Comparison of Analogs of Anandamide
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22 3631
g, 4.38 mmol) in dry acetonitrile (1.5 mL) was heated at 88 °C
in a sealed Reacti-vial with stirring until TLC (ethyl ether-
hexane, 3:7) analysis of an aliquot showed complete consump-
tion of the starting tosylate (4 days). Evaporation of the
acetonitrile in vacuo, addition of a minimal amount of CH2-
Cl2, and trituration with ethyl ether gave 2.1 g (78%) of the
2,2-Dim eth ylocta n a l (14). A solution of 2,2-dimethyloc-
tan-1-ol (3.4 g, 21.5 mmol) in dry CH2Cl2 (30 mL) was added
to pyridinium chlorochromate (7.16 g, 33.2 mmol) in dry CH2-
Cl2 (30 mL) at ambient temperature with stirring. After
stirring for 3 h, the completed reaction was diluted with ethyl
ether (75 mL) which was filtered through a plug of Florisil
followed by 300 mL of ether washes of the tarry residue from
the flask. The resulting pale yellow liquid from evaporation
of the ether in vacuo was chromatographed on silica gel 60
(100 g) eluting with 20% EtOAc-hexane affording 2.9 g (86%)
of the title aldehyde: 1H NMR (CDCl3) δ 9.41 (s, 1H, CHO),
1.42 (m, 2H, 3-CH2), 1.23 (br m, 8H, 4-7-CH2), 1.01 (s, 6H,
gem-Me2), 0.85 (m, 3H, 8-CH3).
(16,16-Dim et h yld ocosa -cis-5,8,11,14-t et r a en oyl)et h a -
n ola m in e (17a ). A solution of the corresponding ester (199
mg, 0.53 mmol), NaCN (2.6 mg, 0.053 mmol), and ethanola-
mine (0.34 mL, 5.5 mmol) in methanol (1 mL) in a sealed
Reacti-vial was heated in a hot block at 50 °C overnight. The
completed reaction was diluted with ethyl ether and washed
consecutively with 1 N HCl, aqueous NaHCO3, and brine.
Drying over Na2SO4, evaporation of the solvent, and chroma-
tography on silica gel 60 (10 g) with 75% EtOAc-hexane
afforded 175 mg (82%) of the title (dimethylheptyl)anandamide
analog: 1H NMR (CDCl3) δ 5.96 (br s, 1H, NH), 5.34 (m, 6H,
5,6,8,9,11,12-vinyl-H), 5.21 (m, 2H, 14,15-vinyl-H), 3.71 (br,
2H, OCH2), 3.42 (q, 2H, J ) 5.2 Hz, N-CH2), 2.92 (t, 2H, J )
5.8 Hz, 13-CH2), 2.82 (m, 4H, 7,10-CH2), 2.21 (t, 2H, J ) 7.7
Hz, 2-CH2), 2.11 (m, 2H, 4-CH2), 1.71 (p, 2H, J ) 7.5 Hz,
3-CH2), 1.25 (m, 10H, 17-21-CH2), 1.08 (s, 6H, gem-Me2), 0.87
(m, 3H, 22-CH3); HRMS calcd for C26H45NO2: 403.3450, found
403.3453; 13C NMR δ 174.1, 139.2, 129.10, 129.08, 128.9, 128.3,
128.2, 127.9, 127.0, 62.7, 44.4, 42.5, 36.4, 36.0, 31.9, 30.2, 29.0,
26.8, 26.7, 25.74, 25.67, 25.5, 24.8, 22.7, 14.1. HPLC, eluant
a, 10.1 min (98%); eluant c, 9.3 min (∼98%).
title compound as a red oil after high-vacuum drying.
A
subsequent, larger scale reaction under atmospheric pressure
reflux (98 °C) and a petroleum ether trituration gave a 96%
yield of comparable material: 1H NMR (CDCl3) δ 7.67 (m, 17H,
PPh3 + ArH2), 6.96 (d, 2H, J ) 7.9 Hz, ArH′2), 5.41 (m, 1H,
vinyl H), 5.22 (m, 5H, vinyl H), 3.57 (s, 3H, OCH3), 3.54 (m,
2H, 14-CH2), 2.55, 2.46 (t, t, 4H, J ) 6.4, 7.1 Hz, 7,10-CH2),
2.32 (br m, 2H, 13-CH2), 2.22 (s, overlap, 3H, Ar-CH3), 2.21
(m, 2H, 2-CH2), 1.97 (m, 2H, 4-CH2), 1.60 (p, 2H, J ) 7.4 Hz,
3-CH2).
