J. H. Spatz et al. / Tetrahedron Letters 50 (2009) 1705–1707
1707
24. Beck, B.; Magnin-Lachaux, M.; Herdtweck, E.; Dömling, A. J. Org. Lett. 2001, 3,
2875.
10
25. Tempest, P.; Ma, V.; Kelly, M. G.; Jones, W.; Hulme, C. Tetrahedron Lett. 2001, 42,
4963.
OH
9
N
O
O
N
26. Umkehrer, M.; Kalinski, C.; Kolb, J.; Burdack, C. Tetrahedron Lett. 2006, 47, 2391.
27. Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 7842.
28. (a) Lindhorst, T.; Bock, H.; Ugi, I. Tetrahedron 1999, 55, 7411; (b) Böll, W. A.;
Gerhart, F.; Nürrenbach, A.; Schöllkopf, U. Angew. Chem. 1970, 82, 482.
29. HPLC–MS/MS spectra (Varian 1200), Polaris, RP C18 column, 3 Â 150 mm,
11
11
O
O
S
5
lm, ProStar 325 (254 nm), 1 ml/min, 3 min gradient from 10% ACN to 90%
7ab
Figure 1. Compounds 7ab and 7m.
7m
ACN (0.1% HCOOH) versus H2O, coupled with
spectrometer using electrospray ionization (ESI).
a Quadrupol MS/MS mass
1
30. NMR:1H/13C: Bruker AV 250: 250.13 MHz, 1HÀ H NOESY: Jeol ECP500:
500.16 MHz.
31. General procedure (GP 1) for the synthesis of MCR products 5a–ae: Amine 1
(1 mmol) and aldehyde 2 (1 mmol) were stirred in 3 mL methanol for 2 h.
Then, carboxylic acid 3 (1 mmol) and isocyanide 4 (1 mmol) were added, and
the reaction mixture was stirred for 16 h at room temperature. The solvent was
removed in vacuo. The resulting crude product was purified by flash
chromatography on silica (ethyl cetate/hexane).
32. General procedure (GP 2) for the synthesis of tetramic acid derivatives 6a–ae:
0.2 mmol of MCR product 5a–ae was dissolved in 4 mL THF (dry), and
0.24 mmol KOtBu were added under nitrogen atmosphere. The reaction
mixture was stirred at room temperature for 1 h. After 1 h of reaction time a
maximum of conversion was reached, and the reaction mixture was
neutralized with 6 N HCl (pH 6–7). The solvent was removed in vacuo. The
resulting crude product was purified by flash chromatography on silica (ethyl
acetate/hexane).
33. Compound 7o was prepared according to GP 2, and purified by flash
chromatography on silica gel with eluent ethyl acetate/hexane = 1:2 (61 mg
of a colourless solid, 99%). m/z = 308 [M+H]+, m/z = 330 [M+Na]+. 1H NMR
(250.13 MHz, CDCl3): d 11.25 (br s, 1H, OH), 7.92–7.90 (m, 2H, CHar), 7.36–7.20
(m, 8H, CHar), 5.00 (d, J = 15.7 Hz, 1H, PhCH2), 4.20 (d, J = 15.7 Hz, 1H, PhCH2),
3.73 (d, J = 2.3 Hz, 1H, NCH), 2.23–2.29 (m, 1H, (CH3)2CH), 0.96 (d, J = 6.9 Hz,
3H, CH(CH3)2), 0.81 (d, J = 6.9 Hz, 3H, CH(CH3)2). 13C NMR (62.90 MHz, CDCl3):
d 172.8 (Cq, CON), 170.0 (Cq, HOCq), 139.2 (Cq, CH2Car), 132.7 (Cq, Car), 129.5 (CH,
CarH), 128.9 (CH, CarH), 128.5 (CH, CarH), 128.3 (CH, CarH), 127.8 (CH, CarH),
126.8 (CH, CarH), 105.5 (Cq, PhCq), 63.7 (CH, NCH), 45.2 (CH2, PhCH2), 29.6 (CH,
(CH3)2CH), 19.9 (CH3, CH(CH3)2), 16.4 (CH3, CH(CH3)2).
ylic acid could successfully be involved in the reaction. The reac-
tion time (rt) for the cyclization is generally short, and the conver-
sions are moderate to good for all compounds. The
chromatographic methods used allow the isolation of products
with high purity (>95%). All compounds were characterized by
NMR30 and HPLC–MS data.
