Synthesis and Activity of Dioxaspiro[5.5]undecanes
J . Org. Chem., Vol. 63, No. 3, 1998 477
(
CDCl
3
) 1.44 (1 H, ddd, J 11ax,11eq ) 13.5 Hz, J 11ax,10ax ) 13.5
18.1, 19.2, 24.9, 25.7, 30.9 (CH
59.9, 60.6 (CH , C-2, C-8), 69.8 (CH, C-5), 96.2 (C, C-6); MS
(CI, NH ) m/z 173 (M + H, 30). Anal. Calcd for C : C,
62.77; H, 9.36. Found: C, 62.83, H, 9.48.
2
, C-3, C-4, C-9, C-10, C-11),
Hz, J 11ax,10eq ) 4.7 Hz, 11ax-H), 1.50-1.81 (4 H, m, 9-, 10-CH
1
Hz, J 4eq,2 ) 1.0 Hz, 4eq-H), 2.00-2.03 (2 H, m, 11eq-H and
OH), 2.42 (1 H, dddd, J 4ax,4eq ) 17.4 Hz, J 4ax,5 ) 4.5 Hz, J 4ax,3
2
),
2
.91 (1 H, dddd, J 4eq,4ax ) 17.4 Hz, J 4eq,5 ) 4.0 Hz, J 4eq,3 ) 4.0
3
9 16 3
H O
[5S*,6S*]-1,7-Dioxa sp ir o[5.5]u n d ec-5-yl Aceta te (17).
Acetate 17 was prepared from alcohol 16 (4 mg, 0.02 mmol),
triethylamine (5 mg, 0.05 mmol), acetic anhydride (3 mg, 0.03
mmol), and 4-(dimethylamino)pyridine (1 mg) using the pro-
cedure described for acetate 14. Removal of the solvent under
reduced pressure gave a colorless oil that was purified by flash
chromatography using pentane-diethyl ether (9:1) as eluent
to afford acetate 17 (4 mg, 80%) as a colorless oil: IR (film)
)
2.5 Hz, J 4ax,2 ) 2.5 Hz, 4ax-H), 3.58 (1 H, ddd, J 5,OH ) 8.5
Hz, J 5,4ax ) 4.5 Hz, J 5,4eq ) 4.0 Hz, 5-H), 3.66 (1 H, dt, J 8eq,8ax
11.5 Hz, J 8eq,9 ) 1.9 Hz, 8eq-H), 3.79 (1 H, ddd, J 8ax,8eq
1.5 Hz, J 8ax,9ax ) 11.7 Hz, J 8ax,9eq 3.2 Hz, 8ax-H), 4.65-4.68
1 H, m, 3-H), 6.25 (1 H, br, d, J 2,3 ) 6.2 Hz, 2-H); 13C NMR
CDCl ) 17.9, 24.9 (CH , C-9, C-10), 25.8 (CH , C-4), 29.4 (CH
, C-8), 68.5 (CH, C-5), 96.9 (C, C-6), 98.6 (CH,
)
1
(
(
)
3
2
2
2
,
C-11), 61.8 (CH
C-3), 139.9 (CH, C-2); MS (EI) m/z 170 (M , 8). Anal. Calcd
for C : C, 63.51; H, 8.29. Found: C, 63.30, H, 8.19.
5S*,6S*]-1,7-Dioxa sp ir o[5.5]u n d ec-3-en -5-yl Aceta te
14). To a solution of [5S*,6S*]-alcohol 7 (22 mg, 0.13 mmol)
in dichloromethane (2 mL) was added triethylamine (26 mg,
.26 mmol), acetic anhydride (20 mg, 0.19 mmol), and 4-(dim-
2
+
-1 1
3031-2843 (CH), 1728 (CdO), 1213 (CO), 1034 (CO) cm ; Η
NMR (CDCl ) 1.23-2.06 (10 H, m, 3-, 4-, 9-, 10-, 11-CH ), 2.08
(3 H, s, Ac), 3.62-3.76 (4 H, m, 2-, 8-CH ), 4.68 (1 H, t, J 5,4
2.9 Hz, 5-H); 13C NMR (CDCl
) 18.0, 19.7, 23.6, 24.9, 31.4 (CH
C-3, C-4, C-9, C-10, C-11), 21.2 (CH , Ac), 59.9, 60.5 (CH , C-2,
C-8), 71.1 (CH, C-5), 94.8 (C, C-6), 170.4 (C, CdO); MS (CI,
NH ) m/z 215 (M + H, 100); HRMS calcd for C11 (M +
H) 215.1283, found 215.1290.
