Job/Unit: O42420
/KAP1
Date: 01-07-14 18:02:56
Pages: 8
Total Synthesis of (–)-Heliespirone A and (+)-Heliespirone C
(CH2), 111.2 (CH), 56.3 (CH3), 44.1 (CH), 32.4 (CH2), 25.9 (CH3), 5,6-dihydroxy-6-methylhept-1-en-3-yl]-4-methoxy-5-methylphenyl
18.0 (CH3), 15.9 (CH3) ppm. HRMS (ESI): calcd. for C16H22O2Na
acetate (mixture of diastereomers; 65 mg, 0.20 mmol) in methanol
(3 mL). The reaction mixture was stirred vigorously for 1 h, then it
was diluted with methanol (10 mL) and filtered. The filtrate was
concentrated in vacuo, and the resulting residue was purified by
flash chromatography on silica (ethyl acetate/light petroleum, 2:3)
to give 23 (39 mg, 70%, 17% ee) as a colourless solid and 24 (8 mg,
14%) as a colourless oil. 23: Rf = 0.25 (ethyl acetate/light petro-
[M + Na]+ 269.1512; found 269.1514.
4-Methoxy-5-methyl-2-(6-methylhepta-1,5-dien-3-yl)phenyl Acetate
(20): A solution of acetic anhydride (260 μL, 2.75 mmol, 2 equiv.)
and triethylamine (380 μL, 2.72 mmol, 2 equiv.) in dichlorometh-
ane (12 mL) was added to a mixture of 4-methoxy-5-methyl-2-(6-
methylhepta-1,5-dien-3-yl)phenol (337 mg, 1.37 mmol) and 4-(di-
methylamino)pyridine (17 mg, 0.14 mmol), and the reaction mix-
ture was stirred at room temperature overnight. The mixture was
then concentrated in vacuo, and the residue was purified by flash
chromatography on silica (ethyl acetate/light petroleum, 1:19) to
give 20 (395 mg, 100%) as a colourless oil. Rf = 0.64 (ethyl acetate/
leum, 1:1). m.p. 157–159 °C. [α]D = –8.0 (c = 0.40, MeOH). IR: ν
˜
= 3398 (br.), 2964, 2929, 1706, 1639, 1512, 1462, 1408, 1376, 1365,
1323, 1199, 1162, 1119, 1073, 1021, 1005 cm–1 1H NMR
.
(300 MHz, [D4]methanol): δ = 6.65 (s, 1 H), 6.56 (s, 1 H), 6.03
(ddd, J = 17.4, 9.9, 8.4 Hz, 1 H), 5.14–5.02 (m, 2 H), 3.92–3.84 (m,
1 H), 3.73 (s, 3 H), 3.44 (ddd, J = 10.2, 1.2 Hz, 1 H), 2.15–2.06 (m,
4 H, CH, CH3), 1.53 (ddd, J = 14.1, 10.8, 3.3 Hz, 1 H), 1.17 (s, 3
H), 1.14 (s, 3 H) ppm. 13C NMR (75 MHz, [D4]methanol): δ =
152.6 (C), 148.8 (C), 142.2 (CH), 130.6 (C), 125.9 (C), 119.0 (CH),
115.2 (CH2), 111.9 (CH), 77.1 (CH), 73.8 (C), 56.6 (CH3), 41.6
(CH), 37.5 (CH2), 25.8 (CH3), 25.0 (CH3), 15.9 (CH3) ppm. HRMS
(ESI): calcd. for C16H24O4Na [M + Na]+ 303.1567; found 303.1567.
Enantiomeric excess was determined by HPLC analysis [CHI-
RALCEL OD-H column, 2% ethanol/hexane, 0.7 mL/min, reten-
tion times 49.3 (minor) and 53.9 (major)]. 24: Rf = 0.32 (ethyl acet-
light petroleum, 1:9). IR: ν = 2927, 1757, 1503, 1464, 1398, 1368,
˜
1256, 1212, 1191, 1174, 1023 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 6.83 (s, 1 H, ArH), 5.96 (ddd, J = 17.1, 10.2, 6.6 Hz, 1 H),
5.13–5.02 (m, 3 H), 3.82 (s, 3 H), 3.44 (dt, J = 7.2, 7.2 Hz, 1 H),
2.47–2.35 (m, 2 H, CH2), 2.29 (s, 3 H), 2.20 (s, 3 H), 1.69 (s, 3 H),
1.61 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.9 (C),
155.6 (C), 141.5 (C), 140.6 (CH), 133.6 (C), 132.7 (C), 125.6 (C),
124.5 (CH), 122.2 (CH), 114.6 (CH2), 109.6 (CH), 55.6 (CH3), 43.3
(CH), 33.1 (CH2), 25.8 (CH3), 21.0 (CH3), 17.9 (CH3), 15.9 (CH3)
ppm. HRMS (ESI): calcd. for C18H24O3Na [M + Na]+ 311.1618;
found 311.1618.
