Conformationally Constrained Analogues of Diacylglycerol. 12
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 43
ammonium hydroxide solution (0.1 mL) with stirring for 20
min. The reaction mixture was quenched with acetic acid (0.1
mL) and concentrated. The residue was purified by flash
column chromatography over silica gel with EtOAc/hexanes
(3:2) as eluant to give 5 (0.250 g, 65% from 19) as a white
31.87, 32.25, 32.56, 51.89, 66.65, 83.83, 121.75, 125.03, 129.66,
130.01, 142.68, 145.24, 166.14, 169.73; FAB MS m/ z (relative
intensity) 449 (MH
+, 26). Anal. (C27H44O5) C, H.
Z-Isom er 8: oil; [R]22D -5.56° (c 0.36, CHCl3); IR (neat) 3440
(OH), 1761 and 1729 (CdO), 1666 cm-1 (CdC); 1H NMR
(CDCl3) δ 0.86 (distorted t, 3 H, CH3(CH2)7CHdCH(CH2)7-
CHdC<), 1.10-1.50 (m, 22 H, CH3(CH2)6CH2CHdCHCH2-
(CH2)5CH2CHdC<), 1.55 (br s, 1 H, OH), 2.00 (m, 4 H,
CH3(CH2)6CH2CHdCHCH2(CH2)5CH2CHdC<), 2.6-2.78 (m,
3 H, CH3(CH2)6CH2CHdCHCH2(CH2)5CH2CHdC<, H-4a), 3.12
(dm, J ) 16.0 Hz, 1 H, H-4b), 3.55-3.80 (m, 5 H, OCH3 and
CH2OH), 5.33 (m, 2 H, CH3(CH2)6CH2CHdCHCH2(CH2)5CH2-
CHdC<), 6.13 (d, J ) 15.6 Hz, 1 H, CH3OCOCHdCH), 6.22
(m, 1 H, CHdC<), 6.86 (d, J ) 15.7 Hz, CH3OCOCHdCH);
13C NMR (CDCl3) δ 14.09, 22.66, 27.19, 27.79, 28.98, 29.18,
29.30, 29.40, 29.50, 29.72, 29.74, 31.88, 32.58, 35.51, 51.88,
66.48, 83.30, 121.83, 123.03, 129.77, 129.95, 145.34, 146.20,
166.17, 168.44; FAB MS m/ z 449 (MH+, 10). Anal. (C27H44O5)
C, H.
solid: mp 58-59 °C; [R]22 -25.8° (c 1.0, CHCl3); IR (CHCl3)
D
3449 (OH), 1778 and 1752 cm-1 (CdO); 1H NMR (CDCl3) δ
0.86 (distorted t, 3 H, CH3(CH2)13), 1.10-1.40 (m, 22 H,
CH3(CH2)11CH2CH2OCO), 1.65 (m, 2 H, CH3(CH2)11CH2CH2-
OCO), 2.08 (m, 2 H, H-4a, OH), 2.42-2.74 (m, 3 H, H-4b, H-3a,b),
3.64 (dd, J ) 12.2, 7.1 Hz, 1 H, CHHOH), 3.79 (dd, J ) 12.2,
5.3 Hz, 1 H, CHHOH), 4.12 (t, J ) 6.7 Hz, 2 H, CH3(CH2)11-
CH2CH2OCO), 6.13 (d, J ) 15.7 Hz, 1 H, CHdCHCO), 6.85
(d, J ) 15.7 Hz, 1 H, CHdCHCO); 13C NMR (CDCl3) δ 14.09,
22.67, 25.88, 28.15, 28.40, 28.56, 29.23, 29.33, 29.49, 29.56,
29.63, 31.90, 65.16, 66.48, 86.98, 122.32, 144.47, 165.71,
176.11; FAB MS m/ z (relative intensity) 383 (MH+,18), 169
(100, MH - C14H29). Anal. (C22H38O5) C, H.