9
H
14
O
3
3
2
[
2
)
2
,
(
3
3
2
0
ethylamino)pyridine (3 mg). The reaction mixture allowed to
stand at room temperature for 1 h and then quenched with
water, extracted with dichloromethane, and dried over sodium
sulfate. Removal of the solvent under reduced pressure gave
a pale yellow oil that was purified by flash chromatography
using hexanes-ethyl acetate (9:1) as eluent to afford acetate
1
1
1
)
1
J
3
J
)
3
18 4
H O
[3S*,4S*,5S*,6S*]-3,4-Epoxy-1,7-dioxaspiro[5.5]undecan-5-
ol and [3R*,4R*,5S*,6S*]-3,4-Epoxy-1,7-dioxaspiro[5.5]undecan-
5-ol (9 and 18).
A solution of [5S*,6S*]-olefin 7 (1.15 g, 6.76 mmol) in dry
dichloromethane (50 mL) under a nitrogen atmosphere was
cooled to 0 °C in an ice/water bath. Sodium acetate (1.11 g,
13.53 mmol) was added, followed by m-chloroperoxybenzoic
acid (2.56 g, 50% w/w, 7.42 mmol) in five portions over 1 min.
The reaction mixture was allowed to warm to room temper-
ature and stirred for 72 h. After filtration through a short
Celite pad, the mixture was washed with sodium sulfite (10%
w/v), saturated sodium hydrogen carbonate, and water and
dried over sodium sulfate. Removal of the solvent under
reduced pressure gave a white solid that was purified by flash
chromatography using hexanes-ethyl acetate (6:4) as eluent
to afford [3S*,4S*,5S*,6S*]-epoxide 9 (1.16 g, 92%) as colorless
prisms: mp 129.5-131.5 °C; IR (Nujol) 3650-3100 (OH), 1270
4 (27 mg, 98%) as a colorless oil: IR (film) 2943-2870 (CH),
735 (CdO), 1081, 1046, 1025 (CO) cm-1; Η NMR (CDCl
)
3
1
.38 (1 H, ddd, J 11ax,11eq ) 12.7 Hz, J 11ax, 10ax ) 12.7 Hz, J 11ax,10eq
4.6 Hz, 11ax-H), 1.50-1.62 (3 H, m, 9-CH , 10-H), 1.73-
2
.85 (2 H, m, 11eq-H, 10-H′), 2.04 (3 H, s, Ac), 3.65 (1 H, ddd,
8ax,8eq ) 11.3 Hz, J 8ax,9ax ) 11.3 Hz, J 8ax,9eq ) 2.9 Hz, 8ax-H),
2
.71-3.75 (1 H, m, 8eq-H), 4.14 (2 H, m, 2-CH ), 4.85 (1 H, d,
5,4 ) 5.3 Hz, 5-H), 5.77-5.81 (1 H, m, 4-H), 6.03 (1 H, dt, J 3,4
1
3
10.2, J 3,2 ) 2.4 Hz, 3-H); C NMR (CDCl
3
) 17.9 (CH
2
, C-9),
, C-2),
2
6
1
0.9 (CH
2.7 (CH
30.8 (CH, C-3), 170.3 (C, CdO); MS (CI, NH
3
, Me), 24.8, 30.3 (CH , C-10, C-11), 60.1 (CH
2
2
2
, C-8), 67.7 (CH, C-5), 95.4 (C, C-6), 120.4 (CH, C-4),
) m/z 213 (M +
: C, 62.26; H, 7.60. Found:
3
H, 60). Anal. Calcd for C11
C, 61.97, H, 7.62.
