Efficient methods for glycosidations with glycals - A key intermediate for the synthesis of mucin core 1-type O-glycan

Article abstract of DOI:10.1055/s-2004-817790

The use of glycals as acceptors in glycosylation reactions is hampered by their sensitivity to acids. We report here on the successful use of mild Lewis acid [Sn(OTf)₂] as catalyst for the glycosylation with O-glycosyl trichloroacetimidates and on the development of this method to construct a key intermediate for the synthesis of mucin type O-glycans. To this end, chemoselective nitration of O-glycosylated glycals, stereoselective threonine addition, and reduction of the nitro group to the amino group by an efficient procedure avoiding the use of an expensive catalyst was performed.

Full text of DOI:10.1055/s-2004-817790

836
LETTER
Efficient Methods for Glycosidations with Glycals – A Key Intermediate for
the Synthesis of Mucin Core 1-Type O-Glycan
Efficient
M
ü
ethods for
G
r
lycosid
g
ations with
G
e
lycals n Geiger, Nadine Barroca, R. R. Schmidt*
Department of Chemistry, University of Konstanz, Fach M 725, 78457 Konstanz, Germany
Fax +49(7531)883135; E-mail: Richard.Schmidt@uni-konstanz.de
Received 19 January 2004
Abstract: The use of glycals as acceptors in glycosylation reactions
is hampered by their sensitivity to acids. We report here on the suc-
cessful use of mild Lewis acid [Sn(OTf)2] as catalyst for the glyco-
sylation with O-glycosyl trichloroacetimidates and on the
development of this method to construct a key intermediate for the
synthesis of mucin type O-glycans. To this end, chemoselective
nitration of O-glycosylated glycals, stereoselective threonine addi-
tion, and reduction of the nitro group to the amino group by an effi-
cient procedure avoiding the use of an expensive catalyst was
performed.
Scheme 1 Synthesis of Gal-b-(1→3)-Gal glycal using DMDO.
Only few examples of glycosylations using other activat-
ed donors and glycals as acceptors have been reported. In
some cases, the use of trichloroacetimidate 411,12 or
fluoride 5,13,14 was described (Figure 1).
Key words: carbohydrates, glycols, glycosylation, Michael addi-
tions, glycopeptides, nitro reduction
Glycals, are among the most versatile chiral building
blocks. Not surprisingly, glycals have been the subject of
considerable interest in carbohydrate chemistry,1 in oli-
gosaccharide synthesis,2 and in the development of com-
binatorial synthesis of oligosaccharide libraries.3 Glycals
as chiral building blocks, serve as precursors for a broad
variety of optically active products.4
Figure 1
Application of glycals to the synthesis of the mucin class
of glycopeptides has recently attracted our attention11 be-
cause of their fundamental importance in biological pro-
cesses such as cell-cell adhesion, cell growth, fertilization,
parasitic infection and inflammation.5–7
We focused our attention to the development of an effi-
cient method using O-galactosyl trichloroacetimidate 6 in
order to generate this linkage with the acid sensitive ga-
lactal 7. A variety of Lewis acids were tested, some results
are given in Table 1.
All mucin core structures contain at the reducing end an
N-acetylgalactosamine a-glycosidically linked to L-serine
or L-threonine. We have already demonstrated that nitro-
galactal concatenation is a well-suited tool for the synthe-
sis of all members of the mucin family8a–d as well as for
the synthesis of S-, P-, and C-glycosides8e,f and of nucleo-
sides.8g Herein, we want to report on our studies to the
synthesis of the important core 1 disaccharide b-D-Gal-
(1→3)-D-GalNac-a-(1→O)Thr.
A wide range of glycosylation methods using glycals as
donors has been developed,9 employing 3,3-dimethyl-
dioxirane (DMDO) for the activation of the double bond.
This methodology was successfully used to prepare
disaccharide 3 with the epoxide of glycal 1 as donor and
glycal 2 as acceptor (Scheme 1).10,11
Scheme 2 Synthesis of Gal-b-(1→3)-Gal glycal.
Table 1 Glycosylation between 6 and 7
Entry
Catalyst (%)
T (°C)
–78
–78
20
Yield (%) a
1
2
3
4
0.01 equiv TMSOTf
0.01 equiv BF3·OEt2
0.5 equiv ZnCl2
–
–
44
75
0.02 equiv Sn(OTf)2
–20
a All reactions were carried out in CH2Cl2.
SYNLETT 2004, No. 5, pp 0836–0840
0
2.
0
4.
2
0
0
4
Advanced online publication: 24.02.2004
DOI: 10.1055/s-2004-817790; Art ID: G02504ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient Methods for Glycosidations with Glycals
837
The most efficient Lewis acid to afford this linkage was In order to confirm that our method can be generalized,
found to be Sn(OTf)2 (Table 1, entry 4). In the presence of different O-glycosyl trichloroacetimidates and glycals
catalytic amounts of Sn(OTf)2, the reaction proceeded were submitted to similar reaction conditions. The results
readily to afford the desired compound 815,16 in good yield are resumed in Table 2 (PA = phenoxyacetyl). All trichlo-
(Scheme 2).
roacetimidates, which were tested, furnished the expected
Table 2 Coupling Reactions of Imidate Glycosides Using Sn(OTf)2 0.1 M as Activatorsa
Donor
Acceptor
T (°C)
Compound
Yield (%)
Ratio (a:b)
7
–20
60
0:1
7
7
–20
60
71
0:1
–20
0:1
7
7
7
r.t.
r.t.
40
61
60
55
2:1b
1<15b
0:1
21
r.t.
55
0:1
a All reactions, unless otherwise stated, were conducted in CH2Cl2.
b Anomeric ratios were determined by isolated products.
Synlett 2004, No. 5, 836–840 © Thieme Stuttgart · New York

