S. Álvarez et al. / Bioorg. Med. Chem. 16 (2008) 9719–9728
9725
24.5, 24.8, 26.7, 29.1, 29.8, 30.5, 31.9, 34.0, 40.3, 47.2, 51.2, 123.5,
131.6, 151.3, 152.8, 163.2 ppm. MS m/z (%) 432 (M+, 11), 282 (20),
267 (13), 203 (12), 165 (100), 152 (27), 135 (10), 121 (13), 109 (11),
91 (15). HRMS (EI) calcd for C25H40N2O2S, 432.2811; found,
432.2809.
ꢀ30.1° (c 0.54, EtOH). IR (NaCl)
m
1710 (s) cmꢀ1
.
1H NMR
(400.13 MHz, CDCl3) d 0.97 (s, 3H), 1.03 (s, 3H), 1.12 (s, 3H),
1.29 (t, J = 7.1 Hz, 3H), 1.3–1.5 (m, 1H), 1.43 (s, 3H), 1.8–1.9
(m, 1H), 1.99 (s, 3H), 2.38 (s, 3H), 2.4–2.5 (m, 1H), 2.5–2.7 (m,
1H), 4.17 (q, J = 7.1 Hz, 2H), 5.54 (s, 1H), 5.77 (s, 1H), 6.05 (d,
J = 11.5 Hz, 1H), 6.22 (d, J = 15.0 Hz, 1H), 6.38 (d, J = 15.7 Hz,
1H), 6.72 (d, J = 15.7 Hz, 1H), 7.10 (dd, J = 15.0, 11.5 Hz, 1H)
ppm. 13C NMR (100.63 MHz, CDCl3) d 13.9, 14.3, 21.1, 24.5,
26.0, 27.7, 30.0, 31.0, 39.2, 41.6, 42.0, 53.4, 59.6, 118.6, 121.5,
128.7, 129.5, 132.8, 134.6, 136.9, 138.2, 143.9, 152.7,
167.2 ppm. UV (EtOH) kmax 272, 366 nm. MS m/z (%) 354 (M+,
8), 219 (15), 191 (23), 175 (51), 149 (29), 135 (27), 119 (34),
109 (36), 107 (47), 97 (91), 91 (51), 83 (60), 69 (100). HRMS
(EI) calcd for C24H34O2, 354.2559; found, 354.2573.
2.9. Ethyl (ꢀ)-(2E,4E,6Z,8E)-3,7-Dimethyl-9-[(1S,4S,5S)-4,6,6-
trimethylbicyclo[3.1.1]hept-2-en-2-yl]nona-2,4,6,8-tetraenoate
(7d)
According to the general procedure described above for the one-
pot Shapiro–Suzuki reaction, hydrazone 5d (0.13 g, 0.31 mmol)
was treated with n-BuLi (0.40 mL, 2.3 M in hexane, 0.92 mmol), fol-
lowed by B(Oi-Pr)3 (0.14 mL, 0.61 mmol), and iodide 9 [previously
generated from stannane 8 (0.12 g, 0.24 mmol)]. After stirring the
mixture for 15 min at 25 °C, purification of the residue by column
chromatography (SiO2, 90:10 hexane/EtOAc) afforded 7d (0.062 g,
2.12. (ꢀ)-(2E,4E,6Z,8E)-3,7-Dimethyl-9-[(1S,5S)-4,4,6,6-tetrame-
thylbicyclo[3.1.1]hept-2-en-2-yl]nona-2,4,6,8-tetraenoic acid
(3e)
75%) as a yellow solid. ½a D24
ꢃ
ꢀ57.4° (c 0.04, EtOH). IR (NaCl)
m
1700 (s) cmꢀ1 1H NMR (400.13 MHz, CDCl3) d 0.92 (s, 3H), 1.12
.