16 4
H O
-
1 1
3
(CO), 1085 (CO), 885 (CO) cm ; Η NMR (CDCl ) 1.39 (1 H,
[
5S*,6S*]-1,7-Dioxa sp ir o[5.5]u n d ec-2-en -5-yl Aceta te
ddd, J 11ax,11eq ) 14.0 Hz, J 11ax,10ax ) 14.0 Hz, J 11ax,10eq ) 5.2
(
15). Acetate 15 was prepared from alcohol 13 (44 mg, 0.26
Hz, 11ax-H), 1.48-1.70 (4 H, m, 9-, 10-CH
2
), 1.87 (1 H, dt,
11eq,11ax ) 14.0 Hz, J 11eq,10 ) 2.8 Hz, 11eq-H), 2.37 (1 H, d,
OH,5 ) 11.1 Hz, OH), 3.34 (1 H, d, J 3,4 ) 3.4 Hz, 3-H), 3.47-
mmol), triethylamine (53 mg, 0.52 mmol), acetic anhydride (40
mg, 0.39 mmol), and 4-(dimethylamino)pyridine (3 mg) using
the procedure described for acetate 14. Removal of the solvent
under reduced pressure gave a pale yellow oil that was purified
by flash chromatography using hexanes-ethyl acetate (9:1)
as eluent to afford acetate 15 (47 mg, 86%) as a colorless oil:
IR (film) 3019-2850 (CH), 1727 (CdO), 1219 (CO) 1029 (CO)
J
J
3.58 (3 H, m, 4-H, 5-H, 8ax-H), 3.65-3.68 (1 H, m, 8eq-H),
3.82 (1 H, d, J 2eq,2ax ) 13.4 Hz, 2eq-H), 3.93 (1 H, d, J 2ax,2eq
13.4 Hz, 2ax-H); 13C NMR (CDCl
) 18.1, 24.8 (CH , C-9, C-10),
29.9 (CH , C-11), 51.2 (CH, C-4), 51.9 (CH, C-3), 57.3 (CH
C-2), 61.8 (CH , C-8), 65.7 (CH, C-5), 95.2 (C, C-6); MS (CI,
NH ) m/z 187, (M + H, 100). The structure of this compound
was also confirmed by X-ray crystallography. Anal. Calcd
for C : C, 58.06; H, 7.58. Found: C, 57.99, H,7.29.
)
3
2
2
2
,
2
-
1
1
cm ; Η NMR (CDCl
Hz, J 11ax,10ax ) 14.1 Hz, J 11ax,10eq ) 4.5 Hz, 11ax-H), 1.51-1.64
3 H, m, 9-CH and 10-H) 1.76-1.86 (2 H, m, 10-H′, 11eq-H),
.93 (1 H, dd, J 4eq,4ax ) 18.2, J 4eq,3 ) 4.1 Hz, 4eq-H), 2.05 (3 H,
s, Ac), 2.44 (1 H, dddd, J 4ax,4eq ) 18.2 Hz, J 4ax,5 ) 4.7 Hz, J 4ax,3
3
) 1.33-1.41 (1 H, ddd, J 11ax,11eq ) 14.1
3
1
2
(
1
2
9 14 4
H O
[3R*,4R*,5S*,6S*]-Epoxide 18 (75 mg, 6%) was also afforded
as a colorless oil: IR (film) 3650-3000, (OH), 2943, 2860 (CH),
-
1 1
)
2.3 Hz, J 4ax,2 ) 2.3 Hz, 4ax-H), 3.63-3.67 (1 H, m, 8eq-H),
1260 (CO), 1036 (CO), 907, 805 [CO (epoxide)] cm ; Η NMR
3
2
4
.77 (1 H, ddd, J 8ax,8eq ) 11.6 Hz, J 8ax,9ax ) 11.6 Hz, J 8ax,9eq
.9 Hz, 8ax-H), 4.69-4.71 (1 H, m, 3-H), 4.87 (1 H, d, J 5,4ax
)
)
(CDCl
3
2
) 1.48-1.83 (6 H, m, 9-, 10-, 11-CH ), 2.35 (1 H, d, J OH,5
) 6.8 Hz, OH), 3.22 (1 H, dd, J 3,2eq ) 3.0 Hz, J 3,4 ) 4.0 Hz,
.7 Hz, 5-H), 6.27 (1 H, dd, J 2,3 ) 5.2 Hz, J 2,4ax ) 2.3 Hz, 2-H);
