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47.3, 56.1, 67.9, 111.4, 115.2, 121.3, 126.0 (2C), 127.3,
132.0, 132.9 (2C), 146.6, 152.1, 158.6, 164.3, 191.7; MS
(EI) m/z (rel int.): 313 (20), 312 (100, M+), 259 (7), 240
(40), 239 (62), 226 (7), 225 (32), 211 (10), 105 (16), 104
(37), 103 (7), 91 (16), 90 (11); HRMS (EI) calcd for
C18H16O5: [M+] 312.0998, found: 312.0999.
2.2 Hz, 1H, 15-H), 8.10–8.19 (m, 2H); 13C NMR
(100.6 MHz, acetone-d6/CDCl3, 1:1): d 31.1, 43.7, 54.7,
55.5, 67.7, 88.0, 110.8, 113.4 (2C), 114.7, 120.6, 121.7,
123.6, 123.8, 128.5, 130.6 (2C), 131.1, 132.3, 132.4,
133.3, 138.5, 146.0, 152.2, 157.9, 159.5, 167.1, 167.5; MS
(EI) m/z (rel int.): 488 (0.6), 445 (26), 444 (100, M+), 414
(13), 354 (6), 240 (25), 226 (12), 221 (11), 135 (84), 121
(12), 91 (14), 90 (11), 57 (12), 44 (44); HRMS (EI) calcd
for C28H24O8 [M+]: 488.1471, found: 488.1458. Anal. Calcd
for C28H24O8$CH3COCH3: C 68.12; H 5.53; found: C
68.08; H 5.58.
3.2.8. Ornatipolide, 4-hydroxy-2,10-dioxatricyclo-
[12.2.2.13,7]nonadeca-1(17),3,5,7(19),14(18),15-hexaene-
11,12-dione (6). A solution of BI3 (540 mg, 1.4 mmol) in
dry CH2Cl2 (9 mL) was slowly added to a solution of 15
(87 mg, 0.28 mmol) in dry CH2Cl2 (10 mL), maintained
under an argon atmosphere in the dark at ꢁ78 ꢀC. The solu-
tion was stirred for 10 min at ꢁ78 ꢀC, then warmed to rt,
treated with 1 N aq NaHSO3 (20 mL), and extracted with
CH2Cl2 (3ꢂ). The combined extracts were washed with
H2O, dried (MgSO4), and concentrated under reduced pres-
sure. Purification of the residue by TLC on silica gel (tolu-
ene/EtOAc/HCO2H, 10:5:3, Rf¼0.62) yielded 6 (20 mg,
25%) as a colorless oil. UV–vis (acetonitrile): lmax (log 3)
276 nm (4.46); 1H NMR (300 MHz, acetone-d6): d 2.68 (ob-
scured by H2O signal, 2H, 8-H), 4.07 (s, 2H, 13-H), 4.14 (dd,
J¼4.7, 4.7 Hz, 2H, 9-H), 4.93 (d, J¼2.0 Hz, 1H, 19-H), 6.55
(dd, J¼8.1, 2.0 Hz, 1H, 6-H), 6.73 (d, J¼8.1 Hz, 1H, 5-H),
7.16 (d, J¼8.5 Hz, 2H, 16-H, 17-H), 7.44 (d, J¼8.5 Hz,
3.2.10. (R,S)-Retipolide E, 4,40-dihydroxy-30-(4-hydroxy-
phenyl)spiro{2.10-dioxatricyclo[12.2.2.13,7]nonadeca-
1(17),3,5,7(19),14(18),15-hexaene-12,20(50H)-furan}-
11,50-dione [(R,S)-5]. A 0.23 M solution of BI3 in CH2Cl2
(7.2 mL, 1.65 mmol) was added to a stirred solution of
16$acetone (90 mg) in dry CH2Cl2 (5 mL), maintained un-
der an argon atmosphere at 0 ꢀC. The mixture was stirred for
10 min at 0 ꢀC and then concentrated under reduced pres-
sure. The solid residue was triturated with ice water
(10 mL), filtered off, and rinsed with water (50 mL). Purifi-
cation by flash chromatography (CHCl3/acetone, 4:1,
Rf¼0.33) afforded (R,S)-5 (36 mg, 47%) as a colorless solid.
