Journal of Natural Products
Note
ether/EtOAc, 70:30) to give 5-iodo-6-methoxy-4-(methoxymethoxy)-
isobenzofuran-1(3H)-one (8, 644 mg).
mmol), and lithium chloride (12.7 mg, 0.3 mmol) in DMF (2 mL)
was added Pd(dba)3 (3 mg, 0.005 mmol, 5 mol %) under nitrogen.
The mixture was stirred at 50 °C for 24 h and then partitioned
between water and CH2Cl2. H2O was added, and the mixture was
extracted with CH2Cl2. The organic layers were washed with brine
and a saturated potassium fluoride solution in 10% NH4OH prior to
being dried to remove tin-containing residues. The organic layers
were dried over Na2SO4 and concentrated. Purification was achieved
using column chromatography on silica gel (petroleum ether/EtOAc,
95:5) to give the coupling product (24 mg).
To a solution of coupling product (24 mg, 0.06 mol) in MeOH (5
mL) was added CSA (33 mg, 0.14 mmol). The mixture was stirred at
room temperature for 70 h and quenched by the addition of TEA.
The mixture was extracted with CH2Cl2. The organic layers were
dried over Na2SO4 and concentrated. Purification was achieved using
column chromatography on silica gel (petroleum ether/EtOAc,
85:15) to give a mixture of isohericenone J and its isomer (17 mg).
The mixture was further purified by HPLC using MeOH/H2O
(70:30, 3.0 mL/min) to give isohericenone J (8.1 mg, tR = 31.0 min)
and its isomer (7.6 mg, tR = 32.0 min).
Isohericenone J: 29%, white solid; mp 95−97 °C; Rf = 0.4 (40%
EtOAc/petroleum ether); 1H NMR (400 MHz, chloroform-d) δ 6.97
(s, 1H), 6.04 (s, 1H), 5.25 (t, J = 7.1 Hz, 1H), 5.21 (s, 2H), 5.03−
4.99(m, 1H), 3.87 (s, 3H), 3.48 (d, J = 7.1 Hz, 1H), 2.17−2.07 (m,
4H), 1.82 (s, 3H), 1.67 (s, 3H), 1.60 (s, 3H); 13C NMR (100 MHz,
chloroform-d) δ 171.8, 159.2, 150.6, 141.1, 132.7, 127.4, 125.3, 123.6,
121.1, 120.4, 98.6, 68.1, 56.4, 39.8, 26.3, 25.8, 23.1, 17.9, 16.4;
HRMS-ESI (m/z) calcd for C19H23O4 (M − H)− 315.1602, found
315.1602.
Isomer 14: 27%, white solid; mp 56−57 °C; Rf = 0.4 (40% EtOAc/
petroleum ether); 1H NMR (500 MHz, chloroform-d) δ 6.97 (s, 1H),
5.95 (s, 1H), 5.24 (t, J = 6.7 Hz, 1H), 5.21 (s, 2H), 5.14 (t, J = 6.7 Hz,
1H), 3.87 (s, 3H), 3.51 (d, J = 6.7 Hz, 2H), 2.30−2.23 (m, 2H),
2.21−2.14 (m, 2H), 1.79 (s, 3H), 1.71 (s, 3H), 1.64 (s, 3H); 13C
NMR (125 MHz, chloroform-d) δ 171.8, 159.2, 150.4, 141.1, 133.1,
130.2, 127.2, 125.3, 123.5, 121.1, 98.6, 68.1, 56.4, 32.2, 26.3, 25.9,
23.6, 22.8, 17.9; HRMS-ESI (m/z) calcd for C19H23O4 (M − H)−
315.1602, found 315.1603.
8: 92%, white solid; mp 163−165 °C; Rf = 0.6 (40% EtOAc/
1
petroleum ether); H NMR (400 MHz, CDCl3) δ 7.07 (s, 1H), 5.40
(s, 2H), 5.17 (s, 2H), 3.97 (s, 3H), 3.58 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 170.6, 160.8, 152.7, 128.7, 101.4, 97.6, 91.7, 77.4,
68.6, 57.4, 57.3; HRMS-ESI (m/z) calcd for C11H12IO5 (M + H)+
350.9724, found 350.9722.
