J. Ruiz et al. / Tetrahedron 69 (2013) 6709e6720
6719
þ
(50%, MNH4þ); HRMS (CI/CH4): calculated for C14H17O5þ 265.1076,
found 265.1060.
m/z HRMS (CI/CH4) calculated for C15H19O5 279.1232, found
279.1242. mp¼63 ꢀC.
5.2.3. Aldehyde (19). White solid mp¼108 ꢀC, Rf (petroleum ether/
EtOAc:90/10) 0.87. 1H NMR (300 MHz, CDCl3) dH 1.84e2.00 (4H, m,
CH2eCH2), 2.01e2.13 (4H, m, CH2eCH2), 9.48 (1H, s, CHO). 13C NMR
(75.47 MHz, CDCl3) dC 28.6 (CH2, CH2eCH2), 28.9 (CH2, CH2eCH2),
35.3 (C, COeCeCO), 38.9 (C, COeCeCO), 113.7 (C, CeCHO), 188.2
5.3.3. Iron(II) reduction of compound (22). Methylated endoper-
oxide 22 (30 mg, 0.10 mmol, 1.00 equiv) was dissolved with 1.10 ml
of degassed acetonitrile under Ar. FeSO4 (30.0 mg, 0.10 mmol,
1.00 equiv) was dissolved with 1.1 ml of degassed water under Ar.
The aqueous solution was added to the organic solution. The
resulting yellow solution was stirred under Ar at room tempera-
ture. After complete consumption of the methylated endoperoxide
(TLC monitoring), the red solution was concentrated at room
temperature to remove acetonitrile and water was lyophilized. The
crude was passed through a column of Chelex 100 resin (100e200
mesh) to remove iron.
(CH, CHO), 191.0 (C, CO), 194.3 (C, CO), 201.7 (C, CO). IR: (KBr) n:
3092, 2856, 1724, 1679, 1631, 1351 cmꢁ1. m/z HRMS (CI/CH4): cal-
þ
culated for C11H11O4 207.0657, found 207.0658.
5.2.4. Epoxide (20). White solid. Rf (petroleum ether/EtOAc:80/
20) 0.55. 1H NMR (300 MHz, CDCl3) dH 0.88 (3H, d, J¼7 Hz,
CHeCH3), 1.14 (3H, d, J¼7 Hz, CHeCH3), 1.61e1.77 (2H, m,
CHe(CH3)2, CH2eCH2), 1.83e1.94 (3H, m, CH2eCH2), 2.09e2.31
(4H, m, CH2eCH2), 3.10 (1H, d, J¼9 Hz, OCHeCH(CH3)2). 13C NMR
(75.47 MHz, CDCl3) dC 18.5 (CH3, CHeCH3), 19.5 (CH3, CHeCH3),
26.4 (CH, CHeCH3), 28.9 (CH2, CH2eCH2), 29.5 (CH2, CH2eCH2),
30.4 (CH2, CH2eCH2), 31.0 (CH2, CH2eCH2), 42.0 (C, COeCeCO),
42.8 (COeCeCO), 68.9 (C, CO(CO)2eC), 77.4 (CH, OCHeCH(CH3)2),
5.3.4. Methyl 2,4-dihydroxy-3,5-bis(2-hydroxyethyl)benzoate (23).
Yellow solid (20%). Rf (petroleum ether/EtOAc:25/75) 0.60. 1H NMR
(500 MHz, CDCl3) dH 2.84 (2H, t, J¼5.7 Hz, eCH2eCH2OH), 3.01 (2H, t,
J¼5.5 Hz, eCH2eCH2OH), 3.87e3.92 (4H, m, eCH2eCH2OH), 3.90
(3H, s, COOCH3), 7.51 (1H, s, CH]CeCOOCH3), 11.16 (1H, s, OH). 13
C
NMR (125.7 MHz, CDCl3) dC 26.1 (CH2, eCH2eCH2OH), 34.3 (CH2,
eCH2eCH2OH), 52.1 (CH3, COOCH3), 63.8 (CH2, eCH2eCH2OH), 64.1
(CH2, eCH2-CH2OH),104.8 (C, CeCOOCH3),114.2 (C, CeCH2eCH2OH),
118.3 (C, CeCH2eCH2OH), 130.3 (CH, CH]CeCOOCH3), 160.4 (C,
CeOH), 160.7 (C, CeOH), 170.9 (C, COOCH3). IR (ATR): 3256 (br s),
1662, 1615, 1437, 1357, 1287, 1207, 1100, 1040 cmꢁ1. m/z (CI/NH3) 274
(3, MNH3þ), 257 (100, þMHþ), 239 (5), 225 (9%); HRMS (CI/CH4):
calculated for C12H16O6 256.0947, found 256.0952.
