Synthesis of Bridged Azabicyclic Structures
hexanes to give 22 in 84% yield as a clear, colorless oil: 1H
NMR (500 MHz, DMSO-d6, 100 °C) δ 7.38-7.28 (comp, 5 H),
6.12 (app t, J ) 1.1 Hz, 2 H), 5.11 (s, 2 H), 4.47 (br s, 2 H),
1.71 (dtt, J ) 17.1, 12.5, 5.5 Hz, 1 H), 1.61 (app tdd, J ) 12.5,
5.1, 3.0 Hz, 2 H), 1.44-1.39 (m, 1 H), 1.32-1.28 (comp, 2 H);
13C NMR (125 MHz, DMSO-d6, 100 °C) δ 151.3, 136.7, 129.8,
127.7, 127.1, 126.8, 65.2, 57.7, 22.9, 15.3; IR (CHCl3) 3019,
1731, 1694, 1521, 1425 cm-1; MS (CI) m/z 244.1333 [C24H24N2O2
(M + 1) requires 244.1338], 136, 244 (base), 272.
3-Oxo-8-a za bicyclo[3.2.1]oct-6-en e-8-ca r boxylic Acid
P h en ylm eth yl Ester (30a ). The RCM of 29a was performed
on a scale of 0.35 mmol according to Method A, and the crude
product was purified by flash chromatography eluting with
15%-30% EtOAc/hexanes to give 30a in 92% yield as a clear,
colorless oil: 1H NMR (500 MHz, DMSO-d6, 100 °C) δ 7.39-
7.29 (comp, 5 H), 6.30-6.27 (m, 2 H), 4.79 (app ddt, J ) 4.4,
1.2, 0.8 Hz, 2 H), 2.64 (dd, J ) 16.5, 4.4 Hz, 2 H), 2.28 (ddd, J
) 16.5, 1.5, 1.2 Hz, 2 H); 13C NMR (125 MHz, DMSO-d6, 100
°C) δ 203.9, 151.7, 136.2, 133.3, 127.8, 127.3, 127.0, 65.9, 55.7,
44.7; IR (CHCl3) 3026, 3011, 2960, 1701, 1422 cm-1; MS (CI)
m/z 258.1128 [C15H15NO3 (M + 1) requires 258.1130], 214, 242,
258 (base).
143.1, 136.3, 127.8, 127.3, 127.0, 126.5, 65.8, 58.7, 55.9, 43.9,
43.6, 12.6; IR (CHCl3) 3019, 2960, 1700, 1422 cm-1; MS (CI)
m/z 272.1293 [C16H17NO3 (M + 1) requires 272.1287], 272
(base), 228, 129.
3-Oxo-8-azabicyclo[3.2.1]oct-6-en e-2,8-dicar boxylic Acid
2-Meth yl Ester 8-P h en ylm eth yl Ester (32). The RCM of
31 was performed according to Method B, and the crude
product was purified by flash chromatography eluting with
30% EtOAc/hexanes to give 32 in 86% yield as a clear, colorless
oil and as an undetermined mixture of diastereomers epimeric
at C(2): 1H NMR (500 MHz, DMSO-d6, 50 °C) δ 7.41-7.31
(comp, 5 H), 6.41-6.33 (comp, 2 H), 5.16-4.79 (comp, 4 H),
3.85 (d, J ) 3.6 Hz, 0.5 H), 3.65 (s, 1.6 H), 3.50 (br s, 1.4 H),
3.40 (s, 0.5 H), 2.78 (dd, J ) 13.6, 4.3 Hz, 0.5 H), 2.75 (dd, J
) 13.6, 4.3 Hz, 0.5 H), 2.38 (d, J ) 16.0 Hz, 0.5 H), 2.29 (dd,
J ) 16.0, 1.4 Hz, 0.5 H); 13C NMR (125 MHz, DMSO-d6, 50
°C) δ 200.9, 200.2, 168.0, 167.7, 151.6, 136.3, 135.9, 134.7,
132.6, 132.5, 128.5, 128.21, 128.18, 127.8, 127.7, 127.5, 127.3,
66.4, 66.2, 61.4, 61.3, 59.1, 58.9, 57.5, 56.5, 56.0, 52.0, 51.6,
44.0, 43.4; IR (CHCl3) 3020, 2955, 1741, 1705, 1425 cm-1; MS
(CI) m/z 316.1192 [C17H17NO5 (M + 1) requires 316.1185], 316,
272 (base), 240.