(d, J = 7.6 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.3–1.5 (m, 1H), 1.38 (s,
3H), 1.97 (s, 3H), 2.0–2.1 (m, 1H), 2.35 (d, J = 0.9 Hz, 3H), 2.5–2.7
(m, 3 H), 4.15 (q, J = 7.1 Hz, 2H), 5.69 (s, 1H), 5.75 (s, 1H), 6.03 (d,
J = 11.5 Hz, 1H), 6.19 (d, J = 15.0 Hz, 1H), 6.38 (d, J = 15.7 Hz, 1H),
6.70 (d, J = 15.7 Hz, 1H), 7.08 (dd, J = 15.0, 11.5 Hz, 1H) ppm. 13C
NMR (100.63 MHz, CDCl3) d 13.9, 14.4, 18.3, 21.1, 23.2, 27.3,
34.2, 37.9, 39.9, 41.5, 47.8, 59.6, 118.6, 121.3, 128.7, 129.6, 132.6,
133.0, 134.6, 138.2, 144.9, 152.7, 167.2 ppm. UV (EtOH) kmax 306,
360 nm. MS m/z (%) 340 (M+, 100), 251 (13), 213 (21), 197 (23),
171 (19), 157 (27), 145 (38), 105 (32), 91 (24). HRMS (EI) calcd
for C23H32O2, 340.2402; found, 340.2399.
According to the general procedure described above for the
hydrolysis of esters, (ꢀ)-7e (0.03 g, 0.08 mmol) in ethanol
(0.2 mL) was treated with a 5 M aqueous KOH solution (0.2 mL)
and then refluxed for 30 min. Purification by chromatography
(SiO2, 95:5 CH2Cl2/MeOH) afforded 0.023 g of 3e (86%), as a yellow
solid (mp 187 °C, hexane/EtOAc). ½a D24
ꢃ
ꢀ33.7° (c 0.08, EtOH). IR
(NaCl)
m .
3400–2900 (br), 1683 (s) cmꢀ1 1H NMR (400.13 MHz,
CD2Cl2) d 0.95 (s, 3H), 1.02 (s, 3H), 1.12 (s, 3H), 1.2–1.4 (m, 1H),
1.41 (s, 3H), 1.8–1.9 (m, 1H), 1.99 (s, 3H), 2.36 (s, 3H), 2.4–2.5
(m, 1H), 2.5–2.7 (m, 1H), 5.55 (s, 1H), 5.79 (s, 1H), 6.07 (d,
J = 11.5 Hz, 1H), 6.26 (d, J = 15.0 Hz, 1H), 6.41 (d, J = 15.7 Hz, 1H),
6.76 (d, J = 15.7 Hz, 1H), 7.17 (dd, J = 15.0, 11.5 Hz, 1H) ppm. 13C
NMR (100.61 MHz, CD2Cl2) d 14.3, 21.3, 24.6, 26.1, 27.8, 30.1,
31.3, 39.5, 41.9, 42.5, 53.8, 117.8, 121.9, 128.9, 130.9, 133.5,
134.7, 137.5, 139.5, 144.5, 155.6, 171.9 ppm. UV (EtOH) kmax 266,
348 nm. MS m/z (%) 326 (M+, 100), 257 (27), 159 (39), 157 (30),
133 (22), 119 (35), 105 (35), 91 (40), 81 (27). HRMS calcd for
C22H30O2, 326.2246; found, 326.2246. Elem. Anal. Calcd for
C22H30O2, C, 80.94%; H, 9.26, found, C, 80.61%; H, 9.73.
2.10. (ꢀ)-(2E,4E,6Z,8E)-3,7-Dimethyl-9-[(1S,4R,5S)-4,6,6-trim-
ethylbicyclo[3.1.1]hept-2-en-2-yl]nona-2,4,6,8-tetraenoic acid
(3d)
According to the general procedure described above for the
hydrolysis of esters, (ꢀ)-7d (0.047 g, 0.14 mmol) in ethanol
(0.3 mL) was treated with a 5 M aqueous KOH solution (0.3 mL)
and then refluxed for 30 min. Purification by chromatography
(SiO2, 95:5 CH2Cl2/MeOH), afforded 0.040 g of 3d (93%), as a yellow
solid (mp 117 °C, hexane/EtOAc). ½a D24
ꢃ
ꢀ21.4° (c 0.49, EtOH). IR
3400–2900 (br), 1699 (s) cm-1 1H NMR (400.13 MHz,
2.13. (ꢀ)-(2S,5S)-2-Methyl-5-propen-2-yl-cyclohexanone 2,4,6-
Tri-isopropylbenzenesulfonylhydrazone (S,S)-5f
(NaCl)
m .
