Journal of Natural Products
Article
acetone/H2O (1:2, 30 mL), and 2,4,6-collidine (0.55 mL, 4.1 mmol)
and AgBF4 (402 mg, 2.10 mmol) were added. The resulting mixture
was heated at 60−70 °C for 1 h. The solvent was removed in vacuo,
and the residue was diluted with H2O (50 mL) and extracted with
EtOAc (3 × 25 mL). The organic layer was washed with 2 N HCl (3
× 25 mL) and brine (3 × 25 mL), dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The residue was separated by
column chromatography (H/MTBE, 3:1) on silica gel to give alcohols
13 (102 mg, 28%) and 14 (88 mg, 24%). Compound 13 was obtained
18.3, 16.0, 15.9, 14.1, −5.4 (2C); HRMS (ESI+) calcd for
C28H50O4NaSi [M + Na]+ 501.3376, found 501.3481.
Compound 7. A mixture of Cp2TiCl2 (112 mg, 0.45 mmol) and
Mn dust (532 mg, 9.68 mmol) in rigorously deoxygenated
tetrahydrofuran (THF) (25 mL) was stirred at room temperature
until the red solution turned green. A solution of oxirane 8 (540 mg,
1.13 mmol), 2,4,6-collidine (0.91 mL, 7.91 mmol), and TMSCl (0.6
mL, 4.52 mmol) in rigorously deoxygenated THF (12 mL) was added
to the solution of Cp2TiCl. The reaction mixture was stirred for 19 h,
diluted with MTBE (25 mL), quenched with 2 N HCl, and extracted
with MTBE (3 × 25 mL). The combined organic layers were washed
with brine (3 × 30 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude product obtained
was purified by column chromatography over silica gel (H/MTBE,
1
as a colorless syrup: H NMR (500 MHz, CDCl3) δ 5.98 (ddd, J =
17.6, 11.0, 0.9 Hz, 1H), 5.15 (dd, J = 17.6, 0.8 Hz, 1H), 5.14 (bt, J =
6.9 Hz, 1H), 5.12 (dd, J = 11.0, 0.8 Hz, 1H), 4.94 (bs, 1H), 4.84 (bs,
1H), 4.04 (t, J = 6.4 Hz, 1H), 2.12−1.95 (m, 8H), 2.01 (s, 3H),
1.90−1.74 (m, 2H), 1.73 (s, 3H), 1.69−1.59 (m, 2H), 1.61 (s, 3H),
1.59 (s, 3H), 1.54 (s, 3H); 13C NMR (125 MHz,CDCl3) δ 170.0,
147.5, 141.8, 135.3, 134.7, 124.6, 123.8, 113.1, 110.9, 82.9, 75.6, 39.7,
39.5, 35.6, 33.1, 26.4, 23.6, 22.2, 22.2, 17.6, 16.0, 15.9; HRMS (ESI+)
calcd for C22H36O3Na [M + Na]+ 371.2562, found 371.2541.
Compound 14 was obtained as a colorless syrup: 1H NMR (400
MHz, CDCl3) δ 5.97 (dd, J = 17.6, 11.0 Hz, 1H), 5.39 (bt, J = 6.4 Hz,
1H), 5.15 (dd, J = 17.6, 0.8 Hz, 1H), 5.14−5.08 (m, 2H), 5.12 (dd, J
= 11.0, 0.8 Hz, 1H), 3.98 (s, 2H), 2.16−1.94 (m, 10H), 2.00 (s, 2H),
1.90−1.69 (m, 2H), 1.66 (s, 3H), 1.60 (s, 3H), 1.59 (s, 3H), 1.54 (s,
3H); 13C NMR (125 MHz,CDCl3) δ 170.0, 141.8, 135.3, 134.7,
134.6, 126.0, 124.4, 123.7, 113.1, 82.9, 68.9, 39.7, 39.6, 39.3, 26.5,
26.2, 23.6, 22.2, 22.2, 16.0, 15.9, 13.7; HRMS (ESI+) calcd for
C22H36O3Na [M + Na]+ 371.2562, found 371.2544.
