L. Ri6as et al. / Tetrahedron Letters 43 (2002) 7639–7641
7641
1
In conclusion, we have realized the first stereoselective
synthesis of aspergillamide B, in short linear steps. In
vitro cytotoxicity assays of aspergillamide B and the
intermediates 6b and 8b were evaluated against the KB
cell line. These products were found to be active in a
micromolar range [IC50: 10 mM for 1b, 3 mM for 6b and
2.3 mM for 8b]. The application of this strategy to the
synthesis of other enamide-natural products and ana-
logues (in indole and non-indole series) together with
the photoisomerization aspergillamide Aasper-
gillamide B is in progress and will be given in due
course.
11. Compound 3a: H NMR (250 MHz, CDCl3): l 8.10 (d,
J=8.1 Hz, 1H), 7.50 (m, 2H), 7.20 (m, 2H), 4.90 (m, 1H),
3.00 (m, 2H), 2.60 (bs, 3H), 1.60 (s, 9H); 13C NMR (62.5
MHz, CDCl3): l 149.60, 135.70, 128.40, 124.40, 122.60,
122.50, 121.99, 119.50, 115.30, 83.60, 66.20, 47.33, 27.74.
HRMS calcd for C15H20N2O3: 276.147. Found: 276.148.
1
Compound 3b: H NMR (400 MHz, CDCl3): l 7.96 (d,
J=8.4 Hz, 1H), 7.86 (m, 2H), 7.71 (d, 1H, J=8.0 Hz),
7.68 (s, 1H), 7.47–7.33 (m, 3H), 7.26 (t, 1H, J=7.7 Hz),
7.14 (t, 1H, J=7.7 Hz), 6.7 (br s, 3H), 5.12 (dd, 1H,
J=3.3 and 4.0 Hz), 3.46–3.28 (m, 2H); 13C NMR (100
MHz, CDCl3): l 137.69, 135.43, 134.26, 129.46, 128.49,
126.95, 125.44, 124.98, 123.82, 120.69, 119.69, 113.81,
71.59, 64.79. MS (ESI+): m/z 633 (2M+1), 317 (MH+),
299 (MH+−H2O).
Acknowledgements
12. N-Boc,N-Me-phenylalanine was prepared in quantitative
yield from N-Boc-phenylalanine (NaH, CH3I, DMF):
[h]D=−28.2° (c 1, EtOH), lit. −28.1° (c 1, EtOH). See:
Omamoto, K.; Abe, H.; Kuromizu, K.; Izumiya, N.
Mem. Fac. Sci. Kyushu Univ. Ser. C 1974, 9, 131–138.
We are grateful to Christiane Tempete for the biologi-
cal evaluation, to Marie-The´re`se Adeline for HPLC
analysis and to CONACYT (Mexico) for a research
grant to L. Rivas (Grant 121999).
1
13. Compound 6b: H NMR (400 MHz, CDCl3): l 9.26 (d,
1H, J=11.0 Hz), 8.01 (d, 1H, J=8.1 Hz), 7.85 (m, 2H),
7.69 (d, 1H, J=7.7 Hz), 7.54–7.45 (m, 2H), 7.38–7.15 (m,
10H), 6.24 (d, 1H, J=14.6 Hz), 3.90 (bs, 1H), 3.39 (dd,
1H, J=4.4 and 7.0 Hz), 3.22 (dd, 1H, J=4.4 and 7.0 Hz),
2.82 (m, 1H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3):
l 171.03, 138.06, 137.00, 135.60, 133.93, 129.36, 129.18,
128.08, 127.21, 126.81, 125.16, 123.69, 123.37, 122.26,
120.46, 119.49, 113.87, 104.09, 65.78, 38.90, 35.38. MS
(ESI+): m/z 482 (M+Na), 460 (M+1), 148.
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15. Synthetic aspergillamide 1b: 1H NMR (400 MHz, ace-
tone-d6): l 10.25 (bs, 1H), 7.81–7.74 (m, 2H), 7.60–7.22
(m, 9H), 7.16–7.05 (m, 2H), 6.69 (d, 1H, J=14.6), 4.99
(dd, 1H, J=3.6 and 10.6 Hz), 4.60 (m, 1H), 3.31 (dd, 1H,
J=3.6 and 14.3 Hz), 3.14 (dd, 1H, J=11.0 and 14.3 Hz),
2.88 (s, 3H), 2.01 (s, 3H), 1.60 (m, 1H), 1.19 (m, 1H),
0.80–0.68 (2d, 6H, J=6.8 Hz), −0.16 (m, 1H); 13C NMR
(100 MHz, acetone-d6): l 172.86, 171.56, 166.18, 138.66,
137.38, 129.87, 129.28, 128.89, 128.32, 126.72, 125.61,
122.97, 121.78, 120.30, 119.48, 119.40, 112.79, 106.98,
62.54, 47.03, 38.01, 33.84, 28.62, 23.96, 22.67, 21.78,
19.75. MS (EI): m/z 474 (M+), 317.
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17. The reverse-phase HPLC analysis was carried out using a
Waters Symmetry (4.6×250 mm) column and heptane–
isopropanol (95/5, v/v) as eluant (1 mL/min).