(R)-5-(Hyd r oxym eth yl)-5-[2-(tetr a d eca n oxyca r bon yl)-
eth yl]tetr a h yd r o-2-fu r a n on e (3). A solution of 5 (0.154 g,
0.4 mmol) in EtOAc (20 mL) was treated with 10% Pd-C (0.4
g) and hydrogenated under a hydrogen balloon for 2 h. The
reaction mixture was filtered, and the filtrate was concen-
trated. The residue was purified by flash column chromatog-
raphy over silica gel with EtOAc/hexanes (2:1) as eluant to
give the title compound 3 (0.151 g, 98%) as white solid: mp
5-O-(ter t-Bu tyld ip h en ylsilyl)-1,2-O-isop r op ylid en e-â-D-
th r eo-p en tofu r a n ose-3-u lose (24). This compound was
prepared in three steps from D-arabinose by the method of
Dahlman et al.9
5-O-(ter t-Bu t yld ip h en ylsilyl)-3-C-(3-h yd r oxyp r op yl)-
1,2-O-isop r op ylid en e-â-D-lyxofu r a n ose (25). A stirred so-
lution of 3-chloropropanol (2.127 g, 22.5 mmol) in dry THF
(20 mL) at -20 °C was treated dropwise with a solution of
methylmagnesium chloride (3M in THF, 7.5 mL) and stirred
for 20 min at the same temperature. The reaction mixture
was warmed to room temperature, and magnesium (0.82 g,
33.8 mmol) was added. The reaction mixture was refluxed for
2 h with periodic addition of dibromomethane (0.025 mL each)
at 0, 1, and 1.3 h intervals. After cooling to 0 °C, a solution of
ketone 24 (3.20 g, 7.5 mmol) in THF (25 mL) was added
dropwise. The reaction was quenched at 0 °C after 1 h by the
addition of saturated NH4Cl solution (25 mL). The layers were
separated, and the aqueous portion was extracted with EtOAc
(2 × 25 mL). The combined organic layer was dried (Na2SO4)
and concentrated. The residue obtained was purified by flash
chromatography over silica gel using EtOAc/hexane (1:1) to
60-61 °C; [R]22 +7.90° (c 1.0, CHCl3). The IR, 1H NMR, and
D
13C NMR were identical to those reported for the racemate 2.1
Anal. (C22H40O5) C, H.
(S)-5-(Hydr oxym eth yl)-5-[2-(m eth oxycar bon yl)-(E)-eth -
en yl]-3-{(E)-[(Z)-9-oct a d ecen ylid en e]}t et r a h yd r o-2-fu -
r a n on e (7) a n d (S)-5-(Hyd r oxym eth yl)-5-[2-(m eth oxy-
ca r bon yl)-(E)-eth en yl]-3-{(Z)-[(Z)-9-octa d ecen ylid en e]}-
tetr a h yd r o-2-fu r a n on e (8). A solution of 211 (0.463 g, 1
mmol) in THF (15 mL) was treated with 2 N HCl solution and
stirred for 5 days at room temperature. The reaction mixture
was then neutralized with solid NaHCO3 while being chilled
over ice, filtered, and concentrated. The residue was diluted
with EtOAc, dried (Na2SO4), and concentrated to give the
corresponding hemiacetal as an oil, which was used for the
next step without further purification. This compound was
dissolved in a mixture of MeOH (20 mL) and H2O (10 mL)
and treated with sodium metaperiodate (0.428 g, 2 mmol).
After stirring at room temperature for 4 h, the reaction
mixture was filtered and concentrated. The residue was
dissolved in ether, dried (Na2SO4), and concentrated to give
aldehyde 22, which was used for the next step without further
purification. Aldehyde 22 was dissolved in benzene (20 mL)
and stirred with methyl (triphenylphosphoranylidene)acetate
(0.067 g, 2.0 mmol) for 4 h. The solvent was evaporated, and
the residue was dissolved in ether and filtered through a short
pad of silica gel with additional ether. The filtrate was
concentrated to give a mixture of four products: the formate
esters and free alcohols of both E/ Z isomers. The mixture
was dissolved in methanol (5 mL), cooled to 0 °C, and treated
with ammonium hydroxide solution (0.05 mL) with stirring
for 20 min. The reaction mixture was quenched with acetic
acid (0.05 mL) and concentrated. The residue was purified
by flash column chromatography over silica gel with hexanes/
EtOAc (2:1) as eluant to give first E-isomer 7, followed by
Z-isomer 8. The combined yield was 0.316 g (70.5% from 21).
give the title compound 25 as a liquid (3.0 g, 82%): [R]D
)
25
+15.16° (c 0.89, CHCl3); IR (neat) 3499 cm-1; 1H NMR (CDCl3)
δ 1.05 (s, 9H, C(CH3)3), 1.30 and 1.40 (singlets, 6 H, CH3),
1.50-1.80 (m, 4 H, (CH2)2CH2OH), 2.5 (br s, 2 H, OH), 3.60
(m, 2 H, CH2OH),3.80-4.10 (m, 3 H, H-5a,b, H-4), 4.20 (d, J )
