C. Chevrier et al. / Tetrahedron Letters 45 (2004) 5363–5366
5365
Figure 1. ORTEP view of adduct 11a.
The 1H NMR spectrum of 11a,b and 12a,b showed
vicinal coupling constants J (H-3a, H-4) ¼ ca. 0, con-
firming a trans relation between both protons H-3a and
H-4. For the minor adduct 11b, exo stereostructure was
proven by the observation of strong NOE of 10% on the
signal of H-6 by irradiation of H-2.
5. Conclusion
Efficient conversion of (3R,4R,5S)-3,4-dihydroxy-5-
methylpyrroline (2) into 2-substituted (2S,3S,4R,5S)-
3,4-dihydroxy-5-methylpyrrolidine have been devel-
oped. The new C-glycosides containing the a-
L-lyxo-
furanosides moiety are not better inhibitors of a-
fucosidase from bovine kidney than 2, except for 15,
which bears a 2-(hydroxymethyl) substituent.
L
-
Transformation of 11a into ester 13 was carried out
according to the Bayon’s method10;11;14 (N-benzylation
with benzyl bromide in CHCl3 and subsequent thermal
rearrangement at 50 °C). Phenyl ester replacement with
hydroxylamine in pyridine at 30 °C11 gave protected
hydroxamic acid 16 in 50% yield. Reduction of 13 with
AlLiH4 in dry ether gave alcohol 14 in 61% yield.
Acknowledgements
Ring opening of phosphonate 12b generated the pyr-
rolidineethylphosphonate 19 in 21% overall yield by
hydrogenolysis of the N–O bond into 18, followed by
N-protection and then elimination of the b-hydroxy
group in two steps. This implied formation of a xan-
thate16–19 by reaction with thiocarbonyldiimidazole in
THF and radical fragmentation with AIBN and
Bu3SnH in toluene heated under reflux.
The support of the Centre National de la Recherche
Scientifique (UMR 7015) is gratefully acknowledged.
ꢁ
We also wish to thank the Ministere de l’Enseignement
et de la Recherche for a Ph.D. grant to C.C.
References and notes
N,O-Deprotection of 14, 16, 18, 19 by hydrolysis with
6 N HCl in EtOH followed by hydrogenolysis over Pd–
C gave the corresponding diols 15, 17, 20, 21 in 87–100%
yield.
1. Fleet, G. W. J.; Shaw, A. N.; Evans, S. V.; Fellows, L. E.
J. Chem. Soc., Chem. Commun. 1985, 841–842.
2. Winchester, Br.; Barker, C.; Baines, S.; Jacob, G. S.;
Namgoong, S. K.; Fleet, G. W. J. Biochem. J. 1990, 265,
277–282.
3. Wischnat, R.; Martin, R.; Takayama, S.; Wong, C.-H.
Bioorg. Med. Chem. Lett. 1998, 8, 3353–3358.
4. Takayama, S.; Martin, R.; Wu, J.; Laslo, K.; Siusdak,
G.; Wong, C.-H. J. Am. Chem. Soc. 1997, 119, 8146–
8151.
4. Inhibition studies
We have evaluated the C-a-fucosides 15, 17, 20, 21 as
inhibitors of bovine kidney L-fucosidase, a model en-
ꢀ
5. Joubert, M. Ph.D. Thesis, Universite de Haute-Alsace
zyme for fucose recognition. The results are reported in
Table 1. For comparison we have also reported Ki values
(France), 2000; Joubert, M.; Defoin, A.; Tarnus, C.;
Streith, J. Synlett 2000, 9, 1366–1368.
for the amino-L L
-lyxose 25 and the imino- -lyxitol 22.5
6. Vasella, A. Helv. Chim. Acta 1977, 60, 1273–1295.
7. Another synthesis of protected 5-deoxyribose 6b was
recently published: Jensen, H. H.; Jensen, A.; Hazell,
R. G.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2002, 1190–
1198.
8. Holzapfel, C. W.; Crous, R. Heterocycles 1998, 48, 1337–
1341.
9. Mizuno, K.; Kimura, Y.; Otsuji, Y. Synthesis 1979, 688,
Used solvent was ethyl ether in place of benzene (yield
65%).
All inhibitors were competitive. Among the various
substitutions explored in this work, it appears clearly
that alcohol 15 is as potent as the amino-L-lyxose 2 with
a Ki value of 8 nM. Compared with 2, 15 is much more
stable in solution.
Table 1. Bovine kidney a- -fucosidase inhibition values (Ki in lM) for
L
pyrrolidine-diols 15, 17, 20, 21, amino-
225
L
-lyxose 25 and imino-
L
-lyxitol
ꢀ
10. Bayon, P.; de March, P.; Figueredo, M.; Font, J.
Tetrahedron 1998, 54, 15691–15700.
11. Chevrier, C.; Defoin, A. Synthesis 2003, 1221–1224.
12. DeShong, Ph.; Dicken, C. M.; Staib, R. R.; Freyer, A. J.;
Weinreb, St. M. J. Org. Chem. 1982, 47, 4397–4403.
Compounds
a- -Fucosidase
2
22
15
17
20
21
L
0.010 0.050 0.008 5.1
0.040 0.1