CD2Cl2) d 0.92 (s, 3H), 1.13 (d, J = 7.5 Hz, 3H), 1.2–1.4 (m, 1H),
1.39 (s, 3H), 1.99 (s, 3H), 2.0–2.2 (m, 1H), 2.35 (d, J = 0.9 Hz, 3H),
2.5–2.8 (m, 3H), 5.73 (s, 1H), 5.79 (s, 1H), 6.08 (d, J = 11.5 Hz,
1H), 6.26 (d, J = 15.0 Hz, 1H), 6.44 (d, J = 15.7 Hz, 1H), 6.76 (d,
J = 15.7 Hz, 1H), 7.18 (dd, J = 15.0, 11.5 Hz, 1H) ppm. 13C NMR
(100.63 MHz, CD2Cl2) d 14.2, 18.4, 21.3, 23.5, 27.3, 34.5, 38.1,
40.4, 41.8, 48.2, 117.4, 121.6, 128.9, 130.9, 133.3, 133.7, 134.6,
139.5, 145.3, 155.8, 171.1 ppm. UV (EtOH) kmax 310 nm. MS m/z
(%) 312 (M+, 18), 181 (8), 157 (10), 145 (15), 131 (9), 119 (12),
105 (30), 91 (100). HRMS (EI) calcd for C21H28O2, 312.2089; found,
312.2095.
Ketone (S,S)-4f (0.96 g, 6.35 mmol) was added with vigorous
stirring to
a
solution of finely powdered 2,4,6-tri-
isopropylbenzenesulfonylhydrazine (1.89 g, 6.35 mmol) in MeOH
(7 mL) and 0.07 mL of concentrated hydrochloric acid. The reac-
tion mixture was stirred at room temperature for 10 min, then
cooled at 0 °C overnight, and the resultant white solid collected.
The crude was taken up in a minimum amount of chloroform,
filtered, evaporated and dried (25 °C, 0.5 mmHg) to afford
1.98 g of (S,S)-5f as a white solid (73%, mp 126 °C). ½a D24
ꢃ
-
18.31° (c 0.013, MeOH). IR (NaCl)
m 3213 (s), 3000–2800 (s),
1321, 1162 (s) cm-1 1H NMR (400.13 MHz, CDCl3) d 0.96 (d,
.
2.11. Ethyl (ꢀ)-(2E,4E,6Z,8E)-3,7-Dimethyl-9-[(1S,5S)-4,4,6,6-
tetramethylbicyclo[3.1.1]hept-2-en-2-yl]nona-2,4,6,8-tetrae-
noate (7e)
J = 6.4 Hz, 3H), 1.3–1.2 (m, 15H), 1.43 (dd, J = 12.5, 3.9 Hz, 1H),
1.7–1.6 (m, 2H), 1.74 (s, 3H), 1.82 (d, J = 13.2 Hz, 1H), 1.93 (dd,
J = 13.1, 3.9 Hz, 1H), 2.03 (t, J = 12.5 Hz, 1H), 2.2–2.1 (m, 1H),
2.67 (d, J = 13.6 Hz, 1H), 2.92 (sept, J = 6.9 Hz, 1H), 4.22 (sept,
J = 6.7 Hz, 2H), 4.73 (s, 1H), 4.78 (s, 1H), 7.18 (s, 2H) ppm. 13C
NMR (100.61 MHz, CDCl3) d 160.9, 152.9, 151.1, 147.8, 131.3,
123.9, 123.4, 109.7, 45.2, 39.1, 35.2, 34.0, 31.3, 30.8, 29.8, 24.8,
24.7,23.4, 20.3, 16.2 ppm. MS m/z (%) 432 (M+, 8), 282 (38),
269 (28), 189 (21), 166 (36), 165 (40), 152 (30), 121 (31), 107
(49), 93 (100), 91 (43), 81 (40), 79 (32). HRMS calcd for
C25H40N2O2S, 432.2811; found, 432.2795.
According to the general procedure described above for the
one-pot Shapiro–Suzuki reaction, hydrazone 5e (0.17 g,
0.38 mmol) was treated with n-BuLi (0.62 mL, 2.3 M in hexane,
1.43 mmol), followed by B(Oi-Pr)3 (0.17 mL, 0.75 mmol), and io-
dide
9
[previously generated from stannane
8
(0.15 g,
0.30 mmol)]. After stirring the mixture for 30 min at 25 °C, puri-
fication of the residue by column chromatography (SiO2, 90:10
hexane/EtOAc) afforded 7e (0.08 g, 79%) as a yellow solid. ½a D24
ꢃ