HETEROCYCLES

Short Paper | Special issue | Vol. 84, No. 2, 2012, pp. 1217-1226
Received, 14th April, 2011, Accepted, 23rd May, 2011, Published online, 26th May, 2011.
DOI: 10.3987/COM-11-S(P)11

■ Access to Some UV Chromophore-Containing Antimalarial Trioxanes Using Hydrogen Peroxide as Source of the Peroxy Bonds

Yun Li, Sergio Wittlin, and Yikang Wu*

State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China

Abstract

Several trioxanes were synthesized through perhydrolysis of an allylic epoxide followed by ketal exchange with a proper dimethyl ketal.

1,2,4-Trioxane is broadly considered as the pharmacophore of qinghaosu (artemisinin, 1), an antimalarial agent discovered by Chinese scientists in the early 1970’s. This natural sesquiterpene endoperoxide was found to be highly potent against malaria parasites including the multi drug-resistant strains and thus attracted many investigators around the world.1 Nowadays the combinations treatments with qinghaosu-derived peroxy compounds as the key ingredient have been recommended as the first-line drugs to treat malaria.

The discovery of qinghaosu has also greatly stimulated the studies on design and synthesis of simple organic peroxides,2 because qinghaosu is still a limited natural resource and its synthesis can be achieved only on small laboratory scales to date. As part of our long-standing study, we have been working on synthesis various organic peroxides using hydrogen peroxide as the source of the peroxy bonds.3
Recently, we developed3d a very mild yet highly efficient protocol for perhydrolysis of epoxides with PMA (phosphomolybdic acid) as the catalyst. The products of such epoxide ring opening reactions are β-hydroxyhydroperoxides, which are apparent precursors to 1,2,4-trioxanes. To exploit this potential, we designed a readily accessible UV-chromophore (which may facilitate detection in e. g. pharmacokinetic/metabolic studies) containing epoxide, from which through perhydrolysis and ketalization a range of 1,2,4-trioxanes can be obtained. The peroxides thus constructed also carry a free hydroxyl group for further derivatization. Here below are the details of this endeavor.

The synthesis merged with the known4 alcohol 2 (Scheme 1). After acetylation with Ac2O in the presence of pyridine, the alkenic bond was oxidized with m-CPBA to afford epoxide 4. It is interesting to note that use of Na2CO3 appears to be necessary in this epoxidation. If the more frequently employed NaHCO3 was used as the buffer, the desired epoxide was isolated in only 28% yield.
The epoxide 4 was then subjected to the perhydrolysis conditions developed3d in our laboratories previously. Again, like observed earlier in a similar case3d with a benzylic epoxide, a deep blue color occurred immediately after addition of the “normal” (10 mol% with respect to the epoxide 4) amounts of PMA. However, if reducing the added PMA to only 1 mol%, the desired ring opening products were formed in 64% isolated yield. The major (cis) isomer 5a was converted to the corresponding acetonide by treatment with Me2C(OMe)2 first in the presence of a catalytic amount of PPTS and then a more acidic catalyst, p-TsOH. Lower yields were observed if the p-TsOH was added from the beginning.

The acetyl group was then hydrolyzed with K2CO3/MeOH to free the hydroxyl group in the side chain, which allowed facile derivatization through simple condensation with different carboxylic acids under the standard DCC conditions to afford esters 8, 9, 10, and 11.
If the perhydrolysis product 5a was treated with other ketals instead of Me2C(OMe)2, the corresponding 1,2,4-trioxanes could also be obtained in good yields (Scheme 2). For instance, reaction with the commercially available 12 resulted in the corresponding ketal exchange product 13, which carries an admantyl framework similar to Vennerstrom’s5 highly potent ozonides, under otherwise the same conditions as described for the synthesis of 6. Similarly, the reaction with 14 led to 15 in a comparable yield. The latter (15) could be further converted to alcohol 16 for further derivatization.
The trioxanes obtained were tested in vitro for their antimalarial activity, with the results shown in Table 1. It seems that the antimalarial activity for most of the trioxanes in this series are rather close to each other, except for 6 and 7, which are substantially less potent.

