^
´
A. de Fatima et al. / Bioorg. Med. Chem. 13 (2005) 2927–2933
2931
25
D
25
D
for M+Æ = 222.12560; found: 222.12026. For (R)-5 ½aꢁ
culated for M+Æ = 200.08373; found: 200.07891. ½aꢁ
+1.7 (c 4.0, CHCl3).
+169 (c 1.7, CHCl3), {lit.53, ½aꢁ25 +170.3 (c 1.38, CHCl3)}.
D
4.1.3. Preparation of sulfone 9.52 To a solution of 1-
phenyl-1H-tetrazole-5-thiol (500 mg, 2.80 mmol) in dry
THF (10 mL), Et3N (0.48 mL, 3.4 mmol) was added,
and the mixture was stirred at room temperature. After
40 min, benzyl bromide (0.40 mL, 3.4 mmol) was added
and the reaction refluxed for 6 h, then diluted with
water (20 mL), and extracted with Et2O (3 · 20 mL).
The combined organic layers were dried and evaporated
at reduced pressure to give the crude thioether. MCPBA
(77% w/w) (2.2 g, 9.8 mmol) was added in small por-
tions to a solution of the crude thioether in CH2Cl2
(19 mL) at 0 ꢁC, and the mixture was stirred at room
temperature for 24 h. The reaction mixture was washed
with NaHSO3 (50 mL), and saturated NaHCO3 solu-
tion (3 · 50 mL). The organic layer was dried, and the
solvent removed by evaporation. The residue was sub-
mitted to flash-chromatography (hexane/AcOEt, 2:1)
to afford compound 9 (753 mg, 89%) as a light yellow
solid (mp: 102–104 ꢁC) after trituration with hexanes.
IR (film): 3064, 2968, 2914, 1593, 1495, 1458, 1348,
4.1.5. Preparation of (R)-1-phenyl-5-hexen-3-ol (13). To
a stirred solution of TiCl4 (13 lL, 0.12 mmol) in CH2Cl2
(2.4 mL) was added Ti(Oi-Pr)4 (110 lL, 0.36 mmol) at
0 ꢁC under argon. The solution was allowed to warm
to room temperature. After 1 h, recently prepared sil-
ver(I) oxide51 (56 mg, 0.24 mmol) was added at rt, and
the whole mixture was stirred 5 h under exclusion of di-
rect light. The mixture was diluted with CH2Cl2 (4 mL),
and treated with (R)-BINOL (138 mg, 0.48 mmol) at rt
for 2 h. After cooling this mixture to ꢀ15 ꢁC, it was trea-
ted sequentially with trans-cinnamaldehyde (12)
(318 mg, 2.41 mmol) and allyltributyltin (871 mg,
2.65 mmol). The whole mixture was allowed to warm
to 0 ꢁC and stirred for 24 h. The reaction mixture was
quenched with satd. NaHCO3, and extracted with ether.
The organic extracts were dried over MgSO4. Evapora-
tion of solvents and purification of this residue by col-
umn chromatography on silica gel (hexane/ethyl
acetate, 9:1) furnished (R)-1-phenyl-5-hexen-3-ol (13)
in 94% yield (394 mg). The enantiomeric purity of 13
was determined to be 94% ee by chiral GC analysis after
their conversion to 14 (column: CP-Chiralsil-DEX CB
fused silica WCOT, 25 m · 0.25 mm · 0.25 lm; condi-
tions—initial temperature/time: 60 ꢁC/1 min, rate:
0.5 ꢁC/min, final temperature/time: 180 ꢁC/70 min, H2
as the carrier gas and FID detector) and comparing with
racemic standard. IR (film): 3356, 3078, 2956, 2933,
2860, 2227, 1641, 1462, 1433, 1379, 1331, 1144, 1036,
1
1155, 1128, 883, 766, 692 cmꢀ1. H NMR (300 MHz,
CDCl3): d 7.55–7.25 (m, 10H), 4.92 (s, 2H). 13C NMR
(125 MHz, CDCl3): d 152.8, 132.7, 131.6, 131.3, 129.8,
129.3, 129.1, 125.2, 124.7, 62.3.