Synthesis of 6-Methoxy-4-(methoxymethoxy)-5-
(trimethylstannyl)isobenzofuran-1(3H)-one, 2, and Methyl
3,5-Dimethoxy-4-(trimethylstannyl)benzoate, 9. 5-Iodo-6-me-
thoxy-4-(methoxymethoxy)isobenzofuran-1(3H)-one (8; 640 mg,
1.83 mmol), bis(tri-tert-butylphosphine)palladium(0) (46.8 mg, 0.09
mmol), and hexamethyldistannane (1.56 mL, 2.75 mmol) were
dissolved in toluene (20 mL) at room temperature under nitrogen.
The mixture was stirred at 100 °C for 24 h. H2O was added, and the
mixture was extracted with CH2Cl2. The organic layers were washed
with a saturated potassium fluoride solution in 10% NH4OH prior to
being dried to remove tin-containing residuals. The organic layers
were dried over Na2SO4 and concentrated. Purification was achieved
using column chromatography on silica gel (petroleum ether/EtOAc,
95:5) to give 6-methoxy-4-(methoxymethoxy)-5-(trimethylstannyl)-
isobenzofuran-1(3H)-one (2, 469 mg).
2: 66%, white solid; mp 93−94 °C; Rf = 0.5 (20% EtOAc/
1
petroleum ether); H NMR (400 MHz, CDCl3) δ 7.05 (s, 1H), 5.38
(s, 2H), 5.04 (s, 2H), 3.82 (s, 3H), 3.50 (s, 3H), 0.33 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 171.3, 166.1, 156.9, 130.3, 129.4, 127.0,
100.5, 96.2, 69.6, 56.8, 55.9, −6.8; HRMS-ESI (m/z) calcd for
C14H21O5Sn (M + H)+ 389.0406, found 389.0402.
9: 69%, white solid; mp 138−139 °C; Rf = 0.5 (40% EtOAc/
petroleum ether); 1H NMR (400 MHz, chloroform-d) δ 7.16 (s, 2H),
3.92 (s, 3H), 3.80 (s, 6H), 0.44−0.16 (m, 10H); 13C NMR (100
MHz, chloroform-d) δ 167.4, 165.1, 133.0, 123.7, 104.2, 55.7, 52.3,
−7.1.
Synthesis of (E)-3,7-Dimethylocta-2,6-dien-1-yl acetate, 13,
(Z)-3,7-Dimethylocta-2,6-dien-1-yl Acetate, 15, and (2E,6E)-
3,7,11-Trimethyldodeca-2,6,10-trien-1-yl Acetate, 10. (E)-3,7-
Dimethylocta-2,6-dien-1-ol (1.00 g, 6.50 mmol), DMAP (15.8 mg,
0.13 mmol), and TEA (1.08 mL, 7.80 mmol) were added, and the
resulting solution was cooled to 0 °C. Acetyl chloride was added
dropwise, and the reaction stirred for 3 h. The reaction mixture was
acidified to pH 2−3 with HCl (1 N). The organic layers were dried
over Na2SO4 and concentrated. Purification was achieved using
column chromatography on silica gel (petroleum ether/EtOAc, 97:3)
to give (E)-3,7-dimethylocta-2,6-dien-1-yl acetate (13, 1.19 g).