EXPERIMENTAL
Although no explosions were experienced in this work, generally speaking organic peroxides are potentially hazardous compounds and must be handled with great care: Avoid direct exposure to strong heat or light, mechanical shock, oxidizable organic materials, or transition-metal ions. A safety shield should be used for all reactions involving H2O2. Dry CH2Cl2 was obtained by distillation over CaH2. All other solvents and reagents were used as received from commercial sources. PE = petroleum ether (chromatography solvent, bp 60−90 °C). Ethereal hydrogen peroxide was prepared using a literature procedure with slight modification as in our previous3d paper. The ethereal layer was then dried over anhydrous MgSO4. The supernatant (ca. 1 M in H2O2 as titrated with 0.1 M KMnO4) was used directly in the PMA catalyzed perhydrolysis.
2-(3,4-Dihydronaphthalen-1-yl)ethyl acetate (3). Ac2O (1.6 mL, 16 mmol), pyridine (1.2 mL, 16 mmol) and DMAP (15 mg, 0.13 mmol) were added in turn to a solution of alcohol 2 (696 mg, 4.0 mmol) in dry CH2Cl2 (20 mL) stirred at ambient temperature. The mixture was then stirred at the same temperature for 10 h before being partitioned between Et2O (100 mL) and water (10 mL). The phases were separated. The aqueous layer was back extracted with Et2O (3×20 mL). The combined organic layers were washed with sat. aq. CuSO4, water, brine (twice each), and dried over anhydrous Na2SO4. Removal of the solvent and column chromatography (50:1 PE/EtOAc) on silica gel gave the acetate 3 as a colorless oil (834 mg, 3.82 mmol, 96%): 1H NMR (300 MHz, CDCl3) δ 7.11-7.31 (m, 4H), 5.92 (t, J = 4.6 Hz, 1H), 4.24 (t, J = 7.2 Hz, 2H), 2.69-2.85 (m, 4H), 2.21-2.32 (m, 2H), 2.05 (s, 3H); FT-IR (film) 2933, 2831, 1738, 1488, 1449, 1364, 1240, 1039, 764, 737 cm–1. ESI-MS m/z 239.1 ([M+Na]+). Anal. Calcd for C14H16O2: C 77.75, H 7.46. Found C 77.75, H 7.44.
2-((1aR*,7bS*)-1a,2,3,7b-Tetrahydronaphtho[2,1-b]oxiren-7b-yl)ethyl acetate (4). Na2CO3 (18 mg, 0.17 mmol) and m-CPBA (75%, 74 mg, 0.32 mmol) were added to a solution of alkene 3 (63 mg, 0.29 mmol) in dry CH2Cl2 (2 mL) stirred in an ice-water bath. The mixture was then stirred at ambient temperature until TLC showed completion of the reaction. Sat. aq. NaHCO3 (2 mL) was added. The mixture was extracted with Et2O (3×40 mL). The combined organic layers were washed with aq. sat. Na2SO3 (15 mL) and brine before being dried over anhydrous Na2SO4. Removal of the solvent and column chromatography (30:1 PE/EtOAc) on silica gel gave the epoxide 4 as a colorless sticky oil (59 mg, 0.25 mmol, 87%): 1H NMR (300 MHz, CDCl3) δ 7.51-7.60 (m, 1H), 7.19-7.30 (m, 2H), 7.07-7.17 (m, 1H), 4.30 (t, J = 7.3 Hz, 2H), 3.58 (d, J = 2.5 Hz, 1H), 2.68-2.91 (m, 2H), 2.56 (dd, J = 5.2, 15.1 Hz, 1H), 2.33-2.45 (m, 1H), 2.20 (dt, J = 7.4, 14.6 Hz, 1H), 2.04 (s, 3H), 1.83 (dt, J = 5.7, 14.0 Hz, 1H); FT-IR (film) 2934, 2849, 1736, 1459, 1461, 1433, 1366, 1237, 1039, 759, 740 cm–1. EI-MS m/z 232 (M+). Anal. Calcd for C14H16O3: C 72.39, H 6.94. Found C 72.41, H 6.98.
2-((1S*,2R*)-1-Hydroperoxy-2-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl acetate (5a) and 2-((1S*,2S*)-1-hydroperoxy-2-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl acetate (5b). A mixture of PMA (1.2 mg, 0.013 mmol) and epoxide 4 (300 mg, 1.27 mmol) in freshly prepared ethereal H2O2 solution (10 mL) was stirred at ambient temperature for 3 h, when TLC showed completion of the reaction. Et2O (100 mL) was added, followed by water (20 mL). The phases were separated. The aqueous layer was back extracted with Et2O (3×20 mL). The combined organic layers were washed with water and brine before being dried over anhydrous Na2SO4. Removal of the solvent and column chromatography (1:1 PE/Et2O) on silica gel gave the cis isomer 5a (169 mg, 0.63 mmol, 50%) and the trans isomer 5b (47 mg, 0.18 mmol, 14%) as colorless oils.
