O. J. Donadel et al. / Bioorg. Med. Chem. Lett. 17 (2007) 18–21
21
Tellado, F.; Mart ´ı n, V. S.; Villar, J. Bioorg. Med. Chem.
Lett. 2005, 15, 2487.
. (a) Garc ´ı a, C.; Mart ´ı n, T.; Mart ´ı n, V. S. J. Org. Chem.
(m, 4H), 2.53 (dd, J = 16.9, 1.9 Hz, 2H), 2.62 (dd, J = 16.9,
4.9 Hz, 2H), 3.46 (m, 2H), 4.15 (ddd, J = 4.2, 4.2, 1.9 Hz,
2H), 4.37 (m, 2H), 5.07 (m, 4H), 5.75 (m, 2H); C NMR
1
3
9
2
001, 66, 1420; (b) Mart ´ı n, T.; Soler, M. A.; Betancort, J.
M.; Mart ´ı n, V. S. J. Org. Chem. 1997, 62, 1570.
0. General procedure for the SmI promoted synthesis of cis-
b-alkoxy-c-alkyl-c-lactones: to solution of
0.405 mmol) in dry THF (4 mL, 0.1 M) at 0 ꢁC were
added sequentially under nitrogen atmosphere n-octanal
(75 MHz, CDCl ): d 13.8 (q), 18.7 (q), 20.3 (q), 22.4 (t), 25.1
3
(t), 25.3 (t), 28.3 (t), 28.9 (t), 29.2 (t), 31.5 (t), 36.5 (t), 37.1 (t),
40.4 (t), 41.1 (t), 72.8 (d), 73.6 (d), 73.8 (d), 74.7 (d), 84.2 (d),
84.4 (d), 117.2 (t), 134.1 (d), 175.3 (s).
1
2
a
2
1
(
Compound 3e: H NMR (300 MHz, CDCl
3
): d 0.88 (m,
6H), 1.15–1.92 (m, 19H), 2.35 (m, 1H), 2.54 (dd, J = 17.3,
2.2 Hz, 1H), 2.64 (dd, J = 17.3, 5.3 Hz, 1H), 3.67 (m, 1H),
4.14 (ddd, J = 5.3, 5.3, 2.2 Hz, 1H), 4.37 (m, 1H), 5.19 (m,
(
(
0.405 mmol), dry MeOH (1.22 mmol), and SmI2
1.22 mmol, 0.1 M in THF). The resultant mixture was
1
3
stirred at 0 ꢁC for 1 h, after which time it was diluted with
EtOAc (25 mL) and a saturated solution of sodium
thiosulfate was added (50 mL). The aqueous phase was
extracted with EtOAc (3· 25 mL), the combined organic
3
2H), 5.67 (m, 1H); C NMR (75 MHz, CDCl ): d 14.0 (q),
24.8 (t), 25.3 (t), 25.6 (t), 28.5 (t), 28.7 (t), 28.9 (t), 29.0 (t),
29.1 (t), 29.4 (t), 29.5 (t), 31.6 (t), 31.7 (t), 35.4 (t), 37.6 (t),
74.5 (d), 76.6 (d), 79.5 (d), 82.7 (d), 84.5 (d), 117.2 (d), 118.1
layers were dried under anhydrous MgSO
4
, filtered, and
(d), 138.2 (t), 139.5 (t), 175.5 (s).
Compound 3f: H NMR (300 MHz, CDCl
1
the solvent was removed under reduced pressure. The
residue was purified by chromatography on silica gel
3
): d 0.90 (t,
J = 6.9 Hz, 12 H), 1.22–1.52 (m, 38H), 1.59 (bs, 2H), 1.72
(m, 4H), 1.81 (m, 4H), 2.44 (d, J = 1.8 Hz, 1H), 2.49 (d,
J = 1.8 Hz, 1H), 2.49 (dd, J = 17.7, 1.7 Hz, 2H), 2.62 (dd,
J = 17.7, 4.7 Hz, 2H), 4.06 (ddd, J = 4.7, 4.7, 1.7 Hz, 2H),
(
1. Compound 3a: H NMR (300 MHz, CDCl
EtOAc/hexane, 1:9) to give c-lactone 3.