2-Meth yl-7-oxo-9-a za bicyclo[3.3.1]n on -2-en e-9-ca r box-
ylic Acid P h en ylm eth yl Ester (30b). The RCM of 29b was
performed on a scale of 0.13 mmol according to Method C, and
the crude product was purified by flash chromatography
eluting with 20%-40% EtOAc/hexanes to give 30b in 84%
yield as a clear, colorless oil: 1H NMR (500 MHz, DMSO-d6,
100 °C) δ 7.42-7.29 (comp, 5 H), 5.40-5.39 (m, 1 H), 5.19 (d,
J ) 12.6 Hz, 1 H), 5.16 (d, J ) 12.6 Hz, 1 H), 4.78 (t, J ) 7.3
Hz, 1 H), 4.63 (d, J ) 4.5 Hz, 1 H), 2.68 (dd, J ) 15.6, 7.3 Hz,
1 H), 2.60 (dd, J ) 14.7, 4.5 Hz, 1 H), 2.55-2.45 (m, 1 H), 2.33
(app dt, J ) 14.7, 1.9 Hz, 1 H), 2.12 (app dt, J ) 15.6, 1.5 Hz,
(6S,10S)-6,7,10,11-Tetr a h yd r o-6,10-im in o-5H-cyclooct-
[b]in d ole-12-ca r boxylic Acid P h en ylm eth yl Ester (43). A
solution of 42 (57 mg, 0.15 mmol) and 9 (12.6 mg, 0.0153 mmol)
in CH2Cl2 (1.5 mL) was stirred at room temperature for 1 h.
The reaction was concentrated under reduced pressure, and
the crude product was purified by flash chromatography
eluting with 30% EtOAc/hexanes to give 43 in 99% yield as a
white solid: mp 66-68 °C; 1H NMR (500 MHz, DMSO-d6, 100
°C) δ 10.5 (br s, 1 H), 7.30 (d, J ) 4.5 Hz, 1 H), 7.29 (d, J ) 8.0
Hz, 1 H), 7.35-7.28 (comp, 5 H), 7.03 (app td, J ) 7.3, 1.2 Hz,
1 H), 6.95 (app td, J ) 7.3, 1.0 Hz, 1 H), 5.80-5.77 (m, 1 H),
5.65 (dd, J ) 10.0, 5.2 Hz, 1 H), 5.43 (d, J ) 5.6 Hz, 1 H), 5.16
(d, J ) 12.7 Hz, 1 H), 5.11 (d, J ) 12.7 Hz, 1 H), 4.97 (br t, J
) 5.3 Hz, 1 H), 2.99 (dd, J ) 15.5, 5.3 Hz, 1 H), 2.65 (ddd, J
) 17.6, 5.6, 2.2 Hz, 1 H), 2.63 (dd, J ) 15.5, 0.9 Hz, 1 H), 2.17
(dd, J ) 17.6, 5.2 Hz, 1 H); 13C NMR (125 MHz, DMSO-d6,
100 °C) δ 153.2, 136.4, 135.4, 134.1, 127.9, 127.8, 127.2, 126.9,
126.4, 123.2, 120.2, 118.0, 116.9, 110.6, 104.6, 65.9, 47.1, 45.6,
29.4, 24.8; IR (CHCl3) 3018, 1694, 1428 cm-1; MS (CI) m/z
345.1597 [C22H20N2O2 (M + 1) requires 345.1603], 301, 345
(base).
(6S,10S)-6,7,10,11-Tetr a h yd r o-9-eth en yl-6,10-im in o-5H-
cyclooct[b]in d ole-12-ca r boxylic Acid P h en ylm eth yl Es-
ter (46). A solution of 45 (233 mg, 0. 63 mmol) and 9 (52 mg,
0.0629 mmol) in CH2Cl2 (6.3 mL) was stirred under an
atmosphere of ethene at room temperature for 1.5 h. The
reaction was concentrated under reduced pressure, and the
crude product was purified by flash chromatography eluting
with 20% EtOAc/hexanes to give 227 mg (97%) of 46 as a white
solid: mp 73-75 °C; 1H NMR (500 MHz, DMSO-d6, 100 °C) δ
10.55 (br s, 1 H), 7.35-7.28 (comp, 7 H), 7.03 (ddd, J ) 8.2,
7.1, 1.2 Hz, 1 H), 6.94 (ddd, J ) 7.9, 7.1, 1.0 Hz, 1 H), 6.23
(dd, J ) 17.9, 11.1 Hz, 1 H), 5.72 (dd, J ) 5.3, 1.9 Hz, 1 H),
5.47 (d, J ) 5.7 Hz, 1 H), 5.28 (d, J ) 17.9 Hz, 1 H), 5.27 (d,
J ) 5.8 Hz, 1 H), 5.18 (d, J ) 12.7 Hz, 1 H), 5.14 (d, J ) 12.7,
1 H), 5.07 (d, J ) 11.1 Hz, 1 H), 3.08 (dd, J ) 15.5, 5.8 Hz, 1
H), 2.78 (br dd, J ) 18.5, 5.7 Hz, 1 H), 2.77 (dd, J ) 15.5, 1.0
Hz, 1 H), 2.32 (dd, J ) 18.5, 5.3 Hz, 1 H); 13C NMR (125 MHz,
DMSO-d6, 100 °C) δ 153.2, 136.4, 136.1, 136.0, 135.5, 133.6,
127.7, 127.2, 126.8, 126.2, 124.9, 120.3, 118.0, 116.9, 111.3,
110.6, 104.9, 66.0, 46.6, 45.3, 30.9, 24.6; IR (film) 3397, 3031,
2894, 1681, 1430, 1317, 1099, 1049, 742 cm-1; MS (CI) m/z
371.1757 [C24H22N2O2 (M + 1) requires 371.1760], 279, 327,
371 (base), 399.