Mp 245–247 ꢀC; UV–vis (acetonitrile): lmax (log 3) 212
(4.02), 2.24 (sh, 3.90), 290 (sh, 3.58), 304 (3.59), 350 nm
(2.84); IR (KBr, cmꢁ1): 3410s, 3300s, 1730s, 1715s,
1585m, 1510m, 1495m, 1430m, 1260s, 1110m, 970m,
915m, 870m, 840m; 1H NMR (400 MHz, acetone-d6):
d 2.59 (dd, J¼17.1, 5.2 Hz, 1H, 8-Ha), 2.84 (dddd, J¼17.1,
11.2, 1.2, 0.9 Hz, 1H, 8-Hb), 3.17 (d, J¼13.8 Hz, 13-Hb),
3.90 (ddd, J¼11.3, 5.2, 1.2 Hz, 1H, 9-Hb), 3.95 (d,
J¼13.8 Hz, 1H, 13-Ha), 4.21 (dd, J¼11.3, 11.2 Hz, 1H, 9-
Ha), 4.79 (dd, J¼2.1, 0.9 Hz, 1H, 19-H), 6.50 (dd, J¼8.0,
2.1 Hz, 1H, 6-H), 6.70 (d, J¼8.0 Hz, 1H, 5-H), 6.95
(AA0BB0-d, J¼8.9 Hz, 2H, 80-H), 6.96 (dd, J¼8.5, 2.5 Hz,
1H, 17-H), 7.20 (dd, J¼8.5, 2.5 Hz, 1H, 16-H), 7.35 (dd,
J¼8.5, 2.5 Hz, 1H, 18-H), 7.65 (dd, J¼8.5, 2.5 Hz, 1H,
15-H), 7.90 (s, 1H, OH), 8.00 (AA0BB0-d, J¼8.9 Hz, 2H,
70-H), 8.72 (s, 1H, OH), 9.24 (br s, 1H, OH); 13C NMR
(100.6 MHz, acetone-d6): d 32.2 (C8), 44.3 (C13), 68.8
(C9), 89.1 (C12), 115.9 (C19), 115.9 (2ꢂC80), 116.3 (C5),
122.2 (C60), 122.3 (C6), 124.65 (C16), 124.72 (C17),
129.9 (C30), 132.1 (2ꢂC70), 132.5 (C7), 133.1 (C14),
133.9 (C18), 134.6 (C15), 139.8 (C40), 144.6 (C4), 152.4
(C3), 158.8 (C-90), 159.3 (C1), 167.8 (C50), 168.7 (C11);
MS (EI) m/z (rel int.): 460 (1.5, M+), 417 (15), 416 (84),
226 (29), 225 (16), 207 (14), 198 (14), 188 (17), 121 (8),
120 (11), 91 (30), 44 (100); HRMS (EI) calcd for
C26H20O8 [M+]: 460.1158, found: 460.1152.
1
2H, 15-H, 18-H), 8.04 (s, 1H, 4-OH); H NMR (600 MHz,
CDCl3): d 2.79 (m, 2H, 8-H), 4.03 (s, 2H, 13-H), 4.17 (m,
2H, 9-H), 4.89 (br s, 1H, 19-H), 5.49 (br s, 1H, 4-OH),
6.53 (d, J¼7.5 Hz, 1H, 6-H), 6.77 (d, J¼7.5 Hz, 1H, 5-H),
7.12 (d, J¼7.5 Hz, 2H, 16-H, 17-H), 7.36 (d, J¼7.5 Hz,
2H, 15-H, 18-H); 13C NMR (150 MHz, CDCl3): d 31.5 (C-
8), 47.3 (C-13), 67.9 (C-9), 114.8 (C-19), 115.0 (C-5),
122.0 (C-6), 125.9 (C-16, C-17), 127.7 (C-14), 131.6 (C-
7), 133.0 (C-15, C-18), 143.0 (C-4), 150.2 (C-3), 158.3 (C-
1), 164.2 (C-11), 191.6 (C-12); MS (EI) m/z (rel int.): 299
(17, M++H), 298 (100, M+), 226 (32), 225 (42), 211 (6),
197 (4), 120 (34), 107 (23), 77 (6).
