Jan-Feb 2002
Studies on Pyrrolidinones
117
Table 5
NMR Spectra of New Compounds
N°
NMR (CDCl ) δ ppm
3
1
11
12
H: 0.16 (s, 4H), 0.19 (s, 5H), 1.85-2.07 (m, 1H), 2.07-2.47 (m, 2H), 2.57-2.86 (m, 1H), 3.20 (s, 1.8H), 3.76 (s, 1.2H), 3.82 (s, 2.1H),
3.86 (s, 6.9H), 3.8-3.9 (0.6H), 4.35 (dd, J = 9, 1.5 Hz, 0.4H), 6.58-6.68 (m, 3H)
1
H: 1.80-2.77 (m, 8H), 3.34 (s, 3H), 3.43 (s, 3H), 3.83 (s, 3H), 3.84 (s, 6H), 4.61 (d, J = 6.8 Hz, 1H), 4.72 (d, J = 7 Hz, 1H), 6.10 (s, 1H),
6.66 (s, 2H)
13
C: 23.2, 24.4, 29.7, 30.7, 51.7, 52.1, 56.2, 59.9, 60.8, 63.1, 68.1, 106.6, 129.8, 138.1, 152.8, 172.0, 173.3, 175.9, 176.2
H: 1.95-2.19 (m, 1H), 2.20-2.60 (m, 2H), 2.60-3 (m, 1H), 3.22 (s, 1.1H), 3.41 (s, 1.1H), 3.45 (s, 1.9H), 3.78 (s, 1.9H), 3.82, 3.83, 3.84,
1
14
3.85, 3.86 (5 s, 9H), 3.8-3.9 (0.6H), 4.27 (dd, J = 8.6, 1.5 Hz, 0.4H), 6.21, (s, 0.6H), 6.22 (s, 0.4H), 6.59 (s, 1.2H), 6.61 (s, 0.8H)
1
15
16
17
H: 3.73 (s, 6H), 3.79 (s, 6H), 3.83 (s, 3H), 5.38 (s, 1H), 6.31 (s, 2H), 6.83 (dt, J = 8.9, 2.6 Hz, 4H), 7.03 (dt, J = 8.9, 2.6 Hz, 4H)
H: 0.10 (s, 9H), 3.80 (s, 6H), 3.83 (s, 3H), 6.74 (s, 2H), 7.27-7.38 (m, 3H), 7.52 (s, 1H), 7.99-8.08 (m, 1H)
H: 0.07 (s, 9H), 5.94 (d, J = 1.3 Hz, 1H), 5.96 (d, J = 1.3 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.93-7.0 (m, 1H), 6.95 (s, 1H), 7.29-7.35
1
1
(m, 3H), 7.48 (t, J = 1.8 Hz, 1H)
1
19a
19b
H: 2.01-2.21 (m, 1H), 2.21-2.55 (m, 2H), 2.55-2.75 (m, 1H), 3.36 (s, 3H), 3.80 (s, 6H), 3.87 (s, 3H), 4.58 (d, J = 7.9 Hz, 1H), 6.57 (s,
2H), 7.44 (td, J = 7.5, 1.1 Hz, 1H), 7.58 (td, J = 7.6, 1.1 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.11 (s, 1H)
13
C: 24.9, 29.1, 52.7, 56.3, 57.1, 60.9, 64.6, 104.9, 110.3, 119.8, 124.6, 128.3, 128.9, 133.8, 138.8, 145.5, 153.7, 171.4, 175.8
H: 1.96-2.20 (m, 1H), 2.30-2.60 (m, 2H), 2.60-2.80 (m, 1H), 3.39 (s, 3H), 3.79 (s, 6H), 3.81 (s, 3H), 5.08 (d, J = 7.9 Hz, 1H), 6.56 (s,
1
2H), 7.34-7.54 (m, 3H), 7.84 (s, 1H), 8.09 (d, J = 7.9 Hz, 1H)
13
C: 24.1, 29.2, 51.9, 56.4, 58.4, 60.8, 66.2, 104.7, 109.9, 118.5, 124.5, 128.0, 128.5, 132.6, 138.7, 144.2, 153.5, 172.4, 175.9
1
20
21
22
25
H: 2-2.18 (m, 1H), 2.3-2.6 (m, 2H), 2.6-2.8 (m, 1H), 3.32 (s, 1.5 H), 3.42 (s, 1.5H), 4.59 (d, J = 7.9 Hz, 0.5H), 5.03 (d, J = 7.9 Hz,
0.5H), 5.95 (dd, J = 2.2, 1.3 Hz, 1H), 6 (s, 1H), 6.7-6.8 (m, 3H), 7.3-7.9 (m, 4H), , 8.09 (d, J = 8Hz, 1H)
1
H: 2.04-2.40 (m, 2H), 2.40-2.79 (m, 2H), 3.87 (s, 3H), 3.89 (s, 6H), 4.16 (dd, J = 8.7, 3.9 Hz, 1H), 6.63 (s, 2H), 7.73 (s, 1H)
13
C: 21.6, 29.6, 56.4, 56.7, 60.9, 76.6, 103.5, 128.4, 138.8, 153.8, 169.3, 174.4
1
H: 0.18 (s, 9.7H), 0.33 (s, 8.3H), 1.80-2.22 (m, 1H), 2.22-2.51 (m, 2H), 2.51-2.79 (m, 1H), 3.76 (dd, J = 8.8, 1.3 Hz, 0.7H), 3.84 (s,
1H), 3.85 (s, 8H), 4.36 (dd, J = 8.8, 1.3 Hz, 0.3H), 6.62 (s, 2H), 6.65 (s, 0.3H), 6.67 (s, 0.7H)
1
H: (CD OD): 1.85-2.05 (m, 1H), 2.1-2.3 (m, 1H), 2.3-2.5 (m, 4H), 2.5-2.75 (m, 2H), 3.78 (s, 3H), 3.83 (s, 6H), 4.51 (dd, J = 7, 1 Hz,
3
1H), 4.62 (dd, J = 7, 2 Hz, 1H), 6.41 (s, 1H), 6.69 (s, 2H)
13
C (CD OD): 24.8, 25.4, 30.4, 31.2, 56.6, 60.9, 61.1, 63.0, 67.6, 107.8, 131.3, 139.3, 154.3, 174.9, 175.5, 178.4, 178.6