Meth yl 16,16-Dim eth yld ocosa -cis-5,8,11,14-tetr a en oa te
(16). A solution of the phosphonium salt (1.46 g, 2.18 mmol)
in anhydrous THF (20 mL) under argon was cooled to -73 °C
and treated with n-BuLi (1.4 mL 1.56 M in hexanes, 2.18
mmol) with stirring. The resulting deep red solution was
stirred at -73 °C for 30 min when 2,2-dimethyl-1-octanal (360
mg, 2.3 mmol) was added. Stirring for 1 h at -73 °C and then
1.5 h at -73 to -30 °C was followed by quenching with pH 7
phosphate buffer and extraction with ethyl ether (3×). The
combined organic layers were washed with brine and dried
over Na2SO4. The residual oily solids upon evaporation of the
volatiles in vacuo were triturated with ethyl ether, refriger-
ated, and filtered to remove triphenylphosphine oxide. Evapo-
ration of the ether and chromatography of the residual oil (0.96
g) on silica gel 60 with CH2Cl2 afforded 463 mg of a mixture
which was readily separated by chromatography on a size B
Merck Prepak C18 reverse phase column eluting with 95%
methanol-water to yield 196 mg (24%) of the title compound:
1H NMR (CDCl3, 500 MHz) δ 5.36 (m, 6H, 5,6,8,9,11,12-vinyl-
H), 5.24 (d, 1H, J ) 12 Hz, 15-vinyl-H), 5.16 (dt, 1H, J ) 12,
7.3 Hz, 14-vinyl-H), 3.66 (s, 3H, OCH3), 2.93 (dt, 2H, J ) 6.4,
0.6 Hz, 13-CH2), 2.81 (m, 4H, 7,10-CH2), 2.32 (t, 2H, J ) 7.5
Hz, 2-CH2), 2.10 (m, 2H, 4-CH2), 1.70 (p, 2H, J ) 7.4 Hz,
3-CH2), 1.28 (m, 10H, 17-21-CH2), 1.09 (s, 6H, gem-Me2), 0.87
(t, 3H, J ) 6.8 Hz, 22-CH3); HRMS calcd for C25H42O2 374.3185,
found 374.3188; 13C NMR δ 174.0, 139.2, 129.0, 128.96, 128.89,
128.22, 128.20, 127.9, 127.0, 51.4, 44.3, 36.4, 33.5, 31.9, 30.2,
29.0, 26.8, 26.6, 25.7, 25.6, 24.8 (overlapped), 22.7, 14.1.
Eth yl 2,2-Dim eth ylocta n oa te (11). Ethyl isobutyrate
(11.7 mL, 87.6 mmol) was added to a commercial solution of
lithium diisopropylamide (2.0 M in heptane-THF-ethylben-
zene) (49.5 mL, 99 mmol) in anhydrous THF (86 mL, distilled
from Na/benzophenone) at -74 °C with stirring. After 30 min,
1-bromohexane (13.5 mL, 96.2 mmol) in HMPA (16.5 mL) was
added, and the reaction was stirred for 10 min at -74 °C and
then allowed to warm slowly to room temperature over
approximately 2 h. The reaction was quenched with water (5
mL), stirred briefly, and treated with solid Na2SO4 followed
by filtration and evaporation in vacuo. The oily mixture was
chromatographed on silica gel (400 g) eluting with ethyl ether
to afford 17.4 g (99%) of the title compound: 1H NMR (CDCl3)
δ 4.11 (q, 2H, J ) 7.1 Hz, OCH2), 1.48 (m, 2H, 3-CH2), 1.23
(m, 11H, 4-7-CH2, OCH2CH3), 1.15 (s, 6H, gem-Me2), 0.87 (t,
3H, J ) 6.4 Hz, 8-CH3).
