The Journal of Organic Chemistry
Note
air, and stirred further for 30 min. The reaction mixture was
concentrated, and the residue was purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1 to 4:1) as eluent
to give 21 (0.112 g, 51%) as yellow oil. [α]25 +7.2 (c 0.6, CHCl ); IR
(3aR,5S,11bR)-3,3a,5,11b-Tetrahydro-6,7,11-trimethoxy-5-
methyl-1,4-dioxacyclopent[a]anthracen-2-one (24). To a sol-
ution of compound 7 (70 mg, 0.22 mmol, 1.0 equiv) in CH
mL) at 0 °C were added acetaldehyde dimethyl acetal (0.046 mL, 0.44
mmol, 2.0 equiv) and BF ·OEt (0.03 mL, 0.24 mmol, 1.1 equiv). The
resulting mixture was stirred at 0 °C to room temperature for 17 h. It
was then quenched with satd aq NaHCO (5 mL), and the solution
was extracted with CH Cl (3 × 20 mL). The combined organic layers
were washed with brine, dried (Na SO ), and concentrated. The
Cl (10
2
2
D
3
(
CHCl ) υ 3372, 1741, 1630, 1602, 1514, 1463, 1438, 986, 911
3
2
3
max
−1
1
cm ; H NMR (400 MHz, CDCl /TMS) δ 1.53 (s, 3H), 1.68 (s,
3
3H), 2.65 (dd, J = 15.2, 7.0 Hz, 1H), 2.74 (dd, J = 15.2, 4.1 Hz, 1H),
3
3
=
.65 (s, 3H), 3.90 (s, 3H), 3.97 (s, 3H), 4.36−4.41 (m, 1H), 4.97 (d, J
2
2
8.9 Hz, 1H), 6.51 (s, 1H), 6.91 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 8.1
2
4
13
Hz, 1H), 7.85 (dd, J = 8.4, 0.8 Hz, 1H), 8.27 (s, 1H, OH); C NMR
100 MHz, CDCl ) δ 26.8, 27.0, 36.1, 52.0, 56.4, 57.7, 77.20, 82.2,
residue was purified by silica gel column chromatography using
petroleum ether/EtOAc (9:1 to 1:1) as eluent to afford 24 (59.5 mg,
(
3
25
1
1
3
06.5, 107.1, 109.8, 111.9, 114.7, 118.3, 126.2, 128.7, 145.3, 150.3,
78%) as white solid. Mp 220−224 °C; [α]
(CHCl ) υmax 1779, 1594, 1574, 996, 906 cm ; H NMR (400 MHz,
CDCl /TMS) δ 1.75 (d, J = 6.2 Hz, 3H), 2.78 (d, J = 17.3 Hz, 1H),
D 3
+225 (c 0.2, CHCl ); IR
+
−1 1
56.6, 170.7; HRMS m/z calcd for [C H O + H] 377.1600, found
3
20
24
7
77.1609.
Methyl (3R,4R)-4-(1,4,5-Trimethoxynaphthalen-2-yl)-3,4-iso-
propylidenedioxybutanoate (22). To a solution of naphthol 21
50 mg, 0.133 mmol, 1.0 equiv) in dry DMF (5 mL) at 0 °C was
3
2.92 (dd, J = 17.3, 4.4 Hz, 1H), 3.74 (s, 3H), 4.02 (s, 3H), 4.09 (s,
3H), 4.37 (dd, J = 4.4, 2.5 Hz, 1H), 5.07 (q, J = 6.3 Hz, 1H), 5.59 (d, J
= 2.4 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 8.2 Hz, 1H), 7.71
(
(dd, J = 8.5, 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl ) δ 22.3, 38.4,
added NaH (6.4 mg, 0.16 mmol, 60% in mineral oil, 1.2 equiv). The
reaction mixture was stirred at room temperature for 20 min and then
cooled to 0 °C, and MeI (0.016 mL, 0.266 mmol, 2.0 equiv) was
added. The reaction mixture was stirred at 0 °C to room temperature
for 3 h. It was then quenched with ice-cold water (5 mL), and the
solution was extracted with EtOAc (3 × 20 mL). The combined
organic layers were washed with water and brine, dried (Na SO ), and
3
56.2, 61.6, 64.4, 70.2, 71.3, 73.0, 107.2, 115.1, 119.2, 121.6, 126.6,
129.1, 130.2, 149.3, 153.1, 156.1, 175.7; HRMS m/z calcd for
+
[C H O + H] 345.1338, found 345.1345.
