
O
O
O
AcO
AcO
AcO
4b
4a
2 · 4
0:1 (61)
0:0 (0)
720
300
0:1 (22)
0:0 (0)
AcO
AcO
OAc
OBn
4
AcO
FmocHN
4
512
OAc
O
OAc
O
AcO
AcO
OAc
O
AcO
AcO
AcO
O
OAc
O
6b
6a
4
4
0:1 (52)
0:0 (0)
720
300
0:1 (10)
0:0 (0)
O
AcO
AcO
O
AcO
OAc
OAc
AcO
OBn
OBn
AcO
FmocHN
6
7
O
OAc
AcO
AcO
OAc
O
OAc
O
AcO
AcO
OAc
O
O
O
AcO
8b
8a
2 · 4
4
0:1 (54)
0:0 (0)
720
300
0:1 (16)
0:0 (0)
O
AcO
O
AcO
FmocHN
AcO
AcO
AcO
8
911
O
OAc
O
OAc
AcO
AcO
O
AcO
AcO
10b
2 · 4
1:0 (85)
—
—
OAc
NHAc
N
O
1119–21
10

J. Seibel et al. / Carbohydrate Research 340 (2005) 507–511
509
quinones or lactones by MagtrieveTM, a magnetically
retrievable oxidant based on tetravalent chromium diox-
ide (CrO2).14 They observed, that the temperature of
MagtrieveTM surface was higher than the boiling point
of toluene, but boiling was not detected at all. This
means that in heterogeneous systems (like FeCl3/tolu-
ene) the temperature of the solid may be higher than
the bulk temperature of the reaction mixture. The higher
temperature of the solid could be responsible for the
higher reaction rates and yields of the product, which
would not be possible under conventional conditions
in an oil bath.
It is believed that b-glycosylation proceeds via neigh-
bouring group participation by an acyl group at O-2 of
the donor, as described by Lemieux.15 The initially
formed oxocarbenium ion is in equilibrium with the
more stable acyloxonium ion formed by participation
of the acyl group.16 A solvent of low polarity like tolu-
ene favours the acyloxonium ion probably by inefficient
solvatation of the oxocarbenium ion.17 Nucleophilic
ring opening of the acyl carbon results in the beta-con-
figurated glycoside (Scheme 2). However, formation of
orthoesters, often described in literature as a serious side
reaction, was not observed. An explanation could be
that the positive charge of the acyloxonium ion is stabi-
lised by the vicinal acetate, which would favour the ther-
modynamic controlled attack of the alcohol at C-1 in a
trans-selective manner. Higher temperature has been re-
ported to support this suggested mechanism.17 We also
found, that 2-acetamido-2-deoxy-1,3,4,6-tetra-O-acetyl-
b-D-glucopyranose 10 reacted very efficient with FeCl3
in CHCl3 under microwave irradiation in 85% yield to
2-methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-a-D-glucopyr-
ano)-[2,1-d]-2-oxazoline 11, which opens a wide reper-
toire of further reactions with glycosyl acceptors,
primary or secondary hydroxy groups, azides and serine
derivatives.18 However, in the presence of 1 we were un-
able to react oxazoline 11 direct to the corresponding
b-O-GlcNAc-Ser under FeCl3 promotion and micro-
wave conditions.
In conclusion, we have shown that glycosyltransfer
reactions of peracetylated mono- and disaccharides with
peptides can be substantially facilitated by microwave
heating. The reaction times are shortened from 5–10 h
to 4 min, the yields are improved and the environmen-
tally safe promotor FeCl3 can replace heavy metals like
AgOTf, HgBr2 and HgCN2 or BF3ÆOEt2. This is the first
report about the use of microwave heating in the glycos-
ylation of amino acids.
The b-anomeric selectivity of the starting acetylated
sugars provides the potential for separation and discrim-
ination of donor substrates for multi-component and
multi-step reactions. Additionally, the glycosidation
method may be also applicable to solid phase glycopep-
tide synthesis containing vulnerable peptide sequences.