3
1
26a
26b
26
H: 2-2.25 (m, 1H), 2.26-2.60 (m, 2H), 2.60-2.87 (m, 1H), 3.75 (s, 3H), 3.79 (s, 6H), 3.83 (s, 3H), 4.16 (t, J = 7.2 Hz, 1H), 6.43 (s, 3H),
6.87 (d, J = 9 Hz, 2H), 7.04 (d, J = 9 Hz, 2H)
H: 2.04-2.29 (m, 1H), 2.29-2.60 (m, 2H), 2.60-2.88 (m, 1H), 3.73 (s, 3H), 3.79 (s, 6H), 3.85 (s, 3H), 4.16 (t, J = 7.2 Hz, 1H), 6.32 (s,
1
2H), 6.39 (s, 1H), 6.75 (d, J = 9 Hz, 2H), 7.15 (d, J = 9 Hz, 2H)
13
C: 24.5, 24.6, 29.8, 55.2, 55.4, 56.1, 56.2, 58.4, 58.6, 59.1, 59.2, 60.7, 60.9, 104.6, 107.7, 113.7, 114.1, 128.5, 129.9, 130.4, 131.9, 133.7,
134.9, 153.1, 153.3, 159.2, 159.5, 176.1, 176.2, 176.3, 176.6
REFERENCES AND NOTES
(165 ml), then triflic acid (2 ml, 3.4 g, 22.8 mmol) was added
(syringe). After 4 hours, diethyl ether was added and the white
solid obtained was filtered. Washing this solid with a sodium
hydrogenocarbonate solution remove pyroglutamic acid and a
very small amount of diacid 25. After drying, the solid was
refluxed in ether to give lactone 21 as a white powder.
[1a] B. Rigo, P. Gautret, A. Legrand, J.-P. Hénichart and D.
Couturier, Synlett, 998 (1997); [b] B. Rigo, P. Gautret, A. Legrand, J.-P.
Hénichart and D. Couturier, J. Heterocyclic Chem., 35, 567 (1998); [c] A.
Legrand, B. Rigo, P. Gautret, J.-P. Hénichart and D. Couturier, J.
Heterocyclic Chem., 36, 1263 (1999).
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Brewer, H. Sternlich, W. J. Gensler and S. B. Horwitz, Cancer Res., 38,
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[3] Developmental Therapeutic Program, Division of Cancer
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Schmidt, J. M. Pettit and E. Hamel, Mol. Pharmacol., 34, 200 (1988).
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249 (1989).
N-(3,4,4',5-Tetramethoxybenzhydryl)pyroglutamic Acid (26).
Triflic acid (0.4 ml, 0.68 g, 4.6 mmol) was slowly added
(syringe) to a stirred mixture of lactone 21 (2 g, 6.5 mmol) and
anisole (2.1 g, 19.5 mmol). After 96 hours methylene dichloride
and a solution of potassium carbonate in water were added. The
aqueous phase was acidified giving acids 26 as a 66/34 mixture
of diastereoisomers.
X-Ray Cristal Structure Determination of B [19].
Crystals of compound B suitable for X-ray investigations were
obtained by slow evaporation of a methanol solution at room
temperature. The structure was solved using the SIR97 program
[22]; the refinement was performed using SHELXL97 [23].
[7] F. Camus, B. Norberg, A. Legrand, B. Rigo, F. Durant and J.
Wouters, Acta Cryst. (C), 56, 193 (2000).
[8a] Separation of the four isomeric esters of HEI 81, obtained
from the reaction described in Scheme 2 [1a], was realized by the Janssen
Research Foundation, by using chiral chromatography. [b] Products 11,
14, 22 were obtained as mixtures of diastereoisomers. Generally speak-
ing, the same ratio of diastereoisomers was never obtained in two seemly
similar experiments. These ratios (and the reaction time) seem to depend
strongly on the exact temperature, reaction time and the amount and
Acknowledgments.
We wish to thank the Norbert Segard Foundation for financial
grants.