838
J. Geiger et al.
LETTER
disaccharides in good to excellent yield. With donors 15, addition of acetyl nitrate and elimination of acetic acid to
17 and particularly 19, an increase of the temperature17 afford the corresponding nitroglycal 28. This Michael-
was necessary to speed up the reaction and generate the type acceptor was glycosylated under standard
desired disaccharide. A similar strategy was applied when conditions8a with 29 or 30 to give the corresponding a-
less reactive benzylidene glucal 21 was used as an accep- glycosides 31 and 32, with 77% and 73% yield, respec-
tor.
tively. The a-linkage was confirmed by the coupling
constant J1,2 = 4 Hz.
With these disaccharides in hand, we were particularly
interested if O-benzylidene protected glycals can be In order to avoid the use of the expensive reagent Raney-
chemoselectively nitrated in the C-2 position. For this Ni T4 (Pt),8a–g usually employed for the reduction of the
purpose, free hydroxy groups were first protected with an nitro group, a cheaper method using excess of zinc dust19
acetyl or benzyl group, and standard conditions8a–g for the and aqueous 1 N HCl in a solvent mixture (HOAc/H2O)
nitration were then applied to get the corresponding was explored. This method, which was first used to reduce
nitrated compounds in good yields (Scheme 3).
hydroxylamines to the corresponding amino derivatives,20
gave access to the desired amino derivatives to afford the
acetamido glycosides 33 and 34. Benzyl groups were ex-
changed for acetyl groups, and the Boc protection on the
amino acid moiety of 33 was removed to afford 35, an in-
termediate in the further synthesis of antifreeze glyco-
proteins. In addition, all protecting groups on the amino
acid moiety of 34 were removed, and finally the Fmoc
group was introduced to give known target building block
36.11,21
As expected, this sequence of reactions furnished 2-nitro
compounds in good yields. In the case of 12,16 the sensi-
tivity of the Fmoc group under basic conditions resulted in
its partial loss during the elimination step and therefore
only 20% of desired product 24 was obtained. This result
was unexpected because complete removal of the Fmoc
group in the corresponding 1-O-silylated monosaccharide
was only achieved after 16 hours,18 however 24 was gen-
erated in only a few minutes. The successful nitration was
confirmed in compounds 23–26 on the basis of their NMR In conclusion, an efficient and simple method for the gly-
spectral data. The shift of the ethylenic proton H-1 from cosylation using glycals as acceptors is described. This
d = 6.5 ppm to d = 8.2 ppm together with the downfield way disaccharides were prepared, which can be used as
shifts of the signals for C-1 from d = 143 ppm to d = 154 key intermediates for the synthesis of various important
ppm and C-2 from d = 103 ppm to d = 137 ppm clearly classes of glycoconjugates. For instance, regioselective
proved the structure of these compounds.
C-2 nitration, then stereoselective threonine addition, and
development of a new, convenient procedure for nitro
group reduction led to useful building blocks for O-glyco-
peptide synthesis.
Having demonstrated the efficiency of this glycosylation
and nitration method, we decided to improve the synthesis
of the key intermediates 35 and 36,11 required for the for-
mation of core 1 derived mucins or for antifreeze glyco-
proteins (Scheme 4).
Acknowledgment
To this end, compound 8 was converted into per-O-benzy-
lated derivative 27 by the sequence desilylation, deacetyl-
ation, and perbenzylation. Next, glycal 27 underwent
This work was supported by the Deutsche Forschungsgemeinschaft,
the European Community (Grant No. HPRN-CT-2000-00001/
GLYCOTRAIN), and the Fonds der Chemischen Industrie. N. B. is
grateful for an E.U. Network Fellowship.
Scheme 3 Nitration of compounds containing a benzylidene acetal.
Synlett 2004, No. 5, 836–840 © Thieme Stuttgart · New York

