Total Synthesis of (+)-Linoxepin and Isolinoxepin
(s, 1.8 H), 3.89 (s, 0.4 H), 3.88 (s, 2.6 H), 3.37 (t, J = 6.5 Hz, 2 H),
IR (neat): ν
= 2974, 2940, 2901, 1736, 1705, 1632, 1458, 1366,
˜
max
2.87–2.78 (m, 2 H), 2.16–2.01 (m, 2 H), 1.52 (s, 9 H) ppm. 13C
1242, 1153, 1049, 934, 802 cm–1. HRMS (ESI): calcd. for [M +
NMR (126 MHz, CDCl3): δ = 166.55, 166.24, 153.18, 151.60, H]+ 563.1275; found 563.1289.
146.97, 138.21, 137.19, 137.16, 137.14, 137.05, 132.69, 129.42,
tert-Butyl
(2E)-3-{2-[(5-Bromo-2H-benzo[d][1,3]dioxol-4-yl)meth-
128.65, 128.63, 128.47, 128.45, 128.39, 128.38, 128.27, 128.25,
128.20, 128.17, 128.09, 128.02, 126.31, 125.44, 125.42, 124.24,
121.34, 118.86, 113.61, 112.95, 112.93, 80.26, 80.21, 75.53, 74.64,
55.99, 55.91, 33.80, 33.04, 31.35, 28.24, 28.23, 28.20 ppm. Due to
dynamic effects, more signals than expected were observed. IR
oxy]-6-(3-hydroxypropyl)-3-methoxyphenyl}prop-2-enoate
(S5,
Scheme 4): Acetate S4 (850 mg, 1.51 mmol) was dissolved in DCM
(3 mL) and MeOH (6 mL) and K2CO3 (208.7 mg, 1.51 mmol) was
then added to the solution. After 2 h at room temp. the reaction
mixture was quenched with water and extracted with DCM three
times. The combined organic phases were dried with MgSO4 and
concentrated in vacuo. The residue was purified by column
chromatography (hexanes/EtOAc, 3:1) to give S5 (757 mg, 96%) as
(neat): νmax = 2977, 2934, 2876, 2358, 2338, 1727, 1722, 1709, 1699,
˜
1617, 1603, 1497, 1477, 1468, 1454, 1386, 1262, 1156, 1150, 1070,
973, 917, 747, 700 cm–1. HRMS (DART): calcd. for [M + H]+
461.13275; found 491.13373.
1
a clear oil. H NMR (500 MHz, CDCl3): δ = 7.54 (d, J = 16.2 Hz,
tert-Butyl
(2E)-3-{2-[(5-Bromo-2H-benzo[d][1,3]dioxol-4-yl)meth-
1 H), 7.00 (d, J = 8.3 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.84 (d,
J = 8.4 Hz, 1 H), 6.64 (d, J = 8.3 Hz, 1 H), 6.43 (d, J = 16.2 Hz,
1 H), 5.93 (s, 2 H), 5.09 (s, 2 H), 3.87 (s, 3 H), 3.63 (t, J = 6.3 Hz,
2 H), 2.77–2.63 (m, 2 H), 1.80–1.73 (m, 2 H), 1.69 (s, 1 H), 1.49 (s, 9
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 166.96, 151.58, 148.49,
147.04, 146.84, 137.33, 134.06, 128.79, 126.20, 125.41, 125.19,
118.91, 116.64, 113.03, 109.63, 102.10, 80.23, 68.48, 62.21, 56.17,
oxy]-6-(3-bromopropyl)-3-methoxyphenyl}prop-2-enoate (5): Pd(OAc)2
(224.5 mg, 1.0 mmol) and PPh3 (557 mg, 2.2 mmol) were dissolved
in dry MeCN (60 mL) and stirred under argon for 10 min in a
sealable reaction vessel. Cs2CO3 (16.30 g, 50.0 mmol), iodophenol
6
(4.63 g, 10.0 mmol), tert-butyl acrylate (6.40 g, 7.26 mL,
50 mmol) and 1,3-dibromopropane (20.18 g, 10.15 mL,
100.0 mmol) were added successively to the reaction mixture. The
vessel was closed by a septum and the mixture was purged for
34.25, 29.48, 28.36 ppm. IR (neat): ν
= 3433, 2970, 2936, 2835,
˜
max
1701, 1628, 1454, 1366, 1258, 1153, 1053, 1015, 934 cm–1. HRMS
(ESI): calcd. for [M + H]+ 521.1169; found 521.1188.
