2096
D. Liang et al. / Tetrahedron 69 (2013) 2093e2097
by preparative HPLC using 30% MeCN/H2O (7 ml/min) to yield
compound 3 (25 mg, tR 43.6 min).
vacuo. The crude boronate 5 was used in the next step without
further purification due to its instability. The reduced side-product
13: 1H NMR (CDCl3, 500 MHz)
d
: 7.86 (1H, d, J¼9.0 Hz), 6.65 (1H, dd,
20
4.3.1. Lysilactone A (1). Pale yellow amorphous powder; [
ꢀ49.5 (c 0.12, MeOH); UV (MeOH) lmax (log
287 (3.95), 298 (3.91), 329 (3.93), 340 (3.92) nm; IR nmax 3363, 2921,
a
]
J¼9.0, 2.5 Hz), 6.42 (1H, d, J¼2.5 Hz), 3.85 (3H, s), 1.72 (6H, s); ESIMS
D
3
) 203 (4.45), 255 (4.51),
m/z 439 [2MþNa]þ.
1668, 1609, 1443, 1347 cmꢀ1
;
1H NMR (DMSO-d6, 500 MHz), 13C
4.4.5. 4-Bromo-5-methyl-1,3-benzenediol (6). Tetrabutylammonium
tribromide (TBABr3, 2 g, 4.13 mmol) was slowly added to a stirring
solution of orcinol (11) (500 mg, 4.03 mmol) in dichloromethane/
methanol (3:2, 50 ml) at room temperature. The mixture was stirred
for 30 min until discoloration of the orange solution took place. The
solvent was removed in vacuo, and water was added to the obtained
residue. The mixture was extracted with EtOAc (4ꢁ30 ml). The or-
ganic layers were dried (MgSO4) and evaporated in vacuo to give
a residue, which was recrystallized from methanol/water (1:3),
affording 6 (753 mg, 3.73 mmol, 93%) as colorless crystals. 1H NMR
NMR (DMSO-d6, 125 MHz) see Table 1; ESIMS m/z 435 [MþH]þ, 457
[MþNa]þ; HR-ESIMS m/z 435.1296 [MþH]þ (calcd for C21H23O10
435.1286), 457.1109 [MþNa]þ (calcd for C21H22O10Na, 457.1105).
,
20
4.3.2. Lysilactone B (2). Pale yellow amorphous powder; [
ꢀ125.3 (c 0.09, MeOH); UV (MeOH) lmax (log ) 204 (4.50), 255
(4.50), 288 (4.01), 299 (3.98), 338 (3.94) nm; IR nmax 3366, 2931,
a]
D
3
1668, 1608, 1454, 1333 cmꢀ1 1H NMR (DMSO-d6, 500 MHz), 13C
;
NMR (DMSO-d6, 125 MHz) see Table 1; ESIMS m/z 465 [MþH]þ, 487
[MþNa]þ; HR-ESIMS m/z 465.1401 [MþH]þ (calcd for C22H25O11,
465.1391), 487.1214 [MþNa]þ (calcd for C22H24O11Na, 487.1211).
(acetone-d6, 500 MHz)
d
: 6.44 (1H, d, J¼2.5 Hz), 6.36 (1H, d,
J¼2.5 Hz), 2.26 (3H, s); ESIMS m/z 201, 203 [MꢀH]ꢀ.
20
4.3.3. Lysilactone C (3). Pale yellow amorphous powder; [
ꢀ307.4 (c 0.07, MeOH); UV (MeOH) lmax (log
(4.34), 339 (3.82), 348 nm (3.80); IR nmax 3336, 2874, 1658, 1607,
a
]
4.4.6. Alternariol 9-methyl ether (4). A mixture of bromide 6 (77 mg,
0.38 mmol), the crude boronate 5, Cs2CO3 (371.4 mg, 1.14 mmol),
D
3
) 208 (4.22), 254
Pd(OAc)2 (2.6 mg, 11.4
mmol), and S-Phos (purity 98%, 9.4 mg,
1431, 1285 cmꢀ1
;
1H NMR (DMSO-d6, 500 MHz), 13C NMR (DMSO-
22.8 mol) in degassed solvent (dioxane/H2O, 7:1, 20 ml) under ni-
m
d6, 125 MHz) see Table 1; ESIMS m/z 451 [MþH]þ, 473 [MþNa]þ;
HR-ESIMS m/z 451.1249 [MþH]þ (calcd for C21H23O11, 451.1235),
473.1060 [MþNa]þ (calcd for C21H22O11Na, 473.1054).
