Synthesis of Functionalized Cannabinoids
J . Org. Chem., Vol. 65, No. 20, 2000 6581
The aqueous phase was extracted with ether (3×), and the
combined organic extracts were washed with brine (1×) and
dried (MgSO4). Purification by flash column chromatography
on silica gel (hexanes to 1.5% EtOAc in hexanes) gave 17 (6.98
g, 81% yield) as a pale yellow oil: Rf ) 0.24 (2.5% EtOAc in
hexanes); 1H NMR (300 MHz, CDCl3) δ 13.29 (s, 1H), 6.54 (d,
J ) 1.5 Hz, 1H), 6.34 (d, J ) 1.5 Hz, 1H), 6.09 (ddt, J ) 17.1,
10.7, 5.6 Hz, 1H), 5.43 (dd, J ) 17.3, 1.2 Hz, 1H), 5.33 (dd, J
) 10.3, 1.0 Hz, 1H), 4.63 (d, J ) 5.6 Hz, 2H), 2.67 (s, 3H), 1.55
(m, 2H), 1.29-0.97 (m, 8H), 1.24 (s, 6H), 0.84 (t, J ) 6.7 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 204.1, 164.3, 159.9, 159.3,
132.6, 118.5, 109.2, 108.5, 100.4, 69.6, 44.0, 38.6, 33.6, 31.7,
29.9, 28.5, 24.6, 22.6, 14.1; IR (neat) 2925, 2855, 1630, 1560,
1410 cm-1; mass spectrum m/z 318 (M+, 9), 205 (100), 180 (80),
179 (41), 165 (50); exact mass calcd for C20H30O3 318.2195,
found 318.2211. Anal. Calcd for C20H30O3: C, 75.4; H, 9.5.
Found: C, 75.54; H, 9.63.
5.38 (dm, J ) 17.1 Hz, 1H), 5.26 (dm, J ) 10.5 Hz, 1H), 4.51-
4.49 (m, 2H), 4.42 (s, 2H), 4.02 (m, 1H), 3.97 (d, J ) 2.2 Hz,
1H), 2.25-2.16 (m, 3H), 1.96 (d, J ) 4.9 Hz, 1H), 1.84-1.49
(m, 5H), 1.78 (s br, 3H), 1.26-1.00 (m, 8H), 1.22 (s, 6H), 0.92
(s, 9H), 0.84 (t, J ) 6.8 Hz, 3H), 0.13 (s, 6H).
Tr icyclic C9 Alcoh ol 20. To a solution of diol 19 (2.00 g,
3.41 mmol) in 175 mL of CHCl3 at 0 °C was added TFA (290
µL, 429 mg, 3.76 mmol). After 3.5 h, the reaction mixture was
quenched with saturated NaHCO3 and diluted with water. The
aqueous phase was extracted with CH2Cl2 (2×) and the
combined organic extracts were washed with brine (1×) and
dried (MgSO4). Purification by flash column chromatography
on silica gel (5% to 10% to 20% EtOAc in hexanes) gave alcohol
20 (1.480 g, 76% yield) as a colorless oil as a 1:1 mixture of
diastereomers: Rf ) 0.29 and 0.21 (20% EtOAc in hexanes);
IR (neat) 3360, 2925, 2855, 2340, 1610, 1565, 1410 cm-1; mass
spectrum m/z 568 (M+, 6), 131 (8), 119 (10), 76 (9), 75 (100);
exact mass calcd for C35H56O4Si 568.3948, found 568.3937.
Anal. Calcd for C35H56O4Si: C, 73.9; H, 9.9. Found: C, 73.92;
H, 9.82. 20, C9-â-hydroxyl: 1H NMR (300 MHz, CDCl3) δ 6.49
(d, J ) 1.5 Hz, 1H), 6.37 (d, J ) 1.7 Hz, 1H), 6.07 (ddt, J )
17.1, 10.5, 5.1 Hz, 1H), 5.40 (dm, J ) 17.3, 1H), 5.27 (dm, J )
10.5 Hz, 1H), 4.55-4.48 (m, 2H), 4.41 (s, 2H), 3.84 (m, 1H),
3.42 (d br, J ) 12.0 Hz, 1H), 2.51 (td, J ) 11.2, 2.7 Hz, 1H),
2.26-2.12 (m, 2H), 1.84 (td, J ) 11.5, 2.0 Hz, 1H), 1.78 (d, J
) 2.9 Hz, 1H), 1.63-0.76 (m, 13H), 1.34 (s br, 3H), 1.21 (s,
6H), 0.92 (s, 9H), 0.84 (t, J ) 7.1 Hz, 3H), 0.13 (s, 6H). 20,
C9-R-hydroxyl: 1H NMR (300 MHz, CDCl3) δ 6.49 (d, J ) 1.7
Hz, 1H), 6.37 (d, J ) 1.7 Hz, 1H), 6.07 (ddt, J ) 17.3, 10.5, 5.1
Hz, 1H), 5.44 (dm, J ) 17.1 Hz, 1H), 5.27 (dm, J ) 10.7 Hz,
1H), 4.53-4.51 (m, 2H), 4.42 (s, 2H), 4.23 (s br, 1H), 3.25 (dm,
J ) 13.7 Hz, 1H), 2.98 (td, J ) 11.2, 2.7 Hz, 1H), 1.99 (t br, J
) 13.2 Hz, 2H), 1.84 (t br, J ) 10.7 Hz, 1H), 1.66-0.79 (m,
14H), 1.39 (s br, 3H), 1.21 (s, 6H), 0.91 (s, 9H), 0.84 (t, J ) 7.2
Hz, 3H), 0.13 (s, 6H).
