Bisfuran Intermediates of Aflatoxin Biosynthesis
J. Am. Chem. Soc., Vol. 121, No. 34, 1999 7745
(CHCl3) 3002, 2863, 1674, 1606, 1573, 1468, 1124, 1046 cm-1; MS
m/z 451 (M+, 1), 439 (1), 409 (3), 407 (7), 363 (3), 281 (3), 280 (19),
236 (4), 235 (11), 234 (6), 220 (9), 218 (5), 204 (6). Exact mass calcd
for C24H38O8Si 482.2336, found 482.2331. Anal. (C24H38O8Si) H,C:
calcd 59.73, found C 59.11%.
pooled and dried over brine and MgSO4. The concentrated brown oil
was purified by silica gel chromatography (5 × 23 cm, 10% EtOAc/
hexanes) to provide the benzophenone as a yellow oil (2.06 g, 85.5%);
TLC Rf 0.46 (80:20 hexane/ethyl acetate); 1H NMR (400 MHz, CDCl3)
δ 6.98 (d, J ) 2.3 Hz, 1H), 6.61 (d, J ) 2.3 Hz, 1H), 6.35 (s, 1H),
5.81 (d, J ) 3.1 Hz, 1H), 5.60 (s, 1H), 5.18 (s, 2H), 5.00 (2H, ABq,
JAB ) 6.3 Hz, ∆νAB ) 18.2 Hz), 4.85 (s, 2H), 4.80 (s, 2H), 4.58 (s,
2H), 3.59 (d, J ) 3.6 Hz, 1H), 3.51 (s, 3H), 3.45 (s, 3H), 3.41 (s, 3H),
3.15 (s, 3H), 3.10 (s, 3H), 2.54 (ddd, J ) 11.6, 3.9, 3.7 Hz, 1H), 1.89
(d, J ) 11.6 Hz, 1H), 1.00-1.10 (m, 21H); 13C NMR (400 MHz,
CDCl3) δ 194.0, 159.6, 156.8, 156.0, 154.4, 153.9, 142.1, 124.4, 120.5,
113.2, 107.7, 105.2, 101.8, 101.4, 99.4, 99.3, 94.5, 94.2, 72.0, 58.6,
57.4, 56.0, 55.8, 55.7, 38.1 29.2, 17.9, 17.8, 12.2; IR (CHCl3) 3010,
2945, 2871, 1649, 1602, 1579, 1464, 1153, 1042 cm-1; MS m/z 722
(M+, 4), 707 (0.2), 677 (13), 661 (16), 585 (13), 459 (14), 437 (11),
383 (17), 268 (100), 253 (26); exact mass calcd for C36H54O13Si
722.3333, found 722.3340. Anal. (C36H54O13Si) C, H.
Methyl 3,5-Bis(O-methoxymethyl)benzyl Ether. The alcohol,
prepared according to the procedure of Townsend36 (1.387 g, 6.080
mmol) in dry THF (24.3 mL, 0.25 M), was treated with 80% sodium
hydride in mineral oil (0.1605 g, 6.688 mmol). After the mixture was
stirred for 15 min, methyl iodide (1.035 g, 7.296 mmol) was added.
The resulting solution was stirred for 12 h at room temperature. Excess
methyl iodide was removed under reduced pressure, and the white
residue was purified by silica gel column chromatography (3 × 20
cm, 20-30% EtOAc/hexanes gradient) to provide 1.21 g of the ether
as a colorless oil (82.4%), which crystallized: mp 52.0-53.0 °C; TLC
1
Rf 0.39 (80:20 hexane/ethyl acetate); H NMR (400 MHz, CDCl3) δ
6.68 (d, J ) 2.4 Hz, 2H), 6.65 (t, J ) 2.0 Hz, 1H), 5.16 (s, 4H), 4.39
(s, 2H), 3.48 (s, 6H), 3.39 (s, 3H); 13C NMR (400 MHz, CDCl3) δ
158.3, 140.8, 108.7, 104.1, 94.4, 74.4, 58.2, 56.1; IR (CHCl3) 3010,
2928, 2827, 1720, 1459, 1293, 1146, 1087, 1041 cm-1; MS m/z 242
(100), 212 (36), 211 (36), 197 (22), 182 (13), 152 (17); exact mass
calcd for C12H18O5 242.1154, found 242.1157. Anal. (C12H18O5) C, H.
