The Journal of Organic Chemistry
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ethyl acetate (300 mL), and washed with water (150 mL), saturated
NaHCO3 solution (150 mL) and brine (150 mL). The organic phase
was dried with Na2SO4, filtered, and concentrated in vacuo to give a
colorless oil. The oil was purified by column chromatography (1:10 →
1:4 ethyl acetate:petroleum spirit) to give the titled compound (387
mg, 71%) as a clear oil: [α]23D −203.5 (c 3.87, CHCl3); 1H NMR (300
MHz CDCl3) δ = 5.78 (d, J = 9.9 Hz, 1H), 5.37 (d, J = 9.9 Hz, 1H),
3.63 (s, 3H), 3.49 (s, 3H), 2.47 (dd, J = 7.5, 14.8 Hz, 1H), 2.26 (t, J =
6.5 Hz, 1H), 2.13 (dd, J = 5.7, 15.0 Hz, 1 H), 1.66 (s, 3H), 1.04 (s,
3H), 0.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 174.4, 146.6,
137.2, 119.9, 116.6, 57.4, 51.6, 47.2, 35.0, 32.9, 26.4, 24.5, 14.7; GC/
MS m/z 224.2 (M+•, 13.0), 152.2 (13.5), 151.1 (100), 149.1 (34.5),
136.2 (35.8), 135.2 (11.6), 121.1 (12.5), 119.2 (12.7), 105.2 (11.9),
91.1 (32.7), 79.1 (14.3), 77.1 (19.7), 43.1 (11.1), 41.1 (22.5); HRMS
(EI) m/z [M]+ for C13H20O3 calcd 224.1412, found 224.1415.
(+)-Cipadonoid B (4) and Diastereoisomers 13 and 15. A solution
of (−)-10 (ee = 83%) (387 mg, 1.73 mmol), (+)-6 (ee > 99%,
obtained from chiral chromatography20) (202.8 mg, 0.78 mmol), and
p-toluenesulfonic acid (27 mg, 0.16 mmol, 20%) in anhydrous xylenes
(5 mL) was stirred for 4 h at 180 °C in a sealed tube under argon.
Following cooling to room temperature, the reaction mixture was
diluted with CH2Cl2 (75 mL), washed with saturated NaHCO3
solution and brine, dried over Na2SO3, and concentrated to give a
yellow oil. Purification using column chromatography on silica (1:4
ethyl acetate:petroleum spirit), gave 4 (88.5 mg, 25%), 11 (69.8 mg,
20%), 13 (25.8 mg, 7%), and 15 (30.0 mg, 9%). Reheating 11 in
xylenes at 180 °C in a sealed tube under argon gave additional crops of
4 to give an overall yield of 34%.
solution was stirred for 15 min, followed by the addition of saturated
aqueous solution of K2CO3 (240 μL). The mixture was then allowed
to warm to room temperature and stirred overnight before pouring
into 0.1 M HCl (20 mL). The mixture was then extracted with CH2Cl2
(3 × 25 mL), and the combined organic extracts were dried over
Na2SO3. Following filtration, the solvent was removed in vacuo to give
an oil that was purified by column chromatography (1:1 → 2:1 diethyl
ether/petroleum ether) affording the titled compound 20 (15.8 mg,
75%) as a single diastereoisomer, which was recrystallized from
chloroform producing colorless needles: mp 207−209 °C; [α]23
D
1
+178.2 (c 1.58, CDCl3); H NMR (500 MHz CDCl3) δ = 7.45 (m,
1H), 7.38 (t, J = 1.7 Hz, 1H), 6.40 (m, 1H), 5.42 (d, J = 1.6 Hz, 1H),
5.16 (s, 1H), 5.09 (s, 1H), 3.68 (s, 3H), 3.45 (d, J = 4.6 Hz, 1H), 3.28
(d, J = 4.5 Hz, 1H), 3.02 (dd, J = 3; 8.5 Hz, 1H), 2.57 (d, 4.6 Hz, 1H),
2.26 (m, 3H), 1.73 (m, 1H), 1.48 (m, 1H), 1.26 (m, 2H), 1.10 (s, 3H),
1.01 (s, 3H), 0.96 (s, 3H), 0.91 (s, 3H); 13C NMR (400 MHz, CDCl3)
δ = 210.4, 173.8, 165.4, 165.4, 142.9, 142.3, 141.0, 122.2, 120.1, 112.5,
109.9, 80.4, 66.0, 57.7, 52.0, 51.7, 48.9, 40.7, 39.4, 36.3, 31.4, 30.1,
26.8, 21.7, 20.2, 19.9, 18.3; LRMS (ESI) m/z [M + Na]+ for
C27H32O7Na calcd 491.2, found 491.3; HRMS (ESI) m/z [M + Na]+
for C27H32O7Na calcd 491.2040, found 491.2043.