1 H), 1.94 (dd, J ) 18.0, 4.9 Hz, 1 H), 1.63-1.62 (m, 3 H); 13
C
NMR (125 MHz, DMSO-d6, 100 °C) δ 205.4, 153.2, 136.3, 133.8,
127.8, 127.2, 126.9, 118.2, 66.1, 51.4, 45.9, 45.8, 42.2, 30.0, 19.2;
IR (CHCl3) 2917, 1695, 1449, 1427, 1321 cm-1; MS (CI) m/z
286.1445 [C17H19NO3 (M + 1) requires 286.1443], 194, 224, 242
(base), 286, 314, 326.
2,3-Dim eth yl-7-oxo-9-a za bicyclo[3.3.1]n on -2-en e-9-ca r -
boxylic Acid P h en ylm eth yl Ester (30c). A solution of 29c
(17 mg, 0.052 mmol) and catalyst 10 (3.6 mg, 0.0043 mmol) in
toluene (4.3 mL) was stirred at 100 °C in a sealed vial for 2 h.
Another portion of catalyst 10 (1.8 mg, 0.0021 mmol) was
added, and stirring was continued at 100 °C for 2 h. Additional
catalyst 10 (1.8 mg, 0.0021 mmol) was added, and stirring was
continued at 100 °C for 15 h. The solvent was removed under
reduced pressure, and the crude product was purified by flash
chromatography eluting with 20%-30% EtOAc/hexanes to give
11 mg (75%) of 30c as a clear, colorless oil: 1H NMR (500 MHz,
DMSO-d6, 100 °C) δ 7.42-7.29 (comp, 5 H), 5.18 (d, J ) 12.6
Hz, 1 H), 5.16 (d, J ) 12.6 Hz, 1 H), 4.77 (t, J ) 7.1 Hz, 1 H),
4.58 (d, J ) 4.5 Hz, 1 H), 2.66 (dd, J ) 15.6, 7.1 Hz, 1 H), 2.56
(dd, J ) 14.6, 4.5 Hz, 1 H), 2.53-2.48 (m, 1 H), 2.31 (ddd, J )
14.6, 2.0, 1.8 Hz, 1 H), 2.12 (ddd, J ) 15.6, 1.8, 1.5 Hz, 1 H),
1.84 (d, J ) 17.6 Hz, 1 H), 1.58 (s, 3 H), 1.55 (s, 3 H); 13C NMR
(125 MHz, DMSO-d6, 100 °C) δ 205.6, 153.1, 136.3, 127.8,
127.2, 126.9, 125.8, 123.4, 66.1, 52.0, 46.7, 45.9, 42.5, 35.9, 17.2,
15.2; IR (CHCl3) 2914, 1695, 1430, 1331 cm-1; MS (CI) m/z
300.1609 [C18H21NO3 (M + 1) requires 300.1600], 208, 256
(base), 300, 328, 340.
6-Meth yl-3-oxo-8-azabicyclo[3.2.1]oct-6-en e-8-car boxyl-
ic Acid P h en ylm eth yl Ester (30d ). The RCM of 29d was
performed on a scale of 0.33 mmol according to Method C, and
the crude product was purified by flash chromatography
eluting with 20% EtOAc/hexanes to give 30d in 92% yield as
a clear, colorless oil: 1H NMR (500 MHz, DMSO-d6, 100 °C) δ
7.38-7.29 (comp, 5 H), 5.83 (app dq, J ) 3.5, 1.7 Hz, 1 H),
5.16 (s, 2 H), 4.70 (br s, 1 H), 4.52 (d, J ) 4.2 Hz, 1 H), 2.62
(dd, J ) 16.6, 4.2 Hz, 1 H), 2.58 (dd, J ) 16.5, 4.3 Hz, 1 H),
2.38 (d, J ) 16.6 Hz, 1 H), 2.22 (d, J ) 16.5 Hz, 1 H), 1.78 (s,
3 H); 13C NMR (125 MHz, DMSO-d6, 100 °C) δ 204.1, 151.6,
(6S,10S)-6,7,10,11-Tetr a h yd r o-9-for m yl-6,10-im in o-5H-
cyclooct[b]in d ole-12-ca r boxylic Acid P h en ylm eth yl Es-
ter (47). A solution of 46 (100 mg, 0.27 mmol) in t-BuOH (3.5
mL) was added to a slurry of K3FeCN6 (267 mg, 0.81 mmol),
K2CO3 (112 mg, 0.81 mmol), K2OsO2(OH)4 (2 mg, 0.0054
mmol), and (DHQ)2PHAL (21 mg, 0.027 mmol) in H2O (2.5 mL)
J . Org. Chem, Vol. 68, No. 23, 2003 8877