1. Experimental
1.1. General
All reactions requiring anhydrous conditions were con-
ducted in flame- or oven-dried apparatus under an atmo-
sphere of Ar. Syringes and needles for the transfer of
reagents were dried at 140 ꢁC and allowed to cool in a
desiccator over P2O5 before use. CHCl3 and toluene were
distilled from CaH2 under Ar. External reaction temper-
atures are reported unless stated otherwise. Reactions
were monitored by TLC using commercially available
plates, precoated with a 0.25 mm layer of silica contain-
ing a fluorescent indicator (E. Merck) and compounds
were sprayed with anisaldehyde reagent followed by
heating. Organic layers were dried over MgSO4 unless
stated otherwise. Column chromatography was carried
out on Kieselgel 60 (40–63 lm). Petroleum ether refers
to the fraction with bp 40–60 ꢁC. 1H and 13C NMR spec-
tra were recorded in CDCl3, unless stated otherwise,
using a Bruker AM-400 instrument, operating at
400 MHz for 1H and at 100 MHz for 13C. Chemical
shifts are reported relative to CHCl3 [dH 7.26, dC (central
of triplet) 77.0] or CH3OH [dH 3.35, dC (central of septet)
49.0]. Melting points were determined on a Melt-Temp 2
microscope. Electrospray-ionisation mass spectra
(ESIMS) were recorded with a Finnigan MAT 8340 on
samples suspended in MeOH. IR spectra in pressed
KBr discs were recorded on a Bio-Rad FTS-25 spectrom-
eter. Optical rotation values were measured with a
Dr. Kernchen sucromat polarimeter.
O
O
O
FeCl
3
OAc
O
RO
RO
FeCl3
X
X
O
O
Nu
O
O
Nu
RO
RO
X
X
1.2. N-9-Fluorenylmethoxycarbonyl-O-(2,3,4,6-tetra-O-
acetyl-b-D-galactopyranosyl)-L-serine benzyl ester 3
O
O
X = O, NH
A soln of 2 (40.0 mg, 102 lmol, 1.0 equiv), Fmoc-Ser-
OBn 1 (42.0 mg, 101 lmol, 1.0 equiv), 4 A molecular
˚
Scheme 2.

510
J. Seibel et al. / Carbohydrate Research 340 (2005) 507–511
sieves (25 mg) in toluene (1 mL) and FeCl3 (17.0 mg,
102 lmol, 1.0 equiv) was reacted 4 min in a microwave
oven (200 W). The reaction mixture was filtered, the
molecular sieves washed with CHCl3 and directly applied
to column chromatography (4:1 diethyl ether–petroleum
ether), which provided 3 as a foamy solid (40.0 mg,
54 lmol, 52%). [a]D +0.2 (c 1.0, CHCl3), lit.11 [a]D ꢀ1.2
(c 1.0, CHCl3); Rf 0.40 (4:1 diethyl ether–petroleum
ether); IR (cmꢀ1): 1159, 1263, 1455, 1738, 2868, 2928,
2956, 3463; 1H and 13C NMR spectra data are in accor-
dance with lit.11 ESIMS: [M+Na]+ calcd for
C39H41NO14[Na]+ 770.2425, found m/z 770.2434.
matic carbons Fmoc), 100.59 (C-10), 95.56 (C-100), 75.11
(C-30), 72.48 (C-40), 72.15 (C-50), 71.97 (C-20), 69.99 (C-
200), 69.63 (C-3), 69.28 (C-300), 68.52 (C-500), 67.97 (C-400),
67.56 (CH2Ph), 67.08 (CH2Fmoc), 62.59 (C-60), 61.43
(C-600), 54.45 (C-2), 47.11 (CHFmoc), 26.88, 20.86,
20.72, 20.63, 20.55, 20.47 (7 CCH3). MS (ESI): m/z
[M+Na]+ calcd for [C51H57NO22]Na+ 1058.3270, found
m/z 1058.3273.