4.1.4. Preparation of (R)-goniothalamin (1) via Julia–
Kociensky olefination. To a stirred solution of oxalyl
chloride (150 lL, 1.77 mmol) in dichloromethane
(1.5 mL) was added a solution of dimethyl sulfoxide
(180 lL, 2.34 mmol) in dichloromethane (1.5 mL) at
ꢀ65 ꢁC under argon atmosphere. After 15 min, (R)-6-
hydroxymethyl-5,6-dihydro-2-pyranone (8) (150 mg,
1.17 mmol) was added and stirring was continued for
30 min. Triethylamine (0.81 mL, 5.85 mmol) was added
and the mixture was stirred for further 15 min at the
same temperature. In another flask, sulfone 9 (527 mg,
1.75 mmol) was dissolved in 1.0 mL of THF and
1.6 mL of 0.75 M KHMDS soln. in THF at 0 ꢁC was
added. The solution was stirred at rt for 20 min and
cooled to ꢀ78 ꢁC when the residue obtained from the
Swern oxidation of 8 in 1.0 mL of THF was added.
The mixture was stirred at ꢀ78 ꢁC for 3 and 8 h at rt.
The reaction mixture was quenched with 10 mL of
Et2O and 10 mL of satd. aq NaHCO3. The organic layer
was separated and aqueous layer was extracted with
dichloromethane (3 · 30 mL). The combined organic
layers were dried over anhydrous magnesium sulfate, fil-
tered, and the solvent was removed under reduced pres-
sure. The residual product was purified by column
chromatography (15% ethyl acetate in hexane, v/v, as
eluent) to afford (R)-goniothalamin (1) as a white solid
(0.042 g, 18% yield). Mp 81–82 ꢁC, {lit.53, mp 85 ꢁC};
1
995, 914 cmꢀ1. H NMR (500 MHz, CDCl3): d 7.41–
7.24 (m, 5H), 6.63 (d, 1H, J 16.0 Hz), 6.27 (dd, 1H, J
16.0; 6.2 Hz), 5.92–5.84 (m, 2H), 5.23–5.17 (m, 2H),
4.40–4.36 (m, 1H), 2.49–2.37 (m, 2H), 2.00 (sl, 1H).
13C NMR (125 MHz, CDCl3): d 136.6, 133.9, 131.5,
130.3, 128.5, 127.6, 126.4, 118.4, 71.6, 41.9. HRMS
(EI) m/z calculated for
174.10496. ½aꢁ +22.2 (c 2.0, CHCl3).
M
+Æ = 174.10447; found:
25
D
4.1.6. Preparation of (R)-1-phenyl-5-hexen-3-ol acrylolyl
ester (14). To (R)-1-phenyl-5-hexen-3-ol (13) (340 mg,
1.95 mmol) dissolved in CH2Cl2 (2.0 mL) and cooled
to 0 ꢁC, were added acryloyl chloride (300 lL,
3.51 mmol) and Et3N (990 lL, 7.04 mmol). The mixture
was warmed to rt and stirred for 2 h. The resulting mix-
ture was filtered through a short pad of Celite, poured
into water, and the product was extracted with CH2Cl2.
Solvent evaporation under reduced pressure and purifi-
cation of this residue by column chromatography on
silica gel (hexane/ethyl acetate, 9:1) furnished (R)-1-phen-
yl-5-hexen-3-ol acrylolyl ester (14) in 80% yield
(356 mg). IR (film): 3083, 3060, 3026, 2979, 2939,
2848, 1722, 1637, 1495, 1404, 1265, 1188, 1043, 964,
918, 750, 692 cmꢀ1 1H NMR (500 MHz, CDCl3): d
.
IR (film): 3055, 3024, 2924, 1720, 1246, 814, 698 cmꢀ1
.
7.41–7.25 (m, 5H), 6.66 (d, 1H, J 16.6 Hz), 6.46 (dd,
1H, J 16.6; 1.5 Hz), 6.19 (ddd, 2H, J 17.5; 11.9;
8.8 Hz), 5.86 (dd, 1H, J 10.4; 1.5 Hz), 5.85–5.78 (m,
1H), 5.61–5.56 (m, 1H), 5.19–5.11 (m, 2H), 2.61–2.51
(m, 2H). 13C NMR (125 MHz, CDCl3): d 165.3, 136.2,
132.9, 132.7, 130.7, 128.6, 128.5, 127.9, 126.8, 126.5,
118.1, 73.9, 39.0. HRMS (EI) m/z calculated for
1H NMR (300 MHz, CDCl3): d 7.41–7.25 (m, 5H),
6.92 (dt, 1H, J 9.5; 4.0 Hz), 6.72 (d, 1H, J 15.9 Hz),
6.27 (dd, 1H, J 15.9; 6.2 Hz), 6.08 (d, 1H, J 9.5 Hz),
5.10 (q, 1H, J 6.9 Hz), 2.56–2.52 (m, 2H). 13C NMR
(75 MHz, CDCl3): d 163.6, 144.5, 135.5, 132.8, 128.5,
128.1, 126.5, 125.5, 121.4, 77.8, 29.8. HRMS (EI) m/z cal-