´
I. P. Jakopovic et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3527–3530
3530
Table 2
Antibacterial activities of macrolides 1–27
Strain
MIC (lg/mL)
1
2
3
4
5
6
7
8
9
10–12
16–18
19–27
S. aureus
32
1
4
0.5
16
0.25
1
>64
32
64
16
>64
4
16
2
2
2
>64
>64
>64
2
2
16
>64
>64
4
32
8
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
S. pneumoniae
S. pyogenes
M. catarrhalis
H. influenzae
<0.125
<0.125
<0.125
8
<0.125
<0.125
<0.125
2
<0.25
<0.25
2
>64
>64
>64
>64
>64
64
the desired 20,30-fused 3-methyl-1,3-oxazolidin-2-ones 16–18 can
be readily achieved using sodium hydride (see Supplementary data
for reaction conditions).
ˇ
´
´
2. (a) Bauer, J.; Vine, M.; Coric, I.; Bosnar, M.; Pašalic, I.; Turkalj, G.; Lazarevski, G.;
ˇ
H.; Hirono, S.; Shima, H.; Akagawa, K. S.; Omura, S.; Sunazuka, T. Bioorg. Med.
Chem. Lett. 2011, 21, 3373; (c) Mereu, A.; Moriggi, E.; Napoletano, M.;
Regazzoni, C.; Manfredini, S.; Mercurio, T. P.; Pellacini, F. Bioorg. Med. Chem.
Lett. 2006, 16, 5801; (d) Fecik, R. A.; Nguyen, P. L.; Venkatraman, L. Curr. Opin.
Drug Discov. Devel. 2005, 8, 741.
In order to attach other alkyl substituents to the 1,3-oxazolidin-
2-one ring of 10–12, N-alkylations using alkyl iodides were ex-
plored. Simple alkylation reactions of compound 10 using a few
chosen alkyl iodides in the presence of a base such as diisopropyl-
ethylamine or sodium hydride proved unsuccessful. Either no
alkylation was observed or, when sodium hydride was used, con-
siderable degradation of macrolides occurred after prolonged reac-
tion times. Successful N-alkylations of 10–12 were achieved in the
presence of tetrabutylammonium iodide and cesium carbonate18
to afford a series of novel 30-N-alkylated macrolides 19–27 in good
yields after chromatographic purifications (Scheme 3).19 N-allyla-
tion of 1,3-oxazolidin-2-one 12 was accomplished using palla-
dium-catalyzed allylation with allyl tert-butyl carbonate
(Scheme 4) to afford 3-allyl-3-oxazolidin-2-one 27 in a good yield
(52%). Structures of all new macrolides were confirmed by combin-
ing NMR (1D and 2D) and MS data (see Supplementary data). In
general, no solubility problems were detected.
3. Morimoto, S.; Misawa, Y.; Asaka, T.; Kondoh, H.; Watanabe, Y. J. Antibiot. 1990,
43, 570.
4. Yoshida, K.; Sunazuka, T.; Nagai, K.; Sugawara, A.; Cho, A.; Nagamitsu, T.;
Harigaya, Y.; Otoguro, K.; Akagawa, K. S.; Omura, S. J. Antibiot. 2005, 58, 79.
5. (a) Heggelund, A.; Romming, C.; Undheim, K. Eur. J. Med. Chem. 2008, 43, 1657;
(b) Heggelund, A.; Undheim, K. Bioorg. Med. Chem. 2007, 15, 3266; (c) Tardrew,
P. L.; Mao, J. C. H.; Kenney, D. Appl. Microbiol. 1969, 18, 159.
6. (a) Breton, P.; Hergenrother, P. J.; Hida, T.; Hodgson, A.; Judd, A. S.; Kraynack, E.;
Kym, P. R.; Lee, W.-C.; Loft, M. S.; Yamashita, M.; Martin, S. F. Tetrahedron 2007,
63, 5709; (b) Martin, S. F.; Yamashita, M. J. Am. Chem. Soc. 1991, 113, 5478.
ˇ ´
7. Vujasinovic´, I.; Marušic´ Ištuk, Z.; Kapic´, S.; Bukvic´ Krajacic, M.; Hutinec, A.;
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´
´
´
Ðilovic, I.; Matkovic-Calogovic, D.; Kragol, G. Eur. J. Org. Chem. 2011, 3, 2507.
8. Maragni, P.; Melotto, E.; Michieletto, I.; Restelli, A. PharmaChem 2006, 5, 28.
9. Lartey, P. A.; Nellans, H. N.; Faghih, R.; Petersen, A.; Edwards, C. M.; Freiberg, L.;
Quigley, S.; Marsh, K.; Klein, L. L.; Plattner, J. J. J. Med. Chem. 1995, 38, 1793.
