Cha et al.
JOCArticle
EtOAc/Hex); IR (neat) νmax 3351, 2924, 2851, 1794, 1705, 1669,
1636, 1608, 1516, 1456, 1375, 1316, 1281, 1254, 1227, 1200, 1159,
1123, 1022, 987, 953, 856, 737, 631; 1H NMR (500 MHz; CDCl3)
δ 6.70 (d, J = 9.7 Hz, 1H), 6.23 (d, J = 9.8 Hz, 1H), 5.55 (s, 1H),
5.25 (m, 1H), 4.66 (m, 1H), 3.80 (s, 3H), 2.79 (t, J = 11.3 Hz,
1H), 2.44 (t, J = 11.7 Hz, 1H), 1.46 (s, 9H). 13C NMR (125 MHz;
CDCl3) δ 186.1, 174.5, 172.4, 171.3, 155.4, 142.6, 129.3, 101.9,
81.3, 56.6, 50.7, 38.6, 28.5; HRMS (ESI/TOF) calcd for
C15H19NO6Na [M þ Na]þ 332.1110, found 332.1104.
1H), 3.90 (dt, J = 9.7, 6.7, 1H), 3.79 (s, 1H), 3.49 (m, 1H), 3.26 (dd,
J = 16.8, 6.3, 1H), 3.00 (m, 1H), 2.60 (dd, J = 13.9, 9.9, 1H), 2.38
(m, 1H), 2.03 (m, 1H), 1.93 (m, 1H), 1.09 (m, 1H), 0.04 (s, 9H); 13
C
NMR (125 MHz; CDCl3) δ 194.4, 174.1, 170.6, 103.1, 77.8, 69.1,
58.3, 57.0, 49.8, 47.5, 47.1, 44.4, 39.5, 26.3, 24.3, 10.3, -1.8; HRMS
(ESI/TOF) calcd for C19H32N2O6SiSNa [M þ Na]þ 467.1648,
found 467.1629.
(2E,4E)-N-(6-Methoxy-2,8-dioxo-1-oxaspiro[4.5]deca-6,9-dien-
3-yl)-N-(2-(trimethylsilyl)ethylsulfonyl)hexa-2,4-dienamide (15). To
a solution of 13 (92 mg, 0.25 mmol, 1.0 equiv) in DCM were added
sorbyl chloride (0.061 mL, 0.50 mmol, 2.0 equiv) and DMAP
(153 mg, 1.25 mmol, 5.0 equiv) at rt. The resulting solution was
allowed to stir for 16 h, at which time the volatile material was
removed in vacuo. The crude residue was purified by flash chro-
matography (5% f 35% EtOAc/CH2Cl2) to provide 15 (94 mg,
80%) as an oil: Rf = 0.37 (35% EtOAc/Hex); IR (neat) νmax 2953,
2924, 2851, 1792, 1670, 1634, 1609, 1601, 1458, 1356, 1314, 1250,
1227, 1196, 1167, 1154, 1123, 1076, 1036, 1003, 928, 899, 856, 793,
758, 739, 696, 621; *this compound exhibited rotomers in the NMR
spectra which broadened several peaks, designated by **; 1H NMR
(500 MHz; CDCl3) δ7.44 (m, 1H), 6.94 (d, J=8.8Hz,1H),6.83(d,
J = 13.3 Hz, 1H), 6.30 (m, 2H), 6.21 (dd, J = 9.9, 1.5 Hz, 1H), 5.55
(d, J = 1.4 Hz, 1H), 5.20 (br s, 1H), 3.82 (s, 3H), 3.40 (m, 1H), 2.72
(m, 1H), 2.57 (m, 1H), 1.90 (d, J = 4.9 Hz, 3H), 1.18 (m, 2H), 0.08
(s, 9H); 13C NMR (125 MHz; CDCl3) δ 186.2, 172.6, 171.1, 166.2,
149.3, 143.2, 142.4, 130.2, 128.9, 117.3, 101.9, 76.7, 56.7, 56.1, 53.2,
35.7, 19.2, 10.1, -1.8; HRMS (ESI/TOF) calcd for C21H29NO7-
SiSNa [M þ Na]þ 490.1332, found 490.1322.
(6S)-N,7-Dimethoxy-N-methyl-9-oxo-2-(trifluoromethyl)-1-oxa-
3-azaspiro[5.5]undeca-2,7,10-triene-4-carboxamide (14). To a solu-
tion of PhI(OAc)2 (29 mg, 0.090 mmol, 1.5 equiv) in CH2Cl2
(3 mL) at rt was added TFA (10. μL, 0.13 mmol, 2.2 equiv). After
being stirred for 30 min, the solution was cannulated over to a
solution of 10 (21 mg, 0.060 mmol, 1.0 equiv) in CH2Cl2 (3 mL).