(6E)-1-[4-(1,1-Dim eth ylh ep tyl)-2-h yd r oxy-6-p r op -2-en -
yloxyp h en yl]-3-h yd r oxy-10-ter t-b u t yld im et h ylsilyloxy-
7-m eth yld ec-6-en -8-yn -1-on e 18. To a solution of diisopro-
pylamine (1.80 mL, 1.30 g, 12.8 mmol) in 24 mL of THF at
-78 °C was added n-BuLi (5.45 mL, 2.37 M in hexanes, 12.9
mmol). After 20 min, a solution of ketone 17 (1.974 g, 6.20
mmol) in 8 mL of THF at -78 °C was added via cannula. After
30 min, a solution of aldehyde 12 (1.533 g, 5.75 mmol) in 8
mL of THF at -78 °C was added via cannula. After 30 min,
the reaction mixture was quenched with acetic acid (1.40 mL,
1.47 g, 24.5 mmol), warmed to room temperature, and diluted
with ether and water. The aqueous phase was extracted with
ether (3×), and the combined organic extracts were washed
with brine (1×) and dried (MgSO4). Purification by flash
column chromatography on silica gel (2.5% to 5% to 10% EtOAc
in hexanes) gave ketone 18 (2.278 g, 68% yield) as a pale yellow
1
oil: Rf ) 0.27 (10% EtOAc in hexanes); H NMR (300 MHz,
CDCl3) δ 13.05 (s, 1H), 6.54 (d, J ) 1.7 Hz, 1H), 6.32 (d, J )
1.5 Hz, 1H), 6.07 (ddt, J ) 17.3, 10.5, 5.6 Hz, 1H), 5.84 (tm, J
) 7.5 Hz, 7.5 Hz, 1H), 5.43 (dd, J ) 17.1, 1.5 Hz, 1H), 5.35
(dd, J ) 10.5, 1.0 Hz, 1H), 4.61 (d, J ) 5.9 Hz, 2H), 4.41 (s,
2H), 4.16 (m, 1H), 3.29 (dd, J ) 18.2, 2.4 Hz, 1H), 3.13 (s, 1H),
3.12 (dd, J ) 18.3, 9.3 Hz, 1H), 2.30-2.16 (m, 2H), 1.79 (s br,
3H), 1.69-1.49 (m, 4H), 1.37-0.98 (m, 8H), 1.23 (s, 6H), 0.90
(s, 9H), 0.83 (t, J ) 6.7 Hz, 3H), 0.12 (s, 6H); 13C NMR (75
MHz, C6D6) δ 206.5, 165.6, 160.4, 159.6, 137.9, 132.8, 118.44,
118.41, 109.9, 109.5, 100.5, 88.4, 85.1, 69.6, 67.0, 52.5, 52.4,
44.3, 38.7, 36.3, 32.2, 30.5, 28.63, 28.60, 26.1, 25.1, 25.0, 23.2,
18.5, 17.3, 14.4, -4.8; IR (neat) 3560, 2915, 2860, 2220, 1630,
1600, 1410, 1370 cm-1; mass spectrum m/z 165 (25), 105 (24),
101 (17); exact mass calcd for C31H47O5Si (M+-- t-Bu) 527.3193,
found 527.3203.