196.7 (C, CO), 198.1 (C, CO), 200.7 (C, CO). IR (KBr) n: 1727, 1679,
1100 cmꢁ1. m/z (CI/NH3): 249 (10, MHþ), 2þ66 (100%, MNH4þ);
HRMS (CI/CH4): calculated for C14H17O4
249.1127, found
249.1128. mp¼122 ꢀC.
5.3. General procedure for methylation
To a solution of the peroxy-alcohol (1.00 equiv) in anhydrous
THF (0.025 M) at ꢁ78 ꢀC, n-BuLi (1.60 M, 1 equiv) was added
dropwise under argon. After 10 min, TfOMe (1.20 equiv) was added
dropwise. The reaction was quenched with an aqueous saturated
solution of NH4Cl. The reaction was diluted with water and phases
were separated. The aqueous layer was extracted with EtOAc. The
combined organic layers were washed with brine, dried over
MgSO4, and concentrated. The crude was purified by flash chro-
matography over silica gel.
5.3.5. Methyl
3-hydroxy-6-(2-hydroxyethyl)-2,2-dimethyl-5-oxo-
2,3,3a,5-tetrahydrospiro[cyclopenta[b]furan-4,10-cyclopropane]-3a-
carboxylate (24). Yellow solid (10%). Rf (petroleum ether/EtOAc:25/
75) 0.35. 1H NMR (500 MHz, CDCl3) dH 0.79e0.84 (1H, m, AA0XX0
system, CH2eCH2), 1.03e1.08 (1H, m, AA0XX0, CH2eCH2), 1.33 (3H, s,
CH3),1.37e1.44 (2H, m, AA0XX0 systems, CH2eCH2),1.53 (3H, s, CH3),
2.48 (2H, t, J¼5.7 Hz, eCH2eCH2OH), 3.08 (1H, m, eCH2eCH2OH),
3.73e3.76 (2H, m, A2M2X, eCH2-CH2OH), 3.77 (3H, s, COOCH3), 3.97
(1H, d, J¼10 Hz, CHeOH), 4.92 (1H, d, J¼10 Hz, CHeOH). 13C NMR
(125.7 MHz, CDCl3) dC 10.8 (CH2, CH2eCH2), 13.3 (CH2, CH2eCH2),
15.9 (CH3, CH3), 26.3 (CH2, eCH2eCH2OH), 28.7 (CH3, CH3), 37.2 (C,
C(CH2eCH2)), 53.6 (CH3, COOCH3), 57.2 (C, CeCOOCH3), 61.2 (CH2,
eCH2eCH2OH), 81.1 (CH, CHOH), 96.3 (C, (CH3)2CeO), 115.9 (C, C]
CeCH2eCH2OH), 173.5 (C, COOCH3), 182.2 (C, C]CeOeC), 204.9 (C,
C]O). IR (ATR): 3434 (br.), 1707, 1639, 1109, 1082, 1050 cmꢁ1. m/z
(CI/NH3) 297 (100%, MHþ); HRMS (CI/CH4, m/z): calculated
5.3.1. Methylated endoperoxide (21). White solid (54%). Rf (petro-
leum ether/EtOAc:90/10) 0.25. 1H NMR (300 MHz, CDCl3) dH
0.33e0.40 (1H, m, CH2eCH2), 0.49 (1H, d, J¼14 Hz, CeCH2eC),
0.53e0.60 (2H, m, CH2eCH2), 0.66e0.77 (2H, m, CH2eCH2),
1.18e1.23 (2H, m, CH2eCH2), 1.30 (3H, s, CeCH3), 1.38 (3H, s,
CeCH3), 1.57e1.63 (1H, m, CH2eCH2), 2.91 (1H, d, J¼14 Hz,
CeCH2eC), 3.47 (3H, s, OCH3), 6.66 (1H, s, C]CHeC). 13C NMR
(75.47 MHz, CDCl3) dC 7.3 (CH2, CH2eCH2), 9.9 (CH2, CH2eCH2), 16.5
(CH2, CH2eCH2), 21.1 (C, CH2eCeCOCH3), 23.7 (CH3, CeCH3), 25.0
(CH3, CeCH3), 26.2 (CH2, CH2eCH2), 27.6 (C, CH2eCeCO), 38.7 (CH2,
CeCH2eC), 50.3 (CH3, OCH3), 78.6 (C, C]CHeC), 98.3 (C, COCH3),
133.7 (C, C]CHeC), 138.2 (CH, C]CHeC), 198.4 (C, CO). IR (KBr):
3087, 1684, 1638, 1144, 1126, 1077 cmꢁ1. m/z (CI/NH3): 192 (100),
233 (16, [MꢁOMe]þ), 265 (6%, MHþ); HRMS (CI/CH4): calculated for
þ
C15H21O6 297.1338, found 297.1339.