The observable tautomer (Fig. 1) in 1H NMR spectra (DMSO-
d6) depends on the substituent at C-11. If the starting material
is acetic acid there is no substituent at C-11 of the resulting
product, and so only the pyrrolidine-2,4-dione-tautomer is ob-
served (CH2-group at 3.02 ppm, carbonyl-carbon at 206 ppm). If
an
a-CH-acidic carboxylic acid is used, the resulting products
contain a phenyl moiety at C-11, and therefore the hydroxy-
dihydropyrrolidone tautomer is the exclusively observable struc-
ture in 1H NMR spectra (DMSO-d6). The enolic structure of com-
pound 7ab was confirmed by NOE-experiments. In DPFGSE-NOE-
spectra of compound 7ab NOEs with methine-proton
9 (d
4.11 ppm) and methine-proton 10 (d 2.36 ppm) of the isopropyl-
group were observed upon excitation of enol-proton at (d
11.47 ppm) and vice versa.
In summary, a novel two-step synthetic procedure for the prep-
aration of substituted tetramic acid derivatives has been described.
34. Compound 7s was prepared according to GP
chromatography on silica gel with eluent ethyl acetate/hexane = 1:1 (19 mg
of
white solid, 69%). m/z = 294 [M+H]+, m/z = 316 [M+Na]+. 1H NMR
2 and purified by flash
a
(250.13 MHz, DMSO): d 8.12–8.06 (m, 2H, CHar), 8.01 (br s, 1H, OH), 7.19–
7.41 (m, 7H, CHar), 4.53 (s, 2H, NCH2), 1.32 (s, 6H, CH3).
35. Compound 7t was prepared according to GP
chromatography on silica gel with eluent ethyl acetate/hexane = 1:2 (45 mg
of
colourless oil, 69%). m/z = 328 [M+H]+, m/z = 350 [M+Na]+. 1H NMR
2 and purified by flash
Amines, carbonyls and
a-CH-acidic carboxylic acid can be varied
broadly, leading to compounds with three potential points of
diversity.
a
(250.13 MHz, CDCl3): d 7.98 (d, J = 7.4 Hz, 1H, CHar), 7.40–7.18 (m, 9H, CHar),
4.53 (s, 2H, PhCH2), 1.26–1.08 (m, 6H, CH(CH3)2). 13C NMR (62.90 MHz, CDCl3):
d 174.0 (Cq, CON), 169.5 (Cq, HOCq), 140.1 (Cq, CH2Car), 128.4 (CH, CarH), 128.2
(Cq, Car), 127.7 (CH, CarH), 127.4 (CH, CarH), 126.7 (CH, CarH), 125.7 (CH, CarH),
101.2 (Cq, PhCar), 60.6 (Cq, NCq(CH3)2), 41.1 (CH2, PhCH2), 23.5 (CH3, Cq(CH3)2),
23.0 (CH3, Cq(CH3)2).
References and notes
1. Segeth, M. P.; Bonnefoy, A.; Bronstrup, M.; Knauf, M.; Schummer, D.; Toti, L.;
Vertesy, L.; Wetzel-Raynal, M. C.; Wink, J.; Seibert, G. J. Antidot. 2003, 56, 114.
2. Schlegel, B.; Schmidtke, M.; Dorfelt, H.; Kleinwachter, P.; Grafe, U. J. Basic
Microbiol. 2001, 41, 179.
3. Sata, N. U.; Wada, S.; Matsunaga, S.; Watabe, S.; van Soest, R. W. M.; Fusetani, N.
J. Org. Chem. 1999, 64, 2331.
4. Marfori, E. C.; Kajiyama, S.; Fukusaki, E.; Kobayashi, A. Phytochemistry 2003, 62,
715.
5. Holzapfel, C. W. Tetrahedron 1968, 24, 2101.
6. Singh, B. K.; Bisht, S. S.; Tripathi, R. B. BJOC 2006, 2, 24.
7. (a) Fitch, D.; Evans, K. A.; Chai, D.; Duffy, K. J. Org. Lett. 2005, 24, 5521; (b) Ley, S.
V.; Woodward, P. R. Tetrahedron Lett. 1987, 283, 345; (c) Ley, S. V.; Smith, S. C.;
Woodward, P. R. Tetrahedron 1992, 48, 1145.
8. Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1997, 53, 5643.
9. Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144.
10. Dömling, A.; Ugi, I. Angew. Chem. 2000, 112, 3300.
11. Dömling, A.; Ugi, I.; Hörl, W. Endeavour 1994, 18, 15.
12. Keating, T. A.; Amstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
13. Ugi, I.; Steinbrückner, C. Chem. Ber. 1961, 94, 734.
14. Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709.
15. Zhu, J. Eur. J. Org. Chem. 2003, 1133.
16. Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471.
17. Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E. M. J. Med.
Chem. 1994, 37, 1233.
18. Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med.
Chem. 1994, 37, 1385.
