Degradation of Antimalarial â-Sulfonyl Endoperoxides
J . Org. Chem., Vol. 66, No. 20, 2001 6539
lutidine (32.4 mg; 0.28 mmol) in THF (1 mL) at 0 °C was added
a solution of 10 (26.2 mg; 0.071 mmol) in NMP (1 mL), and
the mixture was stirred at 0 °C for 1 h, poured into 0.333 M
HCl (10 mL), and extracted with 25% EtOAc/hexane (4 × 25
1.89 (ddd, J ≈ 11.5, 11.5, 13.0 Hz, 1H), 2.08 (br, 1 OH), 2.22
(ddddd, J ≈ 2.0, 4.3, 4.3, 4.0, 13.5 Hz, 1H), 2.46 (br, 1 OH);
2.47 (dddd, J ≈ 2.0, 4.3, 4.0, 13.0 Hz, 1H), 3.51 (dd, J ≈ 4.0,
1
3
11.5 Hz, 1H), 4.01 (dddd, J ≈ 4.3, 4.3, 11.5, 11.5 Hz, 1H);
C
mL). The combined organic extract was dried (Na
2
SO
4
) and
NMR (100 MHz, CDCl
(CH ), 41.80 (CH ), 46.12 (CH), 72.83 (C), 75.90 (CH); IR (KBr)
3
) δ 19.62 (CH
3 2
), 34.68 (CH ), 37.40
concentrated at reduced pressure. FC afforded 37 (19.2 mg;
2
2
7
3% yield).
v 3440 (br, s), 2952 (m), 2923 (m), 2863 (m), 1466 (m), 1437
(m), 1383 (m), 1130 (m), 1071 (s), 1041 (m) cm ; MS (m/z)
Ch a r a cter iza tion . 1-P h en ylsu lfon yla ceton e(11):51 white
-1
1
81
79
crystals; R
400 MHz, CDCl
Ar-H), 7.70 (m, 1H, Ar-H); 7.89 (m, 2H, Ar-H); C NMR (100
MHz, CDCl ) δ 31.34 (CH ), 67.70 (CH ), 129.36 (CH, 2 Ar-C),
29.41 (CH, 2 Ar-C), 134.31 (CH, Ar-C), 138.58 (C, Ar-C),
95.80 (CdO).
5R)-5-Acetoxy-5-m eth yl-6-oxo-1,2-h exen e (14): colorless
f
) 0.4 (EtOAc/hexane 1:1); mp 52-54 °C; H NMR
210 (M + 1, Br, 1), 208.01 (M + 1, Br, 1), 192.99 (17), 190.99
(
3
) δ 2.41 (s, 3H), 4.17 (s, 2H), 7.59 (m, 2H,
(13), 128.08 (100), 111.08 (69), 97.07 (12); HRMS calcd for
Br [M + 1] 208.0099, found 208.0090 (δ 0.9 mDa).
(1R,2R,4R)-1-Meth yl-4-br om o-1-a cetoxycycloh exa n -2-
ol (26): colorless oil; R
(400 MHz, CDCl
1
3
79
C
7
H
13
O
2
3
3
2
1
1
1
f
) 0.35 (EtOAc/hexane 3:7); H NMR
) δ 1.53 (d, 3H, J ≈ 0.5 Hz), 1.65 (ddd, J ≈
3
(
13.5, 13.5, 3.4 Hz, 1H), 1.83 (dddd, J ≈ 13.5, 13.4, 11.4, 3.5
Hz, 1H), 1.92 (ddd, J ≈ 13.4, 11.0, 11.0 Hz, 1H), 2.04 (s, 3H),
2.18 (ddddd, 13.5, 4.2, 4.2, 3.8, 2.2 Hz, 1H), 2.27 (ddd, J ≈
13.5, 3.5, 3.4 Hz, 1H), 2.51 (dddd, J ≈ 13.4, 4.5, 4.2, 2.2 Hz,