1
1
3
): d 0.88 (t,
J = 7.0 Hz, 3H), 1.25–1.51 (m, 16H), 1.60–1.87 (m, 6H),
1
3
2
1
4
.54 (dd, J = 17.4, 2.1 Hz, 1H), 2.64 (dd, J = 17.4, 5.2 Hz,
H), 3.25 (m, 1H), 4.17 (ddd, J = 5.0, 5.0, 2.1 Hz, 1H),
.37 (m, 1H); C NMR (75 MHz, CDCl ): d 14.0 (q), 22.6
3
4.48 (m, 2H), 4.48 (m, 2H); C NMR (75 MHz, CDCl ): d
3
14.1 (q), 22.6 (t), 24.9 (t), 25.0 (t), 25.1 (t), 25.6 (t), 28.4 (t),
28.6 (t), 29.1 (t), 29.2 (t), 29.4 (t), 29.5 (t), 31.7 (t), 35.6 (t),
36.0 (t), 37.2 (t), 67.3 (d), 70.4 (d), 72.8 (d), 74.3 (d), 74.5 (d),
75.7 (d), 83.0 (s), 84.3 (d), 84.4 (d), 175.2 (s).
13
(
(
(
t), 23.7 (t), 23.8 (t), 25.4 (t), 25.6 (t), 28.5 (t), 29.1 (t), 29.4
t), 31.4 (t), 31.7 (t), 33.0 (t), 37.1 (t), 72.9 (t), 76.6 (d), 84.5
d), 175.5 (s).
12. The cis relative stereochemistry for c-lactone 3 was
determined by nOe studies and H– H coupling constants.
1
1
1
Compound 3b: H NMR (300 MHz, CDCl
J = 7.0 Hz, 3H), 1.18–2.03 (m, 18H), 2.57 (dd, J = 17.5,
3
): d 0.89 (t,
2
4
5
1
2
7
1
.4 Hz, 1H), 2.67 (dd, J = 17.5, 5.4 Hz, 1H), 3.84 (m, 1H),
.24 (ddd, J = 5.4, 5.4, 2.4 Hz, 1H), 4.39 (m, 1H), 5.69–
1
3
.74 (m, 1H), 5.87 (m, 1H); C NMR (75 MHz, CDCl ): d
3
4.1 (q), 18.8 (t), 22.6 (t), 25.1 (t), 25.2 (t), 25.4 (t), 28.1 (t),
8.6 (t), 29.1 (t), 29.4 (t), 31.7 (t), 37.0 (t), 37.2 (t), 71.7 (d),
2.1 (d), 73.3 (d), 84.5 (d), 126.2 (d), 127.3 (d), 131.6 (d),
32.0 (d), 176,0 (s).
1
3. In this method, for each drug a dose–response curve is
generated and three levels of effect can be calculated, when
possible. The effect is defined as percentage of growth
1
Compound 3c: H NMR (300 MHz, CDCl
3
): d 0.89 (t,
J = 6.6 Hz, 3H), 1.18–1.51 (m, 9H), 1.74–1.91 (m, 3H), 2.63
dd, J = 17.6, 5.0 Hz, 1H), 2.70 (dd, J = 17.6, 2.3 Hz, 1H),
.17 (ddd, J = 5.0, 5.0, 2.3 Hz, 1H), 4.40 (m, 1H), 4.41 (d,
J = 11.9 Hz, 1H), 4.61 (d, J = 11.9 Hz, 1H), 7.29 (m, 5H);
(
4
(
PG), where 50% growth inhibition (GI50), total growth
inhibition (TGI), and 50% cell killing (LC50) represent the
drug concentration at which PG is +50, 0, and À50,
respectively Skehan, P.; Storeng, P.; Scudeiro, D.; Monks,
A.; McMahon, J.; Vistica, D.; Warren, J. T.; Bokesch, H.;
Kenney, S.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82,
1
3
3
C NMR (75 MHz, CDCl ): d 13.8 (q), 22.4 (t), 25.2 (t),
2
8
8.3 (t), 28.9 (t), 29.2 (t), 31.5 (t), 35.5 (t), 71.1 (t), 74.8 (d),
4.1 (d), 127.4 (d), 127.8 (d), 128.3 (d), 136.9 (s), 174.9 (s).
1
Compound 3d: H NMR (300 MHz, CDCl
J = 7.0 Hz, 6H), 1.11 (d, J = 6.0 Hz, 3H), 1.13 (d,
J = 6.0 Hz, 3H), 1.20–1.45 (m, 20H), 1.72 (m, 4H), 2.18
3
): d 0.89 (t,
1107.
4. Miranda, P. O.; Padr o´ n, J. M.; Padr o´ n, J. I.; Villar, J.;
Mart ´ı n, V. S. ChemMedChem 2006, 1, 323.
1