3-H), 3.25 (1 H, d, J 4,3 ) 4.0 Hz, 4-H), 3.66 (1 H, d, J 5,OH ) 6.8
1
3
C NMR (CDCl
CH , Ac), 23.1 (CH
C, C-6), 98.7 (CH, C-3), 139.6 (CH, C-2), 170.4 (C, CdO); MS
3
) 17.8, 24.8, 30.8 (CH2, C-9, C-10, C-11), 21.1
2
Hz, 5-H), 3.70-3.77 (2 H, m, 8-CH ), 3.92 (1H, dd, J 2eq,2ax )
(
(
(
3
2
, C-4), 61.5 (CH , C-8), 69.4 (CH, C-5), 94.8
2
13.7 Hz, J 2eq,3 ) 3.0 Hz, 2eq-H), 4.07 (1 H, d, J 2ax,2eq ) 13.7
Hz, 2ax-H); 13C NMR (CDCl
) 17.9, 24.7, 26.3 (CH , C-9, C-10,
C-11), 49.3 (CH, C-3), 53.2 (CH, C-4), 60.2 (CH , C-2), 61.9
(CH , C-8), 68.9 (CH, C-5), 97.1 (C, C-6); MS (CI, NH ) m/z
: C, 58.06; H, 7.58.
3
2
+
EI) m/z 170 (M , 10). Anal. Calcd for C11
.60. Found: C, 62.21, H, 7.60.
5S*,6S*]-1,7-Dioxa sp ir o[5.5]u n d eca n -5-ol (16). To a
solution of [5S*,6S*]-alcohol 7 (10 mg, 0.06 mmol) in methanol
5 mL) was added 5% palladium on charcoal (2 mg) and
H
16
O
4
: C, 62.26; H,
2
7
2
3
[
9 14 4
187 (M + H, 100). Anal. Calcd for C H O
Found: C, 58.16; H,7.46.
(
[3R*,5S*,6S*]-1,7-Dioxaspir o[5.5]u n decan e-3,5-diol an d
[4S*,5S*,6S*]-1,7-Dioxaspir o[5.5]u n decan e-4,5-diol (10 an d
22). A solution of [3S*,4S*,5S*,6S*]-epoxide 9 (40 mg, 0.21
mmol) in dry tetrahydrofuran (3.0 mL) under a nitrogen
atmosphere was cooled to 0 °C in an ice/water bath. Lithium
aluminum hydride (35 mg, 0.92 mmol) was added in three
portions over 1 min, and the reaction mixture allowed to stir
at 0 °C for 1 h then room temperature for 12 h. After
quenching with sodium dihydrogen phosphate solution (10%
w/v), the reaction mixture was extracted with ethyl acetate,
and the combined extracts were washed with water and dried
over sodium sulfate. Removal of the solvent under reduced
potassium carbonate (20 mg, 0.14 mmol) and the reaction flask
was flushed with hydrogen. The reaction mixture was stirred
at room temperature under a hydrogen atmosphere for 6 h.
After filtration through a short Celite pad, the solvent was
removed at reduced pressure to give a colorless oil that was
purified by flash chromatography using pentane-diethyl ether
(9:1) as eluent to afford spiroacetal 16 (9 mg, 89%) as colorless
needles: mp 73-75 °C; IR (Nujol) 3620-3150 (OH), 1100,
1
3
050, 1040 (CO) cm-1; Η NMR (CDCl
-, 4-, 9-, 10-, 11-CH , OH), 3.42 (1 H, dt, J 5,OH ) 8.2 Hz, J 5,4
3
3.2 Hz, 5-H), 3.57-3.75 (4 H, m, 2-, 8-CH )
); 13C NMR (CDCl
1
) 1.33-2.10 (11 H, m,
3
2
)
2