Data for 5a (the less polar component): 1H NMR (300 MHz, CDCl3) δ 8.89 (s, 1H), 7.35-7.42 (m, 1H), 7.18-7.25 (m, 2H), 7.10-7.17 (m, 1H), 4.27-4.44 (m, 2H), 3.97-4.10 (m, 1H), 3.04 (dt, J = 8.7, 17.0 Hz, 1H), 2.66-2.87 (m, 2H), 2.12-2.40 (m, 3H), 2.00 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 171.6, 136.8, 133.7, 129.0, 128.1, 127.1, 126.0, 84.1, 70.0, 60.6, 34.5, 26.0, 25.0, 21.0; FT-IR (film) 3370, 2938, 1736, 1453, 1396, 1367, 1241, 1077, 1038, 761 cm–1. ESI-MS m/z 289.1 ([M+Na]+); ESI-HRMS calcd. for C14H18O5Na ([M+Na]+) 289.1047, found 289.1050.
Data for 5b (the more polar component): 1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H), 7.39-7.47 (m, 1H), 7.19-7.28 (m, 2H), 7.07-7.18 (m, 1H), 4.50 (dd, J = 12.0, 4.0 Hz, 1H ), 4.26-4.39 (m, 1H), 4.00-4.23 (m, 2H), 3.05 (br s, 1H), 2.89-3.01 (m, 2H), 2.34-2.48 (m, 1H), 2.08-2.26 (m, 3H), 1.98 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 171.4, 136.7, 135.6, 129.2, 128.1, 126.2, 125.9, 87.2, 70.2, 60.6, 31.9, 27.3, 26.7, 21.0; FT-IR (film) 3398, 2940, 1736, 1489, 1453, 1396, 1368, 1241, 1038, 975, 761 cm–1. ESI-MS m/z 289.1 ([M+Na]+); MALDI-HRMS calcd. for C14H18O5Na ([M+Na]+) 289.1047 found 289.1055.
2-((4aR*,10bS*)-3,3-Dimethyl-4a,5,6,10b-tetrahydronaphtho[2,1-e][1,2,4]trioxin-10b-yl)ethyl acetate (6). A solution of 5a (90 mg, 0.33 mmol), PPTS (20 mg, 0.08 mmol) and Me2C(OMe)2 (200 µL, 1.40 mmol) in CH2Cl2 (2 mL) was stirred at ambient temperature for 3 h. The mixture was then diluted with CH2Cl2 (3 mL). p-TsOH (monohydrate, 3 mg, 0.003 mmol) was introduced. The stirring was continued at the same temperature for another 6 h. Sat. aq. NaHCO3 (5 mL) was added. The phases were separated. The aqueous layer was back extracted with Et2O (3×20 mL). The combined organic layers were washed with water and brine before being dried over anhydrous Na2SO4. Removal of the solvent and column chromatography (20:1 PE/EtOAc) on silica gel gave acetonide 6 as a colorless oil (79 mg, 0.26 mmol, 79%): 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 7.4 Hz, 1H), 7.16-7.28 (m, 2H), 7.09 (d, J = 7.0 Hz, 1H), 4.44 (br, 1H), 4.10-4.31 (m, 2H), 3.07 (dt, J = 9.0, 16.5 Hz, 1H), 2.65 (dt, J = 17.1, 4.0 Hz, 1H), 2.03-2.15 (m, 4H), 2.00 (s, 3H), 1.85 (s, 3H), 1.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 136.6, 128.2, 127.3, 126.7, 126.3, 102.4, 79.7, 66.8, 59.6, 38.3, 25.6, 25.3, 23.7, 20.9, 20.6; FT-IR (film) 2936, 1743, 1451, 1366, 1234, 1097, 1039, 758 cm–1. ESI-MS m/z 329.2 ([M+Na]+); MALDI-HRMS calcd. for C17H23O5 ([M+H]+) 307.1540, found 307.1551.
2-((4aR*,10bS*)-3,3-Dimethyl-4a,5,6,10b-tetrahydronaphtho[2,1-e][1,2,4]trioxin-10b-yl)ethanol (7). A solution of 6 (82 mg, 0.27 mmol) and K2CO3 (110 mg, 0.81 mmol) in MeOH (8 mL) was stirred at ambient temperature for 3 h. Water (2 mL) was added. The mixture was extracted with Et2O (3×40 mL). The combined organic layers were washed with water and brine before being dried over anhydrous Na2SO4. Removal of the solvent and column chromatography (4:1 PE/EtOAc) on silica gel gave alcohol 7 as a colorless oil (68 mg, 0.26 mmol, 96%): 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J = 7.1 Hz, 1H), 7.17-7.30 (m, 2H), 7.10 (d, J = 7.4 Hz, 1H), 4.50 (t, J = 2.6 Hz, 1H), 3.80 (dt, J = 4.0, 6.0 Hz, 1H), 3.07 (dt, J = 17.0, 9.0 Hz, 1H), 2.65 (dt, J = 17.9, 3.8 Hz, 1H), 1.98-2.15 (m, 4H), 1.90 (br s, 1H), 1.72 (s, 3H), 1.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 136.5, 128.3, 127.2, 126.7, 126.2, 102.5, 81.1, 66.9, 58.0, 42.3, 25.6, 25.2, 23.6, 20.6 ; FT-IR (film) 3430, 2994, 2939, 1491, 1453, 1432, 1376, 1259, 1207, 1165, 1061, 1040, 1003, 875, 758 cm–1. ESI-MS m/z 287.2 ([M+Na]+); MALDI-HRMS calcd. for C15H20O4Na ([M+Na]+) 287.1254, found 287.1266.