1.5. N-9-Fluorenylmethoxycarbonyl-O-[2,3,6-tri-O-acet-
yl-4-O-(2,3,4,6-tetra-O-acetyl-b-D-galactopyranosyl)-b-
D-glucopyranosyl]-L-serine benzylester 9
1.3. N-9-Fluorenylmethoxycarbonyl-O-(2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosyl)-L-serine benzyl ester 5
Coupling of 8 (50.0 mg, 74 lmol, 1.0 equiv) and 1
(31.0 mg, 74 lmol, 1.0 equiv) as described in the prepa-
ration of 3 gave 9 as a foamy solid (41.0 mg, 40 lmol,
54%); [a]D +6.6 (c 1.0, CHCl3), lit.11 [a]D ꢀ0.8 (c 1.0,
CHCl3); Rf 0.13 (4:1 diethyl ether–petroleum ether);
IR (cmꢀ1): 1159, 1263, 1455, 1730, 2872, 2932, 2964,
Coupling of 4 (40.0 mg, 102 lmol, 1.0 equiv) and 1
(42.0 mg, 101 lmol, 1.0 equiv) as described in the prep-
aration of 3 gave 5 as a foamy solid (46.0 mg, 62 lmol,
61%); [a]D +2.6 (c 1.0, CHCl3); Rf 0.39 (4:1 diethyl
ether–petroleum ether); IR (cmꢀ1): 1167, 1255, 1459,
1
3431; H NMR (400 MHz, CDCl3) d 7.78 (dd, J 7.4,
2.3 Hz, 2H, Aryl–H), 7.61 (d, J 7.4 Hz, 2H, Aryl–H),
1
1742, 2887, 2946, 3487; H and 13C NMR spectra data
7.31–7.43 (m, 9H, Aryl–H), 5.63 (d, JN,H 8.1 Hz, 1H,
N–H), 5.34 (dd, J3 ,4 3.5, J4 ,5 1.0 Hz, 1H, H-400), 5.19
are in accordance with lit.12 ESIMS: m/z 770.1 100%,
0
00
00 00
[M+Na+].
(m, 2H, H-600), 5.15–5.17 (d, J3 ,4 = J4 ,5 9.1 Hz, 1H,
0
0
0
0
H-40), 5.16 (d, J1 ,2 9.1 Hz, 1H, H-10), 5.09–5.14 (dd,
00
0
1.4. N-9-Fluorenylmethoxycarbonyl-O-[2,3,6-tri-O-acet-
yl-4-O-(2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl)-b-D-
glucopyranosyl]-L-serine benzylester 7
J2 ,3 10.4, J1 ,2 7.8 Hz, 1H, H-200), 4.94–4.97 (dd,
00 00 00 00
J2 ,3 10.4 J3 ,4 3.5 Hz, 1H, H-300), 4.84–4.88 (dt, J5 ,6
00 00
0
00
00 00
8.2, J4 ,5 1.0 Hz, 1H, H-500), 4.70 (s, 2H, CH2OBn),
00 00
4.47 (m, 2H, H2-60), 4.44 (d, J1 ,2 7.8 Hz, 1H, H-100),
00 00
Coupling of 6 (50.0 mg, 74 lmol, 1.0 equiv) and 1
(31.0 mg, 74 lmol, 1.0 equiv) as described in the prepa-
ration of 3 gave 7 as a foamy solid (40.0 mg, 39 lmol,
52%); mp: 121 ꢁC; [a]D +45.0 (c 1.0, CHCl3); Rf 0.29
(4:1 diethyl ether–petroleum ether); IR (cmꢀ1): 1159,
1255, 1459, 1734, 2864, 2936, 2960, 3471; 1H NMR
(400 MHz, CDCl3) d 7.78 (d, J 7.5 Hz, 2H, Aryl–H),
7.61 (d, J 7.40 Hz, 2H, Aryl–H), 7.19–7.42 (m, 9H,
4.20–4.28 (m, 2H, H-3a, Fmoc-CH), 4.03–4.15 (m, 4H,
H-30, 2-H, Fmoc-CH2), 3.84–3.87 (m, 1H, Hb-3), 3.73–
3.78 (t, J1 ,2 = J2 ,3 9.1, 1H, H-20), 3.48–3.52 (m, 1H,
H-50), 2.15, 2.07, 2.06, 2.05, 1.99, 1.97 (7s, 21H,
–CH3); 13C NMR (100 MHz, CDCl3) d 170. 64,
170.43, 170.36, 170.00, 169.87, 169.37 (eight ester CO,
C-1), 156.15 (NHCOO), 143.94, 141.61, 140.91, 140.53
(four aromatic quaternary carbons Fmoc), 135.42 (qua-
ternary aromatic carbon CH2Ph), 128.48, 128.82, 127.28
(five tertiary aromatic carbons CH2Ph), 128.93, 128.86,
128.09, 127.94, 127.42, 125.31, 120.36 (eight tertiary aro-
matic carbons Fmoc), 101.36 (C-100), 101.21 (C-10), 76.38
(C-20), 73.02 (C-50), 72.87 (C-40), 71.81 (C-500), 71.28 (C-
300), 61.76 (CH2Fmoc), 69.86 (C-3), 69.40 (C-200), 67.87
(C-600), 67.44 (C-60), 66.92 (C-400), 65.66 (CH2Bn),
62.19 (C-30), 61.13 (C-2), 47.42 (CHFmoc), 29.99,
22.98, 22.98, 21.08, 20.93, 20.80 (7 CCH3). ESIMS:
m/z 1058.3 100%, [M+Na+].
