6
Tetrahedron
crude aldehyde was used for the next reaction without further
in THF (0.1 mL) at 0 °C under argon atmosphere and the mixture
ACCEPTED MANUSCRIPT
purification.
was stirred for 8 h at room temperature. The reaction was
quenched with saturated NH4Cl aq. and the organic materials
were extracted with AcOEt three times. The organic layer was
washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography with hexane-AcOEt (1:0–10:1) to afford
To a solution of cyanophosphonate ester 8 (76.5 mg, 0.213
mmol) in dry toluene (200 µL) was added KHMDS (426 µL,
0.213 mmol, 0.5 M in toluene) and the mixture was stirred for 15
min at 0 °C under argon atmosphere. To the mixture was added
the above crude aldehyde in toluene (800 µL) and stirred for 0.5
h at –78 °C. The reaction was quenched with saturated NH4Cl aq.
and the organic materials were extracted with AcOEt three times.
The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
purified by silica gel column chromatography with hexane-
AcOEt (10:1–1:2) to afford 21 (47.6 mg, 71%, as a single
isomer) as a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 1.47–1.58
(m, 4H), 1.66 (s, 3H), 1.57–1.71 (m, 1H), 1.77–1.83 (m, 1H),
2.03–2.13 (m, 4H), 2.22–2.27 (m, 4H), 2.28 (dd, J = 6.6, 12.7 Hz,
1H), 2.56 (dd, J = 6.8, 12.7 Hz, 1H), 3.47 (ddd, J = 4.0, 5.2, 11.2
Hz, 1H), 3.81 (d, J = 12.0 Hz, 1H), 3.84 (dd, J = 2.7, 7.8, 11.2
Hz, 1H), 3.97 (d, J = 11.5 Hz, 1H), 3.99 (d, J = 11.5 Hz, 1H),
4.07 (d, J = 12.0 Hz, 1H), 4.38 (td, J = 3.7, 9.0 Hz, 1H), 4.42 (d,
J = 11.8 Hz, 1H), 4.43 (s, 2H), 4.47 (d, J = 11.8 Hz, 1H), 4.56
(dd, J = 4.2, 4.2 Hz, 1H), 4.93 (tdd, J = 1.3, 1.3, 10.3 Hz, 1H),
4.97 (tdd, J = 1.3, 1.3, 16.9 Hz, 1H), 5.35 (brs, 1H), 5.40 (t, J =
6.9 Hz, 1H), 5.75 (tdd, J = 6.4, 10.3, 16.9 Hz, 1H), 6.00 (d, J =
9.0 Hz, 1H), 7.24–7.31 (m, 10H); 13C NMR (CDCl3, 125 MHz) δ
14.2, 19.5, 25.4, 26.2, 27.2, 30.6, 33.7, 34.2, 40.4, 62.2, 67.3,
71.26, 71.29, 72.2, 72.42, 72.44, 97.7, 114.9, 116.5, 116.9, 124.4,
127.5, 127.70, 127.76 (2C), 127.81, 127.82, 128.3 (4C), 131.7,
132.3, 134.2, 137.96, 137.99, 138.4; IR νmax 3064, 3030, 2939,
2922, 2854, 2366, 2214, 1736, 1641, 1497, 1454, 1358, 1321,
1261, 1201, 1182, 1155, 1117, 1068, 1020, 978, 943, 906, 868
cm–1; HRMS (ESI): calcd for C37H47NO4Na: [M+Na]+: 592.3403;
found: 592.3393.