(−)-Proceranolide (2). To a solution of 20 (10 mg, 0.021 mmol) in
EtOH/H2O/THF/saturated NaHCO3 (87:48:30:3 v/v, 1 mL) under
argon was added freshly amalgamated aluminum pieces (prepared
from aluminum foil57). The reaction mixture was sonicated (Unisonics
FXP12 M ultrasonic cleaner, 150 W, 40 kHz) at room temperature
and monitored by TLC with additional aluminum pieces added if
required. After 1 h, ethyl acetate (1 mL) was added, the mixture
filtered through a plug of diatomaceous earth, and the filter cake
washed with additional ethyl acetate (1 mL). The organic extract was
dried with MgSO4, filtered, and concentrated in vacuo to give a
colorless oil (12 mg). HPLC [Phenomenex luna C18(2) (250 mm ×
4.6 mm × 5 μm) methanol water gradient] of the crude mixture gave
proceranolide (2) (3 mg, 30%): [α]22D −116.5 (c 0.125, CHCl3) [lit.12
[α]20D −141 (c 0.70, CHCl3)]; 1H NMR (500 MHz CDCl3) δ = 7.54
(m, 1H), 7.37 (t, J = 1.7 Hz, 1H), 6.47 (m, 1H), 5.56 (s, 1H), 4.04 (dt,
J = 21; 2.5 Hz, 1H), 3.72 (d, J = 10 Hz, 1H), 3.67 (s, 3H), 3.44 (dt, J =
21; 2.5 Hz, 1H), 3.22 (dd, J = 10.5; 2.8 Hz 1H), 3.17 (dd, J = 14; 2.5
Hz, 1H), 3.02 (m, 1H), 2.34 (m, 1H), 1.95 (m, 2H), 1.76 (m, 3H),
1.10 (s, 3H), 1.01 (s, 3H), 0.79 (s, 3H), 0.71 (s, 3H); 13C NMR (500
MHz, CDCl3) δ =219.9, 174.4, 171.5, 142.6, 141.7, 131.3, 128.2, 120.8,
110.1, 80.2, 53.6, 52.0, 51.8, 50.0, 39.3, 39.3, 37.9, 33.5, 33.3, 33.1,
28.6, 25.3, 23.8, 20.1, 18.7, 17.5, 16.9; LRMS (ESI) m/z [M + Na]+ for
C27H34O7Na calcd 493.2, found 493.3; HRMS (ESI) m/z [M + Na]+
for C27H34O7Na calcd 493.2197, found 493.2204.
(+)-Cipadonoid B (4) white amorphous solid: [α]22 +296.4 (c
D
1.07, CDCl3) [lit.16 [α]20 +294.4 (c 0.015, CHCl3)]; H NMR (500
1
D
MHz CDCl3) δ = 7.43 (m, 1H), 7.37 (m, 1H), 6.67 (d, J = 10.0 Hz,
1H), 6.39 (d, J = 1.5 Hz, 1H), 6.00 (s, 1H), 5.91 (d, J = 10.5 Hz, 1H),
5.48 (d, J = 1.5 Hz, 1H), 5.29 (s, 1H), 5.01 (s, 1H), 3.69 (s, 3H), 2.83
(dd, J = 6.0, 4.5 Hz, 1H), 2.43 (m, 3H), 2.04 (dq, J = 15.5, 3.0 Hz,
1H), 1.74 (m, 1H), 1.38 (td, J = 14.0, 4.5 Hz, 1H), 1.11 (s, 9H), 1.06,
(dt, J = 13.5, 4.5 Hz, 1H), 0.97 (s, 3H); 13C NMR (100 MHz, CDCl3)
203.5, 174.1, 166.2, 166.0, 159.1, 143.4, 142.7, 141.1, 127.0, 121.4,
120.4, 111.6, 110.1, 79.9, 52.1, 50.7, 47.6, 43.6, 39.3, 37.1, 31.7, 30.2,
29.5, 24.0, 21.1, 21.0, 18.5; LRMS (ESI) m/z [M + Na]+ for
C27H32O6Na calcd 475.21, found 475.20; HRMS (ESI) m/z [M +
Na]+ for C27H32O6Na calcd 475.2091, found 475.2089.
Compound 15: slightly yellow oil: ;1H NMR (500 MHz CDCl3) δ
= 7.50 (m, 1H), 7.41 (m, 1H), 6.47 (d, J = 10.5 Hz, 1H), 6.44 (d, J =
1.5 Hz, 1H), 5.94 (s, 1H), 5.83 (d, J = 10.0 Hz, 1H), 5.25 (s, 1H), 5.18
(s, 1H), 4.71 (s, 1H), 3.70 (s, 3H), 3.14 (t, J = 5.5 Hz, 1H), 2.68 (dd, J
= 16.5, 4.5 Hz, 1H), 2.54 (m, 2H), 1.88 (m, 1H), 1.81 (m, 1H), 1.73
(m, 1H), 1.29 (ddd, J = 13.5, 6.5, 3.5 Hz, 1H), 1.20 (s, 3H), 1.07 (s,
3H), 1.05 (s, 3H), 0.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ =
202.2, 173.8, 166.5, 164.9, 155.4, 143.2, 143.1, 141.2, 124.5, 120.7,
120.1, 113.1, 110.0, 79.9, 54.7, 52.2, 48.5, 43.5, 39.5, 37.4, 32.7, 31.4,
31.0, 23.0, 22.0, 18.7, 17.6; LRMS (ESI) m/z [M + Na]+ for
C27H32O6Na calcd 475.21, found 475.20; HRMS (ESI) m/z [M +
Na]+ for C27H32O6Na calcd 475.2091, found 475.2094.
