4
650 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 12
Xu et al.
1
3
J = 6.4 Hz, 3H). C NMR (CDCl
3
) δ: 156.27, 152.06, 151.42,
07.43, 107.14, 99.49, 98.98, 92.70, 74.05, 69.32, 47.66, 47.53,
5.38, 29.69, 22.97, 22.84, 22.59, 18.77, 18.63, 16.09, 15.76,
Xyloketal B Acid (11). The title compound was obtained from
2,4,6-trihydroxybenzoic acid and 2,4-dimethyl-3-hydroxy-
methyl-4,5-dihydrofuran with a procedure similar to that for
compound 1. Yield, 84.2%; white solid; mp 159-160 °C. H
3
NMR (CDCl , 400 MHz) δ: 11.462 (s, 1H), 4.124(m, 2H), 3.511
1
3
1
3
1
0.65. HREIMS m/z 388.2245 (calculated for C23
88.2244).
H
32
O
5
,
Xyloketal B Butyl Ether (6). The title compound was obtained
from 3 and 1-bromobutane with a procedure similar to that for
(t, J = 8.5 Hz, 2H), 2.827 (m, 2H), 2.600 (m, 2H), 2.028 (m, 2H),
1.922 (m, 2H),1.533 (s, 3H), 1.470 (s, 3H), 1.025 (s, 6H).
1
3
C
1
compound 4. Yield, 91.1%; white solid; mp 124-125 °C. H
NMR (CDCl ) δ: 171.08, 161.37, 156.59, 151.19, 111.40, 108.66,
3
NMR (CDCl , 400 MHz) δ: 5.992 (s, 1H), 4.171 (apparent t, J =
99.68, 98.09, 93.92, 74.54, 74.07, 47.41, 46.89, 35.08, 34.95,
22.81, 22.50, 18.14, 17.96, 15.62, 15.51. HREIMS m/z
390.1672 (calculated for C21H O , 390.1673).
26 7
3
8.4 Hz, 2H), 3.882 (t, J = 6.4 Hz, 2H), 3.519 (t, J = 8.4 Hz, 2H),
2.822 (m, 2H), 2.638 (m, 2H), 2.119 (m, 2H), 1.879 (m, 2H),
1.749 (m, 2H), 1.499 (s, 3H), 1.484 (s, 3H), 1.252 (m, 2H), 1.058
Xyloketal B Methyl Formate (12). Potassium hydroxide (215
mg, 3.83 mmol) was dissolved in 6 mL of EtOH. This solution
was treated with Diazald (164 mg, 0.765 mmol). The diazo-
methane generated at 0 °C was blown via a stream of nitrogen
(
Hz, 3H). C NMR (CDCl
d, J = 6.4 Hz, 3H), 1.029 (d, J = 6.4 Hz, 3H), 0.968 (t, J = 7.2
13
3
) δ: 156.37, 152.07, 151.43, 107.54,
07.32, 99.48, 98.97, 92.64, 74.04, 67.57, 47.65, 47.53, 35.37,
1
3
1
4
1.32, 29.68, 22.97, 22.74, 19.34, 18.72, 18.56, 16.09, 15.93,
3.86. HREIMS m/z 402.2396 (calculated for C H O ,
02.2397).
Xyloketal B Hexyl Ether (7). The title compound was ob-
tained from 3 and 1-bromohexane with a procedure similar to
2
into a flask containing 11 (90 mg, 0.26 mmol) in Et O at 0 °C.
Nitrogen was continually blown into the flask until the yellow
color in both flasks disappeared. The ether solution was con-
centrated to give 12 (76.9 mg, 100% yield) as a light-yellow solid;
2
4
34
5
1
mp 47-48 °C. H NMR (CDCl
3
, 400 MHz) δ: 4.159 (m, 2H),
1
that for compound 4. Yield, 89.4%. H NMR (CDCl , 400
3
3.901 (s, 3H), 3.553 (t, J = 8.5 Hz, 1H), 3.480 (q, J = 8.5 Hz,
1H), 2.904 (dd, J = 17.0, 3.5 Hz, 1H), 2.081 (t, J = 15.5 Hz, 1H),
2.631 (m, 2H), 2.066 (m, 2H), 1.909 (m, 2H),1.524 (s, 3H), 1.514
MHz) δ: 5.985 (s, 1H), 4.163 (q, J = 8.5 Hz, 1H), 4.154 (q, J =
8
3
2
1
.5 Hz, 1H), 3.872 (t, J = 6.5 Hz, 2H), 3.507 (q, J = 8.5 Hz, 1H),
.502 (q, J = 8.5 Hz, 1H), 2.818 (apparent t, J = 8.0 Hz, 2H),
.632 (m, 2H), 2.100 (m, 2H), 1.869 (m, 2H), 1.754 (m, 2H),
.491 (s, 3H), 1.485 (s, 3H), 1.446 (m, 2H), 1.327 (m, 4H), 1.052
1
3
C
(s, 3H), 1.079 (d, J = 7.0 Hz, 3H), 1.047 (d, J = 7.0 Hz, 3H).