1
corresponding bromide 31 (34.4 mg, 91%) as a yellow oil. H
NMR (CDCl3, 500 MHz) δ 1.77 (s, 3H), 2.04–2.14 (m, 4H),
2.22–2.28 (m, 4H), 2.29 (dd, J = 6.6, 13.7 Hz, 1H), 2.56 (dd, J =
6.8, 13.7 Hz, 1H), 3.90 (s, 2H), 3.98 (d, J = 11.7 Hz, 1H), 3.99
(d, J = 11.7 Hz, 1H), 4.38 (ddd, J = 6.6, 6.8, 9.0 Hz, 1H), 4.39 (d,
J = 12.0 Hz, 1H), 4.43 (s, 2H), 4.47 (d, J = 12.0 Hz, 1H), 4.94
(tdd, J = 1.5, 1.5, 10.3 Hz, 1H), 4.98 (tdd, J = 1.5, 1.5, 16.7 Hz,
1H), 5.41 (t, J = 6.6 Hz, 1H), 5.48 (brs, 1H), 5.76 (tdd, J = 6.4,
10.3, 16.7 Hz, 1H), 6.01 (d, J = 9.0 Hz, 1H), 7.24–7.32 (m, 10H);
13C NMR (CDCl3, 125 MHz) δ 14.9, 26.6, 27.2, 33.69, 33.73,
40.4, 40.7, 67.3, 71.3, 72.2, 77.0, 114.9, 116.0, 116.8, 127.5,
127.72, 127.76 (2C), 127.78 (2C), 128.0, 128.33 (2C), 128.34
(2C), 131.7, 132.3, 134.2, 137.9, 138.0, 138.4, 148.0; IR νmax
3064, 3030, 2922, 2858, 2214, 1722, 1701, 1639, 1497, 1452,
1437, 1367, 1263, 1205, 1088, 1068, 1028, 999, 910 cm–1;
HRMS (ESI): calcd for C32H38BrNO2Na: [M+Na]+: 570.1984;
found: 570.1987.
To a suspension of sodium hydride (60% in mineral oil, 36.1
mg, 0.903 mmol) in dry THF (500 µL) was added a solution of
methyl 2-chloroacetoacetate (108 µL, 0.900 mmol) in THF (300
µL) at 0 °C and the mixture was stirred for 15 min at room
temperature under argon atmosphere. To the mixture was added
n-butyl lithium (577 µL, 0.900 mmol, 1.56 M in hexane) at 0 °C
and stirred for 10 min at room temperature. Subsequently, a
solution of corresponding bromide 31 (98.7 mg, 0.180 mmol) in
THF (1.2 mL) was added at 0 °C and the mixture was stirred for
20 min at that temperature. The reaction was quenched with
saturated NH4Cl aq. and the organic materials were extracted
with AcOEt three times. The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography with hexane-AcOEt (50:1–10:1) to
afford a 6.0:1 mixture of 22 and its enol tautomer (111 mg, 76%)
as a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 1.61 (s, 3H), 2.03–
2.11 (m, 4H), 2.18–2.22 (m, 4H), 2.25–2.30 (m, 3H), 2.54–2.60
(m, 1H), 2.73–2.80 (m, 2H), 3.80 (s, 3H), 3.97 (d, J = 12.0 Hz,
1H), 3.99 (d, J = 12.0 Hz, 1H), 4.38 (brdd, J = 6.6, 9.0 Hz, 1H),
4.39 (d, J = 11.5 Hz, 1H), 4.43 (s, 2H), 4.47 (d, J = 11.5 Hz, 1H),
4.74 (s, 1H), 4.94 (brdd, J = 1.5, 10.0 Hz, 1H), 4.98 (brdd, J =
1.5, 16.6 Hz, 1H), 5.08 (brs, 1H), 5.41 (t, J = 7.3 Hz, 1H), 5.75
(tdd, J = 6.1, 10.0, 16.6 Hz, 1H), 6.00 (d, J = 9.0 Hz, 1H), 7.24–
7.31 (m, 10H); 13C NMR (CDCl3, 125 MHz) δ 14.0, 16.2, 23.1,
26.5, 27.2, 33.0, 33.7, 34.3, 37.5, 40.4, 67.3, 71.3, 72.2, 114.9,
116.5, 116.6, 117.0, 123.0, 127.5, 127.72 (2C), 127.76 (3C),
127.79 (2C), 128.3 (3C), 131.7, 132.2, 135.1, 137.9, 138.4,
147.6, 165.5, 198.3; IR νmax 3064, 3032, 2956, 2908, 2864, 2216,
2033, 1728, 1641, 1606, 1497, 1452, 1439, 1360, 1257, 1201,
1167, 1090, 1066, 1028, 1001, 912, 818 cm–1; HRMS (ESI):
calcd for C37H44ClNO5Na: [M+Na]+: 640.2806; found: 640.2836.