General procedure for acylation of alcohol 7 leading to esters 8-11. A solution of 7 (20 mg, 0.075 mmol), the carboxylic acid (0.44 mmol), DMAP (3 mg, 0.02 mmol) and DCC (45 mg, 0.22 mmol) in dry CH2Cl2 (1 mL) was stirred at ambient temperature for 8 h. Sat. aq. NaHCO3 (5 mL) was added. The mixture was extracted with Et2O (3×40 mL). The combined organic layers were washed with water and brine before being dried over anhydrous Na2SO4. Removal of the solvent and column chromatography on silica gel gave the corresponding ester as a colorless oil.
(R)-2-((4aR*,10bS*)-3,3-Dimethyl-4a,5,6,10b-tetrahydronaphtho[2,1-e][1,2,4]trioxin-10b-yl)ethyl-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoate (8). Data for 8 (yield 78%): 1H NMR (300 MHz, CDCl3) δ 7.72-7.81 (m, 2H), 7.63-7.61 (m, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.01-7.29 (m, 8H), 5.09 (dd, J = 4.4, 5.9 Hz, 1H), 4.23-4.48 (m, 3H), 3.40-3.59 (m, 2H), 3.01 (dt, J = 15.9, 9.0 Hz, 1H), 2.58 (dt, J = 17.0, 4.0 Hz, 1H), 1.89-2.16 (m, 4H), 1.64 (d, J = 11.7 Hz, 3H), 1.12 (d, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 168.6, 167.3, 136.5, 134.1, 131.4, 128.7, 128.5, 128.2, 127.3, 126.8, 126.6, 126.2, 123.4, 102.3, 79.4, 66.5, 61.1, 53.2, 53.1, 37.9, 34.5, 34.4, 25.5, 25.1, 23.5, 20.5; FT-IR (film) 2937, 2856, 1777, 1746, 1715, 1468, 1455, 1387, 1238, 1206, 1104, 1086, 911, 720 cm–1. ESI-MS m/z 564.2 ([M+Na]+); ESI-HRMS calcd. For C32H31NO7Na ([M+Na]+) 564.19927 found 564.19967.
2-((4aR*,10bS*)-3,3-Dimethyl-4a,5,6,10b-tetrahydronaphtho[2,1-e][1,2,4]trioxin-10b-yl)ethyl-2-cyclohexenylacetate (9). Data for 9 (yield 73%): 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J = 7.1 Hz, 1H), 7.16-7.29 (m, 2H), 7.09 (d, J = 7.2 Hz, 1H), 5.54 (s, 1H), 4.46 (s, 1H), 4.11-4.37 (m, 2H), 3.08 (dt, J = 16.4, 9.2 Hz, 1H), 2.90 (s, 2H), 2.65 (dt, J = 17.1, 4.4 Hz, 1H), 1.92-2.20 (m, 8H), 1.70 (s, 3H), 1.49-1.67 (m, 4H), 1.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 171.7, 137.0, 136.5, 130.8, 128.2, 127.3, 126.6, 126.3, 125.9, 102.3, 79.6, 66.5, 59.6, 43.6, 38.3, 28.3, 25.6, 25.2, 23.6, 22.6, 21.9, 20.6; FT-IR (film) 2932, 2857, 1737, 1453, 1435, 1374, 1255, 1207, 1166, 1065, 1002, 758 cm–1. ESI-MS m/z 409.1 ([M+Na]+); MALDI-HRMS calcd. for C23H30O5Na ([M+Na]+) 409.1986 found 409.2003.
(2E,4E)-2-((4aR*,10bS*)-3,3-Dimethyl-4a,5,6,10b-tetrahydronaphtho[2,1-e][1,2,4]trioxin-10b-yl)ethyl-hexa-2,4-dienoate (10). Data for 10 (yield 82%): 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J = 7.2 Hz, 1H), 7.14-7.29 (m, 3H), 7.09 (d, J = 7.6 Hz, 1H), 6.06-6.25 (m, 2H), 5.72 (d, J = 15.6 Hz, 1H), 4.49 (s, 1H), 4.18-4.42 (m, 2H), 3.08 (dt, J = 16.8, 8.2 Hz, 1H), 2.65 (dt, J = 17.0, 4.2 Hz, 1H), 2.03-2.23 (m, 4H), 1.85 (d, J = 5.3 Hz, 3H), 1.70 (s, 3H), 1.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.9, 145.4, 139.8, 137.1, 136.5, 129.7, 128.2, 127.2, 126.6, 126.2, 118.4, 102.3, 79.6, 66.5, 59.3, 38.4, 25.6, 25.2, 23.6, 20.6, 18.7; FT-IR (film) 2926, 2854, 1714, 1642, 1616, 1537, 1453, 1243, 1064, 1001 cm–1. ESI-MS m/z 381.2 ([M+Na]+); ESI-HRMS calcd. for C21H6O5Na ([M+Na]+) 381.16725 found 381.16705.
2-((4aR*,10bS*)-3,3-Dimethyl-4a,5,6,10b-tetrahydronaphtho[2,1-e][1,2,4]trioxin-10b-yl)ethyl-undec-10-enoate (11). Data for 11 (yield 76%): 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J = 7.4 Hz, 1H), 7.16-7.30 (m, 2H), 7.09 (d, J = 7.1 Hz, 1H), 5.72-5.90 (m, 1H), 4.98 (d, J = 14.1 Hz, 1H), 4.93 (d, J =10.3 Hz, 1H), 4.46 (s, 1H), 4.11-4.34 (m, 2H), 3.08 (dt, J = 16.7, 8.1 Hz, 1H), 2.65 (dt, J = 17.1, 4.2 Hz, 1H), 2.25 (t, J = 7.2 Hz, 2H), 1.98-2.15 (m, 6H), 1.70 (s, 3H), 1.21-1.44 (m, 12H), 1.16 (s, 3H); FT-IR (film) 2928, 2855, 1738, 1579, 1454, 1373, 1207, 1169, 1119, 993, 757 cm–1. ESI-MS m/z 453.3 ([M+Na]+); ESI-HRMS calcd. for C26H38O5Na ([M+Na]+) 453.2603, found 453.2603.