1H), 3.78 (dd, J ≈ 11.0, 4.5 Hz, 1H), 3.81 (br, s, 1OH), 3.99
1
oil; R
f
3
) 0.75 (EtOAc/hexane 1:1); H NMR (400 MHz, CDCl )
δ 1.45(s, 3H), 1.75 (ddd, J ≈ 5.7, 10.8, 14.1 Hz, 1H), 1.91 (ddd,
J ≈ 5.5, 10.9, 14.1 Hz, 1H), 2.08-2.2 (m, 2H), 2.13 (s, 3H), 5.0
(
1
dddd, J ≈ 1.1, 1.3, 1.3, 10.2 Hz, 1H), 5.05 (dddd, J ≈ 1.5, 1.6,
1
3
.6, 17.0 Hz, 1H), 5.78 (dddd, 6.5, 6.5, 10.2, 17.0 Hz, 1H), 9.50
(dddd, J ≈ 11.4, 11.4, 4.2, 4.2 Hz, 1H); C NMR (100 MHz,
3 3 3 2 2
1
3
(
s, 1H); C NMR (100 MHz, CDCl
CH ), 27.02(CH ), 34.37(CH ,), 84.42(C), 115.37 (CH
CHd), 198.64 (CHdO); IR (CHCl ) v 3110 (m), 2937 (m), 2853
3
) δ: 18.64 (CH
3
), 20.91-
d), 137.23
CDCl
) δ 16.18 (CH
), 22.34 (CH ), 33.78 (CH ), 34.78 (CH ),
(
(
(
(
3
2
2
2
41.28 (CH
2
), 45.43 (CH), 73.74 (CH), 86.07 (C), 171.51 (CdO,
ester); IR (neat) v 3427 (br, s), 1731 (s), 1416 (m), 1370 (m),
3
-
1
m), 1783 (s), 1641 (m), 1451 (m), 1372 (s), 1257 (m) cm ; MS
m/z) 171.10 (M + 1, 99), 141.08 (24), 127.08 (46), 111.08 (100),
1274 (m), 1245 (m), 1112 (m), 1076 (m), 1046(m), 1024 (m)
-
1
81
79
cm ; MS (m/z) 253.03 (M + 1, Br 55), 251.03 (M + 1, Br,
9
1
9.10 (22); HRMS calcd for C
71.0982 (δ 3.9 mDa).
9
H
15
O
3
[M + 1] 171.1021, found:
52), 235.03 (55), 233.77 (52), 192.99 (98), 190.99 (100), 171.10
(31), 111.08 (37); HRMS calcd for C
251.0283, found 251.0338 (δ 5.5 mDa).
(1R,2R,4R)-2-H yd r oxy-4-[(1R)-1-h yd r oxy-1-m et h yl-2-
7
9
7
H
13
O
2
Br [M + 1]
(
4R,5R)-5-Methyl-4-(3-oxobutyl)-5-phenylsulfonylmethyl-
tetr ah ydr o-2-fu r an yl acetate (15) (3:2 m ixtu r e of epim er s):
5
0
) 0.15 (EtOAc/hexane 1:1). Major epimer: 1H NMR
) δ 1.36 (s, 3H), 1.50 (m, 1H), 1.80 (ddd, J ≈
oil; R
400 MHz, CDCl
3.0, 13.0, 4.7 Hz, 1H), 1.93 (s, 3H), 2.00-2.08 (m, 1H), 2.14
dd, J ≈ 13.0, 6.8 Hz, 1H), 2.19 (s, 3H), 2.50-2.54 (m, 3H),
.41 (s, 2H), 6.14 (d, J ≈ 4.7 Hz, 1H), 7.56-7.62 (m, 3H, Ar-
f
p h en ylsu lfon yleth yl]-1-m eth ylcycloh exyl a ceta te (27):
1
(
1
(
3
3
colorless oil; R
CDCl
f
) 0.10 (EtOAc/hexane 1:1); H NMR (400 MHz,
3
) δ 1.08 (dddd, J ≈ 3.3, 12.6, 12.6, 13.5 Hz, 1H), 1.2 (1H,
ddd, J ≈ 11.5, 12.6, 12.6 Hz, 1H), 1.42 (s, 3H), 1.46 (s, 3H),