10. Denis, A.; Renou, C. Tetrahedron Lett. 2002, 43, 4171.
11. Stenmark, H. G.; Brazzale, A.; Ma, Z. J. Org. Chem. 2000, 65, 3875.
12. Flynn, E. H.; Murphy, H. W.; McMahon, R. E. J. Am. Chem. Soc. 1955, 77, 3104.
13. Liu, Y. Int. Patent WO 2007/067281. CAN 147:53099.
The antibacterial activities of novel macrolides having N-
substituted 1,3-oxazolidin-2-ones fused to the desosamine sugar
were assessed on a panel of five common respiratory pathogens
and compared with parent macrolides 1–3, as well as with the
3’-N-demethylated compounds 4–6 and 30-N,N-didemethylated
compounds 7–9 (Table 2.).20 The removal of one methyl group
from 30-N-position (4–6) already slightly diminishes antibacterial
activity. Removal of the second methyl group (7–9) further reduces
antibacterial activity but not completely for 2 and 3. However, for-
mation of 1,3-oxazolidin-2-ones 10–12, as well as N-substituted-
1,3-oxazolidin-2-ones (16–27) completely abolishes antibacterial
activity of parent macrolides 1–3.
In conclusion, a simple method for the synthesis of novel 14-
and 15-membered macrolide derivatives having N-substituted-
1,3-oxazolidin-2-ones fused to the desosamine sugar have been
envisioned and developed. The method is suitable for large scale
synthesis of prospective drug candidates. Since these desos-
amine-modified macrolides completely suppress the antibacterial
activity of the parent antibacterial macrolides, their evaluation as
potential agents for other biological targets is currently ongoing.
14. General procedure for 30-N,N-didemethylation: To a solution of the 30-N-demethyl
macrolide 4–58 in methanol (c = 0.06 g/L), cooled to 0 °C, sodium methoxide
(13 equiv), tris(hydroxymethyl)-aminomethane (13 equiv), and iodine (3 equiv)
were added. In the case of scaffold 68 addition of tris(hydroxymethyl)-
aminomethane was not necessary. The reaction mixture was stirred for 5 h at
0 °C and then at rt overnight. The solvent was evaporated, residue dissolved in
dichloromethane, washed with saturated aq NaHCO3 solution, and dried over
Na2SO4. The solvent was evaporated and the product purified using column
chromatography (eluent CH2Cl2/CH3OH/NH4OH (90:9:1.5)).
15. Garigipati, R. S.; Freyer, A. J.; Whittle, R. R.; Weinreb, S. M. . J. Am. Chem. Soc.
1984, 106, 7861.
16. Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987, 26, 894.
17. General procedure for 20,30-(1,3-oxazolidine-2-one) formation: To a solution of the
30-N,N-didemethyl macrolide 7–9 in dichloromethane (c = 0.025 g/L), cooled to
0 °C, 4-nitrophenyl chloroformate (1.15 equiv) and triethylamine (1.15 equiv)
were added. The reaction mixture was stirred for 2 h at 0 °C and overnight at rt,
diluted with dichloromethane, washed with saturated aq NaHCO3 solution, and
dried over K2CO3. The solvent was evaporated and products purified by column
chromatography (eluent CH2Cl2/CH3OH/NH4OH (90:5:0.5)).
18. Salvatore, R. N.; Shin, S. I.; Flanders, V. L.; Woon Jung, K. Tetrahedron Lett. 2001,
42, 1799.
19. General procedure for the alkylation of 10–12: To a solution of the corresponding
30-N,N-didemethylated macrolides 4–6 in N,N-dimethylformamide (c = 0.06 g/
mL) under nitrogen atmosphere, cesium carbonate (1.5 equiv) and
tetrabutylammonium iodide (1.5 equiv) were added. After stirring for 30 min
at rt, corresponding alkyl iodide or benzyl bromide (1.5 equiv) was added and
stirring continued for 5 h. The reaction mixture was diluted with ethyl acetate,
washed with saturated aq NaHCO3 solution, and dried over Na2SO4. The solvent
was evaporated and products purified by column chromatography (eluent
CH2Cl2/CH3OH/NH4OH (90:2.5:0.25)).
20. Minimum inhibitory concentrations (MICs) were determined for all new
compounds on a panel of macrolide susceptible Gram-positive (Staphylococcus
aureus ATCC13709, Streptococcus pneumoniae ATCC149619, Streptococcus
pyogeneses ATCC700294) and Gram-negative (Haemophilus influenzae
ATCC49247, Morexella catarrhalis ATCC23246) bacterial strains MIC values
were determined using microdillution method as recommended by CLSI21 in
appropriate media (Mueller–Hinton broth (MHB) for S. aureus and M. catarrhalis,
MHB supplemented with 5% horse serum for streptococci, and Hemophilus test
medium for H. influenzae) media. Tested compounds were dissolved in DMF
(5 mg/mL) and double diluted in media to give concentration ranges from 64 to
Supplementary data
Supplementary data associated with this article can be found, in
References and notes
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21. Clinical Laboratory Standard Institute CLSI. 2005. Performance Standards for
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S15. Clinical Laboratory Standards Institute, Wayne, PA.
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