trogen was stirred at 80 ꢂC for 3 h. The mixture was cooled to room
temperature, saturated aqueous NH4Cl-solution (15 ml) was added,
and the mixture was extracted with EtOAc (4ꢁ40 ml). The organic
layers were dried (MgSO4), concentrated, and purified by chroma-
tography (silica gel, petroleum ether/acetone, 10:1) yielding 4
(62 mg, 38% over two steps from 10) as a pale yellow amorphous
4.3.4. Acid hydrolysis and sugar analysis. The determination of the
absolute configuration of the sugar in compounds 1e3 was con-
ducted as described previously by our group.12
powder. 1H NMR (DMSO-d6, 500 MHz)
(1H, d, J¼2.5 Hz), 6.63 (1H, d, J¼2.5 Hz), 6.60 (1H, d, J¼2.5 Hz), 3.90
(3H, s), 2.72 (3H, s); 13C NMR (DMSO-d6, 125 MHz)
: 166.1, 164.6,
d: 7.21 (1H, d, J¼2.5 Hz), 6.71
4.4. Synthetic procedures
d
164.1, 158.5, 152.6, 138.4, 137.7, 117.5, 108.8, 103.3, 101.6, 99.1, 98.4,
55.8, 24.9; HR-ESIMS m/z 295.0577 [MþNa]þ (calcd for C15H12O5Na,
295.0577).
4.4.1. 5,7-Dihydroxy-2,2-dimethylbenzo[1,3]dioxin-4-one
(8). Following a published procedure,29 2,4,6-trihydroxybenzoic
acid monohydrate (7) (4.7 g, 25.0 mmol) was condensed with
acetonide to give aryl acetonide 8 (3 g, 14.3 mmol, 57%). 1H NMR
4.4.7. 3-O-(2,3,4,6-Tetra-O-acetyl-
methoxy-1-methyl-6H-dibenzo[b,d]pyran-6-one (12). A two-phase
mixture of the aglycone (10.9 mg, 0.04 mmol), aceto-
b-D-glucopyranosyl)-7-hydroxy-9-
(acetone-d6, 300 MHz) d: 6.06 (1H, br s), 6.00 (1H, br s), 1.70 (6H, s);
13C NMR (acetone-d6, 75 MHz)
d
: 167.2, 165.8, 164.0, 158.1, 110.6,
4
107.6, 98.0, 96.2, 25.6 (2C); ESIMS m/z 211 [MþH]þ, 233 [MþNa]þ.
bromoglucose (32.8 mg, 0.08 mmol), Bu4NBr (12.9 mg, 0.04 mmol),
and K2CO3 (27.6 mg, 0.2 mmol) in CHCl3/H2O (1:1, 3 ml) was stirred
at 50 ꢂC for 18 h and then neutralized by the addition of 1 M HCl.
The organic layer was dried (MgSO4), concentrated, and purified by
preparative TLC (silica gel, petroleum ether/acetone, 2:1) to provide
12 (21 mg, 0.035 mmol, 87%) as a pale yellow amorphous powder.