19
20
6
(3aR,5S,11bR)-3,3a,5,11b-Tetrahydro-7-methoxy-5-methyl-
1,4-dioxacyclopent[a]anthracen-2,6,11-trione (25). CAN oxida-
tion of compound 24 (0.060 g, 0.174 mmol) by a similar procedure as
used for conversion of 7 to 23 produced the corresponding quinone
2
4
concentrated. The residue was purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1 to 4:1) as eluent
to give 22 (44 mg, 85%) as yellow oil. [α]25 +34.5 (c 0.3, CHCl ); IR
25 (0.048 g, 88%) as an orange crystalline solid. Mp 183−185 °C
25
(decomp); [α]
−160 (c 0.3, CHCl
); IR (CHCl
) υmax 1795, 1670,
/TMS) δ 1.56
D
3
D
3
3
−1
1
−1 1
(
CHCl ) υ 1743, 1599, 1588, 1459, 911 cm ; H NMR (400 MHz,
1640, 1590, 995, 900 cm ; H NMR (400 MHz, CDCl
3
3
max
CDCl /TMS) δ 1.57 (s, 3H), 1.67 (s, 3H), 2.71 (dd, J = 16.0, 8.5 Hz,
(d, J = 6.7 Hz, 3H), 2.72 (d, J = 17.6 Hz, 1H), 2.90 (dd, J = 17.6, 4.7
Hz, 1H), 4.00 (s, 3H), 4.33 (dd, J = 4.5, 2.6 Hz, 1H), 4.78 (dq, J = 6.7,
1.5 Hz, 1H), 5.28 (d, J = 1.8 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.70 (t,
J = 8.0 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H); 13C NMR (100 MHz,
3
1H), 2.83 (dd, J = 16.1, 3.2 Hz, 1H), 3.61 (s, 3H), 3.86 (s, 3H), 3.97
(
s, 6H), 4.24−4.29 (m, 1H), 5.23 (d, J = 8.5 Hz, 1H), 6.89 (d, J = 7.2
Hz, 1H), 6.96 (s, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.63 (dd, J = 8.4, 0.9
Hz, 1H); 13C NMR (100 MHz, CDCl ) δ 27.1, 27.3, 36.7, 51.8, 56.5,
CDCl
133.4, 135.3, 152.4, 159.3, 174.6, 182.5, 183.3; HRMS m/z calcd for
) δ 19.9, 37.1, 56.4, 68.9, 69.7, 71.1, 118.0, 19.1, 120.1, 132.2,
3
3
5
1
6.6, 62.2, 76.7, 78.8, 103.5, 106.9, 109.6, 114.7, 118.4, 125.4, 126.9,
+
31.1, 147.5, 154.1, 157.5, 171.2; HRMS m/z calcd for [C H O +
[C17
H
14
O
6
+ H] 315.0868, found 315.0875.
(+)-Kalafungin (1). To the solution of quinone 25 (0.035 g, 0.111
mmol) in CH Cl (5 mL) under N atmosphere at −50 °C was added
BBr (1 mL, 1 M solution in CH Cl , 1 mmol, 9 equiv) dropwise over
21
26
7
+
H] 391.1757, found 391.1746.
(
4R,5R)-4-Hydroxy-5-(1,4,5-trimethoxynaphth-2-yl)-
2
2
2
dihydrofuran-2(3H)-one (7). To a solution of the compound 22 (22
3
2
2
mg, 0.056 mmol, 1.0 equiv) in CH Cl (4 mL) were added TFA/H O
5 min. After 25 min at −50 °C, the reaction mixture was allowed to
warm to room temperature and was stirred for 2 h. Water (5 mL) was
added and stirred for 30 min. The reaction mixture was extracted with
CH Cl (3 × 10 mL), and the combined organic layers were washed
2
2
2
(
9:1, 0.2 mL) and 2 drops of conc HCl. The resulting solution was
stirred at room temperature for 24 h. It was then quenched with satd
aq NaHCO (2 mL) and extracted with CH Cl (3 × 20 mL). The
3
2
2
2
2
combined organic layers were washed with brine, dried (Na SO ), and
with water, dried (Na SO ), and concentrated. The residue was
2
4
2 4
concentrated. The residue was purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1 to 4:1) as eluent
purified by flash column chromatography using petroleum ether/
EtOAc (2:1 to 3:2) as eluent to give 66:34 mixture of kalafungin 1 and
5-epi-1 (27.4 mg, 82%) as an orange crystalline solid. To the epimer
mixture (27.4 mg) was added concentrated H SO (1 mL) dropwise at
2
5
to give 7 (15.2 mg, 85%) as white solid. Mp 136−137 °C; [α]
D
−
12.5 (c 0.6, CHCl ); IR (CHCl ) υ 3469, 1780, 1734, 1623, 1601,
586, 981, 905 cm ; H NMR (400 MHz, CDCl /TMS) δ 1.77 (brs,
3 3 max
2
4
−1 1
1
1
3
room temperature. The dark red solution was stirred at room
temperature for 25 min and carefully poured into brine in a separating
funnel. A yellow solid precipitated out. It dissolved upon shaking with
CH Cl (30 mL). The organic layer was separated, and the aqueous
3
H), 2.72 (d, J = 17.5 Hz, 1H), 2.92 (dd, J = 17.7, 5.4 Hz, 1H), 3.87 (s,
H), 3.93 (s, 3H), 3.95 (s, 3H), 4.81−4.83 (m, 1H), 5.84 (d, J = 3.5
Hz, 1H), 6.87 (s, 1H), 6.88 (dd, J = 7.7, 0.7 Hz, 1H), 7.41 (t, J = 8.1
Hz, 1H), 7.56 (dd, J = 8.4, 1.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 38.3, 56.5, 56.7, 61.9, 69.7, 81.8, 103.8, 107.1, 114.3, 118.4, 122.4,
2
2
layer was extracted with CH Cl (2 × 30 mL). The combined organic
2
2
layers were washed with brine, dried (Na SO ), and concentrated. The
2
4
1
27.2, 130.6, 145.8, 153.9, 157.5, 175.7; HRMS m/z calcd for
17 18 6
residue was purified by flash silica gel column chromatography using
petroleum ether/EtOAc (2:1 to 3:2) as eluent to give a 93:7 mixture
of kalafungin 1 and 5-epi-1. A single recrystallization gave pure
+
[
C H O + Na] 341.1001, found 341.0998.