2-((4a'R*,10b'S*)-4a',5',6',10b'-Tetrahydrospiro[admantane-1,3'-naphtho[2,1-e][1,2,4]trioxine]-10b'-yl)ethyl acetate (13). A solution of 5a (60 mg, 0.22 mmol), PPTS (11 mg, 0.04 mmol) and ketal 12 (86 mg, 0.44 mmol) in CH2Cl2 (2 mL) was stirred at ambient temperature for 3 h. The mixture was then diluted with CH2Cl2 (3 mL). p-TsOH (monohydrate, 3 mg, 0.003 mmol) was introduced. The stirring was continued at the same temperature for another 6 h. Sat. aq. NaHCO3 (5 mL) was added. The phases were separated. The aqueous layer was back extracted with Et2O (3×20 mL). The combined organic layers were washed with water and brine before being dried over anhydrous Na2SO4. Removal of the solvent and column chromatography (20:1 PE/EtOAc) on silica gel gave 13 as a colorless oil (66 mg, 0.17 mmol, 78%): 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J = 7.4 Hz, 1H), 7.14-7.31 (m, 2H), 7.08 (d, J = 7.2 Hz, 1H), 4.41 (s, 1H), 4.11-4.29 (m, 2H), 3.04-3.25 (m, 1H), 2.90-3.04 (m, 1H), 2.55-2.69 (m, 1H), 2.02-2.26 (m, 6H), 2.00 (s, 3H), 1.17-1.95 (m, 11H); 13C NMR (100 MHz, CDCl3) δ 170.8, 136.7, 128.2, 127.2, 126.8, 126.2, 104.5, 79.3, 65.1, 59.7, 38.2, 37.2, 35.8, 33.4, 33.3, 27.2, 27.1, 25.5, 23.7, 20.9; FT-IR (film) 2934, 2856, 1743, 1489, 1469, 1451, 1366, 1235, 1085, 1001, 761, 733 cm–1. ESI-MS m/z 421.2 ([M+Na]+); MALDI-HRMS calcd. for C24H30O5Na ([M+Na]+) 421.1986, found 421.1988.