10 min with argon through
a needle. Norbornene (4.70 g,
50.0 mmol) was added to the reaction mixture and the reaction
mixture flushed rapidly with argon before the vessel was sealed.
After 16 h at 90 °C the reaction mixture was filtered through Ce-
lite® with DCM as eluent and concentrated in vacuo. After purifi-
cation by column chromatography (hexanes/EtOAc, 25:1Ǟ10:1) 5
(4.79 g, 82%) was obtained as a colourless oil. 1H NMR (500 MHz,
CDCl3): δ = 7.50 (d, J = 16.2 Hz, 1 H), 7.00 (d, J = 8.3 Hz, 1 H),
6.93 (d, J = 8.4 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 1 H), 6.64 (d, J =
8.3 Hz, 1 H), 6.40 (d, J = 16.2 Hz, 1 H), 5.94 (s, 2 H), 5.09 (s, 2
H), 3.87 (s, 3 H), 3.48 (t, J = 6.4 Hz, 2 H), 2.83–2.74 (m, 2 H), 1.99–
1.90 (m, 2 H), 1.50 (s, 9 H) ppm. 13C NMR (126 MHz, CDCl3): δ
= 171.30, 166.70, 151.82, 148.52, 147.07, 146.80, 137.00, 132.69,
128.99, 126.57, 125.69, 125.19, 118.86, 116.62, 112.91, 109.67,
102.13, 80.23, 68.45, 60.55, 56.16, 44.36, 33.83, 31.74, 30.29, 28.36,
22.80, 21.20, 14.35, 14.27 ppm. Due to dynamic effects, more sig-
tert-Butyl
(2E)-3-(2-[(5-Bromo-2H-benzo[d][1,3]dioxol-4-yl)meth-
oxy]-3-methoxy-6-{3-[(2-nitrophenyl)selanyl]propyl}phenyl)prop-2-
enoate (S6, Scheme 4): Alcohol S5 (337.8 mg, 0.65 mmol) and 1-
nitro-2-selenocyanatobenzene (295 mg, 1.30 mmol) were dissolved
in THF (6 mL). PBu3 was added to the solution and the reaction
mixture was stirred for 3 h at room temp. The solvent was evapo-
rated under reduced pressure, and the residue was adsorbed on
silica. Purification by column chromatography (hexanes/EtOAc,
5:1) gave S6 (401 mg, 88%) obtained as a red oil. 1H NMR
(500 MHz, CDCl3): δ = 8.27 (dd, J = 8.3, 1.5 Hz, 1 H), 7.52 (d, J
= 16.2 Hz, 1 H), 7.49 (ddd, J = 8.0, 7.2, 1.5 Hz, 1 H), 7.39 (dd, J
= 8.1, 1.3 Hz, 1 H), 7.29 (ddd, J = 8.4, 7.2, 1.3 Hz, 1 H), 6.99 (d,
J = 8.3 Hz, 1 H), 6.93 (d, J = 8.4 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 1
H), 6.63 (d, J = 8.2 Hz, 1 H), 6.42 (d, J = 16.1 Hz, 1 H), 5.94 (s, 2
H), 5.10 (s, 2 H), 3.88 (s, 3 H), 2.88–2.77 (m, 4 H), 2.02–1.94 (m,
2 H), 1.49 (s, 9 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 166.72,
151.82, 148.50, 147.06, 146.89, 137.08, 133.80, 133.55, 132.89,
129.03, 128.88, 126.61, 126.48, 125.62, 125.41, 125.20, 118.86,
116.61, 112.97, 109.69, 102.12, 80.29, 68.49, 56.17, 33.54, 30.01,
nals than expected were observed. IR (neat): ν
= 2970, 1705,
˜
max
1632, 1454, 1366, 1261, 1153, 1053, 1022, 976, 802 cm–1. HRMS
(ESI): calcd. for [M + Na]+ 605.0144; found 605.0114.
