Stereoselective glycosidations of olefinated sugars

Article abstract of DOI:10.1016/S0040-4039(02)02251-7

The glycosidation of olefinated sugars using a catalytic amount of boron trichloride or triphenylphosphine hydrobromide proceeded in a highly stereoselective fashion to give the α anomers with good to high yields. The use of camphorsulphonic acid also afforded high stereoselectivity but lower yields were obtained.

Full text of DOI:10.1016/S0040-4039(02)02251-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9065–9068
Stereoselective glycosidations of olefinated sugars†
Pedro A. Colinas,a Albrecht Lieberknechta,b,* and Rodolfo D. Bravoa,*
aLaboratorio de Estudio de Compuestos Orga´nicos, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115,
1900 La Plata, Argentina
bInstitut fu¨r Organische Chemie der Universita¨t Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Received 17 September 2002; revised 7 October 2002; accepted 11 October 2002
Abstract—The glycosidation of olefinated sugars using a catalytic amount of boron trichloride or triphenylphosphine hydrobro-
mide proceeded in a highly stereoselective fashion to give the a anomers with good to high yields. The use of camphorsulphonic
acid also afforded high stereoselectivity but lower yields were obtained. © 2002 Elsevier Science Ltd. All rights reserved.
During the last years the chemistry of C-glycosides has
attracted much attention and the synthesis of C-gly-
cosides analogues of biologically active molecules
became of interest.1 Particular useful are exo-glycals
which are valuable in biological investigations: such
compounds could be used as substrates for glycosidases
to elucidate the enzymatic mechanism.2 Also they are
interesting intermediates in the synthesis of more com-
plex C-glycosidic structures due to the highly reactive
enol ether function.3
Toshima et al. reported the glycosidation of glycals and
different alcohols catalyzed by boron trichloride or
tribromide.5 The method afforded the glycosides with
excellent stereoselectivity in high yields.
The glycosidation of exo-glycals is less addressed in the
literature. Only recently Ikegami et al. have studied the
syntheses of 1%-C-methyl-a-disaccharides by O-glycosi-
dation of 1-methylene sugars catalyzed by trifl-
uoromethansulfonic acid at −78°C.6 During the writing
of this work, Lin et al. reported the addition of alcohols
to exo-glycals, synthesized by a nucleophilic addition of
sugar lactones and subsequent dehydration.7 In that
method no preparation of disaccharides was reported.
Various methods for glycosidations of endo-glycals
have been reported. Mioskowski and Falck described
the preparation of 2-deoxy-glucosides from glucals
using triphenylphosphine hydrobromide.4 The glu-
cosides were obtained with good stereoselectivity (pre-
dominance of the a-anomer in all the cases). Later on
For several years we have been interested in the synthe-
ses of olefinated sugars at the anomeric center via
Scheme 1. Wittig reactions of phosphonium salt 1.
Keywords: Wittig reaction; exo-glycals; O-glycosidation; disaccharides.
* Corresponding authors. Tel.: +54-221-422-6977; fax: +54-221-4222-6947; e-mail: rdb@exactas.unlp.edu.ar
†
Part of this work was presented at XII Argentinian Congress of Chemistry, Santa Fe, Argentina, 9–11 August 2002, Colinas, P. A.; Bravo, R.
D.; Lieberknecht, A.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02251-7