Methyl 2-Bromo-3,5-bis(O-methoxymethyl)benzyl Ether (68). A
procedure comparable to that used in the preparation of 64 furnished
bromide 68 as a colorless oil in 94.7% yield, which crystallized: mp
[7-(2′-Methyl formate-3′,5′-bis(O-methoxymethyl)-r-benzoyl)-2,5-
methano-6,8-bis(O-methoxymethyl)-1,3-benzodioxepan-4-yloxy]tris-
(1-methylethylsilane) (70). The benzophenone (3.875 g, 5.361 mmol)
in dry DCM (21 mL, 0.25 M) was treated with triethylbenzylammonium
permanganate (3.505 g, 11.26 mmol) according to the procedure of
Schmidt.58 The reaction mixture was stirred at room temperature for
5 d and purified directly on silica gel (22 × 3 cm, 10-20% EtOAc/
hexanes) to provide the methyl ester 70 (2.17 g, 55.4%; 85% based on
recovered starting material) as well as 1.32 g of starting benzophenone
(34.0%): 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J ) 2.4 Hz, 1H),
6.88 (d, J ) 2.3 Hz, 1H), 6.36 (s, 1H), 5.82 (d, J ) 3.2 Hz, 1H), 5.61
(s, 1H), 5.19 (s, 2H), 5.11 (2H, ABq, JAB ) 6.7 Hz, ∆νAB ) 19.2 Hz),
4.96 (s, 2H), 4.75 (2H, ABq, JAB ) 6.7 Hz, ∆νAB ) 8.8 Hz), 3.74 (s,
3H), 3.63 (d, J ) 3.7 Hz, 1H), 3.54 (s, 3H), 3.46 (s, 3H, 3.25 (s, 3H,
3.12 (s, 3H), 2.56 (ddd, J ) 11.4, 3.8, 3.7 Hz, 1H), 1.91 (d, J ) 11.3
Hz, 1H), 1.15-1.05 (m, 21H); 13C NMR (400 MHz, CDCl3) δ 190.8,
167.6, 158.3, 157.1, 155.7, 155.5, 155.5, 132.6, 128.2, 117.7, 113.5,
109.6, 106.3, 105.1, 102.2, 99.5, 99.4, 94.7, 94.5, 94.3, 57.4, 56.2, 56.1,
55.8, 52.4, 38.0, 29.1, 17.9, 17.8, 12.1; IR (CHCl3) 3010, 2954, 2871,
1727, 1654, 1602, 1575, 1464, 1153, 1038 cm-1; MS m/z 615 (4), 534
(3), 490 (7), 413 (3), 283 (30), 269 (6), 234 (5). Exact mass calcd for
C36H52O14Si 736.3126, found 736.3137. Anal. (C36H52O14Si) C, H.
