B. Zhu et al. / Tetrahedron Letters 46 (2005) 1783–1785
1785
H
N
Acknowledgements
O
CHO
O
R
O
O
O
The authors wish to thank Darren Abbanat and Bar-
bara D. Foleno for conducting the microbiological tests.
NH
a, b
O
NH
OAc
O
O
OH
N
O
O
N
O
O
O
O
O
O
N
References and notes
O
O
11
10
1. For recentreviews, see: (a) Zhanel, G. G.; Dueck, M.;
Hoban, D. J.; Vercaigne, L. M.; Embil, J. M.; Gin, A. S.;
Karlowsky, J. A. Drugs 2001, 61, 443–498; (b) Blondeau,
J. M.; DeCarolis, E.; Metzler, K. L.; Hansen, G. T. Exp.
Opin. Investigat. Drugs 2002, 11, 189–215.
2. (a) Amsden, G. W. J. Antimicrob. Chemother. 1999, 44, 1–
6; (b) Lonks, J. R.; Garau, J.; Mederios, A. A. J.
Antimicrob. Chemother. 2002, 50, 87–91.
R =
R =
N
11b (23%)
11a (39%)
R =
R =
N
N
N
11d (46%)
11c (45%)
3. For recentreviews, see: (a) Wu, Y.-J.; Su, W.-G. Curr.
Med. Chem. 2001, 8, 1727–1758; (b) Zhanel, G. G.;
Walters, M.; Noreddin, A.; Vercaigne, L. M.; Wierzbow-
ski, A.; Embil, J. M.; Gin, A. S.; Douthwaite, S.; Hoban,
D. J. Drugs 2002, 62, 1771–1804; (c) Asaka, T.; Manaka,
A.; Sugiyama, H. Curr. Top. Med. Chem. 2003, 3, 961–
989.
4. Denis, A.; Agouridas, C.; Auger, J.-M.; Benedetti, Y.;
Bonnefoy, A.; Bretin, F.; Chantot, J.-F.; Dussarat, A.;
Fromentin, C.; Gouin DÕAmbrieres, S.; Lachaud, S.;
Laurin, P.; Le Martret, O.; Loyau, V.; Tessot, N.; Pejac,
J.-M.; Perron, S. Bioorg. Med. Chem. Lett. 1999, 9, 3075–
3080.
5. Kaneko, T.; McArthur, H.; Sutcliffe, J. Exp. Opin. Ther.
Patents 2000, 10, 403–425.
6. Baker, W. R.; Clark, J. D.; Stephens, R. L.; Kim, K. H. J.
Org. Chem. 1988, 53, 2340–2345.
7. Jones, P. H.; Perun, T. J.; Rowley, E. K.; Baker, E. J. J.
Med. Chem. 1972, 15, 631–634.
Scheme 3. Reagents and conditions: (a) ROC(O)NH2, Et3SiH, TFA,
CH3CN, 60 °C; (b) MeOH, rt, yields are for two steps.
hol 9. Under the acidic hydrolysis conditions, the di-
methyl acetal moiety on the C11,C12-benzoxazine was
also converted to the corresponding aldehyde. The C3-
hydroxyl group of compound 9 was then oxidized to
give the corresponding C3-ketone 10 (Scheme 2).
Compound 10 was then reacted with a number of pri-
mary carbamates under reductive alkylation conditions
(triethylsilane, trifluoroacetic acid, acetonitrile) to install
the aryl side chains through a carbamate linkage. Final-
ly, deprotection of the C20-hydroxyl group led to the
fully elaborated 11,12-benzoxazine ketolide compounds
11 in modestot good yields ( Scheme 3).
8. Elliott, R. L.; Pireh, D.; Griesgraber, G.; Nilius, A. M.;
Ewing, P. J.; Bui, M. H.; Raney, P. M.; Flamm, R. K.;
Kim, K.; Henry, R. F.; Chu, D. T. W.; Plattner, J. J.; Or,
Y. S. J. Med. Chem. 1998, 41, 1651–1659.
9. The reaction initially gave a mixture of 4 and presumably
its C10-epimer, which subsequently equilibrated to 4
under basic conditions. Similar results were observed in
the formation of C11,C12-cyclic carbamate, see Phan, L.
T.; Clark, R. F.; Rupp, M.; Or, Y. S.; Chu, D. T. W.; Ma,
Z. Org. Lett. 2000, 2, 2951–2954.
10. (a) Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1965,
87, 5661; (b) Agouridas, C.; Denis, A.; Auger, J.-M.;
Benedetti, Y.; Bonnefoy, A.; Bretin, F.; Chantot, J.-F.;
Dussarat, A.; Fromentin, C.; Gouin DÕAmbrieres, S.;
Lachaud, S.; Laurin, P.; Le Martret, O.; Loyau, V.;
Tessot, N. J. Med. Chem. 1998, 41, 4080–4100.
11. Prepared from reaction of 4-fluoro-3-nitrobenzaldehyde
with trimethyl orthoformate [CH(OCH3)3] with catalytic
pyridinum p-toluenesulfonate in CH2Cl2.
In conclusion, the synthesis of a novel series of 3-keto-
11,12-benzoxazine derivatives of erythromycin A was
developed. The C11,C12-benzoxazine structure was con-
structed by a mild and stereoselective intramolecular
Michael addition. Ketolide compound 10 was a versatile
intermediate for incorporation of a variety of aryl side
chains. However, preliminary microbiological tests
showed that the unsubstituted and substituted 11,12-
benzoxazine ketolides 5 and 11 were significantly less ac-
tive than telithromycin. These results indicated that the
benzoxazine ring is not well tolerated at the C11,C12
positions of the ketolides. The presence of this group
in that region may actually perturb binding of the keto-
lides to the bacterial ribosome. Therefore, our future
work will focus on the design and synthesis of ketolides
with alternate functionalities at the C11/C12 region to
achieve improved antibacterial activity.