4.4.2. 5-Hydroxy-7-methoxy-2,2-dimethylbenzo[1,3]dioxin-4-one
(9). Acetonide 8 (1.05 g, 5.0 mmol) was methylated following
a published procedure29 yielding methyl ether 9 (0.95 g, 4.24 mmol,
85%). 1H NMR (acetone-d6, 300 MHz)
d
: 6.16 (1H, d, J¼2.1 Hz), 6.07
(1H, d, J¼2.1 Hz), 3.86 (3H, s), 1.71 (6H, s); 13C NMR (acetone-d6,
1H NMR (DMSO-d6, 500 MHz)
d: 7.29 (1H, br s), 7.00 (1H, br s), 6.94
75 MHz)
d
: 168.8, 165.7, 163.9, 157.9, 110.6, 107.8, 96.4, 95.1, 56.4,
(1H, br s), 6.69 (1H, br s), 5.72 (1H, d, J¼8.0 Hz), 5.39 (1H, t,
J¼9.0 Hz), 5.10 (1H, dd, J¼10.0, 9.5 Hz), 5.01 (1H, t, J¼10.0 Hz), 4.34
(1H, m), 4.18 (1H, dd, J¼12.5, 6.0 Hz), 4.10 (1H, dd, J¼12.0, 2.0 Hz),
3.92 (3H, s), 2.79 (3H, s, Me), 2.03 (3H, s, OAc), 2.024 (3H, s, OAc),
25.6 (2C); positive-ion ESIMS m/z 247 [MþNa]þ.
4.4.3. 7-Methoxy-2,2-dimethyl-5-(trifluoromethylsulfonyloxy)benzo
[1,3]-dioxin-4-one (10). Following a published procedure,29 the
phenol synthesized above (896 mg, 4.0 mmol) was converted into
2.017 (3H, s, OAc),1.97 (3H, s, OAc); 13C NMR (DMSO-d6,125 MHz)
d:
170.0, 169.6, 169.4, 169.1, 166.2, 164.3, 164.1, 156.3, 152.3, 138.9,
137.0, 118.0, 112.0, 104.3, 102.3, 100.0, 98.9, 96.4, 71.9, 71.1, 70.5,
68.0, 61.7, 55.9, 24.9, 20.45, 20.41, 20.36, 20.29; HR-ESIMS m/z
625.1535 [MþNa]þ (calcd for C29H30O14Na, 625.1528).
triflate 10 (1.22 g, 3.43 mmol, 86%). 1H NMR (CDCl3, 300 MHz)
d:
6.52 (1H, br s), 6.48 (1H, br s), 3.87 (3H, s), 1.73 (6H, s); 13C NMR
(CDCl3, 75 MHz)
d
: 165.5, 158.8, 157.1, 149.9, 118.7 (q, J¼319 Hz),
106.6, 105.3, 101.1, 56.3, 25.5 (2C); ESIMS m/z 357 [MþH]þ, 379
[MþNa]þ.
4.4.8. Lysilactone A (1). Sodium methoxide (71.3 mg in 361 ml MeOH,
25 w/w%, 1.33 mmol) was added to a solution of 12 (20 mg,
0.033 mmol) in dry methanol (4 ml), and the mixture was stirred at
5 ꢂC for 2 h. Methanol was removed under reduced pressure, and the
residue was subjected to ion-exchange (IR-120 H) chromatography.
The resulting aqueous solution was concentrated in vacuo and fur-
ther purified by preparative TLC (silica gel, EtOAc/EtOH/H2O, 8:2:1)
yielding lysilactone A (1) (12.8 mg, 0.029 mmol, 89%) as a pale yellow
amorphous powder, with spectral data that matched the isolated
compound.
4.4.4. 7-Methoxy-2,2-dimethyl-5-(4,4,5,5-tetramethyl[1,3,2]dioxa-
borolan-2-yl)benzo[1,3]dioxin-4-one (5) and 7-methoxy-2,2-
dimethylbenzo[1,3]dioxin-4-one (13). Freshly distilled Et3N (250 ml,
1.8 mmol) and Pd(PPh3)4 (34.65 mg, 0.03 mmol) were added to
a solution of triflate 10 (213.6 mg, 0.6 mmol) in anhydrous dioxane
(8 ml). The oxygen was displaced by nitrogen three times, and
pinacol borane (261
ml, 1.8 mmol) was added dropwise. The solu-
tion was stirred for 2 h at 80 ꢂC, and the solvent was removed in