4.10. Methyl (6E,10Z,14Z)-(2R*,12S*)-12-benzyloxy-14-
(benzyloxy)methyl-2-chloro-10-cyano-6-methyl-3-oxononadeca-
6,10,14,18-tetraenoate (22)
To a solution of 21 (47.6 mg, 0.084 mmol) in MeOH (1.0 mL)
was added pyridinium p-toluenesulfonate (4.2 mg, 0.017 mmol)
and the mixture was stirred for 21 h at 40 °C. The reaction
mixture was concentrated and added saturated NaHCO3 aq. The
organic materials were extracted with AcOEt three times. The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
purified by silica gel column chromatography with hexane-
AcOEt (10:1–3:1) to afford corresponding alcohol 30 (37.7 mg,
1
92%) as a colorless oil. H NMR (CDCl3, 500 MHz) δ 1.41 (brs,
1H), 1.66 (s, 3H), 2.04–2.13 (m, 4H), 2.24–2.28 (m, 4H), 2.28
(dd, J = 6.6, 13.7 Hz, 1H), 2.57 (dd, J = 5.6, 13.7 Hz, 1H), 3.95
(s, 2H), 2.98 (d, J = 2.2 Hz, 2H), 4.38 (ddd, J = 5.6, 6.6, 9.3 Hz,
1H), 4.39 (d, J = 11.5 Hz, 1H), 4.47 (s, 2H), 4.67 (d, J = 11.5 Hz,
1H), 4.94 (tdd, J = 1.7, 1.7, 10.2 Hz, 1H), 4.97 (tdd, J = 1.7, 1.7,
16.8 Hz, 1H), 5.32 (brs, 1H), 5.42 (t, J = 6.8 Hz, 1H), 5.75 (tdd, J
= 6.3, 10.2, 16.8 Hz, 1H), 6.00 (d, J = 9.3 Hz, 1H), 7.24–7.32 (m,
10H); 13C NMR (CDCl3, 125 MHz) δ 13.8, 26.0, 27.2, 33.7, 34.2,
40.3, 67.3, 68.4, 71.3, 72.2, 77.0, 114.9, 116.5, 117.0, 122.7,
127.6, 127.73, 127.77 (2C), 127.79 (2C), 128.3 (2C), 128.4 (2C),
131.63, 132.3, 137.0, 137.95, 137.98, 138.3, 147.8; IR νmax 3444,
3066, 3032, 2917, 2858, 2216, 1641, 1497, 1454, 1365, 1259,
1205, 1086, 1065, 1026, 1007, 910 cm–1; HRMS (ESI): calcd for
C32H39NO3Na: [M+Na]+: 508.2828; found: 508.2822.
4.11. Dimethyl (2E,6Z,10Z,14E)-(9R*,19S*)-9-benzyloxy-7-
benzyloxy)methyl-19-chloro-11-cyano-15-methyl-18-oxoicosa-
2,6,10,14-tetraenedioate (6)
To a solution of 22 (18.8 mg, 0.030 mmol) in dry CH2Cl2 (100
µL) was added methyl acrylate (40.3 µl, 0.450 mmol) and a
solution of 2nd generation Grubbs catalyst (3.0 mg, 3.53 µmol) in
dry CH2Cl2 (400 µL), and the mixture was stirred for 11 h at
room temperature under argon atmosphere. The reaction mixture
To a solution of corresponding alcohol 30 (33.6 mg, 0.069
mmol) and triethylamine (23.1 µL, 0.166 mmol) in dry CH2Cl2
(0.5 mL) was added methanesulfonic anhydride (24.1 mg, 0.138
mmol) and a solution of lithium bromide (30.0 mg, 0.345 mmol)