1598 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 9
Muthyala et al.
to a solution of methyl ethers (0.5 M solution in CH2Cl2) and
was stirred at room temperature for 8-12 h. After the mixture
was cooled to 0 °C, ethyl acetate (20 mL) was added to dilute
the reaction mixture and the reaction was quenched by the
addition of 5 mL of 10% HCl. Extraction with an additional
20 mL of EtOAc, followed by evaporation of the solvent in
vacuo, furnished the crude phenols, which were subsequently
chromatographed using 30% EtOAc/hexane as the eluent.
9-[Bis(4-h yd r oxyp h e n yl)m e t h yle n e ]b icyclo[3.3.1]-
n on a n e (8). Following the general procedure A and using
ketones 6 and 7 as the reactants, the isolated yield of 8 was
0.240 g (78%). 1H NMR (acetone-d6): δ 8.18 (s, 2H), 6.97 (d,
8.5 Hz, 4H), 6.75 (d, 8.5 Hz, 4H), 2.69 (br s, 2H), 2.09-1.98
(m, 3H), 1.84-1.72 (m, 10H), 1.59-1.53 (m, 2H). 13C NMR: δ
156.2, 143.9, 135.2, 131.8, 130.7, 115.3, 34.6, 34.0, 22.0. MS
(EI, 70 eV) m/z: 320 (M+, 100%). HRMS (EI, 70 eV) calcd for
A and using ketones 5 and 7 as the reactants, the isolated
yield of the cross-coupled product was 0.21 g (61%). H NMR:
1
δ 7.19 (t, 8 Hz, 1H), 7.11(d, 8.5 Hz, 2H), 7.09 (d, 8 Hz, 1H),
6.78 (d, 8.5 Hz, 1H), 6.74 (s, 1H), 3.79 (s, 3H), 3.78 (s, 3H),
2.74 (m,1H), 2.71 (m, 1H), 2.09-2.00 (m, 2H), 1.88-1.77 (m,
8H), 1.63-1.58 (m, 2H). 13C NMR: δ 159.2, 157.8, 145.4, 144.8,
135.3, 130.6, 130.3, 128.8, 121.8, 115.0, 113.3, 111.1, 55.1, 55.0,
34.2, 33.9, 33.7, 21.6. HRMS (EI, 70 eV) calcd for C24H28O2,
348.2089; found, 348.2080.
Dep r otection . Starting from 0.1 g (0.26 mmol) of the
McMurry coupling product and using the general procedure
B, the yield of compound 12 was 0.064 g (69%). 1H NMR: δ
7.17 (t, 8 Hz, 1H), 7.15 (d, 8.2 Hz, 2H), 7.07 (d, 8 Hz, 1H), 6.58
(d, 8.5 Hz, 1H), 6.74 (s, 1H), 2.73 (m,1H), 2.69 (m, 1H), 2.08-
2.00 (m, 2H), 1.85-1.74 (m, 8H), 1.61-1.52 (m, 2H). 13C
NMR: δ 158.2, 156.8, 145.1, 144.8, 134.6, 129.6, 129.3, 128.5,
120.5, 113.9, 113.4, 111.3, 34.1, 34.0, 33.4, 21.5. HRMS (EI,
70 eV) calcd for C22H24O2, 320.1776; found, 320.1772.
2-[Bis(4-h yd r oxyp h en yl)m eth ylen e]a d a m a n ta n e (14).
Following the general procedure A and using ketones 1 and
13 as the reactants, the isolated yield of the cross-coupled
C
22H24O2, 320.1776; found, 320.1774.
9-[(4-F lu or op h e n yl)(4-h yd r oxyp h e n yl)m e t h yle n e ]-
bicyclo[3.3.1]n on a n e (9). Using ketones 2 and 7 as the
reactants and following the general procedure A, the isolated
1
yield of 9 was 0.210 g (67%). H NMR (acetone-d6): δ 8.4 (br
1
s, 1H), 7.26 (dd, 9 Hz, 6.5 Hz, 2H), 7.12 (t, 9 Hz, 2H), 7.09 (d,
9 Hz, 2H), 6.87 (d, 8.5 Hz, 2H), 2.81 (bs. s, 1H), 2.70 (br s,
1H), 2.18-2.09 (m, 2H), 1.93-1.82 (m, 8H), 1.67-1.63 (m, 2H).
13C NMR (acetone-d6, 125 MHz): δ 162.6, 160.7, 156.3, 145.3,
140.1, 140.08, 134.4, 131.3, 131.2, 130.8, 130.6, 115.3, 115.1,
product was 0.190 g (54%). H NMR: δ 7.05 (d, 8.5 Hz, 4H),
6.82 (d, 8.5 Hz, 1H), 3.79 (s, 6H), 2.81 (br s, 2H), 2.1-1.84 (m,
9H). 13C NMR: δ 157.7, 145.7, 135.8, 130.6, 129.5, 113.2, 55.1,
39.5, 39.2, 37.4, 37.1, 28.2. mp 145-146 °C.