5.3.6. Compound (25). Yellow solid (7%). Rf (petroleum ether/
EtOAc:25/75) 0.10. 1H NMR (500 MHz, CDCl3) dH 1.36 (3H, s, CH3),
1.54 (3H, s, CH3), 1.67e1.85 (8H, m, AA0XX0 systems, CH2eCH2,
CH2eCH2), 2.01 (3H, s, NHeCOeCH3), 5.05 (1H, d, J¼6.5 Hz, CHeNH),
5.66 (1H, br d, CHeNH). 13C NMR (125.7 MHz, CDCl3) dC 21.7 (CH3,
CH3), 22.7 (CH2, CH2eCH2), 23.2 (CH3, CH3), 23.8 (CH2, CH2eCH2),
26.9 (CH2, CH2eCH2), 27.3 (CH3, COeCH3), 27.7 (CH2, CH2eCH2),
29.7 (C, COeC(CH2eCH2)eCeO), 38.9 (C, COeC(CH2eCH2)eCO),
58.6 (CH, CHeNH), 95.2 (C, C(CH3)2), 111.9 (C, C]CeO), 170.9 (C,
CH3eCOeNH),176.5 (C, C]CeO),189.2 (C, C]CeCOeC(CH2eCH2)),
204.1 (C, C(CH2eCH2)eCOeC(CH2eCH2)). IR (ATR): 3349, 1694,
1671, 1616, 1533, 1078 cmꢁ1. m/z (CI/NH3) 290 (100, MHþþ), 265 (95),
247 (42%); HRMS (CI/CH4): calculated for C16H20NO4 290.1392,
found 290.1394.
þ
C15H21O4 265.1440, found 265.1448. mp¼113 ꢀC.
5.3.2. Methylated endoperoxide (22). White solid (71%). Rf (petro-
leum ether/EtOAc:95/5) 0.20. 1H NMR (300 MHz, CDCl3) dH
0.63e0.70 (1H, ddd, J¼9.9, 7.2, 3.6 Hz, CH2eCH2), 1.00e1.07 (1H,,
J¼9.3, 7.5, 3.9 Hz, CH2eCH2), 1.36 (3H, s, CeCH3), 1.39e1.46 (1H, m,
CH2eCH2), 1.44 (3H, s, CeCH3), 1.67e1.91 (3H, m, CH2eCH2), 1.99
(1H, ddd, J¼9.6, 8.4, 1.8 Hz, CH2eCH2), 6.98 (1H, s, C]CHeC). 13
C
NMR (75.47 MHz, CDCl3) dC 10.0 (CH2, CH2eCH2), 15.8 (CH2,
CH2eCH2), 23.6 (CH3, CeCH3), 24.5 (CH2, CH2eCH2), 24.8 (CH3,
CeCH3), 30.3 (CH2, CH2eCH2), 34.1 (C, COeCeCOH), 40.1 (C,
COeCeCO), 51.9 (CH3, OCH3), 78.7 (C, C(CH3)2), 96.8 (C, COH), 132.4
(C, C]CH), 140.3 (CH, C]CHeC), 193.6 (C, CH]CeCOeC), 202.3 (C,
5.4. Spin trapping-EPR assays
The nitrone POBN was purchased from SigmaeAldrich (St. Louis,
MO). Spin adducts were produced by mixing the dienolic precursor
CeCOeC). IR (KBr): 3094, 3014, 1682, 1639, 1123, 1094, 1061 cmꢁ1
.