(−)-Khayasin (1). To a stirring solution of proceranolide (2) (13.2
mg, 0.028 mmol) in CH2Cl2 (400 μL) were successively added N,N-
dimethylaminopyridine (13.7 mg, 0.112 mmol, 4 equiv), isobutyric
acid (5.26 μL, 0.058 mmol, 2 equiv), and EDCI (16.1 mg, 0.084 mmol,
3 equiv). The resultant solution was stirred at room temperature for 4
h and gradually darkened to orange and then brown. When the
reaction was deemed complete (TLC), the mixture was diluted with
diethyl ether (1 mL) and 0.2 M HCl (1 mL) added. The organic phase
was separated and the remaining aqueous phase extracted with diethyl
ether (2 × 1 mL). The combined organic extracts were then washed
with saturated NaHCO3 and brine, dried over MgSO4, and passed
through a plug of silica. Concentration in vacuo gave a clear oil.
Following column chromatography (CH2Cl2/ethyl acetate, 9:1),
1
Compound 13: colorless crystals (MeOH); mp 195 − 196 °C; H
NMR (500 MHz CDCl3) δ = 7.51 (m, 1H), 7.39 (t, J = 1.5 Hz, 1H),
6.59 (d, J = 10.0 Hz, 1H), 6.46 (m, 1H), 5.82 (d, J = 10.0 Hz, 1H),
5.74 (s, 1H), 5.49 (s, 1H), 5.42 (d, J = 1.5 Hz, 1H), 5.39 (s, 1H), 3.69
(s, 3H), 2.92 (dd, J = 8.1, 3.0 Hz, 1H), 2.63 (dd, J = 6.3, 3.3 Hz, 1H),
2.45 (dd, J = 8.5, 17.0 Hz, 1H), 2.37 (dd, J = 17.0, 2.5 Hz, 1H), 2.19
(td, J = 13.0, 4.0 Hz, 1H), 1.99 (dq, J = 4.2, 14.7 Hz, 1H), 1.69 (m,
1H), 1.19 (s, 3H), 1.13 (dt, J = 4.2, 13.5 Hz, 1H), 1.07 (s, 3H), 1.02 (s,
3H), 0.96 (s, 3H); 13C NMR (100 MHz, CDCl3) 203.1, 174.5, 166.2,
165.6, 158.8, 143.4, 142.7, 141.2, 127.8, 122.0, 120.4, 112.3, 110.2,
79.9, 52.1, 47.0, 44.1, 39.6, 37.0, 31.7, 29.4, 29.3, 24.4, 22.1, 19.4, 18.4;
LRMS (ESI) m/z [M + Na]+ for C27H32O6Na calcd 475.21, found
475.20; HRMS (ESI) m/z [M + H]+ for C27H33O6 calcd 453.2272,
found 453.2272.
khayasin (1) was obtained as a white solid (10.7 mg, 71%): [α]24
D
−87.2 (c 1.02, acetone) [lit.3 [α]25 −79.5 (c 0.86, acetone)]; H
1
D
NMR (500 MHz CDCl3) δ = 7.53 (m, 1H), 7.39 (t, J = 1.7 Hz, 1H),
6.45 (m, 1H), 5.65 (s, 1H), 5.28 (s, 1H), 4.94 (d, J = 10 Hz, 1H), 3.71
(d, J = 20 Hz, 1H), 3.68 (s, 3H), 3.43 (dt, J = 20 Hz; 3 Hz, 1H), 3.22
(dd, J = 9 Hz, 3.6 Hz, 1H), 3.14 (m, 1H), 2.78 (dd, J = 15; 2 Hz, 1H),
2.63 (septet, J = 7 Hz, 1H) 2.35 (m, 2H), 2.10 (m, 1H), 2.03 (br s,
1H), 1.79 (m, 1H), 1.72 (m, 2H), 1.21 (d, J = 7 Hz, 3H), 1.19 (d, J = 7
Hz, 3H), 1.13 (s, 3H), 1.09 (m, 1H), 1.04 (s, 3H), 0.79 (s, 3H), 0.70
(s, 3H); 13C NMR (500 MHz, CDCl3) δ = 218.1, 176.6, 174.2, 170.0,
142.8, 141.7, 131.7, 127.8, 120.6, 109.9, 80.7, 78.0, 52.9, 52.2, 52.1,
48.1, 40.8, 38.5, 38.1, 34.4, 33.5, 33.2, 29.1, 23.2, 20.6, 19.9, 18.8, 18.6,
(S,S)-2,3-Epoxycipadonoid B (20). To a stirring solution of
(−)-cipadonoid B (4) (19.8 mg, 0.044 mmol) in MeOH (3.8 mL)
at 0 °C was added 30% H2O2 (77 μL, 0.679 mmol) dropwise. The
G
dx.doi.org/10.1021/jo301182f | J. Org. Chem. XXXX, XXX, XXX−XXX