4.1 Hz, 1 H, H-2), 5.68 (d, J ) 4.1 Hz, 1 H, H-1), 7.30-7.40
(m, 6 Η, Ph), 7.60-7.80 (m, 4 Η, Ph); 13C NMR (CDCl3) δ 19.13,
26.56, 26.67, 26.81, 26.89, 35.01, 62.74, 63.62, 78.04, 84.17,
85.30, 104.45, 113.91, 127.70, 129.70, 133.04, 133.27, 135.62,
135.68. Anal. (C27H38O6Si) C, H.
(5S,6R,8S,9S)-6-[[(ter t-Bu tyld ip h en ylsilyl)oxy]m eth yl]-
8,9-O-isop r op ylid en e-2-k et o-1,7-d ioxa sp ir o[4.4]n on a n e
(26). A stirred suspension of powdered molecular sieves (4
Å, 7.5 g) and 25 (3.67g, 7.54 mmol) in anhydrous CH2Cl2 (100
mL) was treated with pyridinium chlorochromate (5.69 g, 26.4
mmol) at room temperature. After stirring for 1 h, the reaction
mixture was diluted with ether (200 mL) and filtered through
a short pad of silica gel. The silica gel pad was washed with
ether (ca. 100 mL), and the filtrate was concentrated and
purified by flash chromatography over silica gel using hexane/
EtOAc (7:3) to give the title compound 26 (3.12 g, 85.7%) as a
solid: mp 122-123 °C (EtOAc/hexane); [R]D25 ) -9.72° (c 1.07,
E-Isom er 7: white solid; mp 53-54 °C; [R]22 +20.32° (c
1
CHCl3); IR (KBr) 1793 cm-1; H NMR (CDCl3) δ 1.02 (s, 9 H,
D
0.62, CHCl3); IR (CHCl3) 3447 (OH), 1755 and 1722 (CdO),
C(CH3)3), 1.30 and 1.48 (singlets, 6 H, CH3), 2.10-2.22 (m, 1
H, H-4a), 2.30-2.70 (m, 3 H, H-4b, H-3a,b), 3.80-4.10 (m, 3 H,
(CH3)3SiOCH2, H-6), 4.48 (d, J ) 4.5 Hz, 1 H, H-9), 5.72 (d, J
) 4.5 Hz, 1 H, H-8), 7.30-7.50 (m, 6 H, Ph), 7.60-7.70 (m, 4
H, Ph); 13C NMR (CDCl3) δ 19.08, 26.46, 26.77, 27.50, 27.75,
30.93, 62.20, 83.82, 86.17, 86.51, 104.12, 115.81, 127.77,
127.81, 129.82, 132.89, 135.53, 175.18. Anal. (C27H34O6Si) C,
H.
1
and 1676 cm-1 (CdC); H NMR (CDCl3) δ 0.86 (distorted t, 3
H, CH3(CH2)7CHdCH(CH2)7CHdC<), 1.10-1.50 (m, 22 H,
CH3(CH2)6CH2CHdCHCH2(CH2)5CH2CHdC<), 2.00 (m, 4 H,
CH3(CH2)6CH2CHdCHCH2(CH2)5CH2CHdC<), 2.15 (m, 2 H,
CH3(CH2)6CH2CHdCHCH2(CH2)5CH2CHdC<), 2.68 (dm, J )
16.7 Hz, 1 H, H-4a), 3.05 (dm, J ) 16.7 Hz, 1 H, H-4b), 3.62
(AB d, J ) 12.0 Hz, 1 H, CHHOH), 3.74 (s, 3 H, CH3O), 3.78
(AB d, J ) 12.0 Hz, 1 H, CHHOH), 5.33 (m, 2 H, CH3(CH2)6-
CH2CHdCHCH2(CH2)5CH2CHdC<), 6.13 (d, J ) 15.7 Hz, 1
H, CH3OCOCHdCH), 6.76 (m, 1 H, CHdC<), 6.89 (d, J ) 15.7
Hz, CH3OCOCHdCH); 13C NMR (CDCl3) δ 14.07, 22.64, 27.12,
27.19, 28.00, 29.10, 29.25, 29.28, 29.48, 29.66, 29.72, 30.30,
(5R)-5-[(1R)-2-[(ter t-Bu tyldiph en ylsilyl)oxy]-1-h ydr oxy-
eth yl]-5-[2-(tetr a d eca n oxyca r bon yl)-(E)-eth en yl]tetr a h y-
d r o-2-fu r a n on e (28). A solution of 26 (3.07g, 6.36 mmol) in
THF (125 mL) was treated with a 1 N HCl solution (57 mL)
and stirred for 11 h at room temperature. The reaction