tert-Butyl (2E)-3-{6-[3-(Acetoxy)propyl]-2-[(5-bromo-2H-benzo[d]-
[1,3]dioxol-4-yl)methoxy]-3-methoxyphenyl}prop-2-enoate
(S4,
28.37, 25.30 ppm. IR (neat): ν
= 2974, 2936, 1701, 1589, 1512,
˜
max
Scheme 4): In a sealable vessel, alkyl bromide 5 (4.87 g, 8.33 mmol)
was dissolved in dry MeCN (40 mL) and 18-crown-6 (4.40 g,
16.67 mmol) and KOAc (1.64 g, 16.67 mmol) were added to the
solution. The sealed vessel was heated at 80 °C overnight. The reac-
tion was cooled to room temp. and diluted with H2O. The aqueous
phase was extracted with DCM three times and the organic phases
were dried with MgSO4 and concentrated in vacuo. After purifica-
tion by column chromatography (hexanes/EtOAc, 10:1Ǟ3:1), S4
(4.26 g, 91%) was obtained as a colourless solid, m.p. 74 °C. 1H
NMR (399 MHz, CDCl3): δ = 7.53 (d, J = 16.2 Hz, 1 H), 7.00 (d,
1454, 1304, 1261, 1053, 934, 729 cm–1. HRMS (ESI): calcd. for [M
+ H – C4H8]+ 649.9923; found 649.9903.
tert-Butyl
(2E)-3-{2-[(5-Bromo-2H-benzo[d][1,3]dioxol-4-yl)meth-
oxy]-3-methoxy-6-(prop-2-enyl)phenyl}prop-2-enoate (4): Selenide
S6 (240 mg, 0.34 mmol) was dissolved in THF (4 mL) and H2O2
(30% in H2O, 175 μL) was added at 0 °C. The reaction mixture
was warmed to room temp. overnight and then diluted with water.
The aqueous phase was extracted with EtOAc three times and the
combined organic phases washed with a saturated solution of
J = 8.3 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 1 Na2SO3 and water. The organic phase was dried with MgSO4 and
H), 6.64 (d, J = 8.3 Hz, 1 H), 6.39 (d, J = 16.2 Hz, 1 H), 5.94 (s, 2
H), 5.09 (s, 2 H), 4.03 (t, J = 6.4 Hz, 2 H), 3.87 (s, 3 H), 2.75–2.64
concentrated in vacuo. Purification by column chromatography
1
(hexanes/EtOAc, 5:1) yielded 4 (166 mg, 97%) as a yellow oil. H
(m, 2 H), 2.06 (s, 3 H), 1.88–1.79 (m, 2 H), 1.50 (s, 9 H) ppm. 13C NMR (500 MHz, CDCl3): δ = 7.55 (d, J = 16.2 Hz, 1 H), 6.99 (d,
NMR (126 MHz, CDCl3): δ = 171.21, 166.61, 151.59, 148.44, J = 8.3 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 1
146.98, 146.74, 137.12, 133.85, 133.10, 128.87, 126.24, 125.39,
125.31, 125.10, 121.70, 118.80, 116.54, 115.89, 112.91, 112.57,
H), 6.63 (d, J = 8.3 Hz, 1 H), 6.32 (d, J = 16.2 Hz, 1 H), 5.94 (s, 2
H), 5.96–5.87 (m, 1 H), 5.10 (s, 3 H), 5.05 (dq, J = 10.1, 1.6 Hz, 2
109.62, 109.57, 102.05, 101.99, 80.07, 68.37, 65.80, 63.85, 63.64, H), 4.93 (dq, J = 17.1, 1.8 Hz, 2 H), 3.87 (s, 3 H), 3.36 (dt, J =
56.40, 56.08, 31.65, 30.36, 30.02, 29.49, 28.29, 21.07, 21.04 ppm.
Due to dynamic effects, more signals than expected were observed.
5.6, 1.4 Hz, 1 H), 1.50 (s, 9 H) ppm. 13C NMR (126 MHz, CDCl3):
δ = 166.66, 151.73, 148.55, 147.06, 146.64, 137.57, 137.31, 131.56,
Eur. J. Org. Chem. 2014, 4053–4069
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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