Tr icyclic C9 Keton e 21. To a solution of alcohol 20 (1.40
g, 2.46 mmol) in 100 mL of CH2Cl2 at 0 °C was added Dess-
Martin periodinane (1.375 g, 3.76 mmol). After 30 min, addi-
tional periodinane (155 mg, 0.37 mmol) was added. The
reaction mixture was stirred for 30 min at 0 °C, warmed to
room temperature, and stirred for 30 min, and additional perio-
dinane (180 mg, 0.42 mmol) was added. After 1 h, the reaction
mixture was quenched with saturated NaHCO3, and sodium
thiosulfate pentahydrate (1.965 g, 7.92 mmol) was added. The
two-phase mixture was stirred for 15 min and diluted with
water. The aqueous phase was extracted with CH2Cl2 (2×),
and the combined organic extracts were washed with brine
(1×) and dried (MgSO4). Purification by flash column chro-
matography on silica gel (2.5% to 5% EtOAc in hexanes) gave
ketone 21 (956 mg, 69% yield) as a colorless oil: Rf ) 0.31
(6E )-1-[4-(1,1-Dim e t h ylh e p t yl)-2-h yd r oxy-6-p r op -2-
en yloxyp h en yl]-10-ter t-bu tyld im eth ylsilyloxy-7-m eth yl-
d ec-6-en -8-yn e-1,3-d iol 19. To a solution of ketone 18 (2.128
g, 3.64 mmol) in 50 mL of MeOH at room temperature was
added NaBH4 (207 mg, 5.47 mmol) in one portion. After 5 min,
the reaction mixture was quenched with acetic acid (1.5 mL)
and diluted with ether and water. The aqueous phase was
extracted with ether (4×), and the combined organic extracts
were washed with brine (1×) and dried (MgSO4). Purification
by flash column chromatography on silica gel (5% to 10% to
20% to 30% EtOAc in hexanes) gave diol 19 (2.064 g, 97% yield)
as a colorless oil as a 1:1 mixture of diastereomers: Rf ) 0.20
and 0.16 (20% EtOAc in hexanes); IR (neat) 3320, 2925, 2855,
1620, 1580, 1415 cm-1; mass spectrum m/z 151 (30), 192 (53),
191 (37), 177 (18), 165 (26); exact mass calcd for C35H56O4Si
(M+ - H2O) 568.3948, found 568.3929. syn -19: 1H NMR (300
MHz, CDCl3) δ 9.01 (s, 1H), 6.49 (d, J ) 1.7 Hz, 1H), 6.34 (d,
J ) 1.5 Hz, 1H), 6.02 (ddt, J ) 17.3, 10.5, 5.1 Hz, 1H), 5.79 (t
br, J ) 7.1 Hz, 1H), 5.57 (ddd, J ) 9.3, 3.7, 1.5 Hz, 1H), 5.37
(dm, J ) 17.1 Hz, 1H), 5.27 (dm, J ) 10.5 Hz, 1H), 4.53-4.46
(m, 3H), 4.42 (s, 2H), 3.94 (m, 1H), 2.40 (d, J ) 3.7 Hz, 1H),
2.17 (q br, J ) 7.6 Hz, 2H), 2.05-1.85 (m, 2H), 1.77 (s br, 3H),
1.60-1.49 (m, 2H), 1.26-0.99 (m, 10H), 1.22 (s, 6H), 0.91 (s,
9H), 0.84 (t, J ) 6.8 Hz, 3H), 0.13 (s, 6H). a n ti-19: 1H NMR
(300 MHz, CDCl3) δ 8.97 (s, 1H), 6.48 (d, J ) 1.5 Hz, 1H),
6.33 (d, J ) 1.5 Hz, 1H), 6.01 (ddt, J ) 17.3, 10.7, 5.1 Hz, 1H),
5.83 (t br, J ) 7.3 Hz, 1H), 5.72 (dt, J ) 10.3, 2.1 Hz, 1H),
1
(10% EtOAc in hexanes); H NMR (300 MHz, CDCl3) δ 6.52
(d, J ) 1.7 Hz, 1H), 6.38 (d, J ) 1.7 Hz, 1H), 6.05 (ddt, J )
17.3, 10.5, 5.1 Hz, 1H), 5.39 (dm, J ) 17.3 Hz, 1H), 5.28 (dm,
J ) 10.5 Hz, 1H), 4.53 (dm, J ) 5.4 Hz, 2H), 4.42 (s, 2H), 3.82
(ddd, J ) 15.1, 3.7, 2.0 Hz, 1H), 2.87 (td, J ) 12.0, 3.7 Hz,
1H), 2.66-2.38 (m, 3H), 2.28 (td, J ) 11.7, 2.2 Hz, 1H), 2.11
(dd, J ) 14.9, 12.9 Hz, 1H), 1.68-1.48 (m, 3H), 1.39 (s, 3H),
1.24-0.98 (m, 8H), 1.21 (s, 6H), 0.92 (s, 9H), 0.84 (t, J ) 6.8
Hz, 3H), 0.14 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 210.3, 156.9,
152.5, 150.7, 133.2, 117.5, 108.9, 108.6, 102.5, 85.6, 84.0, 74.2,
68.9, 51.7, 46.5, 45.7, 44.4, 40.8, 37.8, 33.8, 31.8, 30.0, 28.79,
28.76, 27.5, 25.8, 24.6, 22.7, 19.3, 18.3, 14.1, -5.0; IR (neat)
2930, 2860, 2340, 1710, 1610, 1565, 1415 cm-1; mass spectrum
m/z 566 (M+, 9), 91 (8), 85 (8), 76 (9), 75 (100); exact mass
calcd for C35H54O4Si 566.3791, found 566.3796. Anal. Calcd for
C
35H54O4Si: C, 74.2; H, 9.6. Found: C, 74.13; H, 9.75.
Tr icyclic Meth yl En ol Eth er 22. To a suspension of
(methoxymethyl)triphenylphosphonium chloride (1.073 g, 3.13
mmol) in 15 mL of benzene at room temperature was added
sodium tert-amylate (6.20 mL, 0.55 M in benzene, 3.4 mmol).
After 10 min, a solution of ketone 21 (356 mg, 0.63 mmol) in
15 mL of benzene was added via cannula at room temperature.
After 15 min, the reaction mixture was diluted with water and
the aqueous phase was extracted with ether (3×). The com-
bined organic extracts were washed with brine (1×) and dried
(MgSO4). Purification by flash column chromatography on