LETTER
Efficient Methods for Glycosidations with Glycals
839
Scheme 4 Example of a synthesis of a core 1 building block used for glycopeptide synthesis. a) TBAF, THF; b) NaOMe, MeOH; c) BnBr,
NaH, DMF, (61% three steps); d) HNO3, Ac2O; e) Et3N, CH2Cl2, (75% two steps); f) t-BuOK, Toluene; g) Zn, HCl/HOAc/H2O/THF; h) Ac2O,
pyridine; i) Pd/C, H2, HOAc, MeOH; j) Ac2O, pyridine, 71% (two steps); k) TFA, CH2Cl2, (90%); l) Fmoc-ONSu, NaHCO3, MeCN, H2O, 81%.
Schmidt, R. R. Synlett 2003, 1355. (g) Winterfeld, G. A.;
Das, J.; Schmidt, R. R. Eur. J. Org. Chem. 2000, 3047.
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(15) General Procedure for the Glycosylation: A mixture of
trichloroacetimidate (4.2 mmol), and galactal (4.7 mmol) in
anhyd CH2Cl2 (70 mL) was stirred for 1 h at r.t. under dry Ar,
Synlett 2004, No. 5, 836–840 © Thieme Stuttgart · New York

840
J. Geiger et al.
LETTER
then cooled to –20 °C. A solution of 0.1 M Sn(OTf)2 in
MeCN (0.42 mmol) was added, and the mixture was stirred
for 10 min at –20 °C. Et3N was added. Evaporation of the
solvent and purification by chromatography on silica gel
yielded the target disaccharide.
(18) Following one referee, this result may be due to nitration of
Fmoc.
(19) Oppolzer, W.; Tamura, O. Tetrahedron Lett. 1990, 31, 991.
(20) General Procedure for the Reduction of the Nitro
Group: The nitro compound (0.98 mmol) was dissolved in
a mixture of THF (75 mL), concd HCl (3 mL), HOAc (16
mL), H2O (30 mL) and cooled to 0 °C. Zn dust (24 mmol)
was added. After stirring for 2 h at 0 °C the Zn was filtrated,
the reaction mixture was diluted with CH2Cl2, washed with
H2O, sat. aq NaHCO3, and H2O, and dried over anhyd
MgSO4. Evaporation of the solvents and conventional
acetylation (Ac2O in pyridine) of the residue followed by
concentration of the mixture and purification by
chromatography on silica gel afforded the corresponding N-
acetamido glycoside.
(21) (a) Lüning, B.; Norberg, T.; Tejbrant, I. Glycoconjugate J.
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Chem. Soc., Perkin Trans. 1 1997, 2359.
(16) NMR-physical data: 8 [d (1-Hb) = 4.52, J1,2 = 8.0 Hz); 10 {d
(1-Hb) = 4.70, J1,2 = 7.9 Hz, [a]D +2 (c 0.5, CHCl3)}; 12 {d
(1-Hb) = 4.90, J1,2 = 7.9 Hz, [a]D +24 (c 1.6, CHCl3)}; 14 {d
(1-Hb) = 4.88, J1,2 = 8.0 Hz}; 16 {b: d (1-Hb) = 4.51, J1,2
7.3 Hz, a: d (1-Hb) = 4.95, J1,2 = 3.5 Hz}; 18 after
=
debenzylation and peracetylation [d (1-Hb) = 4.63, J1,2 = 7.7
Hz]; 20 [d (1-Hb) = 4.68, J1,2 = 8.1 Hz]; 22 [d (1-Hb) = 4.69,
J1,2 = 7.81 Hz); 31 [d (1-Ha) = 5.43, J1,2 = 4.8 Hz,
d (1-Hb) = 4.77, J1,2 = 7.9 Hz]; 32 [d (1-Ha) 5.39, J1,2
=
4.1 Hz, d (1-Hb) 4.74, J1,2 = 7.3 Hz]; 33 [d (1-Ha) = 4.87,
J1,2 = 3.6 Hz]; 36 [d (1-Ha) 4.85, J1,2 = 3.6 Hz].
(17) Belot, F.; Rabuka, D.; Fukuda, M.; Hindsgaul, O.
Tetrahedron Lett. 2002, 43, 7743.
Synlett 2004, No. 5, 836–840 © Thieme Stuttgart · New York