1.55 (ddd, J ≈ 3.6, 13.5, 13.5 Hz, 1H), 1.76 (ddd, J ≈ 3.3, 3.3,
12.6 Hz, 1H), 1.79 (dddd, J ≈ 3.3, 3.3, 12.6, 12.6 Hz, 1H), 2.04
(s, 3H), 2.08 (m, 1H), 2.28 (ddd, J ≈ 3.3, 3.3, 13.5 Hz, 1H),
3.24 (d, J ≈ 14.0 Hz, 1H), 3.34 (d, J ≈ 14.0 Hz, 1H), 3.77 (s, 1
OH), 3.79 (dd, J ≈ 4.9, 11.5 Hz, 1H), 4.0 (br, 1 OH), 7.60 (m,
1
3
H), 7.91-7.93 (m, 2H, Ar-H); C NMR (100 MHz, CDCl
2
4
3
) δ
), 37.72 (CH ),
2
), 85.14 (C), 96.78 (CH,
1.31 (CH
2.50 (CH
3
), 21.89 (CH
3
), 23.52 (CH
2
), 29.90 (CH
SO
3
2
2
), 43.65 (CH), 66.51 (CH
2
acetal-C), 127.83 (CH, 2 Ar-C), 129.15 (CH, 2 Ar-C), 133.60
CH, Ar-C); 142.0 (C, Ar-C), 169.93 (CdO, ester); 207.86 (Cd
O, ketone); IR (neat) v 3618 (w), 3585 (m), 3063 (s), 2980 (m),
928 (m), 1740 (s), 1716 (s), 1446 (m), 1413 (w), 1377 (m), 1363
m), 1306 (s), 1238 (s), 1145 (s), 1085 (s), 1014 (s); MS (m/z)
09.12 (M + 1 - AcOH, 10), 250.07 (10), 199.04 (31), 167.10
100), 153.09 (56), 149.09 (90), 121.10 (70); HR-MS molecular
ion peak absent, calcd for C16 S [M + 1 - AcOH]
09.1161, found 309.1160 (δ 0.1 mDa). Minor epimer:
NMR (100 MHz, CDCl ) δ 21.31 (CH ), 21.86 (CH ), 22.48
), 37.20 (CH ), 42.31 (CH ), 44.14 (CH), 66.41
), 84.54 (C), 97.17 (CH, acetal-C), 127.98 (CH, 2 Ar-
1
3
(
2H, Ar-H), 7.68 (1H, m, Ar-H), 7.92 (2H, m, Ar-H); C NMR
(100 MHz, CDCl
3
) δ 15.63 (CH
3
), 22.40 (CH
3
), 23.60 (CH
2
),
),
2
(
3
(
24.29 (CH ), 31.20 (CH
3
2
), 35.70 (CH
2
), 45.63 (CH), 63.42 (CH
2
73.68 (C), 74.67 (CH), 87.67 (C), 127.48 (CH, 2 Ar-C), 129.47
(CH, 2Ar-C), 133.95 (CH, Ar-C), 141.1 (C, Ar-C), 171.91 (Cd
O, ester); IR (neat) v 3457 (br, s), 3060 (m), 2948 (m), 2874
(m), 1721 (s), 1447 (m), 1370 (m), 1260 (m) cm- ; MS (m/z)
371.16 (M + 1, 27), 311.14 (19) 293.01 (20), 275.11 (8), 250.07
(12), 199.04 (38), 151.11(100), 133.09 (21); HRMS calcd for
1
21 4
H O
1
3
3
C
3
3
3
(
(
CH
CH
2
2
), 29.95 (CH
SO
3
2
2
C
18
H
27
O
6
S [M + 1] 371.1528, found 371.1590 (δ 6.2 mDa).
(4R,5R)-4-Acetoxy-5-h ydr oxy-4-m eth ylcycloh exen e (35):
2
1
C), 129.08 (CH, 2 Ar-C), 133.62 (CH, 1 Ar-c), 140.97(C, 1 Ar-
C), 169.97 (CdO, ester), 207.95 (CdO).
