The Journal of Organic Chemistry
Article
Preparation of (R)-4-Hydroxy-1-(3,5-dimethoxyphenyl)-7-(2-
methyl-1,3-dioxolan-2-yl)heptan-2-one (12). Dithiane 22 (1.50 g,
3.39 mmol) was dissolved in THF/H2O (4:1, 35 mL) and CaCO3
(3.39 g, 33.9 mmol) and then cooled to 0 °C, whereupon iodine (2.60
g, 10.2 mmol) was added portionwise. The reaction mixture was then
allowed to stir for 30 min before quenching with saturated Na2S2O3
(20 mL) solution. The aqueous phase was separated and extracted
with EtOAc. The combined organic extracts were washed with brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The crude
residue was purified by column chromatography to give hydroxy
3.72−3.67 (m, 1H), 3.51 (s, 3H), 3.48−3.41 (m, 1H), 2.60 (d, J = 7.2
Hz, 2H), 1.86−1.50 (m, 6H), 1.30−1.18 (m, 2H), 1.17 (d, J = 6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 160.3, 157.9, 136.8, 115.9,
103.8, 96.7, 95.1, 73.9, 73.7, 62.2, 55.6, 55.2, 54.5, 42.4, 34.5, 33.3,
31.8, 23.8, 22.0; HRMS (EIS) calcd for C19H28NaO5 [M + Na]+
359.1829, found 359.1826.
Preparation of (R)-3,4-Dihydro-3-(((2R,6R)-tetrahydro-6-
methyl-2H-pyran-2-yl)methyl)-6,8-dimethoxyisochromen-1-
one (24). The same procedure as described for the preparation of 19
was used in the preparation of 24. To a cooled (0 °C) solution of 23
(0.166 g, 0.494 mmol) in acetone (2.5 mL) was added 3.0 M Jones
oxidant (0.5 mL, 1.482 mmol). The reaction mixture was then warmed
to rt and stirred for 1 h. After quenching by addition of water, the
resulting mixture was diluted with EtOAc. The layers were separated,
and the aqueous layer was extracted with EtOAc. The combined
organic layers were dried over anhydrous Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography to afford
24 as a yellowish oil (0.117 g, 74%): [α]20D = +126.0 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 6.39 (s, 1H), 6.28 (s, 1H), 4.69−4.64
ketone 12 (1.05 g, 88%) as a colorless oil: [α]20 = −33.0 (c = 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.37 (s, 1H), 6.33 (d, J = 2.0
Hz, 2H), 4.01 (m, 1H), 3.95−3.86 (m, 4H), 3.78 (s, 6H), 3.63 (s, 2H),
3.01 (s, 1H), 2.66−2.52 (m, 2H), 1.67−1.33 (m, 6H), 1.30 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 209.3, 161.0, 135.7, 109.9, 107.4, 99.0,
67.4, 64.5, 55.2, 51.0, 48.1, 38.8, 36.4, 23.7, 19.9; HRMS (EIS) calcd
for C19H28NaO6 [M + Na]+ 375.1778, found 375.1779.
Preparation of (2R,4R)-1-(3,5-Dimethoxyphenyl)-7-(2-meth-
yl-1,3-dioxolan-2-yl)heptane-2,4-diol (11). To a stirred solution
of Me4NBH(OAc)3 (4.2 g, 16 mmol) in acetonitrile (10 mL) was
added acetic acid (12 mL), and the mixture was stirred at room
temperature for 30 min. The mixture was cooled to −30 °C, and an
acetonitrile solution of compound 12 (0.7 g, 2 mmol in 5 mL of
acetonitrile) was added. The mixture was stirred at the same
temperature for 12 h. The reaction was quenched with 1 N NaOH,
and the resulting mixture was diluted with EtOAc. The layers were
separated, and the aqueous layer extracted with EtOAc. The combined
organic layers were dried over Na2SO4 and concentrated in vacuo. The
(m, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.72−3.67 (m, 1H) 3.46−3.39
(m, 1H), 2.90−2.76 (m, 2H), 1.89−1.77 (m, 2H), 1.73−1.66 (m, 1H),
1.58−1.51 (m, 3H), 1.25−1.15 (m, 2H), 1.10 (d, J = 6.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 164.3, 163.0, 162.9, 144.1, 107.1, 103.8,
97.7, 73.8, 73.6, 73.0, 56.1, 55.5, 41.7, 35.5, 33.2, 31.6, 23.5, 22.0;
HRMS (EIS) calcd for C18H25O5 [M + H]+ 321.1697, found 321.1705.