9:1) to obtain tricycle 7 as a colorless syrup (151 mg, 32%): [α]D
=
+13.2 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 5.37−5.32 (m,
1H), 3.70 (d, J = 9.2 Hz, 1H), 3.60 (dd, J = 11.5, 5.0 Hz, 1H), 3.36
(d, J = 9.2 Hz, 1H), 2.12−2.04 (m, 1H), 2.00 (dd, J = 14.6, 6.8, 1.5
Hz, 1H), 1.89−1.82 (m, 1H), 1.83 (dt, J = 13.2, 6.6 Hz, 1H), 1.73 (s,
3H), 1.68−1.58 (m, 4H), 1.52−1.42 (m, 2H), 1.28−1.10 (m, 3H),
0.99−0.89 (m, 3H), 0.92 (s, 9H), 0.88 (s, 3H), 0.83 (s, 3H), 0.82 (s,
3H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
141.3, 122.5, 76.8, 74.0, 64.5, 50.7, 46.4, 44.2, 41.7, 38.4, 37.9, 35.8,
34.6, 26.3, 25.8 (3C), 25.3, 20.5, 20.4, 19.0, 18.1, 16.2, 11.6, −5.7
(2C); HRMS (ESI+) calcd for C26H48O2SiNa [M + Na]+ 443.3321,
found 443.3317. Enantiomeric excess: 87%. The enantiomeric excess
was calculated using chiral-phase liquid chromatography: column,
Chiralcel OD; column size, 0.46 cm i.d. × 25 cm; eluent, Hex/IPA,
9.5/0.5; flow rate, 1.0 mL/min; temperature, 25 °C.
Compound 15. A mixture of powdered, activated 4 Å molecular
sieves (208 mg) and dry CH2Cl2 (4.5 mL) was cooled to 0 °C. L-
(+)-Diethyl tartrate (0.08 mL, 0.44 mmol), titanium isopropoxide
(0.11 mL, 0.36 mmol), and tert-butylhydroperoxide (5−6 M in
decane, 0.65 mL, 3.56 mmol) were added sequentially. After 20 min,
the mixture was cooled to −20 °C, and 14 (620 mg, 1.78 mmol) in
dry CH2Cl2 (2 mL) was added dropwise over 15 min. After 3.5 h of
stirring at −20 °C, the reaction mixture was warmed to 0 °C,
quenched with water (10 mL), and warmed to room temperature.
NaOH (5 mL, 40% aqueous solution) was added, and the mixture
was stirred for 20 min and filtered through a pad of Celite. The
organic phase was separated, and the aqueous phase was extracted
with CH2Cl2 (3 × 20 mL). The combined organic extracts were dried
over anhydrous Na2SO4, filtered, and concentrated. The crude
product was purified by column chromatography over silica gel (H/
MTBE, 1:1) to afford epoxide 15 as a colorless syrup (500 mg, 77%):
(−)-Valparan-2,15-diene (1). PCl5 (150 mg, 0.72 mmol) was
added to a cold (−15 °C) solution of 7 (100 mg, 0.24 mmol) in dry
CCl4 (8 mL) under an argon atmosphere. The mixture was kept at
that temperature with stirring for 25 min. The mixture was diluted
with CH2Cl2 and quenched via dropwise addition of a saturated
aqueous NaHCO3 solution until bubbling stopped. The organic phase
was washed with brine, dried with anhydrous Na2SO4, and
concentrated. The product crude was dissolved in dry THF (6 mL)
at 0 °C, and LiAlH4 (9 mg) was added under an argon atmosphere
and vigorous stirring. After 20 min the reaction was diluted with
MTBE and water (1 drop), and a 6 N NaOH solution (1 drop) and
water (3 drops) were successively added. The resulting mixture was
stirred for 10 min, filtered through a bed of Na2SO4 and silica gel,
washed with MTBE, and concentrated to afford a crude product,
which was chromatographed over silica gel (H/MTBE, 9:1) to obtain
a 5:1 mixture of the corresponding epimeric alcohols (21 mg, 31%,
two steps). To a solution of this mixture in 1.5 mL of THF were
added tri-n-butylphosphine (10 mg, 0.048 mmol) and o-nitrophenyl-
selenocyanate (11 mg, 0.048 mmol). After stirring under an argon