5-[2′-Methyl formate-4′,6′-dihydroxy-r-benzoyl]-2-methoxy-4,6-
dihydroxybenzo[furo]furan. The bicyclic TIPS acetal 70 (0.8741 g,
1.185 mmol) and phloroglucinol (0.5975 g, 4.738 mmol) were dissolved
in 5:2 dichloromethane/methanol (47 mL, 0.025 M). Next, 49% aqueous
HF (236 drops, 200 drops/mmol) was added dropwise, and the solution
was stirred for 26 h at room temperature. The solution was neutralized
with NaHCO3, filtered, concentrated, and subjected to radial chroma-
tography in 5% MeOH/dichloromethane to furnish the desired methyl
acetal (0.1363 g, 28.3%) as a pasty yellow solid: 1H NMR (300 MHz,
acetone-d6) δ 9.35 (s, 1H), 8.70 (s, 1H), 8.6 (br s, 1H), 8.00 (s, 1H),
7.00 (d, J ) 2.3 Hz, 1H), 6.65 (d, J ) 2.3 Hz, 1H), 6.08 (d, J ) 6.4
Hz, 1H), 5.92 (s, 1H), 5.03 (dd, J ) 3.0, 2.4 Hz, 1 H), 3.79 (dd, J )
1
55.0-57.0 °C; H NMR (400 MHz, CDCl3) δ 6.88 (d, J ) 2.8 Hz,
1H), 6.80 (d, J ) 2.8 Hz, 1H), 5.23 (s, 2H), 5.16 (s, 2H), 4.50 (s, 2H),
3.52 (s, 3H), 3.47 (s, 6H); 13C NMR (400 MHz, CDCl3) δ 157.2, 154.3,
139.7, 109.3, 104.9, 104.0, 95.2, 94.5, 76.7, 58.7, 56.4, 56.2; IR (CHCl3)
3015, 2932, 2831, 1591, 1453, 1319, 1227, 1149, 1089 cm-1; MS m/z
323 (12), 322 (86), 321 (13), 320 (91), 292 (23), 291 (100), 290 (21),
289 (99), 211 (6), 165 (8); exact mass calcd for C12H17BrO5 320.0260,
found 320.0267. Anal. (C12H17BrO5) C, H, Br.
[7-(2′-Methoxymethyl-4′,6′-bis(O-methoxymethyl)-r-benzyloxy)-
2,5-methano-6,8-bis(O-methoxymethyl)-1,3-benzodioxepan-4-yloxy]-
tris(1-methylethylsilane) (69). The bromide 68 (1.67 g, 5.19 mmol)
in dry ether (19.0 mL, 0.2 M) was cooled to -43 °C, and s-BuLi (4.42
mL, 5.75 mmol) was added just after cooling began before the solution
froze. The mixture was stirred under argon for 5 min at -43 °C, and
aldehyde 67 (1.79 g, 3.71 mmol) was transferred by cannula as an
ethereal solution (19.0 mL, 0.2 M) and stirring continued at -43 °C
for 5 h. The reaction mixture was poured into water and ether, and the
aqueous phase was extracted with ether (4×). The extracts were pooled
and dried with brine and MgSO4. The concentrated oil was purified by
silica gel chomotography (5 × 17 cm, 5-20% EtOAc/hexanes), to
furnish 2.42 g of a thick yellow oil consisting of the two diastereomeric
benzhydrols 69 (90.0%): TLC Rf 0.19 and 0.14 (80:20 hexane/ethyl
acetate); 1H NMR (400 MHz, CDCl3) δ 6.75 (d, J ) 2.4 Hz, 1H), 6.71
(d, J ) 2.5 Hz, 1H), 6.37 (s, 1H), 6.37 (d, J ) 7.4 Hz, 1H), 5.77 (d,
J ) 3.4 Hz, 1H), 5.62 (s, 1H), 5.12 (2H, ABq, JAB ) 6.8 Hz, ∆νAB
)
6.9 Hz), 5.02 (2H, ABq, JAB ) 6.7 Hz, ∆νAB ) 29.5 Hz), 4.97 (2H,
ABq, JAB ) 6.0 Hz, ∆νAB ) 56.7 Hz), 4.89 (d, J ) 7.4 Hz, 1H), 4.85
6.4, 4.2, 1H), 3.65 (s, 3H), 2.84 (s, 3H, 2.14 (dd, J ) 2.8, 2.8, 2H); 13
C
NMR (300 MHz, acetone-d6) δ 198.6, 166.6, 166.1, 162.2, 160.2, 158.8,
156.1, 130.5, 125.1, 114.0, 108.7, 107.8, 107.6, 107.0, 96.2, 54.7, 52.0,
42.7, 38.0; IR (CHCl3) 3690, 3018, 2984, 2929, 1732, 1602, 1446,
1046 cm-1; MS m/z 418 (21), 400 (19), 389 (12), 386 (11), 372 (31),
357 (16), 339 (87), 325 (43) 312 (19), 297 (12), 280 (18), 221 (29),
195 (47), 189 (18), 168 (58), 163 (22), 154 (16); exact mass calcd for
C20H18O10 418.0900, found 418.0896.