2-((4a'R*,10b'S*)-4a',5',6',10b'-Tetrahydrospiro[cyclohexane-1,3'-naphtho[2,1-e][1,2,4]trioxine]-10b'-yl)ethyl acetate (15). A solution of 5a (90 mg, 0.33 mmol), PPTS (16 mg, 0.07 mmol) and ketal 14 (150 mg, 1.0 mmol) in CH2Cl2 (2 mL) was stirred at ambient temperature for 3 h. The mixture was then diluted with CH2Cl2 (3 mL). p-TsOH (monohydrate, 3 mg, 0.003 mmol) was introduced. The stirring was continued at the same temperature for another 6 h. Sat. aq. NaHCO3 (5 mL) was added. The phases were separated. The aqueous layer was back extracted with Et2O (3×20 mL). The combined organic layers were washed with water and brine before being dried over anhydrous Na2SO4. Removal of the solvent and column chromatography (20:1 PE/EtOAc) on silica gel gave 15 as a colorless oil (96 mg, 0.27 mmol, 84%): 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J = 7.5 Hz, 1H), 7.15-7.29 (m, 2H), 7.08 (d, J = 7.2 Hz, 1H), 4.46 (br s, 1H), 4.11-4.31 (m, 2H), 3.08-3.18 (m, 1H), 2.57-2.69 (m, 1H), 2.24-2.44 (m, 1H), 2.02-2.17 (m, 5H), 1.99 (s, 3H), 1.26-1.59 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 170.7, 137.1, 136.6, 128.1, 127.2, 126.6, 126.2, 102.4, 79.7, 65.7, 59.6, 38.2, 34.6, 29.5, 25.5, 25.3, 23.6, 22.5, 22.1, 20.8; FT-IR (film) 2936, 2859, 1742, 1452, 1365, 1234, 1097, 1039, 757 cm–1. ESI-MS m/z 369.2 ([M+Na]+); MALDI-HRMS calcd. for C20H26O5Na ([M+Na]+) 369.16725 found 369.16714.