Dep r otection . Starting from 0.1 g of the McMurry coupling
product and using the general procedure B, the yield of
compound 14 was 0.085 g (93%). 1H NMR: δ 7.00 (d, 8 Hz,
4H), 6.71 (d, 8 Hz, 1H), 2.86 (br s, 2H), 2.0-1.84 (m, 9H). 13C
NMR: δ 153.7, 140.7, 133.8, 130.5, 128.7, 113.0, 39.4, 39.1,
114.9, 34.6, 34.4, 33.8, 21.9. HRMS (EI, 70 eV) calcd for C22H23
FO, 320.1733; found, 320.1730.
-
9-[(4-Hyd r oxyp h en yl)p h en ylm eth ylen e]bicyclo[3.3.1]-
n on a n e (10). Following the general procedure A and using
ketones 3 and 7 as the reactants, the isolated yield of the cross-
36.4, 38.1, 28.7. HRMS (EI, 70 eV) calcd for
332.1776; found, 332.1774.
C23H24O2,
1
coupled product was 0.26 g, (82%). H NMR: δ 7.34 (t, 8 Hz,
2H), 7.25 (s, 1H), 7.24 (d, 8 Hz, 2H), 7.16 (d, 8.5 Hz, 2H), 6.89
(d, 8.5 Hz, 2H), 3.84 (s, 3H), 2.82 (br s, 1H), 2.76 (br s, 1H),
2-[Bis(4-h yd r oxyp h e n yl)m e t h yle n e ]b icyclo[2.2.1]-
h ep ta n e (16). Following the general procedure A and using
ketones 6 and 15 as the reactants, the isolated yield of the
2.65-2.06 (m, 2H), 1.96-1.82 (m, 9H), 1.69-1.65 (m, 2H). 13
C
1
NMR: δ 157.8, 145.3, 143.3, 135.5, 130.7, 130.3, 129.2, 127.9,
125.8, 113.3, 55.0, 34.1, 34.02, 33.7, 21.6. MS (EI, 70 eV) m/z:
318 (M+, 100%). HRMS (EI, 70 eV) calcd for C23H26O, 318.1984;
found 318.1984.
cross-coupled product 16 was 0.19 g (65%). H NMR: δ 8.12
(s, 1H), 8.10 (s, 1H), 7.12 (dd, 8 Hz, 2 Hz, 1H), 7.01 (d, 7 Hz,
2H), 6.86 (dd, 8.5 Hz, 2 Hz, 1H), 6.70 (d, 8.5 Hz, 1H), 6.70 (d,
8.3 Hz, 2H), 6.64 (dd, 8 Hz, 2.5 Hz, 1H), 1.86-1.81 (m, 2H),
1.72 (tt, 4.5 Hz, 11.5 Hz, 1H), 1.62 (br s, 1H), 1.52 (tt, 4.5 Hz,
12.5 Hz, 1H), 1.40 (td, 5 Hz, 12.5 Hz, 1H). 13C NMR: δ 156.05,
156.03, 154.2, 137.7, 136.6, 134.5, 131.5, 130.9, 129.9, 115.3,
114.6, 114.4, 52.2, 50.6, 46.95, 46.93, 46.0, 37.7, 26.41. HRMS
(EI, 70 eV) calcd for C20H20O2, 292.1463; found, 292.1460.
5-[Bis(4-h ydr oxyph en yl)m eth ylen e]octah ydr o-4,7-m eth -
a n oin d en e (18). Following the general procedure A and using
ketones 1 and 17 as the reactants, the isolated yield of the
Dep r otection . Starting from 0.1 g (0.31 mmol) of the
McMurry coupling product and using the general procedure
B, 0.082 g (87%) of compound 10 was obtained. 1H NMR
(acetone-d6): δ 8.2 (br s, 1H), 7.26 (d, 8 Hz, 2H), 7.12 (t, 9 Hz,
2H), 7.09 (d, 9 Hz, 2H), 6.87 (d, 8.5 Hz, 2H), 2.81 (bs. s, 1H),
2.70 (br s, 1H), 2.18-2.09 (m, 2H), 1.93-1.82 (m, 8H), 1.67-
1.63 (m, 2H). 13C NMR (acetone-d6, 125 MHz): δ 161.6, 160.5,
155.3, 143.3, 142.1, 139.08, 131.4, 130.3, 130.2, 129.8, 129.6,
113.3, 112.1, 111.9, 33.6, 32.4, 31.8, 20.9. HRMS (EI, 70 eV)
calcd for C22H24O, 304.1827; found, 304.1827.