NMR (CDCl ) δ: 172.03, 160.74, 156.15, 153.49, 108.42, 108.32,
3
99.28, 98.22, 96.12, 74.12, 73.86, 51.93, 47.54, 47.20, 35.87,
35.13, 23.10, 22.75, 18.88, 18.28, 15.96, 15.82. HREIMS m/z
404.1815 (calculated for C H O , 404.1814).
1
3
(d, J = 6.0 Hz, 3H), 1.023 (d, J = 6.0 Hz, 3H). C NMR
(CDCl ) δ: 156.37, 152.07, 151.43, 107.54, 107.32, 99.48, 98.9,
3
22 28
7
9
2
4
2.64, 74.04, 67.57, 47.65, 47.53, 35.37, 31.32, 29.68, 22.97,
2.74, 19.37, 18.72, 18.56, 16.09, 15.93, 13.86. HREIMS m/z
Xyloketal B Formamide (13). A mixture of compound 12 (105
mg, 0.26 mmol) and 5 mL of ammonia was stirred at 50 C for 6
o
30.2713 (calculated for C26
H
38
O
5
, 430.2714).
Xyloketal B Propargyl Ether (8). The title compound was
h and then poured into water. The aqueous layer was extracted
with Et O (3 ꢀ 20 mL). The combined organic extracts were
2
obtained from 3 and propargyl bromide with a procedure
similar to that for compound 4. Yield, 93.4%. H NMR
4
washed with saturated brine, dried over anhydrous MgSO , and
1
concentrated in vacuo. Purification by flash chromatograghy
using petroleum ether and ethyl acetate as the eluant afforded
the title compound (88.3 mg, 87.3%) as a light-yellow solid; mp
(
CDCl , 400 MHz) δ: 6.110 (s, 1H), 4.619(d, J = 2.5 Hz, 2H),
3
4
2
1
3
1
7
1
.160 (t, J = 8.0 Hz, 2H), 3.510 (t, J = 8.0 Hz, 2H), 2.831 (m,
H), 2.650 (m, 2H), 2.511 (t, J = 2.5 Hz, 1H), 2.121 (m, 2H),
.886 (m, 2H),1.400 (s, 3H), 1.489 (s, 3H), 1.050 (d, J = 7.0 Hz,
1
152-153 °C. H NMR (CDCl
(apparent q, J = 8.4 Hz, 2H), 3.556 (t, J = 8.4 Hz, 2H), 2.865
3
, 400 MHz) δ: 5.878 (s, 1H), 4.163
1
3
H), 1.037 (d, J = 7.0 Hz, 3H). C NMR (CDCl ) δ: 155.02,
(m, 2H), 2.637 (m, 2H), 2.099 (m, 2H), 1.938 (m, 2H), 1.556 (s,
3
1
3
52.14, 151.78, 107.65, 107.23, 100.18, 99.92, 93.28, 78.74, 75.28,
4.00, 56.01, 47.59, 47.49, 35.45, 35.35, 22.97, 22.73, 18.72,
8.56, 16.08, 15.86. HREIMS m/z 384.1929 (calculated for
3
3H), 1.509 (s, 3H), 1.069 (d, J = 6.0 Hz, 6H). C NMR (CDCl )
δ: 172.519, 161.804, 155.060, 151.387, 109.508, 108.217, 99.182,
97.708, 95.962, 74.319, 74.188, 47.399, 47.179, 35.446, 35.202,
23.091, 22.821, 18.585, 18.318, 16.052, 15.933. HREIMS m/z
C H O , 384.1931).
2
3
28
5
Xyloketal B Allenic Ether (9). The title compound was
obtained from 3 and 4-bromobuta-1,2-diene with a procedure
similar to that for compound 4. Yield, 87.8%; light-yellow solid;
27 6 1
389.1834 (calculated for C21H O N , 389.1833).
Preparation of Compound 14. The title compound was ob-
tained from 12 and methylamine with a procedure similar to that
1
mp 38-39 °C. H NMR (CDCl , 400 MHz) δ: 6.011 (s, 1H),
for compound 13. Yield, 90.8%; light-yellow solid; mp 53-54 °C.