3.2.9. (R,S)-Retipolide E dimethyl ether (16). A solution of
15 (1.00 g, 3.20 mmol), methyl 3-(4-methoxyphenyl)pyru-
vate (1.67 g, 8.00 mmol), and NEt3 (2.23 mL, 16.0 mmol) in
dry EtOAc (25 mL) was stirred for 5 h under an argon atmo-
sphere at rt. The solution was diluted with EtOAc (200 mL),
washed with 1 N aq NaHCO3 (100 mL), water (2ꢂ100 mL),
and brine (100 mL), dried (MgSO4), and concentrated under
reduced pressure. Flash chromatography (CHCl3/acetone,
gradient 50:1–10:1) yielded a yellowish solid, which on
crystallization from acetone afforded 16 (1.57 g, 90%) as
colorless crystals, containing 1 mol of acetone per mol.
Mp 252–254 ꢀC; Rf¼0.25 (CHCl3/acetone, 50:1), 0.45
(CHCl3/acetone, 20:1); UV–vis (acetonitrile): lmax (log 3)
214 (4.29), 2.26 (sh, 4.21), 290 (sh, 3.92), 304 nm (3.94);
IR (KBr, cmꢁ1): 3360s (br), 1755s, 1720s, 1600m, 1255s;
1H NMR (200 MHz, CDCl3): d 2.54 (dd, J¼17.3, 5.3 Hz,
1H, 8-Ha), 3.00 (dddd, J¼17.3, 11.0, 1.8, 0.5 Hz, 1H, 8-
Hb), 3.03 (d, J¼13.8 Hz, 1H, 13-Hb), 3.50 (br s, 1H, OH),
3.86 (ddd, J¼11.1, 5.3, 1.8 Hz, 1H, 9-Hb), 3.87, 3.94 (each
s, 3H, OMe), 3.98 (d, J¼13.8 Hz, 1H, 13-Ha), 4.28 (dd,
J¼11.1, 11.0 Hz, 1H, 9-Ha), 4.76 (dd, J¼2.2, 0.5 Hz, 1H,
19-H), 6.55 (dd, J¼8.2, 2.2 Hz, 1H, 6-H), 6.73 (d,
J¼8.2 Hz, 1H, 5-H), 6.97–7.06 (m, 2H), 7.01 (dd, J¼8.4,
2.4 Hz, 1H, 17-H), 7.25 (dd, J¼8.4, 2.4 Hz, 1H, 16-H),
7.32 (dd, J¼8.4, 2.2 Hz, 1H, 18-H), 7.62 (dd, J¼8.4,
3.3. Synthesis of (R,S)-retipolide E via intramolecular
nucleophilic aromatic substitution
3.3.1. Methyl 4-hydroxy-3-(4-methoxyphenyl)-5-oxo-2,5-
dihydrofuran-2-carboxylate (19). A solution of dimethyl
fumarate (4.32 g, 30.0 mmol) in EtOAc (200 mL) was
cooled to ꢁ78 ꢀC and treated with ozone until the solution
remained light blue. The excess of ozone was then removed
by bubbling argon through the solution. Dimethyl sulfide
(6.60 mL, 90.0 mmol) was added and the solution warmed
to rt. The mixture was treated with methyl 3-(4-methoxyphe-
nyl)pyruvate (18) (13.5 g, 65.0 mmol) and NEt3 (9.10 mL,