After being stirred for 10 min, the mixture was quenched with SiO2
and solid NaHCO3 and then filtered through a small pad of SiO2,
eluting with EtOAc. The solution was then concentrated in vacuo.
The crude oil was purified by flash chromatography (45% f 70%
EtOAc/Hex) to give 14 as an oil (10 mg, 48%, 4:1 dr). *Values for
the major diastereomer are listed: Rf = 0.36 (5% MeOH/CH2Cl2);
IR (neat) νmax 2942, 2853, 1701, 1670, 1638, 1605, 1458, 1437, 1364,
1341, 1298, 1225, 1215, 1154, 1094, 1065, 991, 964, 901, 855, 766;
1H NMR (500 MHz; CDCl3) δ6.59 (d, J = 10.0 Hz, 1H), 6.24 (dd,
J = 9.9, 1.6 Hz, 1H), 5.56 (d, J = 1.6 Hz, 1H), 4.97 (br s, 1H), 3.84
(s, 3H), 3.83 (s, 3H), 3.25 (s, 3H), 2.39 (t, J = 14.4 Hz, 1H), 2.09
(dd, J = 14.6, 5.3 Hz, 1H); 13C NMR (125 MHz; CDCl3) δ 185.7,
172.3, 142.9, 139.3, 129.6, 129.2, 103.1, 101.9, 73.4, 62.1, 56.7,
49.7, 32.7, 30.5; HRMS (ESI/TOF) calcd for C14H15N2O5F3Na
[M þ Na]þ 371.0831, found 371.0814.
(2E,4E)-N-(6-Hydroxy-8-methoxy-2-oxo-2H-chromen-3-yl)-
hexa-2,4-dienamide (16). To a stirred solution of 15 (30 mg, 0.06
mmol, 1.0 equiv) in DMF (2.0 mL) at rt was added in one portion
CsF (98 mg, 0.65 mmol, 10 equiv) and then H2O (0.2 mL). The
resulting solution was stirred for 6 h and then diluted with EtOAc
(15 mL). The organic solution was washed with brine (5 ꢀ 5 mL),
dried over Na2SO4, filtered, and concentrated in vacuo. The crude
residue was purified by flash chromatography with NEt3 doped
SiO2 (15% f 55% EtOAc/Hex) to give 16 as an oil (16 mg, 88%).
*Note: this compound is both light (ambient and UV) and acid
sensitive: Rf = 0.24 (35% EtOAc/Hex); IR (neat) νmax 3322, 3270,
3131, 3028, 2942, 2849, 1778, 1688, 1663, 1636, 1607, 1530, 1456,
1379, 1343, 1300, 1229, 1157, 1132, 1103, 1067, 1032, 995, 910, 856,
N-((3S,5S)-6-Methoxy-2,8-dioxo-1-oxaspiro[4.5]deca-6,9-dien-
3-yl)-2-(trimethylsilyl)ethanesulfonamide (13). To a solution of
PhI(OAc)2 (2.4 g, 7.5 mmol, 1.5 equiv) in CH2Cl2 (150 mL) at rt
was added TFA (0.86 mL, 11.2 mmol, 2.2 equiv). After being
stirred for 30 min, the solution was cannulated over to a solution of
11 (2.1 g, 5.0 mmol, 1.0 equiv) in CH2Cl2 (150 mL). After being
stirred for 10 min, the mixture was quenched with SiO2 (5 g) and
filtered through a small pad of SiO2, eluting with EtOAc. The
solution was then concentrated in vacuo. The crude oil was purified
by flash chromatography (45% f 70% EtOAc/Hex) to give 13 as
an oil (1.2 g, 64%, 5.5:1 dr): Rf = 0.28 (50% EtOAc/Hex); IR
(neat) νmax 3271, 2953, 2922, 2851, 1792, 1669, 1634, 1607, 1456,
1377, 1337, 1227, 1196, 1171, 1136, 1074, 1018, 990, 964, 858, 842,
797, 758, 739, 698, 629; *values for the major diastereomer are
listed; 1H NMR (400 MHz; CDCl3) δ 6.58 (d, J = 9.8 Hz, 1H),
6.27 (d, J = 9.9 Hz, 1H), 5.58 (s, 1H), 5.32 (d, J = 7.9 Hz, NH),
4.79 (ddd, J = 10.7, 9.3, 7.5 Hz, 1H), 3.83 (s, 3H), 3.17 (m, 2H),
2.94 (dd, J = 15.5, 7.5 Hz, 1H), 2.37 (dd, J = 15.8, 8.6 Hz, 1H),
1.12 (m, 2H), 0.09 (s, 9H); 13C NMR (125 MHz; CDCl3) δ 185.9,
174.3, 170.7, 141.9, 129.8, 102.1, 76.5, 56.9, 52.7, 51.4, 40.0, 10.7,
-1.8; HRMS (ESI/TOF) calcd for C15H23NO6SiSNa [M þ Na]þ
396.0913, found 396.0907.