3
1
5
(
.383 (tt, J = 6.8 Hz, 1H), 4.856 (dt, J = 6.4, 2.4 Hz, 2H), 4.488
dt, J = 6.8, 2.4 Hz, 2H), 4.181 (apparent t, J = 8.0 Hz, 2H),
3
H NMR (CDCl , 400 MHz) δ: 4.168 (t, J = 8.0 Hz, 2H), 3.547
(t, J = 8.0 Hz, 2H), 2.948 (q, J = 4.8 Hz, 3H), 2.860 (m, 2H),
2.629 (m, 2H), 2.085 (m, 2H), 1.935 (m, 3H), 1.536 (s, 3H), 1.509
3
2
.508 (m, 2H), 2.837 (dd, J = 17.6, 5.6 Hz, 2H), 2.645 (m, 2H),
.112 (m, 2H), 1.883 (m, 2H), 1.400 (s, 3H), 1.492 (s, 3H), 1.062
1
3
3
(s, 3H), 1.074 (d, J = 6.0 Hz, 6H). C NMR (CDCl ) δ: 170.914,
1
3
(
d, J = 6.8 Hz, 3H), 1.036 (d, J = 6.8 Hz, 3H). C NMR
CDCl ) δ: 209.17, 155.62, 152.11, 151.68, 107.55, 107.32, 99.81,
9.52, 93.19, 87.24, 76.46, 73.98, 65.72, 47.62, 47.53, 35.45,
5.36, 22.95, 22.71, 18.80, 18.63, 15.98, 15.74. HREIMS m/z
98.2087 (calculated for C24 , 398.2088).
Xyloketal B Cinnamyl Ether (10). The title compound was
161.186, 154.376, 150.838, 109.226, 108.135, 99.273, 97.367,
96.552, 74.310, 74.094, 47.450, 47.186, 35.529, 35.188, 26.066,
23.142, 22.842, 18.643, 18.357, 16.023, 15.903. HREIMS m/z
(
3
9
3
3
29 6 1
403.1987 (calculated for C22H O N , 403.1989).
H
30
O
5
Preparation of Compound 15. The xyloketal acid 11 (90 mg,
0.26 mmol) and HCl salt Ala-OMe (61.4 mg, 0.39 mmol) were
dissolved in 5 mL of CH Cl . This solution was treated with
obtained from 3 and cinnamyl bromide with a procedure similar
to that for compound 4. Yield, 94.4%; light-yellow solid; mp
2
2
BOP (174.9 mg, 0.39 mmol) and DIEA (107.7 μL, 6 mmol).
After being stirred at room temperature for 12 h, the reaction
mixture was then diluted with 100 mL of ethyl acetate. The
resultant solution was washed with a saturated aqueous solution
of ammonium chloride, brine, dried over anhydrous magnesium
sulfate, and concentrated in vacuo. Purification by flash chro-
matograghy using petroleum ether and ethyl acetate as the
1
5
2
6
0
7-58 °C. H NMR (CDCl , 400 MHz) δ: 7.414 (d, J = 7.2 Hz,
3
H), 7.321 (m, 2H), 7.247 (m, 2H), 6.715 (d, J = 16.0 Hz, 1H),
.408 (dt, J = 16.0, 5.6 Hz, 1H), 6.065 (s, 1H), 4.615 (dd, J = 5.6,
.8 Hz, 2H), 4.179 (apparent t, J = 8.4 Hz, 2H), 3.533 (apparent
t, J = 8.4 Hz, 2H), 2.858 (m, 2H), 2.677 (m, 2H), 2.130 (m, 2H),
1
3
1
1
3
4
.899 (m, 2H), 1.508 (s, 3H), 1.504 (s, 3H), 1.063 (d, J = 6.4 Hz,
1
3
H), 1.034 (d, J = 6.4 Hz, 3H). C NMR (CDCl
3
) δ: 155.85,
eluant afforded the title compound (113.1 mg, 91.6% yield) as
1
52.10, 151.50, 136.45, 132.53, 128.49, 127.75, 126.48, 124.68,
07.41, 107.31, 99.60, 99.39, 92.67, 73.98, 68.51, 47.55, 47.45,
5.31, 22.92, 22.68, 18.84, 18.52, 15.98, 15.71. HREIMS m/z
62.2403 (calculated for C H O , 462.2401).
a yellow solid; mp 42-43 °C. H NMR (CDCl , 400 MHz) δ:
3
4.696 (dt, J = 1.6, 7.2 Hz, 1H), 4.168 (apparent q, J = 8.4 Hz,
2H), 3.779 (s, 3H), 3.546 (apparent t, J = 8.4 Hz, 2H), 2.902
(apparent d, J = 17.0 Hz, 1H), 2.850 (apparent d, J = 17.0 Hz,
2
9
34
5