(R)-(16,16-Dim eth yld ocosa -cis-5,8,11,14-tetr a en oyl)-1′-
h yd r oxy-2′-p r op yla m in e (17b). A methanol solution (1 mL)
of the corresponding ester (204 mg, 0.55 mmol), NaCN (2.7
mg, 0.055 mmol), and (R)-(-)-2-amino-1-propanol (0.45 mL,
5.8 mmol) heated overnight in a hot block at 50 °C, worked
up as for the corresponding ethanolamide, and chromato-
graphed on silica gel 60 (40 g) eluting with 50% EtOAc-hexane
afforded some recovered ester and 176 mg (77%) of the title
amide: 1H NMR (CDCl3) δ 5.73 (br d, 1H, J ) 6.5 Hz, NH),
5.36 (m, 6H, 5,6,8,9,11,12-vinyl-H), 5.21 (m, 2H, 14,15-vinyl-
H), 4.04 (m, 1H, N-CH), 3.64 (br m, 1H, OCH), 3.52 (br m,
1H, OCH′), 3.18 (br s, 1H, OH), 2.91 (t, 2H, J ) 5.9 Hz, 13-
CH2), 2.79 (m, 4H, 7,10-CH2), 2.18 (t, 2H, J ) 7.6 Hz, 2-CH2),
2.08 (m, 2H, 4-CH2), 1.71 (p, 2H, J ) 7.4 Hz, 3-CH2), 1.27 (m,
10H, 17-21-CH2), 1.15 (d, 3H, J ) 6.8 Hz, N-C-CH3), 1.08 (s,
6H, gem-Me2), 0.86 (m, 3H, 22-CH3); HRMS calcd for C27H47
-
NO2 417.3607, found 417.3609; 13C NMR δ carbonyl and
quaternary carbon too weak to be seen, 139.2, 129.1 (over-
lapped), 128.9, 128.3, 128.2, 127.9, 127.0, 67.5, 47.9, 44.4, 36.1,
31.9, 30.2, 29.0, 26.8, 26.7, 25.74, 25.67, 25.5, 24.8, 22.7, 17.1,
14.1; HPLC, eluant a, 10.7 min (99%); eluant c, 9.1 min
(∼99%).
(S)-(16,16-Dim eth yld ocosa -cis-5,8,11,14-tetr a en oyl)-2′-
h yd r oxy-1′-p r op yla m in e (17c). A methanol solution (0.5
mL) of the corresponding ester (100 mg, 0.27 mmol), NaCN
(1.4 mg, 0.028 mmol), and (S)-(+)-1-amino-2-propanol (0.21
mL, 2.7 mmol) heated 2 days in a hot block at 50 °C resulted
in the formation of product along with residual ester (TLC).
The reaction was worked up as for the corresponding ethano-
lamide and chromatographed on silica gel 60 (5 g) eluting with
50% to 75% EtOAc-hexane mixtures to afford ∼20 mg of the
recovered ester and 72 mg (65%) of the title amide: 1H NMR
(CDCl3) δ 5.99 (br s, 1H, NH), 5.36 (m, 6H, 5,6,8,9,11,12-vinyl-
H), 5.18 (m, 2H, 14,15-vinyl-H), 3.89 (m, 1H, O-CH), 3.42 (m,
1H, NCH), 3.10 (m, 1H, NCH′), 2.92 (t, 2H, J ) 6.1 Hz, 13-
CH2), 2.81 (m, 4H, 7,10-CH2), 2.21 (t, 2H, J ) 7.6 Hz, 2-CH2),
2.09 (m, 2H, 4-CH2), 1.71 (p, 2H, J ) 7.5 Hz, 3-CH2), 1.25 (br
m, 10H, 17-21-CH2), 1.18 (d, 3H, J ) 6.3 Hz, O-C-CH3), 1.08
2,2-Dim eth ylocta n -1-ol (12). A solution of LiAlH4 in THF
(45 mL, 1.0 M, 45 mmol) was added to a ice-bath-cooled
solution of ethyl 2,2-dimethyloctanoate (17.4 g, 87 mmol) in
anhydrous ethyl ether (100 mL) with stirring. After the
vigorous reaction subsided, the cooling bath was removed and
stirring was continued overnight at ambient temperature. The
reaction was cooled in an ice bath and quenched by sequential
addition of water (5 mL), 15% NaOH (5 mL), and water (15
mL) with stirring. After 45 min, the slurry was filtered,
washing the solids with ethyl ether. The aqueous phase was
separated, and the ether solution was dried over Na2SO4. The
residue obtained upon evaporation in vacuo was chromato-
graphed on silica gel (200 g) eluting with CH2Cl2 affording 12.5
g (93%) of the title alcohol: 1H NMR (CDCl3) δ 4.11 (s, 2H,
OCH2), 1.61 (br, 1H, OH), 1.22 (br "d", 10H, 3-7-CH2), 0.85,
0.83 (m, s, overlap, 9H, 8-CH3, gem-Me2).
(s, 6H, gem-Me2), 0.87 (m, 3H, 22-CH3); HRMS calcd for C27H47
-
NO2 417.3607, found 417.3609; 13C NMR δ 173.9, 139.1, 129.0
(overlapped), 128.8, 128.2, 128.1, 127.8, 126.9, 67.6, 47.0, 44.3,
36.3, 35.9, 31.8, 30.1, 28.9, 26.7, 26.6, 25.65, 25.58, 25.4, 24.7,