Notes
J . Org. Chem., Vol. 64, No. 17, 1999 6521
and 5.06 (t, 1H, J ) 1.4); 13C NMR δ 17.5, 19.1, 25.2, 25.6, 29.8,
30.2, 32.2, 36.4, 68.9, 94.0, 124.3, and 131.3; EI/MS 210 (M+,
34) and 109 (100). Anal. Calcd for C13H25NO4: C, 60.21; H, 9.72.
N, 5.40. Found: C, 59.88; H, 9.64; N, 5.40.
123.1, 124.3, 125.8, 131.4, 135.7, and 161.2; EI/MS 275 (M+, 100);
HRMS calcd for M+ (C17H25NO2) 275.1885, found 275.1884.
E t h yl 4-(3,7-d im et h yloct -2-en yl)p yr r ole-2-ca r b oxyla t e
(11b) was obtained in 61% yield from the reaction of 10b in the
presence of DBU in THF: IR (NaCl) 3312 and 1682 cm-1; yellow
oil; 1H NMR δ 1.91 (d, 3H, J ) 6.10), 1.30 (m, 2H, 2H and 1H),
1.35 (t, 3H, J ) 7.17), 1.60 (s, 3H), 1.68 (s, 3H), 1.96 (m, 2H),
2.47 (m, 2H), 4.30 (q, 2H, J ) 7.0), 5.09 (m, 1H), 6.73 (d, 1H,
J ) 3.7), 6.75 (d, 1H, J ) 2.1), and 9.62 (br s, 1H); 13C NMR δ
14.3, 17.5, 19.3, 24.0, 25.3, 31.8, 36.8, 38.1, 60.0, 114.7, 120.4,
124.3, 124.8, 126.6, 130.9, and 161.2; EI/MS 277 (M+, 48) and
153 (100); HRMS calcd for M+ (C17H27NO2) 277.2042, found
277.2027.
(2R*,3R*)- a n d (2R*,3S*)-6,10-Dim eth yl-3-n itr od eca -5,9-
d ien -2-ol (8c). To a stirred solution of nitro compound 6 (3.39
g, 17.18 mmol) and distilled acetaldehyde (1.14 mL, 11.4 mmol)
was added Amberlyst A21 (4 g) at 0 °C. After 16 h the reaction
mixture was filtrated through a Celite pad and washed with
hexane (3 × 10 mL). The hexane layer was washed with water
(2 × 10 mL) and brine (20 mL), dried over Na2SO4, and
concentrated. The residue was purified by column chromatog-
raphy on silica gel (10% EtOAc/hexane). The title compound 8c
was obtained (2.36 g, 57%): colorless oil; IR (NaCl) 341.5, 1552,
1450, and 1376 cm-1; 1H NMR δ 1.30 (m, 3H), 1.59 (s, 3H), 1.62
(s, 3H), 1.68 (s, 3H), 2.03 and 2.25 (m, 4H), 2.5 and 2.77 (m,
2H), 4.13 and 2.23 (m, 1H), 4.39 (m, 1H), and (m, 2H); 13C NMR
δ 16.1, 17.7, 19.1, 19.9, 25.6, 29.3, 39.6, 67.8, 93.5, 116.5, 123.7,
131.8, and 140.8. Anal. Calcd for C13H23NO‚(1/2)H2O: C, 64.43;
H,9.98; N, 5.78. Found: C, 63.98; H, 9.56; N, 5.75.
Eth yl 3-m eth yl-4-(3,7-d im eth ylocta -2,6-d ien yl)p yr r ole-
2-ca r boxyla te (11c) was obtained in 60% yield from the
reaction of 10c in the presence of DBU in THF: yellow oils; IR
(NaCl) 3322 and 1670 cm-1 1H NMR δ 1.35 (t, 3H, J ) 7.2),
;
1.60 (s, 3H), 1.68 (s, 3H), 1.72 (s, 3H), 2.08 (m, 4H), 2.28 (s, 3H),
3.11 (d, 2H, J ) 7.3), 4.31 (q, 2H, J ) 14.6, 7.3), 5.10 (m, 1H),
5.26 (m, 1H), 6.63 (s, 1H), and 8.75 (br s, 1H); 13C NMR δ 10.3,
14.5, 16.0, 17.7, 23.9, 25.7, 26.6, 39.6, 59.8, 119.7, 122.7, 123.4,
124.2, 124.3, 125.0, 131.4, 135.6, and 161.8; EI/MS 289 (M+, 86)
and 174 (100); HRMS calcd for M+ (C18H27NO2) 289.2042, found
289.2034.