colorless oil; R
CDCl
f
) 0.46 (EtOAc/hexane 1:1); H NMR (400 MHz,
3
) δ 1.48 (s, 3H), 2.03 (s, 3H), 2.06 (m, 1H), 2.39 (m, J ≈
(
1R,2R,4S)-1-Meth yl-4-br om o-1,2-cycloh exa n ed iol (24):
17.0 Hz, 1H), 2.46 (m, J ≈ 3 Hz, 1H), 2.53 (br s, 1 OH), 2.83
(m, J ≈ 4.0, 17.0 Hz, 1H), 4.05 (ddd, J ≈ 9.0, 5.8, 3.0 Hz, 1H),
1
white needle crystals; R
f
) 0.15 (EtOAc/hexane 1:1); H NMR
, 50 °C) δ 1.23 (3H, s), 1.6 (br, 1 OH), 1.75
ddd, J ≈ 4.1, 7.0, 13.6 Hz, 1H), 1.85 (ddd, J ≈ 4.2, 8.8, 13.6
5.54 (m, 2H); 13C NMR (100 MHz, CDCl
(
(
400 MHz, CDCl
3
3
3
) δ 16.13 (CH ), 22.48
3 2 2
(CH ), 31.36 (CH ), 36.22 (CH ), 71.25 (CH), 83.94 (C), 123.46
Hz, 1H), 1.90 (br, 1 OH), 1.96 (m, 1H), 2.00 (m, 1H), 2.10
ddddd, J ≈ 1.3, 4.2, 7.0, 6.5, 14.3 Hz, 1H), 2.37 (dddd, J ≈
.3, 3.8, 6.7, 14.2 Hz, 1H), 3.90 (dd, J ≈3.8, 7.8 Hz, 1H), 4.51
(CH), 124.40 (CH), 170.55 (CdO, Ester); IR (neat) v 3455 (s,
(
br), 3031 (w), 2984 (w), 2937 (m), 2856 (w), 1728 (s), 1657 (w),
-
1
1
1437 (m), 1367 (m), 1254 (s), 1080 (s) cm ; MS (m/z) 171.10
(M + 1, 6), 153.8 (6) 139.12 (11), 125.08 (20), 110.98 (100);
1
3
(
dddd, J ≈ 3.8, 3.1, 6.5, 6.5 Hz, 1H); C NMR (100 MHz,
CDCl ) δ 22.1 (CH , br), 32.74 (CH ), 34.37 (CH ), 40.03 (CH ),
9.43 (CH), 74.00 (CH); IR (KBr) v 3330 (s, br), 2920 (m, br.),
847 (m), 1465 (m), 1433 (m), 1128 (m), 1071 (m), 1040 (m)
9 15 3
HRMS calcd for C H O [M + 1] 171.1021, found 171.1027.
3
3
2
2
2
4
2
(δ 0.6 mDa).
(1R,2R)-1-Acetoxy-2-h ydr oxy-1-m eth ylcycloh exan e (36):
-
1
81
79
colorless oil; R ) 0.50 (EtOAc/hexane 1:1);
1
H NMR (400 MHz,
) δ 1.25-1.2 (m, 4H), 1.48 (s, 3H), 1.5-1.7 (m, 2H), 1.92
(m, 1H), 2.03 (s, 3H), 2.17 (m, 1H), 3.63 (br s, 1OH), 3.77 (dd,
cm ; MS (m/z) 210 (M + 1, Br, 1), 208.01 (M + 1, Br, 1.5)
1
HR-MS calcd for C
f
92.99 (16), 190.99 (17), 128.08 (100), 111.08 (69), 97.07 (12);
CDCl
3
7
9
7
H
13
O
2
Br [M + 1] 208.0099, found 208.0085
1
3
(δ 1.4 mDa).
J ≈ 4.3, 9.6 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ 16.51 (CH
3
),
),
2
2.45 (CH ), 22.49 (CH ), 23.09 (CH ), 30.73 (CH
3
2
2
2
), 35.71 (CH
2
(
1R,2R,4R)-1-Meth yl-4-br om o-1,2-cycloh exa n ed iol (25):
1
74.40 (CH), 87.70 (C); 171.67 (CdO, ester); MS (m/z) 173.12
M + 1, 25), 130.09 (10), 113.12 (100), 112.12 (93), 95.08 (28);
HRMS calcd for C [M + 1] 173.1178, found 173.1180 (δ
.2 mDa).
1R,4R)-4-[(1R)-1-Hyd r oxy-1-m eth yl-2-p h en ylsu lfon yl-
eth yl]-1-m eth yl-2-oxocycloh exyl a ceta te (37): oil; R ) 0.10
) δ 1.46 (s, 3H),
1.51 (s, 3H), 1.52 (dddd, J ≈ 3.6, 13.1, 14.0, 14.0 Hz, 1H), 1.92-
white needle crystals; R
400 MHz, CDCl
) δ 1.27 (s, 3H), 1.46 (ddd, J ≈ 4.0, 13.5, 13.5
Hz, 1H), 1.79 (ddd, J ≈ 3.9, 3.9, 13.4 Hz, 1H), 1.83 (m, 1H),
f
) 0.25 (EtOAc/hexane 1:1); H NMR
(
(
3
9
17 3
H O
0
(
(51) The NMR data of 11 match the data reported in the literature:
f
Thomsen, M. W.; Handwerker, B. M.; Katz, S. A.; Belser, R. B. J . Org.
Chem. 1988, 53, 906-907. These authors also report an IR spectrum
and a correct elemental analysis.
1
(EtOAc/hexane 1:1); H NMR (400 MHz, CDCl
3