atmosphere for 35 min at room temperature, the reaction crude was
diluted with MTBE and quenched with the dropwise addition of 5%
NH4Cl. The organic layer was washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude
product (33 mg), which was redissolved in dry THF (1.5 mL) under
argon, and 30% H2O2 (0.02 mL) was added. The mixture was stirred
for 30 min at 45 °C, diluted with Et2O (10 mL), washed with brine (3
× 5 mL), and worked up as usual. The crude product was column
chromatographed over silica gel (H/MTBE, 97:3) to afford diene 1 as
a colorless syrup (17 mg, 89% after two steps): [α]D = +10.1 (c 1.0,
1
[α]D = −9.5 (c 1.0, CH2Cl2); H NMR (500 MHz, CDCl3) δ 5.98
(dd, J = 17.5, 11.0 Hz, 1H), 5.19−5.09 (m, 4H), 3.67 (dd, J = 12.1,
4.5 Hz, 1H), 3.57 (dd, J = 12.1, 8.5 Hz, 1H), 3.02 (t, J = 6.3 Hz, 1H),
2.19−2.04 (m, 4H), 2.02 (s, 3H), 2.01−1.96 (m, 5H), 1.90−1.83 (m,
1H), 1.80−1.65 (m, 3H), 1.62 (s, 3H), 1.59 (s, 3H), 1.55 (s, 3H),
1.29 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.0, 141.8, 135.2,
133.9, 125.0, 123.8, 113.1, 82.9, 65.4, 60.9, 59.9, 39.7, 39.5, 36.2, 26.8,
26.5, 23.6, 22.2 (2C), 16.0, 15.9, 14.3; HRMS (ESI+) calcd for
C22H36O4Na [M + Na]+ 387.2511, found 387.2508.
Compound 8. Imidazole (238 mg, 3.50 mmol) was added to a cold
(0 °C) solution of 15 (490 g, 1.35 mmol) in dry CH2Cl2 (21 mL)
under an argon atmosphere and stirred for 15 min, and TBSCl (405
mg, 2.69 mmol) was added. The mixture was kept at room
temperature for 45 min, diluted with CH2Cl2 (25 mL), and washed
with H2O (3 x15 mL), 2 N HCl (3 × 15 mL), saturated aqueous
NaHCO3 solution (3 × 15 mL), and brine (3 × 15 mL). The organic
layer was dried over anhydrous Na2SO4, filtered, and concentrated.
The crude product was purified by column chromatography over silica
gel (H/MTBE, 9:1) to obtain epoxide 8 as a colorless syrup (540 mg,
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 5.37−5.33 (m, 1H), 4.79
(bs, 1H), 4.78 (bs, 1H), 2.70 (q, J = 8.7 Hz, 1H), 2.22−2.13 (m, 1H),
1.98 (dd, J = 14.4, 6.5 Hz, 1H), 1.91−1.77 (m, 3H), 1.75 (s, 3H),
1.73 (s, 3H), 1.67−1.42 (m, 7H), 1.37 (q, J = 13.4 Hz, 1H), 1.21 (td,
J = 11.6, 4.1 Hz, 1H), 1.13−1.05 (m, 2H), 0.80 (s, 3H), 0.70 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 148.6, 141.0, 122.9, 110.3, 64.1, 55.4,
1
84%): H NMR (500 MHz, CDCl3) δ 5.98 (dd, J = 17.6, 10.9 Hz,
1H), 5.19−5.09 (m, 4H), 3.59 (d, J = 11.4 Hz, 1H), 3.56 (d, J = 11.4
Hz, 1H), 2.85 (t, J = 6.3 Hz, 1H), 2.20−1.96 (m, 4H), 2.02 (s, 3H),
2.01−1.96 (m, 4H), 1.90−1.82 (m, 1H), 1.80−1.72 (m, 1H), 1.70−
1.60 (m, 2H), 1.62 (s, 3H), 1.60 (s, 3H), 1.55 (s, 3H), 1.28 (s, 3H),
0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 169.9, 141.8, 135.3, 134.0, 124.8, 123.7, 113.1, 82.9, 67.9,
61.0, 60.7, 39.8, 39.6, 36.3, 27.0, 26.6, 25.8 (3C), 23.6, 22.2, 22.1,
47.1, 46.7, 46.4, 45.1, 41.7, 34.9, 36.2, 27.3, 25.8, 25.1, 24.0, 22.2,
20.9, 16.2. The spectroscopic data of this compound were consistent
with those previously reported.1b,c
Isolation of (+)-Nerolidol (16) from the Extract of Inula
viscosa. Fresh aerial parts of Inula viscosa (8 kg) were macerated two
times with MTBE (25 L) for 20 min each time. Evaporation under
E
J. Nat. Prod. XXXX, XXX, XXX−XXX