(E)-5,9-Dim eth yl-2-n itr od eca -4,8-d ien yl Aceta te (10a ). To
a stirred solution of nitroalcohol 8a (2.68 g, 11.69 mmol) in acetic
anhydride (12 mL) was added pyridine (0.95 mL, 11.69 mmol)
with cooling to 0 °C. After the reaction mixture was stirred at
rt for 2 h, aqueous saturated NaHCO3 (20 mL) and hexane (20
mL) were added. The mixture was extracted with hexane (2 ×
10 mL). The combined organic layers were washed with water
(2 × 10 mL) and brine (20 mL), dried over Na2SO4, and
concentrated to give 3.04 g of the crude 10a in 98% yield: orange
(E)-4-(3,7-Dim et h yloct a -2,6-d ien yl)p yr r ole-2-ca r b oxyl-
ic Acid (12a , P yr r olosta tin ). To lithium hydroxyde monohy-
drate (0.35 g, 8.57 mmol) in water (4.5 mL) was added ethyl
pyrrole-2-carboxylate 10a (2.36 g, 8.57 mmol) in dioxane (4.5
mL), and the resulting mixture was warmed at 40 °C under a
nitrogen atmosphere. The solution was stirred for 19 h, and then
buffer solution (pH 3.5), diethy ether, and NaCl were added. The
aqueous layer was extracted with diethyl ether (10 mL). The
organic layer was washed with water (2 × 20 mL) and saturated
brine (50 mL) and dried with Na2SO4. After evaporation of the
solvent, the residue was purified by recrystallization from diethyl
ether/hexane to give 1.55 g of pyrrolostatin (12a ) in 73% yield
as a pale yellow crystal: mp 117-119 °C; IR (KBr) 3353, 2917,
1
liquids; H NMR δ 1.59 (s, 3H), 1.62 (s, 3H), 1.68 (s, 3H), 2.03
(m, 4H), 2.06 (s, 3H), 2.54 and 2.69 (m, 2H), 4.42 (m, 2H), 4.68
(m, 1H), and 5.09 (m, 2H); EI/MS 269 (M+, 0.5) and 109 (100).
This material was used for the next step without further
purification.
(2R*,5R*)- a n d (2R*,5S*)-5,9-Dim et h yl-2-n it r od eca -8-
en yl a ceta te (10b) was obtained in 98% yield from the reaction
of 9b and acetic anhydride in the presence of pyridine: yellow
oil; IR (NaCl) 1714, 1532, and 1370; EI/MS 271 (M+, 2) and 109
(100). This material was used for the next step without further
purification.
(2R*,3R*)- a n d (2R*,3S*)-6,10-Dim eth yl-3-n itr od eca -5,9-
d ien -2-yl a ceta te (10c) was obtained in 98% yield from the
reaction of 9c and acetic anhydride in the presence of pyridine:
yellow oil; 1H NMR δ 1.33 (m, 3H), 1.56 (s, 3H), 1.59 (s, 3H),
1.68 (s, 3H), 2.22 (m, 4H), 2.08 (s, 3H), 2.48 and 2.69 (m and m,
2H), 4.52 and 4.63 (m and m, 1H), 5.03 (m, 2H), and 5.26 (m,
1H). This material was used for the next step without further
purification.
and 1686 cm-1 1H NMR δ 1.59 (s, 3H), 1.66 (s, 3H), 1.67 (s,
;
3H), 2.07 (m, 4H), 3.15 (d, 2H, J ) 6.84), 5.10 (m, 1H), 5.31 (m,
1H), 6.65 (d, 1H, J ) 1.5), and 6.69 (d, 1H, J ) 1.0); 13C NMR δ
16.0, 17.7, 25. 2, 25.7, 26.6, 39.6, 116.8, 121.4, 121.9, 122.8, 124.2,
126.4, 131.4, 135.9, and 165.2; EI/MS 257 (M+, 52) and 69 (100).
Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; O, 5.66. Found:
C, 72.68; H, 8.48; O, 5.70. 12b and 12c were obtained by the
same procedure.
4-(3,7-Dim et h yloct a -2-en yl)p yr r ole-2-ca r b oxylic a cid
(12b): mp 115-117 °C; IR (KBr) 3372 and1688 cm-1; 1H NMR
δ 0.92 (d, 3H, J ) 6.35), 1.18 (m, 2H), 1.45 (m, 1H and 2H), 1.60
(s, 3H), 1.68 (s, 3H), 1.98 (m, 2H), 2.48 (m, 2H), 5.10 (t, 1H, J )
6.9), 6.80 (s, 1H), 6.90 (s, 1H), 9.15 (br s, 1H), and 11.00 (br s,
1H); 13C NMR δ 17.7, 24.2, 25.8, 32.0, 37.0, 38.2, 117.0, 121.3,
Eth yl 4-(3,7-Dim eth ylocta -2,6-d ien yl)p yr r ole-2-ca r box-
yla te (11a ). To a stirred solution of â-nitro acetate 10a (3.04 g,
11.29 mmol) in anhydrous 1:1 THF/tBuOH (28 mL) were added
dropwise ethyl isocyanoacetate (1.23 mL, 11.29 mmol) and DBU
(3.38 mL, 22.58 mmol) with cooling to 0 °C, and the resulting
mixture was stirred for 26 h. Then water (30 mL) and EtOAc
(30 mL) were added. The mixture was extracted with EtOAc
(2 × 20 mL). The combined organic layer was washed with water
(2 × 20 mL) and brine (30 mL), dried over Na2SO4, and
concentrated. The residue was purified by column chromatog-
raphy on silica gel (10%, EtOAc/hexane) to give 2.36 g of 11a in
122.0, 124.9, 127.6, 131.1, and 165.3. Anal. Calcd for C15H23
-
NO2: C, 72.25; H, 9.30; N, 5.62. Found: C, 72.20; H, 9.11; N,
5.66.
3-Met h yl-4-(3,7-d im et h yloct a -2,6-d ien yl)p yr r ole-2-ca r -
boxylic a cid (12c): mp 121-122 °C; IR (KBr) 3367, 2968, 2858,
2632, 1678, 1469, 1332, and 1394 cm-1; 1H NMR δ 1.60 (s, 3H),
1.68 (s, 3H), 2.06 (m, 4H), 2.31 (s, 3H) 3.12 (d, 2H, J ) 7.0), 5.10
(m, 1H), 5.26 (t, 1H, J ) 6.1), 6.70 d, 1 H, J ) 3.1), and 8.80 (br
s, 1H); 13C NMR δ, 10.3, 16.0, 17.6, 17.7, 23.4, 23.7, 23.9, 25.7,
26.5, 26.6, 32.0, 39.7, 118.5, 121.2, 122.5, 123.2, 124.2, 124.3,
125.5, 128.2, 131.4, 135.9, and 166.4; EI/MS 261 (M+, 100) and
148 (94). Anal. Calcd for C16H23NO2‚(1/2)H2O: C, 73.20; H, 9.20;
N, 5.34. Found: C, 72.80; H, 8.90; N, 5.36.
1
18% yield: yellow oil; IR (NaCl) 3315 and 1681 cm-1; H NMR
δ 1.32 (t, 3H, J ) 7.1), 1.57 (s, 3H), 1.61 (s, 3H), 1.68 (s, 3H),
2.10 (m, 4H), 3.18 (d, 2H, J ) 7.1), 1.57 (s, 3H), 1.61 (s, 3H),
1.68 (s, 3H), 2.10 (m, 4H), 3.18 (d, 2H, J ) 7.3), 4.30 (q, 2H, J )
7.3), 5.10 and 5.33 (dd, dd, 1H, 1H, J ) 7.3, 7.6, and J ) 7.3,
5.3), 6.74 (s, 1H), 6.74 (s, 1H), and 8.87 (br s, 1H); 13C NMR δ
14.5, 16.0, 17.7, 25.3, 25.4, 26.6, 39.6, 60.2, 114.78, 120.4, 120.7,
J O990666F