00
0
00
0
00 00
Aryl–H), 5.65 (d, JN,H 8.1 Hz, 1H, N-H), 5.40 (d, J1 ,2
3.7 Hz, 1H, H-100), 5.39 (dd, J3 ,4 9.9, J2 ,3 10.5 Hz,
0
00
00 00
1H, H-300), 5.23 (t, J2 ,3 = J3 ,4 9.2 Hz, 1H, H-30), 5.19
00
0
0
0
(s, 2H, OCH2Bn), 5.07 (t, J3 ,4 9.9 Hz, 1H, H-400), 4.87
0
00
(dd, J1 ,2 3.7, J2 ,3 10.5, 1H, H-200), 4.77 (t, J1 ,2
0
00 00
00 00
00
8.1 Hz, 1H, H-20), 4.45 (d, J1 ,2 8.1 Hz, 1H, H-10),
4.36–4.54 (m, 4H, Aryl–CH–CHa–O, 2-H, H2-60),
4.21–4.29 (m, 3H, H-3a, H-60a0, CHCH2–), 4.12 (dd, J
00
0
00
00
12.2, 4.3 Hz, 1H, Aryl–CH–CHb–O), 4.04 (dd, J6a ,6b
2.2, J5 ,6 12.6 Hz, 1H, H-60b0), 3.95 (m, 2H, H-500, H-
40), 3.88 (dd, J3a,3b 3.2, J3b,2 10.8 Hz, 1H, H-3b), 3.47
(m, 1H, H-50), 2.10, 2.09, 2.06, 2.03, 2.01, 1.98 (6s,
21H, –CH3). 13C NMR (100 MHz, CDCl3) d 170.49,
170.47, 170.38, 170.11, 169.90, 169.56 (seven ester
CO), 169.38 (C-1), 155.82 (NHCOO), 143. 76, 143.62,
141.30 (four aromatic quaternary carbons Fmoc),
135.11 (quaternary aromatic carbon CH2Ph), 128.23,
128.52, 128.60 (five tertiary aromatic carbons CH2Ph),
120.00, 124.98, 125.09, 127.09, 127.75 (eight tertiary aro-
00 00
1.6. 2-Methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-a-D-gluco-
pyrano)-[2,1-d]-2-oxazoline 1119–21
˚
A soln of 10 (100.0 mg, 256 lmol, 1.0 equiv), 4 A mole-
cular sieves (25 mg) in CHCl3 (10 mL) and FeCl3
(60.0 mg, 353 lmol, 1.4 equiv) was reacted 2 · 4 min in
a microwave oven (200 W). The reaction mixture was
filtered, the molecular sieves washed with CHCl3 and

J. Seibel et al. / Carbohydrate Research 340 (2005) 507–511
511
Seeberger, P. H. Adv. Carbohydr. Chem. Biochem. 2003,
58, 35–54.
directly applied to column chromatography (20:1
CHCl3–MeOH), which provided 11 as a colourless solid
(71.7 mg, 217 lmol, 85%). The 1H NMR20 spectrum
data was in accordance with lit. [a]D +15.0 (c 1.0,
CHCl3), lit.21 [a]D +16.3 (c 1.0, CHCl3); Rf 0.30 (20:1
CHCl3–MeOH).
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Financial support from the Deutsche Bundesstiftung
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