9066
P. A. Colinas et al. / Tetrahedron Letters 43 (2002) 9065–9068
Table 1. Wittig reaction of the phosphonium salt 1a
The mixture of the E and Z isomers was not separated
and used directly in the next step. To a mixture of the
enol ether (0.1 mmol) and the glycosyl acceptors (0.15
mmol) in dry methylenchloride, was added, under
nitrogen, 0.05 equiv. of the catalyst in methylenchloride
at the temperature indicated in Table 2.
exo-Glycal
R
Base
Yield (%) Ratio (E/Z)
2a
2b
p-Chlorophenyl- BuLi
t-BuOK 70
BuLi 65
62
39/61
52/48
18/82
Methyl
a The reactions were carried out in THF at −90°C (2 h) and then 12
h at room temperature.
Purification as usual afforded the glycosides 4a–b and
disaccharides 6a–b and 8a–b (Scheme 2).11 In all the
cases only the a anomeric isomer was found (in the
1
reaction mixture and purified compound). The H, 13C
NMR, 2D COSY (H–H, H–C) and NOESY experi-
ments supported the proposed structures. The presence
of NOE effect between the hydrogen of the methyl
group and the H-5% in compounds 4a–b, the H-5 and
H-5% in compound 6a–b, and H-6 and H-5%in com-
pounds 8a–b confirms the configuration of the gly-
cosides. The high selectivity of the reaction and the
stereochemical outcome is in accord with previous
results found by us and other research groups in the
additions to exo-glycals,3b,6,7,9 and can be explained in
terms of the approach of the nucleophile to the less
hindered face of the enol ether, and also in the forma-
tion of the most thermodynamic stable a-isomer. The
use of 0.10 equiv. of the catalyst only led to lower yields
and they were not improved by using higher quantities
of the glycosyl acceptor. The use of the different cata-
lysts showed no effects on the stereoselectivity of the
reaction but on the yields. Lower quantities of
triphenylphosphine hydrobromide or camphorsul-
phonic acid showed no effect on the yields but longer
reaction times were necessary.
Wittig reaction of glycosyl phosphonium tetra-
fluorborates.8 This methodology was also applied as a
key step in the preparation of a galactopyranosyl ala-
nine.9 Here we describe the stereoselective glycosidation
of tri-substituted exocyclic enol-ethers using boron
trichloride, triphenylphosphine hydrogenbromide or
camphorsulphonic acid as catalyst.
The exo-glycals were prepared by the Wittig reaction of
the a,b-mixture of the 2-deoxigalactosyl phophonium
salt9 1 with p-chlorobenzaldehyde or acetaldehyde to
give the olefinated sugars 2a and 2b (Scheme 1).
After filtration on silica gel the exocyclic enol ethers
were obtained spectroscopically pure in the yields and
E/Z ratios shown in Table 1. The E and Z configura-
tions could be assigned by the chemical shift of the
vinyl protons according to increment calculations done
for olefinic compounds10a and related enol ethers.10b
The vinylic protons of the E isomers are shifted 0.3–0.7
ppm to a lower field than in the case of the Z isomers.
This general trend was found previously by us in the
synthesis of ribofuranosyl exo-glycals8,9 and was confi-
rmed by X-ray analysis of one E-isomer.8 This trend
was applied later by Taylor et al. to assign the configu-
ration of exo-glycals prepared using the Bamberg–
Ba¨cklund rearrangement.8d
In our method very low temperatures are not needed as
in a previous reported synthesis6 and it is possible to
obtain a very valuable class of compounds, which could
be used as marker in biological studies due to the
presence of an aromatic substituent at the anomeric
tetrasubstitued carbon. Also, our methodology used
lower quantities of the nucleophiles as in other recently
reported method.7
Table 2. Glycosidations of enol ethers 2a–b
Enol ether
ROH
Catalyst
Time (min)
Temperature (°C)
Yield (%)
2a
3
BCl3
HBr·PPh3
CSA
BCl3
HBr·PPh3
CSA
BCl3
HBr·PPh3
CSA
BCl3
HBr·PPh3
CSA
BCl3
HBr·PPh3
CSA
BCl3
HBr·PPh3
CSA
30
60
60
10
15
15
30
60
60
10
15
15
30
60
60
10
15
15
0
84
73
56
80
61
48
89
72
60
78
70
50
77
57
30
78
53
40
Rt
Rt
0
Rt
Rt
0
Rt
Rt
0
Rt
Rt
0
Rt
Rt
0
Rt
Rt
2b
2a
2b
2a
2b
3
5
5
7
7