1
cross-coupled product was 0.23 g, (64%). H NMR: δ 7.14 (d,
8.5 Hz, 2H), 7.11 (d, 8.5 HZ, 2H), 6.84 (d, 9 Hz, 2H), 6.83 (d,
9 Hz, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 2.70 (br s, 1H), 2.42 (dd,
16.5 Hz, 4.5 Hz, 1H), 2.22 (dd, 17 Hz, 8 Hz, 1H), 2.13 (d, 4.5
Hz, 1H), 1.98 (dd, 8 Hz, 17 Hz, 1H), 1.95-1.88 (m, 2H), 1.81
(dd, 3 Hz, 16.5 Hz, 1H), 1.70 (dt, 12 Hz, 6 Hz, 1H), 1.49 (d, 10
Hz, 1H), 1.31-1.21 (m, 3H), 1.04-0.95 (m, 2H). 13C NMR: δ
157.63, 157.56, 144.0, 136.1, 135.9, 130.4, 130.3, 129.6, 113.26,
113.19, 113.14, 55.11, 55.09, 47.6, 47.2, 47.1, 40.9, 38.3, 33.2,
9-[(3,4-Dih ydr oxyph en yl)(4-h ydr oxyph en yl)m eth ylen e]-
bicyclo[3.3.1]n on a n e (11). Following the general procedure
A and using ketones 4 and 7 as the reactants, the isolated
yield of the cross-coupled product was 0.210 g (67%). 1H
NMR: δ 7.08 (d, 8.5 Hz, 2H), 6.81 (d, 8.5 Hz, 2H), 6.78 (d, 8.5
Hz, 1H), 6.69 (dd, 8.5 Hz, 1.5 Hz, 1H), 6.67 (d, 1.5 Hz, 1H),
3.85 (s, 3H), 3.82 (s, 3H), 3.77 (s, 3H), 2.71 (br s, 2H), 2.08-
2.00(m, 4H), 1.85-1.78 (m, 8H), 1.61-1.55 (m, 2H). 13C NMR:
δ 157.7, 148.2, 147.1, 144.9, 136.2, 135.5, 130.4, 130.2, 121.4,
113.2, 112.6, 110.6, 55.6, 55.0, 34.24, 34.21, 34.02, 33.72, 33.70,
21.6. MS (EI, 70 eV) m/z: 378 (M+, 100%), 347 (M - 31, 14%).
32.4, 31.6, 27.6. HRMS (EI, 70 eV) calcd for
360.2089; found, 360.2086.
C25H28O2,
Dep r otection . Using 0.1 g (0.27 mmol) of the product from
the McMurry reaction and using the general procedure B, the
yield of compound 18 was 0.082 g (90%). 1H NMR (acetone-
d6): δ 7.14 (d, 8.5 Hz, 2H), 7.11 (d, 8.5 HZ, 2H), 6.84 (d, 9 Hz,
2H), 6.83 (d, 9 Hz, 2H), 2.70 (br s, 1H), 2.42 (dd, 16.5 Hz, 4.5
Hz, 1H), 2.22 (dd, 17 Hz, 8 Hz, 1H), 2.13 (d, 4.5 Hz, 1H), 1.98
(dd, 8 Hz, 17 Hz, 1H), 1.95-1.88 (m, 2H), 1.81 (dd, 3 Hz, 16.5
Hz, 1H), 1.70 (dt, 12 Hz, 6 Hz, 1H), 1.49 (d, 10 Hz, 1H), 1.31-
1.21 (m, 3H), 1.04-0.95 (m, 2H). 13C NMR: δ 155.63, 156.5,
141.0, 136.1, 135.9, 130.4, 130.3, 129.6, 113.26, 113.19, 113.14,
55.09, 47.6, 47.2, 47.1, 40.9, 38.3, 33.2, 32.4, 31.6, 27.6. HRMS
(EI, 70 eV) calcd for C23H24O2, 332.1776; found, 332.1774.
1,1,5,5-Tetr a m eth ylocta h yd r o-2,4a -m eth a n on a p h th a -
len -7-on e (20). Lithium was added in three portions to liquid
ammonia at -78 °C. The dark-blue solution was stirred for
15 min. The enone 19 ((-)-isolongifolenone, 0.5 g, 2.3 mmol)
HRMS (EI, 70 eV) calcd for
378.2193.
C25H30O3, 378.2195; found,
Dep r otection . Starting from 0.1 g (0.26 mmol) of the
McMurry coupling product and using the general procedure
B, 0.075 g (85%) of compound 11 was obtained. 1H NMR-
(acetone-d6): δ 6.97 (d, 8.5 Hz, 2H), 6.75 (d, 8 Hz, 1H), 6.73
(d, 8.5 Hz, 2H), 6.62 (d, 2 Hz, 1H), 6.51 (dd, 8 Hz, 2 Hz, 1H),
2.75 (br s, 1H), 2.67 (br s, 1H), 2.07-1.98 (m, 3H), 1.84-1.71
(m, 8H), 1.58-1.52 (m, 2H). 13C NMR (acetone-d6): δ 155.9,
144.7, 143.7, 143.5, 135.7, 134.9, 131.7, 130.4, 120.9, 116.6,
114.9, 34.3, 33.7, 21.8. HRMS (EI, 70 eV) calcd for C22H24O3,
336.1725; found, 336.1720.
9-[(4-H yd r oxyp h en yl)(3-h yd r oxyp h en yl)m et h ylen e]-
bicyclo[3.3.1]n on a n e (12). Following the general procedure