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Abstract—The bacterial translocase MraY has recently been demonstrated as a prime target for the development of new antibiotics. We
describe a straightforward synthesis of a new inhibitor 1 of this enzyme. The two key steps involve a tandem nucleophilic epoxide ring
opening of C2-symmetrical bis-epoxide and subsequent O-heterocyclisation, followed by O-glycosylation. The in vitro biological
evaluation of 1 at 2 mM showed an 81% of inhibition of the MraY activity. Therefore, congeners of 1 should permit detailed SAR
investigations for the discovery of novel antibacterials.
Ó 2008 Elsevier Ltd. All rights reserved.
OH O OH
O - O- O
HOO NH O O HO
P 8 2 O
AcHN O- O- O AcHN O- O-
O O O N O O O O
P P O P P
O O 8 2
Pentapeptide O
O O Pentapeptide O O
HO OH NH
UDP-Mur-N-Ac-pentapeptide - O- Lipid I
O O N O
P O
O
HO OH
* Corresponding authors. Tel.: +33 142862181 (C.G.-P.); tel.: +33 142862176; fax: +33 142868387 (Y.L.M.); e-mail addresses: christine.gravier-
pelletier@univ-paris5.fr; yves.le-merrer@univ-paris5.fr
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.037
398 A. Clouet et al. / Tetrahedron: Asymmetry 19 (2008) 397–400
R2
R3O2C O CO2H O
O O
O N O NH
O
N NH
O NH N O
O N O N O
O O O O O O
O 2 O
H2N H2N
H2N OH 3'
HO HO OH HO OH
HO R1 HO OH HO OH
O O
O O NH
NH F
N3
NH 4 N O
N O
H O
O O N O O O O O
BSTFA, CH3CN O N3
HO
BnO OBn
BnO OBn then Mg(ClO4)2, Δ BF3.OEt2, CH2Cl2
O O
BnO OBn M.S., -60°C
46%
2 3 87% 5
O O
NH NH
N O N O
O O
O O H2, Pd, AcOH O O TFA, H2O
H2N N3
HO OH 72% BnO OBn 80%
HO OH HO OH
1 6
13. Brandish, P. E.; Kimura, K.; Inukai, M.; Southagate, R.; (c) Saladino, R.; Ciambecchini, U.; Hanessian, S. Eur. J. Org.
Lonsdale, J. T.; Bugg, T. D. H. Antimicrob. Agents. Chemo- Chem. 2003, 4401; (d) Busca, P.; McCort, I.; Prangé, T.; Le
ther. 1996, 40, 1640. Merrer, Y. Eur. J. Org. Chem. 2006, 2403.
14. Dini, C.; Didier-Laurent, S.; Drochon, N.; Feteanu, S.; 19. There are some typographical errors in Ref. 18c. For
Guillot, J. C.; Monti, F.; Uridat, E.; Zhang, J.; Aszodi, J. example, in Scheme 1, bis-epoxide 3 and related compounds
Bioorg. Med. Chem. Lett. 2002, 12, 1209. 4–9 are described with a L -manno and a D -gulo configuration,
15. For correlation of molecular flexibility and inhibitory activ- respectively, instead of a D -manno or a L -gulo configuration
ities, see for example: (a) Mai, A.; Massa, S.; Ragno, R.; and in Scheme 2, compounds 13–18 should have an L -gluco
Cerbara, I.; Jesacher, F.; loidl, P.; Brosch, G. J. Med. Chem. configuration.
2003, 46, 512; (b) Narsinghani, T.; Chaturvedi, S. C. Bioorg. 20. Hirano, S.; Ichikawa, S.; Matsuda, A. Angew. Chem., Int. Ed.
Med. Chem. Lett. 2006, 16, 461. 2005, 44, 1854.
16. Dini, C.; Drochon, N.; Guillot, J.-C.; Mauvais, P.; Walter, P.; 21. For similar glycosylation reaction involving the 5-azido-1,5-
Aszodi, J. Bioorg. Med. Chem. Lett. 2001, 11, 533. dideoxy-2,3-di-O-isopropylidene-1-fluoro-D -ribofuranose, see:
17. Poitout, L.; Le Merrer, Y.; Depezay, J.-C. Tetrahedron Lett. Ginisty, M.; Gravier-Pelletier, C.; Le Merrer, Y. Tetrahedron:
1994, 35, 3293. Asymmetry 2006, 17, 142.
18. For analogous tandem reaction on bis-epoxides, see: (a) 22. Nevertheless, a sample of pure compound 1 could be
Poitout, L.; Le Merrer, Y.; Depezay, J.-C. Tetrahedron Lett. obtained after HPLC and flash chromatographic purification.
1995, 36, 6887; (b) Le Merrer, Y.; Sanière, M.; McCort, I.; 23. Bouhss, A.; Crouvoisier, M.; Blanot, D.; Mengin-Lecreulx,
Dupuy, C.; Depezay, J.-C. Tetrahedron Lett. 2001, 42, 2661; D. J. Biol. Chem. 2004, 279, 29974.