Preparation of Isocladosporin ((−)-2). The same procedure as
described for the preparation of 1 was used in the preparation of
(−)-2. A suspension of Al powder (0.38 g, 14.1 mmol) in dry benzene
(5 mL) was treated with I2 (1.34 g, 5.27 mmol) under Ar, and the
violet mixture was stirred under reflux for 30 min until the color had
changed to a colorless mixture. After the mixture was cooled to 0 °C, a
few crystals of TBAI (12 mg, 0.033 mmol) and phloroglucinol (0.21 g,
1.67 mmol) were added before a solution of lactone 24 (0.105 g, 0.328
mmol) in dry benzene (1 mL) was added in one portion. The resulting
green-brown suspension was stirred for 30 min at 0 °C before
saturated Na2S2O3 solution (5 mL) and ethyl acetate (5 mL) were
added. After separation of the layers, the aqueous phase was extracted
with ethyl acetate. The combined organic layers were washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by column chromatography to afford (−)-2 (0.085 g,
residue was purified by column chromatography to give diol 11 (0.64
1
g, 91%) as a colorless oil: [α]20 = +3.5 (c = 1.0, CHCl3); H NMR
D
(400 MHz, CDCl3): δ 6.35 (s, 2H), 6.31 (d, J = 1.6 Hz, 1H), 4.16−
4.11 (m, 1H), 3.96−3.86 (m, 5H), 3.75 (s, 6H), 2.80 (br s, 2H), 2.69
(d, J = 6.8 Hz, 2H), 1.63−1.34 (m, 8H), 1.28 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 160.8, 140.7, 109.9, 107.2, 98.3, 69.8, 68.8, 64.5, 55.2,
44.3, 42.0, 38.9, 37.4, 23.6, 20.1; HRMS (EIS) calcd for C19H31O6 [M
+ H]+ 355.2115, found 355.2111.
Preparation of (R)-1-((2R,6R)-Tetrahydro-6-methyl-2H-
pyran-2-yl)-3-(3,5-dimethoxyphenyl)propan-2-ol (cis-4). To a
cooled (0 °C) solution of 11 (0.4 g, 1.13 mmol) and triethylsilane
(0.66 g, 5.65 mmol) in CH2Cl2 was added TMSOTf (0.33 g, 1.49
mmol). After being stirred for 30 min at 0 °C, the reaction was
quenched with saturated aqueous NaHCO3 solution, the resulting
mixture was diluted with Et2O. The layers were separated, and the
aqueous layer was extracted with Et2O. The combined organic layers
were dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography to afford cis 4 as a
colorless oil (0.31 g, 93%): [α]20D = −0.5 (c = 2.0, CHCl3); 1H NMR
(400 MHz, CDCl3): δ 6.40 (d, J = 2.0 Hz, 2H), 6.34 (dd, J = 2.0, 2.4
Hz, 1H), 4.19−4.13 (m, 1H), 3.79 (s, 6H), 3.72-.367 (m, 1H), 3.50−
3.43 (m, 1H), 3.13 (d, J = 3.6 Hz, 1H), 2.72 (d, J = 6.4 Hz, 2H), 1.84−
1.79 (m, 1H), 1.73−1.62 (m, 2H), 1.57−1.45 (m, 3H), 1.40−1.30 (m,
1H), 1.24−1.14 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 160.6, 141.2, 107.2, 98.1, 75.4, 74.0, 69.4, 55.1, 44.2,
41.5, 33.0, 30.7, 23.5, 22.1; HRMS (EIS) calcd for C17H27O4 [M + H]+
295.1904, found 295.1915.