ate/light petroleum, 1:1). [α]D = –19.62 (c = 0.52, CHCl ). IR: ν =
˜
3
3376 (br.), 2972, 2926, 1705, 1637, 1501, 1463, 1410, 1364, 1200,
1
1165, 1079, 1023, 1001 cm–1. H NMR (300 MHz, [D4]methanol):
2-[(3R,5S)-5,6-Dihydroxy-6-methylhept-1-en-3-yl]-4-methoxy-5-
methylphenyl Acetate (21) and 2-[(3S,5S)-5,6-Dihydroxy-6-meth-
ylhept-1-en-3-yl]-4-methoxy-5-methylphenyl Acetate (22): Water
(10 mL) and tert-butyl alcohol (10 mL) were added to a mixture of
AD-mix-α (2.74 g, Aldrich, 1.4 g per mmol of olefin) and methane-
sulfonamide (232 mg, 2.44 mmol). The mixture was stirred vigor-
ously until complete dissolution had taken place, then the solution
was cooled to 0 °C. A solution of 4-methoxy-5-methyl-2-(6-meth-
ylhepta-1,5-dien-3-yl)phenyl acetate (555 mg, 1.92 mmol) in water
(10 mL) and tert-butyl alcohol (10 mL) was then added. The reac-
tion mixture was stirred at 0 °C for 1 h, then it was allowed to
return to room temperature, and stirred for a further 24 h. The
mixture was diluted with water (25 mL), then sodium sulfite (1.0 g)
was added, and the mixture was stirred for a further 1 h. The mix-
ture was extracted with dichloromethane (3ϫ 50 mL), and the
combined organic extracts were dried with Na2SO4 and concen-
trated in vacuo. The residue was purified by flash chromatography
on silica (ethyl acetate/light petroleum, 1:1) to give a mixture of 23
and 24 (329 mg, 53%) as a pale pink oil. Rf = 0.35 (ethyl acetate/
δ = 6.61 (s, 1 H), 6.59 (s, 1 H), 6.12 (ddd, J = 17.1, 10.2, 6.6 Hz, 1
H), 5.06–4.95 (m, 2 H), 3.96–3.89 (m, 1 H), 3.72 (s, 3 H), 3.06 (dd,
J = 10.5, 1.2 Hz, 1 H), 2.12–2.03 (m, 4 H, CH, CH3), 1.68 (ddd, J
= 14.1, 10.8, 3.9 Hz, 1 H), 1.12 (s, 3 H), 1.08 (s, 3 H) ppm. 13C
NMR (75 MHz, [D4]methanol): δ = 152.8 (C), 149.6 (C), 143.9
(CH), 128.0 (C), 126.3 (C), 119.1 (CH), 113.3 (CH2), 112.3 (CH),
77.1 (CH), 73.7 (C), 56.5 (CH3), 40.9 (CH), 37.3 (CH2), 25.4 (CH3),
25.2 (CH3), 15.9 (CH3) ppm. HRMS (ESI): calcd. for C16H24O4Na
[M + Na]+ 303.1567; found 303.1568.