13: 94%, colorless oil; Rf = 0.7 (10% EtOAc/petroleum ether); 1H
NMR (400 MHz, chloroform-d) δ 5.32 (t, J = 7.1 Hz, 1H), 5.06 (t, J
= 7.1 Hz, 1H), 4.56 (d, J = 7.1 Hz, 2H), 2.12−2.05 (m, 2H), 2.05−
1.98 (m, 2H), 2.03 (s, 3H), 1.68 (s, 3H), 1.66 (s, 3H), 1.58 (s, 3H);
13C NMR (100 MHz, chloroform-d) δ 171.2, 142.4, 131.9, 123.8,
11 (mixtures): colorless oil; Rf = 0.3 (20% EtOAc/petroleum
1
ether); H NMR (400 MHz, CDCl3) δ 7.23 (s, 2H), 5.24−5.03 (m,
3H), 3.91 (s, 3H), 3.86 (s, 6H), 3.43−3.35 (m, 2H), 2.29−1.87 (m,
8H), 1.79−1.53 (m, 12H).
12 (mixtures): colorless oil; Rf = 0.2 (10% EtOAc/petroleum
ether); 1H NMR (400 MHz, chloroform-d) δ 7.13 (s, 1H), 5.38−5.36
(m, 2H), 5.20−5.09 (m, 2H), 5.08−5.04 (m, 3H), 3.89−3.87 (m,
3H), 3.54−3.52 (m, 3H), 3.48−3.41 (m, 2H), 2.16−1.87 (m, 8H),
1.70−1.55 (m, 12H).
ASSOCIATED CONTENT
■
118.3, 61.5, 39.6, 26.3, 25.8, 21.1, 17.8, 16.5; HRMS-ESI (m/z) calcd
for C12H20O2Na (M + Na)+ 219.1356, found 219.1349.
15: 95%, colorless oil; Rf = 0.7 (10% EtOAc/petroleum ether); 1H
NMR (400 MHz, chloroform-d) δ 5.36 (t, J = 7.1 Hz, 1H), 5.13−5.05
(m, 1H), 4.56 (d, J = 7.1 Hz, 2H), 2.15−2.07 (m, 4H), 2.05 (s, 3H),
1.77 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H); 13C NMR (100 MHz,
chloroform-d) δ 171.3, 142.8, 132.3, 123.7, 119.2, 61.2, 32.3, 26.7,
25.8, 23.7, 21.2, 17.8.
sı
* Supporting Information
The Supporting Information is available free of charge at
1H, 13C, and NOE NMR spectra of all compounds
1
10: 93%,colorless oil; Rf = 0.7 (10% EtOAc/petroleum ether); H
NMR (400 MHz, DMSO-d6) δ 5.31−5.25 (m, 1H), 5.13−5.01 (m,
2H), 4.51 (d, J = 7.1 Hz, 2H), 2.11−1.99 (m, 5H), 1.99−1.96 (m,
3H), 1.96−1.89 (m, 2H), 1.66 (s, 3H), 1.63 (s, 3H), 1.56 (s, 6H);
13C NMR (100 MHz, DMSO-d6) δ 170.2, 141.2, 134.7, 130.6, 124.1,
123.5, 118.6, 60.5, 39.2, 38.9, 26.2, 25.6, 25.5, 20.7, 17.5, 16.1, 15.8;
HRMS-ESI (m/z) calcd for C17H29O2 (M + H)+ 265.2162, found
265.2157.
Synthesis of Isohericenone J and Its Isomer and Com-
pounds 11 and 12. To a mixture of 6-methoxy-4-(methoxyme-
thoxy)-5-(trimethylstannyl)isobenzofuran-1(3H)-one 2 (116 mg, 0.3
mmol), (E)-3,7-dimethylocta-2,6-dien-1-yl acetate (13; 19.6 mg, 0.1
AUTHOR INFORMATION
■
Corresponding Author
Yu Tang − Key Laboratory of Marine Drugs, Chinese Ministry of
Education, School of Medicine and Pharmacy, Ocean University
of China, Qingdao 266003, People’s Republic of China;
Laboratory for Marine Drugs and Bioproducts, , Qingdao
National Laboratory for Marine Science and Technology,
Qingdao 266237, People’s Republic of China; orcid.org/
D
J. Nat. Prod. XXXX, XXX, XXX−XXX