5-[2′-Methyl formate-4′,6′-diacetoxy-r-benzoyl]-2-methoxy-4,6-
diacetoxybenzo[furo]furan (71). The unprotected methyl acetal
(0.0099 g, 0.024 mmol), acetic anhydride (0.061 g, 0.056 mmol), and
sodium acetate (0.039 g, 0.47 mmol) were dissolved in reagent-grade
toluene (0.95 mL, 0.025 M). The reaction mixture was stirred at room
temperature for 2 h. The salts were removed by filtration and washed
with dichloromethane. The tetraacetylated methyl acetal 71 was purified
by radial chromatography with a 30-50% ethyl acetate/hexanes
gradient, to yield 0.0128 g as a yellow solid (92.1%): 1H NMR (300
MHz, CDCl3), as a rotameric pair, δ 7.74 (br d, 2H), 7.26 (br d, 2H),
6.34 (br s, 2H), 6.04 (dd, 2H), 5.06 (br d, 2H), 3.78 (s, 3H), 3.76
(s, 3H), 3.7 (dd, 2H), 3.01 (s, 6H), 2.33 (s, 12H), 2.29 (s, 12H), 2.12
(2H, ABq, JAB ) 6.9 Hz, ∆νAB ) 50.7 Hz), 4.56 (2H, ABq, JAB
)
11.7 Hz, ∆νAB ) 71.0 Hz), 3.59 (s, 3H), 3.52 (d, J ) 3.7 Hz, 1H),
3.44 (s, 3H), 3.40 (s, 3H), 3.27 (s, 3H), 3.04 (s, 3H), 2.52 (ddd, J )
11.3, 4.3, 3.8 Hz, 1H), 1.85 (d, J ) 11.3 Hz, 1H), 1.05-1.15 (m, 21H);
13C NMR (300 MHz, CDCl3) δ 156.3, 155.9, 155.5, 153.4, 152.0, 138.1,
124.5, 118.8, 112.5, 110.1, 105.2, 103.1, 101.2, 99.9 (1, C-4), 99.2,
94.6, 94.4, 93.7, 73.2, 66.5, 58.3, 57.5, 55.9, 55.9, 55.5, 38.4, 29.2,
17.9, 17.8, 12.1; IR (CHCl3) 3499, 3010, 2945, 2869, 1610, 1588, 1463,
1295, 1035 cm-1; MS m/z 722 (M+, 10), 709 (7), 707 (41), 681 (0.3),
647 (13), 631 (92), 601 (29), 429 (12), 384 (11), 285 (16), 270 (90),
238 (14), 225 (100); exact mass calcd for C36H55O12Si 707.3463 for
M-OH, found 707.3474. Anal. (C36H56O13Si) C, H.
[7-(2′-Methoxymethyl-3′,5′-bis(O-methoxymethyl)-r-benzoyl)-2,5-
methano-6,8-bis(O-methoxymethyl)-1,3-benzodioxepan-4-yloxy]-
tris(1-methylethylsilane). The diastereomeric benzhydrols 69 (2.42 g,
3.34 mmol) and DDQ (0.796 g, 3.51 mmol) were dissolved in reagent-
grade p-dioxane (50 mL, 0.05 M). The solution was stirred at room
temperature overnight and partitioned between water and ether. The
aqueous phase was extracted with ether (4×) and the extracts were