2-[(3R,5S)-5,6-Dihydroxy-6-methylhept-1-en-3-yl]-5-methylcyclo-
hexa-2,5-diene-1,4-dione (4): A solution of cerium ammonium
nitrate (153 mg, 0.28 mmol, 2 equiv.) in water (1 mL) was added
dropwise to a stirred mixture of (3S,5R)-5-(2-hydroxy-5-methoxy-
4-methylphenyl)-2-methylhept-6-ene-2,3-diol (39 mg, 0.14 mmol) in
acetonitrile (1 mL) at 0 °C. The mixture was stirred at 0 °C for
5 min, then it was diluted with water (10 mL), and extracted with
ethyl acetate (3 ϫ 10 mL). The combined organic extracts were
dried with Na2SO4 and concentrated in vacuo. The residue was
purified by flash chromatography on silica (ethyl acetate/light pe-
troleum, 1:1) to give 4 (13 mg, 35%) as a yellow oil. Rf = 0.39 (ethyl
acetate/light petroleum, 1:1). [α]D = –15.0 (c = 0.29 CHCl3) [ref.[6]
light petroleum, 1:1). [α]D = –5.87 (c = 0.47, CHCl ). IR: ν = 3466,
˜
3
2976, 2931, 1736, 1503, 1465, 1398, 1370, 1218, 1192, 1176, 1070,
1
1044, 1025 cm–1. H NMR (300 MHz, CDCl3): δ = 6.77–6.60 (m,
2 H, ArH), 5.94–5.82 (m, 1 H, HC=CH2), 5.13–4.94 (m, 2 H,
HC=CH2), 3.78–3.66 (m, 4 H, OCH3, CH), 3.42 (d, J = 10.2 Hz,
1 H, major isomer CH), 3.08 (d, J = 10.2 Hz, 1 H, minor isomer
CH), 2.83 (br. s, 1 H, OH), 2.78 (br. s, 1 H, OH), 2.28 (s, 3 H,
major isomer CH3), 2.26 (s, 3 H, minor isomer CH3), 2.16 (s, 3 H,
minor isomer CH3), 2.15 (s, 3 H, major isomer CH3), 1.83–1.75 (m,
1 H, CH), 1.60–1.51 (m, 1 H, CH), 1.16 (s, 3 H, CH3), 1.10 (s, 3
H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.9, 170.5,
155.8, 155.6, 141.9, 141.5, 140.9, 139.5, 134.3, 131.9, 126.0, 125.6,
124.4, 115.8, 113.8, 109.2, 75.8, 75.3, 72.9, 72.7, 55.5, 39.8, 39.1,
36.6, 35.8, 26.1, 23.4, 23.2, 20.8, 15.7 ppm. HRMS (ESI): calcd. for
C18H26O5Na [M + Na]+ 345.1673; found 345.1673.
[α]D = –63.2 (c = 0.38 CHCl )]. IR: ν = 3431 (br.), 2975, 2926,
˜
3
1651, 1609, 1442, 1301, 1351, 1257, 1239, 1135, 1070, 1005 cm–1.
1
UV: λ (ε) = 329 (sh, 420), 414 (sh, 60 Lmol–1 cm–1) nm. H NMR
(300 MHz, CDCl3): δ = 6.59 (q, J = 1.6 Hz, 1 H), 6.53 (d, J =
0.9 Hz, 1 H), 5.77 (ddd, J = 17.9, 9.8, 8.6 Hz, 1 H), 5.24–5.18 (m,
2 H), 3.72 (td, J = 9.2, 3.7 Hz, 1 H), 3.45 (d, J = 10.5 Hz, 1 H),
2.33 (br. s, 1 H, OH), 2.03 (d, J = 1.2 Hz, 3 H), 1.77–1.69 (m, 1
H), 1.53 (ddd, J = 14.2, 10.6, 3.9 Hz, 1 H), 1.20 (s, 3 H), 1.14 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 188.4 (C), 187.3 (C),
151.5 (C), 145.5 (C), 137.5 (CH), 133.9 (CH), 132.0 (CH), 118.2
(CH2), 76.1 (CH), 73.0 (C), 39.6 (CH), 35.9 (CH2), 26.5 (CH3),
23.7 (CH3), 15.5 (CH3) ppm. HRMS (ESI): calcd. for C15H20O4Na
[M + Na]+ 287.1254; found 287.1255.
(3S,5R)-5-(2-Hydroxy-5-methoxy-4-methylphenyl)-2-methylhept-6-
ene-2,3-diol (23) and (3S,5S)-5-(2-Hydroxy-5-methoxy-4-meth-
ylphenyl)-2-methylhept-6-ene-2,3-diol (24): Potassium carbonate
(84 mg, 0.61 mmol, 3 equiv.) was added to a solution of 2-[(5S)-
(–)-Heliespirone A (1) and (+)-Heliespirone C (2): Cesium carbonate
(295 mg, 0.91 mmol, 5 equiv.) was added to a solution of 2-
[(3R,5S)-5,6-dihydroxy-6-methylhept-1-en-3-yl]-5-methylcyclo-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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