(2S,3aS,7aR)-3a-Hydroxy-4-methoxy-2-(pyrrolidine-1-carbonyl)-
1-(2-(trimethylsilyl)ethylsulfonyl)-3,3a,7,7a-tetrahydro-1H-in-
dol-6(2H)-one (18). To a solution of dienone 13 (20 mg, 0.05 mmol,
1.0 equiv) in CH2Cl2 (2.5 mL) at 0 °C was added pyrrolidine
(10. μL, 0.12 mmol, 2 equiv). The yellow solution was allowed to stir
for 2 h at rt and then diluted with EtOAc (10 mL) and satd NH4Cl
(10 mL). The layers were separated, and the aqueous layer was
extracted with EtOAc (3 ꢀ 5 mL). The combined organic layers
were washed with brine (1 ꢀ 15 mL), dried over Na2SO4, filtered,
and concentrated in vacuo. The crude residue was purified by flash
chromatography (0% f 15% MeOH/CH2Cl2) to provide 18
(15 mg, 67%) as an oil: Rf = 0.5 (20% acetone/CH2Cl2); IR (neat)
1
779, 731, 648; H NMR (500 MHz; CDCl3) δ 7.79 (s, 1H), 7.35
(m, 1H), 7.17 (s, 1H), 6.33 (m, 2H), 6.24 (m, 2H), 5.95 (d, J=14.8,
1H), 5.68 (d, J=1.2, 1H), 3.73 (s, 3H), 1.89 (d, J=4.6, 3H); 13C
NMR (125 MHz; CDCl3) δ 186.0, 169.5, 167.6, 165.0, 145.2, 141.3,
139.1, 130.6, 129.6, 127.8, 127.2, 126.1, 119.3, 103.7, 56.6, 19.0;
HRMS (ESI/TOF) calcd for C16H15NNaO5 [M þ Na]þ 324.0848,
found 324.0842.
(S)-Methyl 3-(4-Hydroxy-2-methoxyphenyl)-2-((2E,4E)-5-(tr-
imethylsilyl)penta-2,4-dienamido)propanoate (22). To a solution of
8 (2.8 g, 6.6 mmol, 1.0 equiv) in CH2Cl2 (60 mL) was added TFA
(20 mL). The solution was stirred at rt for 24 h and concentrated in
vacuo using a water aspirator. The crude residue was azeotroped
with hexanes (3 ꢀ 50 mL) and placed under high vacuum
(0.03 mmHg) for 3 h. The resulting crude trifluoroacetate salt
was redissolved in DMF (7 mL), and to this was added a solution
of acid 20 (1.46 g, 8.56 mmol, 1.3 equiv) in DMF (7 mL), EDCI
(1.64 g, 8.57 mmol, 1.3 equiv), and then NEt3 (4.6 mL, 33 mmol, 5.0
equiv). The resulting solution was stirred for 16 h at rt and then
partitioned between EtOAc (50 mL) and brine (50 mL). The layers
were separated, and the organic layer was washed with brine (3 ꢀ
25 mL), satd NH4Cl (3 ꢀ 25 mL), satd NaHCO3 (3 ꢀ 25 mL), H2O
(2 ꢀ 25 mL), and brine (1 ꢀ 50 mL). The solution was then dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (30% f 45% EtOAc/Hex) to
give 22 (1.69 g, 68%) as a white solid: mp 202-204 °C; Rf = 0.41
(50% EtOAc/Hex); IR (neat) νmax 3295, 2953, 1744, 1732, 1657,
1651, 1615, 1582, 1557, 1537, 1512, 1470, 1454, 1435, 1366, 1348,
νmax 3194, 3094, 2953, 2924, 2851, 1728, 1661, 1622, 1615, 1456, 1424,
1339, 1289, 1251, 1250, 1229, 1211, 1167, 1148, 1132, 1094, 1046,
1036, 978, 860, 843, 741, 702; 1H NMR (500 MHz; CDCl3) δ 7.79
(s, 1H), 5.42 (s, 1H), 4.92 (d, J = 9.1, 1H), 4.33 (dd, J = 11.4, 6.3,
1368 J. Org. Chem. Vol. 76, No. 5, 2011