Preparation of (1R,3R)-3,4-Dihydro-3-(((2R,6R)-tetrahydro-6-
methyl-2H-pyran-2-yl)methyl)-1,6,8-trimethoxy-1H-isochro-
mene (23). The same procedure as described above for the
preparation of 18 was used in the preparation of 23. To a solution
of cis-4 (0.282 g, 0.96 mmol) and trimethyl orthoformate (2.5 mL) in
CH2Cl2 (10 mL) was added pTSA (19 mg, 0.096 mmol). After being
stirred for 1 h, the reaction mixture was quenched by addition of
saturated aqueous NaHCO3 solution, and the resulting mixture was
diluted with Et2O. The layers were separated, and the aqueous layer
was extracted with Et2O. The combined organic layers were dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was
89%) as a white solid: [α]20 = −5.0 (c = 1.0, CHCl3); mp 158−159
D
1
°C; H NMR (400 MHz, CDCl3): δ 11.07 (d, J = 2.0 Hz, 1H), 7.83
(m, 1H), 6.34 (d, J = 2.0 Hz, 1H), 6.17 (s, 1H), 4.83−4.78 (m, 1H),
3.72−3.66 (m, 1H), 3.49−3.45 (m, 1H), 2.84−2.71 (m, 2H), 1.92−
1.71 (m, 3H), 1.60−1.50 (m, 3H), 1.27−1.20 (m, 2H), 1.15 (d, J = 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.3, 164.2, 163.3, 141.9,
106.8, 101.9, 101.3, 76.0, 74.1, 73.2, 41.7, 33.6, 33.1, 31.6, 23.4, 22.0;
HRMS (EIS) calcd for C16H21O5 [M + H]+ 293.1384, found 293.1394.
Preparation of (S)-1-((2R,6R)-Tetrahydro-6-methyl-2H-
pyran-2-yl)-3-(3,5-dimethoxyphenyl)propan-2-ol (25). To a
stirred, cooled (0 °C) mixture of cis-4 (0.50 g, 1.7 mmol),
triphenylphosphine (0.50 g, 2.57 mmol), and 4-nitrobenzoic acid
(0.43 g, 2.57 mmol) in THF (20 mL) was added dropwise diisopropyl
azodicarboxylate (0.41 g, 2.57 mmol), and the mixture was stirred at rt
overnight. After removal of the solvent, the residue was loaded directly
onto a silica gel column, and elution with PE and EtOAc yielded the
desired 4-nitrobenzoate as a yellow oil (0.58 g, 78%).
To a MeOH solution of the 4-nitrobenzoate obtained above was
added K2CO3 (0.36 g, 2.6 mmol), and the resulting mixture was stirred
at rt for 1 h before water and EtOAc were added. After separation of
the layers, the aqueous phase was extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. Purification by column
chromatography to afford 25 (0.354 g, 92%) as a colorless oil:
[α]20D = −18.0 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.39
(d, J = 2.0 Hz, 2H), 6.32 (d, J = 2.0 Hz, 1H), 4.31 (s, 1H), 4.12−4.05
(m, 1H), 3.78 (s, 6H), 3.59−3.44 (m, 2H), 2.79 (dd, J = 6.4, 13.2 Hz,
1H), 2.58 (dd, J = 6.4, 13.2 Hz, 1H), 1.80−1.75 (m, 1H), 1.58−1.43
(m, 5H), 1.27−1.17 (m, 2H), 1.15 (d, J = 6.0 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 160.6, 141.2, 107.4, 98.1, 79.3, 74.0, 73.2, 55.2, 44.3,
purified by column chromatography to afford 23 (0.306 g, 95%) as a
1
white solid: [α]20 = −31.0 (c = 1.0, CHCl3); mp 104−105 °C; H
D
NMR (400 MHz, CDCl3): δ 6.29 (d, J = 2.0 Hz, 1H), 6.20 (d, J = 2.0
Hz, 1H), 5.53 (s, 1H), 4.53−4.47 (m, 1H), 3.81 (s, 3H), 3.77 (s, 3H),
5661
dx.doi.org/10.1021/jo300805n | J. Org. Chem. 2012, 77, 5656−5663