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5. Jungheim, L. N.; Boyd, D. B.; Indelicato, J. M.; Pasini, C.
E.; Preston, D. A.; Alborn, W. E., Jr. J. Med. Chem. 1991,
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Cohen. This could explain the poor activity of 1d. On
ꢀ
the other hand, acid 1g with a distance of 3.22 A should
have been more active.
6. (a) Nozaki, Y.; Katayama, N.; Ono, S.; Tsubotani, S.;
Harada, S.; Okazaki, H.; Nakao, Y. Nature 1987, 325,
179; (b) Nakao, Y. In Recent Advances in the Chemistry of
b-Lactam Antibiotics; Bentley, P. H., Southgate, R., Eds.;
RSC: London, 1989; Special Publication No 70, Chapter
8, p 119.
7. (a) Williams, R. M.; Lee, B. H. J. Am. Chem. Soc. 1986,
108, 6431; (b) Williams, R. M.; Lee, B. H.; Miller, S.;
Anderson, O. P. In Recent Advances in the Chemistry of b-
Lactam Antibiotics; Bentley, P. H., Southgate, R., Eds.;
RSC: London, 1989; pp 106–118.
8. Greenberg, A. In Strucutre and Reactivity; Liebman, J. F.,
Greenberg, A., Eds.; VCH: New York, 1988; Vol. 7,
pp 139–178.
9. Hall, H. K., Jr.; El-Shekeil, A. Chem. Rev. 1983, 83, 549.
10. Beddoes, R. L.; Davies, M. P.; Thomas, E. J. J. Chem.
Soc., Chem. Commun. 1992, 7, 538.
As there is almost no difference of activity between 1d
and 1g and that both compounds displayed comparable
short half-lives, we think that the chemical stability is
probably an important limiting factor for the activity.
Furthermore, the data of inhibition of the PBPs and the
b-lactamases recorded after a short pre-incubation per-
iod with the enzymes indicated that the compounds were
poorly recognized by these enzymes. Therefore, we
assumed that chemical stability is not the only factor that
could account for the weak activity of the compounds.
We think that the presence of a methylene bridge of the
c-lactam could create unfavorable steric interaction with
the enzyme at the Michaelis complex stage.
In summary we have designed a novel family of anti-
Bredt bicyclo[3.2.1] c-lactams as PBP and b-lactamase
inhibitors. Work is in progress to clarify and solve the
above-mentioned issues namely: chemical stability and
unfavorable steric interaction with the targeted enzymes.
Two solutions are currently being explored by substi-
tuting a carbon atom for a heteroatom, oxygen, or
nitrogen. On one hand, the introduction of a hetero-
atom a to the carbonyl of the lactam should lead to a
more stable carbamoyl or ureido linkage. On the other
hand, replacement of the methylene bridge by a het-
eroatom should reduce steric hindrance.
11. Cama, L. D.; Christensen, B. G. Tetrahedron Lett. 1978,
19, 4233.
12. IR data (CHCl3) 1b: 1498, 1524, 1589, 1608, 1709,
1765 cmꢀ1. 1c: 1495, 1525, 1709, 1743 cmꢀ1 1H NMR
.
(400 MHz, CDCl3) d (ppm) 1b: 2.35 (2H, m), 2.74 (1H,
ddd, J ¼ 2:0, 5.0, 18.0 Hz), 2.85–2.95 (3H, m), 3.28 (1H,
m), 3.82 (3H, s), 5.26 (1H, d, J ¼ 14:0 Hz), 5.48 (1H, d,
J ¼ 14:0 Hz), 7.63 (2H, d, J ¼ 8:5 Hz), 8.20 (2H, d,
J ¼ 8:5 Hz). 1c: 2.48 (1H, dd, J ¼ 4:0, 16.0 Hz), 2.70
(1H, dd, J ¼ 4:0, 16.0 Hz), 2.96 (1H, m), 3.11 (1H, ddd,
J ¼ 1:0, 2.0, 11.5 Hz), 3.51 (3H, s), 3.58 (1H, ddd, J ¼ 1:0,
4.0, 11.5 Hz), 4.71 (1H, d, J ¼ 1:0 Hz), 5.11 (1H, dt,
J ¼ 5:0, 1.0 Hz), 5.32 (2H, AB, J ¼ 13:5 Hz), 7.53 (2H, d,
J ¼ 8:5 Hz), 8.22 (2H, d, J ¼ 8:5 Hz).
13. Pfaendler, H. R.; Gosteli, J.; Woodward, R. B.; Rihs, G.
J. Am. Chem. Soc. 1981, 103, 4526.
14. 1H NMR (200 MHz, d6-acetone) d (ppm) 1d: 2.05 (1H, dd,
J ¼ 4:0, 16.0 Hz), 2.60 (1H, dd J ¼ 4:0, 16.0 Hz), 2.80 (1H,
m), 2.95 (1H, dd, J ¼ 2:0, 11.0 Hz), 3.35 (3H, s), 3.45 (1H,
dd, J ¼ 4:0, 11.0 Hz), 4.30 (1H, s), 5.10 (d, J ¼ 6:0 Hz,
1H).
15. (a) Sakamoto, M.; Iguhi, H.; Okamura, K.; Hori, S.;
Fukagawa, Y.; Ishikura, T.; Lein, J. J. Antibiot. 1979, 32,
272; (b) Yamamoto, K.; Yoshioka, T.; Kato, Y.; Shiba-
moto, N.; Okamura, K.; Shimauchi, Y.; Ishikura, T.
J. Antibiot. 1980, 33, 796.
Acknowledgements
We are grateful to the Analytical Department (Aventis,
Romainville) for performing the spectral analysis and
Dr. H. Paulus Analytical Sciences (Aventis, Frankfurt)
for the determination of the 3D structure of compound
1h by single crystal X-ray analysis.
16. IR data (CHCl3) 1f: 1496, 1524, 1588, 1608, 1707,
1
1761 cmꢀ1. H NMR (300 MHz, CDCl3) d (ppm) 1f: 1.10
References and notes
(3H, t, J ¼ 7:5 Hz), 1.58 (1H, m), 1.80 (1H, m), 2.25 (1H,
ddd, J ¼ 2:5, 6.0, 9.0 Hz), 2.36 (1H, d, J ¼ 18:0 Hz), 2.58
(1H, m), 2.81 (1H, dd, J ¼ 3:0, 12.0 Hz), 2.96 (1H, dd,
J ¼ 5:5, 18.0 Hz), 3.39 (1H, dd, J ¼ 2:5, 12.0 Hz), 3.82
(3H, s), 5.25 (1H, d, J ¼ 14:0 Hz), 5.51 (1H, d,
J ¼ 14:0 Hz), 7.64 (2H, d, J ¼ 8:5 Hz), 8.21 (2H, d,
J ¼ 8:5 Hz). 1H NMR (300 MHz, d6-acetone) d (ppm)
1g: 1.07 (3H, t, J ¼ 7:5 Hz), 1.66 (2H, m), 2.32 (1H, m),
2.56 (1H, dt, J ¼ 18:5, 1.0 Hz), 2.65 (1H, m), 2.80 (1H, dd,
J ¼ 2:5, 11.5 Hz), 3.07 (1H, dd, J ¼ 5:5, 18.5 Hz), 3.31
(1H, dd, J ¼ 2:5, 11.5 Hz), 3.83 (3H, s).
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20. CCDC 222934.