(
2R,3R)-2-(3-Hydroxy-5-oxotetrahydrofuran-2-yl)-5-methox-
ynaphthalene-1,4-dione (23). The title compound was prepared
from compound 7 (35 mg, 0.11 mmol) following literature
(
+)-kalafungin 1 (15.3 mg, 56%) as yellow needles. Mp 168−170 °C,
3c 3c
25
lit. 171−173 °C; [α] +160.6 (c 0.3, CHCl ), lit. +160 (c 0.3,
D
3
6j
−1
procedure to afford 23 (30 mg, 94%) as yellow solid. Mp 172−
CHCl ); IR (CHCl ) υ 1795, 1730, 1670, 1655, 1625, 905 cm ;
3
3
max
25
D
1
1
6
75 °C; [α] −58.2 (c 0.3, MeOH). H NMR (400 MHz, acetone-
1
H NMR (400 MHz, CDCl /TMS) δ 1.57 (d, J = 6.9 Hz, 3H), 2.70
3
d ) δ 2.46 (d, J = 17.4 Hz, 1H), 3.12 (dd, J = 17.3, 5.3 Hz, 1H), 3.93
(d, J = 17.7 Hz, 1H), 2.98 (dd, J = 17.7, 5.2 Hz, 1H), 4.70 (dd, J = 5.1,
.0 Hz, 1H), 5.01 (q, J = 6.9 Hz, 1H), 5.26 (d, J = 3.0 Hz, 1H), 7.30
(
1
s, 3H), 4.84−4.86 (m, 1H), 5.62 (dd, J = 3.6, 1.7 Hz, 1H), 6.73 (d, J =
3
.6 Hz, 1H), 7.51 (dd, J = 8.5, 0.8 Hz, 1H), 7.64 (dd, J = 7.6, 1.1 Hz,
13
(dd, J = 7.1, 2.6 Hz, 1H), 7.64−7.71 (m, 2H), 11.83 (s, 1H, OH);
C
1
H), 7.76 (dd, J = 7.8, 7.6 Hz, 1H). Other spectral and analytical data
NMR (100 MHz, CDCl ) δ 18.5, 36.8, 66.2, 66.4, 68.6, 114.7, 119.7,
6j
3
is same as reported earlier.
1
24.8, 131.4, 135.0, 137.2, 149.7, 161.8, 174.0, 181.5, 187.9; HRMS m/
(
−)-Juglomycin A (4). The title compound was prepared from 23
+
z calcd for [C H O + H] 301.0711, found 301.0718.
6j
16 12
6
(
30 mg, 0.104 mmol) following literature procedure to give 4 (26
(
3aR,5S,11bR)-3,3a,5,11b-Tetrahydro-6,7,11-trimethoxy-5-
mg, 92%) as yellow solid. Mp 172−174 °C (decomp at 171 °C);
propyl-1,4-dioxacyclopent[a]anthracen-2-one (26a) in a 70:30
Mixture with (3aR,5R,11bR)-3,3a,5,11b-Tetrahydro-6,7,11-tri-
methoxy-5-propyl-1,4-dioxacyclopent[a]anthracen-2-one
2
5
6a
[
α] −51.8 (c 0.3, DMSO), lit. −51.9 (c 0.42, DMSO). Spectral
D
6j
and analytical data is same as reported earlier.
1
0458
dx.doi.org/10.1021/jo3019939 | J. Org. Chem. 2012, 77, 10455−10460