2-((4a'R*,10b'S*)-4a',5',6',10b'-Tetrahydrospiro[cyclohexane-1,3'-naphtho[2,1-e][1,2,4]trioxine]-10b'-yl)ethanol (16). A solution of 15 (50 mg, 0.15 mmol) and K2CO3 (59 mg, 0.43 mmol) in MeOH (4 mL) was stirred at ambient temperature for 3 h. Water (2 mL) was added. The mixture was extracted with Et2O (3×40 mL). The combined organic layers were washed with water and brine before being dried over anhydrous Na2SO4. Removal of the solvent and column chromatography (4:1 PE/EtOAc) on silica gel gave alcohol 16 as a colorless oil (42 mg, 0.14 mmol, 91%): 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 7.7 Hz, 1H), 7.16-7.32 (m, 2H), 7.10 (d, J = 7.1 Hz, 1H), 4.51 (br s, 1H), 3.74-3.90 (m, 2H), 3.01-3.18 (m, 1H), 2.58-2.71 (m, 1H), 2.24-2.45 (m, 1H), 1.94-2.16 (m, 5H), 1.79 (br s, 1H), 1.30-1.60 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 137.1, 136.6, 128.2, 127.2, 126.8, 126.2, 102.4, 79.7, 65.9, 58.1, 42.23, 34.6, 29.6, 25.5, 25.2, 23.6, 22.5, 22.01; FT-IR (film) 3420, 2935, 2859, 1490, 1451, 1363, 1273, 1157, 1098, 997, 757 cm–1. ESI-MS m/z 327.2 ([M+Na]+); MALDI-HRMS calcd. for C18H24O4Na ([M+Na]+) 327.1567, found 327.1563.

ACKNOWLEDGEMENTS
This work was supported by the National Basic Research Program of China (the 973 Program, 2010CB833200), the National Natural Science Foundation of China (21032002, 20921091, 20672129, 20621062, 20772143), and the Chinese Academy of Sciences (KJCX2.YW.H08). We thank Christian Scheurer for assistance in performing the antimalarial assays.

References

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