36. Compound 7y was prepared according to GP
2 and purified by flash
chromatography on silica gel with eluent ethyl acetate/hexane = 9:1 (68 mg
of
a
colourless oil, 93%). m/z = 374 [M+H]+, m/z = 396 [M+Na]+. 1H NMR
(250.13 MHz, CDCl3): d 7.96 (d, 3J = 8.1 Hz, 2H, CHar), 7.21 (d, 3J = 8.1 Hz, 2H,
CHar), 7.08 (d, 3J = 8.6 Hz, 2H, CHar), 6.77 (d, 3J = 8.6 Hz, 2H, CHar), 4.74 (s, 1H,
NCH), 3.74 (s, 3H, OCH3), 3.53–3.71 (m, 2H, CH2), 3.34–3.38 (m, 1H, CH2), 3.20
(s, 3H, CH2OCH3), 2.77–2.86 (m, 1H, CH2).
37. Compound 7ab was prepared according to GP
chromatography on silica gel with eluent ethyl acetate/hexane = 9:1 (48 mg
of
white solid, 85%). m/z = 282 [M+H]+, m/z = 304 [M+Na]+. 1H NMR
2 and purified by flash
a
(500.16 MHz, d6-DMSO): d 11.47 (br s, 1H, OH), 7.47 (dd, J = 1.1, 2.5 Hz, 1H,
CHar), 7.24 (dd, J = 1.1, 2.5 Hz, 1H, CHar), 6.92 (dd, J = 1.6, 8.7 Hz, 1H, CHar), 4.00
(s, 1H, H3COCH2), 3.85–3.75 (m, 1H, H3COCH2), 3.47–3.43 (m, 2H, NCH2), 3.13
(s, 3H, OCH3), 3.08–2.98 (m, 1H, NCH), 2.35 (m, 1H, (CH3)2CH), 0.90 (d,
J = 7.0 Hz, 3H, CH(CH3)2), 0.67 (d, J = 7.0 Hz, 3H, CH(CH3)2).13
C NMR
(62.90 MHz, DMSO-d6): d 171.0 (Cq, HOCq), 167.2 (Cq, CON), 143.7 (Cq, SCar),
133.3 (CH, CarH), 126.9 (CH, CarH), 124.0 (CH, CarH), 102.3 (Cq, Car), 78.1 (CH,
NCH), 70.5 (CH2, H3COCH2), 64.1 (CH3, OCH3), 58.6 (CH2, NCH2), 29.5 (CH,
(CH3)2CH), 19.8 (CH3, CH(CH3)2), 15. (CH3, CH(CH3)2).
38. Compound 7ae was prepared according to GP
chromatography on silica gel with eluent ethyl acetate/hexane = 9:1 (54 mg
of
white solid, 99%). m/z = 276 [M+H]+, m/z = 298 [M+Na]+. 1H NMR
2 and purified by flash
a
(250.13 MHz, CDCl3): d 7.73 (d, J = 8.5 Hz, 2H, CHar), 7.23 (t, J = 7.5 Hz, 2H,
CHar), 7.09 (d, J = 7.4 Hz, 1H, CHar), 3.93 (d, J = 2.2 Hz, 1H, NCH), 3.85–3.75 (m,
2H, H3COCH2), 3.14 (s, 3H, OCH3), 3.10–2.98 (m, 2H, NCH2), 2.19 (m, 1H,
(CH3)2CH), 0.89 (d, J = 7.0 Hz, 3H, CH(CH3)2), 0.75 (d, J = 7.0 Hz, 3H, CH(CH3)2).
13C NMR (62.90 MHz, CDCl3): d 171.6 (Cq, CON), 169.2 (Cq, HOCq), 132.1 (Cq,
Car), 128.0 (CH, CarH), 127.7 (CH, CarH), 126.1 (CH, CarH), 105.1 (Cq, PhCar), 70.3
(CH, NCH), 63.5 (CH2, H3COCH2), 58.2 (CH3, OCH3), 38.7 (CH2, NCH2), 30.0 (CH,
(CH3)2CH), 18.9 (CH3, CH(CH3)2), 16.1 (CH3, CH(CH3)2).
19. Dömling, A. Comb. Chem. High Throughput Screen. 1998, 1, 1.
20. Dömling, A. Chem. Rev. 2006, 106, 17.
21. Ugi, I.; Meyer, R.; Fetzer, U.; Steinbrückner, C. Angew. Chem 1959, 71, 386.
22. Kalinski, C.; Umkehrer, M.; Ross, G.; Kolb, J.; Burdack, C.; Hiller, W. Tetrahedron
Lett. 2006, 47, 3423.
23. Xiang, Z.; Luo, T.; Lu, K.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.; Yang, Z. J. Org. Lett.
2004, 6, 3155.