P. A. Colinas et al. / Tetrahedron Letters 43 (2002) 9065–9068
9067
Scheme 2. Reagents and conditions: (i) Catalyst (0.05 equiv.), CH2Cl2, temperature and time as indicated in Table 2.
Further applications of the above method for the syn-
thesis of various disaccharides will be presented in due
course. Also, the deprotection of the disaccharides and
enzymatic studies are currently in progress.
3. (a) Ousset, J. B.; Mioskowski, C.; Yang, Y.-L.; Falck, J.
R. Tetrahedron Lett. 1984, 25, 5903–5906; (b) Rajan-
Babu, T. V.; Reddy, G. S. J. Org. Chem. 1986, 51,
5458–5461; (c) Paterson, D. E.; Griffin, F. K.; Alcaraz,
M. L.; Taylor, R. K. Eur. J. Org. Chem. 2002, 1323–
1336; (d) Yang, W.-B.; Yang, Y.-Y.; Gu, Y.-F.; Wang,
S.-H.; Chang, C.-C.; Lin, C. H. J. Org. Chem. 2002, 67,
3773–3782.
Acknowledgements
The authors wish to thank Setcip (Argentina) the DLR
(Germany) for numerous short-term appointments as
well as for financial support, Dr. M. Coyanis and Mr.
J. Rebell for NMR measurements, Mrs. G.
Kraschewski and Professor Dr. V. Ja¨ger for general
support.
4. Bolit, V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J. Org.
Chem. 1990, 55, 5812–5813.
5. Toshima, K.; Nagai, H.; Ushiki, Y.; Matsumura, S.
Synlett 1998, 1007–1008.
6. Li, X.; Ohtake, H.; Takahashi, H.; Ikegami, S. Tetra-
hedron 2001, 57, 4283–4295.
7. Chang, C.-F.; Yang, W.-B.; Chang, C.-C.; Lin, C.-H.
Tetrahedron Lett. 2002, 43, 6515–6519.
References
8. Lieberknecht, A.; Griesser, H.; Bravo, R. D.; Colinas, P.
A.; Grigera, R. J. Tetrahedron 1998, 54, 3159–3168. For
other syntheses, see: (a) Somsa´k, L. Chem. Rev. 2001,
101, 81–135 and references cited therein; (b) Csuk, R.;
Gla¨nzer, B. I. Tetrahedron 1991, 47, 1655–1664; (c) Xie,
J.; Molina, A.; Czernecki, S. J. Carbohydr. Chem. 1999,
481–489; (d) Griffin, F. K.; Paterson, D. E.; Murphy, P.
V.; Taylor, R. J. K. Eur. J. Org. Chem. 2002, 1305–1322.
1. Levy, D. E.; Tang, C. The Chemistry of C-glycosides;
Pergamon Express: Oxford, 1995.
2. (a) Lehmann, J.; Schlesselmann, P. Carbohydr. Res. 1983,
113, 93–99; (b) Hehre, E. J.; Brewer, C. F.; Uchiyama, T.;
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P. A. Colinas et al. / Tetrahedron Letters 43 (2002) 9065–9068
9. Lieberknecht, A.; Griesser, H.; Kra¨mer, B.; Bravo, R. D.;
8:2) to give the product 6a as a colorless syrup. IR (neat):
2936.3, 1492.6, 1453.6, 1369.8, 1208.3, 1093.8, 961.4,
869.4, 735, 697. 1H NMR l=1.32 (s, 3H, CH3-C-O), 1.49
(s, 3H, CH3-C-O), 1.83 (dd, 1H, J=4.4, J=12.0, 2%-Ha),
1.95 (t, 1H, J=12.0, 2%-Hb), 2.84 (AB, 1H, J=14.1,
CH2-Ph-Cl), 2.93 (AB, 1H, J=14.1, CH2-Ph-Cl), 3.28 (s,
3H, CH3-O), 3.53 (m, 2H, 5-H), 3.63 (m, 2H, 6%-H), 3.8
(t, 1H, J=6.4, 4%-H), 3.87 (bs, 1H, 3%-H), 3.9 (m, 1H,
5%-H), 4.5 (t, 1H, J=2.3, 4-H), 4.26–2.6 (m, 7H, 2-H,
3-H, 2×CH2-Ph, 1H, CH2-Ph), 4.87 (AB, 1H, J=11.7,
CH2Ph), 4.96 (bs, 1H, 1-H), 7.14–7.34 (m, 19H, Ph). 13C
Colinas, P. A.; Grigera, R. J. Tetrahedron 1999, 55,
6475–6482.
10. (a) Pascual, C.; Meier, J.; Simon, W. Helv. Chim. Acta
1969, 49, 164–168; (b) Pretsch, E.; Bu¨hlmann, P.;
Affolter, C. Structure Determination of Organic Com-
pounds; 3rd English ed.; Springer Verlag: Berlin, 2000.
11. Preparation of glycoside 6a: To a mixture of 55 mg (0.1
mmol) of the enol ether 2a (aprox E/Z 52:48) and 31 mg
(0.15 mmol) of the methyl-2,3-di-O-isopropilidenribo-
furanoside 5 in 1 ml of dry methylenchloride was added,
under nitrogen, 0.05 equiv. of the catalyst in
methylenchloride. After stirring for the time indicated,
the mixture was quenched with saturated NaHCO3. The
organic layer was separated and washed with brine, dried
over anhydrous Na2SO4, and concentrated in vacuo to
afford a yellow oil. The residue was purified by chro-
matography on silica gel (eluent: hexane/ethyl acetate,
NMR l=25.0 (C
42.2 (CH2-Ph-Cl), 54.9 (C
70.5 (CH2Ph), 71.6 (C-4%), 72.0 (C-5%), 73.4 (C
(CH2Ph), 75.7 (C-3%), 82.3 (C-4), 85.2 (C-2), 85.5 (C-3),
101.3 (C-1%), 109.4 (C-1), 112.3 ((CH3)2C), 127.2–128.4,
6
H3-C-O), 26.5 (C
H3-O), 61.0 (C-5), 69.3 (C-6%),
H2Ph), 73.7
6 H3-C-O), 33.4 (C-2%),
6
6
6
6
6
131.6, 134.8, 138.1, 138.4, 139.1. HRMS (FAB): calcd for
C43H49O9ClNa: 767.2963, found: 767.2954.