A. E. Pasqua et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
5
(0.5 mL) in a 2.0–5.0 mL microwave vial, was treated dropwise
with a solution of (Z)-methyl 2-(6-iodohex-5-enamido)acetate 9
2.9:7.0:0.1) to afford the desired enamide 18 as a white gum in
51% yield (29 mg, 82 mol). Rf 0.46 (EtOAc/PE/Et3N, 2.9:7.0:0.1);
l
(6.60 mg, 21
l
mol) in anhydrous, degassed THF (0.5 mL). The
1H NMR (500 MHz, acetone-d6): d 9.90 (1H, bd, J = 7.2 Hz), 8.78
(1H, s), 8.17 (1H, dd, J = 8.6, 1.7 Hz), 8.09 (1H, d, J = 7.7 Hz), 8.02
(2H, d, J = 9.0 Hz), 7.81 (1H, br s), 7.65 (2H, dqn, J = 6.9, 1.5 Hz),
7.07 (1H, t, J = 9.0 Hz), 4.93 (1H, q, J = 8.6 Hz), 4.08 (2H, d,
J = 5.5 Hz), 3.59 (3H, s), 2.44–2.34 (4H, m), 1.82 (2H, qn,
J = 6.9 Hz); 13C NMR (125 MHz, acetone-d6): d 175.8, 171.8, 166.0,
136.6, 134.4, 132.9, 130.7, 129.9, 129.5, 129.3, 129.2, 128.2,
126.3, 125.4, 112.3, 52.8, 42.5, 34.9, 26.9, 26.1; mmax (film) 3300,
3071, 2951, 2928, 2855, 1748, 1647, 1520, 1499, 1437, 1370,
1294, 1204 and 1180 cmꢀ1; HRMS (CI+/ISO) calcd for C20H22N2O4
[M]+: 354.1580. Found: 354.1581.
resulting reaction mixture was stirred at 70 °C for 24 h. The result-
ing blue-purple suspension was diluted with ethyl acetate (1 mL)
and filtered through a short pad of silica gel (previously deacti-
vated with Et3N) using EtOAc (10 mL) as eluent. The filtrate was
then concentrated under vacuum to afford a crude green-yellow
oil. The crude oil was purified by flash column chromatography
on silica gel previously deactivated with triethylamine (EtOAc/
DCM/Et3N, 2.9:7.0:0.1) to afford semi-crude (+)-crocacin D 4 as a
yellow gum in 70% yield (8.00 mg, 15 lmol). Rf 0.38 (EtOAc/PE/
Et3N, 4.9:5.0:0.1); 1H NMR (500 MHz, acetone-d6): dH 9.21 (1H,
bd, J = 10.5 Hz), 7.61–7.52 (1H, m), 7.51 (2H, d, J = 7.3 Hz), 7.35
(2H, dd, J = 7.4, 7.4 Hz), 7.27 (1H, dd, J = 7.4, 7.4 Hz), 6.80 (1H, dd,
J = 10.4, 9.0 Hz), 6.62 (1H, d, J = 16.0 Hz), 6.29 (1H, dd, J = 16.1,
7.3 Hz), 6.15–6.10 (2H, m), 5.95 (1H, d, J = 1.0 Hz), 4.71 (1H, dt,
J = 9.0, 7.3 Hz), 4.12 (1H, dd, J = 7.4, 1.6 Hz), 3.98 (2H, d,
J = 6.0 Hz), 3.71 (3H, s), 3.56 (3H, s), 3.30 (3H, s), 3.22 (1H, dd,
J = 9.5, 2.4 Hz), 2.65–2.57 (1H, m), 2.31 (3H, d, J = 1.0 Hz), 2.29
(2H, t, J = 7.1 Hz), 2.11 (2H, dt, J = 7.2, 6.8 Hz), 1.67 (2H, tt, J = 7.2,
6.8 Hz), 1.56–1.55 (1H, m), 1.22 (3H, d, J = 6.8 Hz), 0.91 (3H, d,
J = 7.1 Hz); mmax (film) 3302, 2924, 1744, 1653, 1603, 1514, 1262,
1089 and 972 cmꢀ1; LRMS (ESI): [M+H]+: 541.8; [M+Na]+: 563.8.
3.7. Methyl 2-(6-cinnamamidohex-5Z-enamido)acetate, 19
A suspension of cinnamamide 13 (30 mg, 204
carbonate (66 mg, 204 mol), CuI (2 mg, 10 mol) and N,N’-methy-
lenediamine (2.2 L, 204 mol) in degassed and dry THF (1 mL) in
a 2.0–5.0 mL microwave vial, was treated dropwise with a solution
of (Z)-methyl 2-(6-iodohex-5-enamido)acetate (55 mg,
186 mol) in degassed and dry THF (2 mL). The reaction mixture
lmol), cesium
l
l
l
l
9
l
was stirred at 70 °C for 18 h and then allowed to cool down to rt.
The light-green suspension was diluted with EtOAc (3 mL), filtered
through a short pad of silica (previously deactivated with Et3N)
using EtOAc (15 mL) as eluent. The filtrate was concentrated under
vacuum to afford a crude green-yellow oil which was purified by
flash column chromatography (silica gel, EtOAc/DCM/Et3N,
2.9:7.0:0.1) to afford the desired enamide 19 as a white gum in
3.5. Methyl 2-(6-benzamidohex-5Z-enamido)acetate, 17
A suspension of benzamide 11 (5.3 mg, 44
carbonate (14 mg, 44 mol), CuI (1 mg, 5 mol) and N,N’-methy-
lenediamine (1 L, 9 mol) in anhydrous, degassed THF (0.5 mL)
in a 2.0–5.0 mL microwave vial, was treated dropwise with a solu-
tion of (Z)-methyl 2-(6-iodohex-5-enamido)acetate (10 mg,
38 mol) in anhydrous degassed THF (0.5 mL). The resulting reac-
lmol), cesium
l
l
l
l
55% yield (34 mg, 103 lmol). Rf 0.21 (EtOAc/DCM/Et3N,
2.9:7.0:0.1); 1H NMR (500 MHz, acetone-d6): d 9.59 (1H, bd,
J = 9.5 Hz), 7.77 (1H, br s), 7.66 (1H, d, J = 15.9 Hz), 7.65–7.63 (2H,
m), 7.49–7.40 (3H, m), 6.91 (1H, t, J = 8.9 Hz), 6.89 (1H, d,
J = 15.9 Hz), 4.84 (1H, q, J = 8.6 Hz), 4.07 (2H, d, J = 5.6 Hz), 3.71
(3H, s), 2.36 (2H, t, J = 6.6 Hz), 2.22 (2H, q, J = 6.7 Hz), 1.77 (2H,
qn, J = 6.7 Hz); 13C NMR (125 MHz, acetone-d6): d 175.6, 171.9,
164.2, 142.1, 137.0, 131.2, 130.5, 129.3, 124.8, 123.1, 111.5, 52.9,
42.5, 35.2, 26.8, 26.2; mmax (film) 3297, 2951, 2361, 1750, 1651,
1520, 1206, 1182, 980, 766 and 682 cmꢀ1; HRMS (CI+/ISO) calcd
for C18H22N2O4 [M]+: 330.1580. Found: 330.1577.
9
l
tion mixture was stirred at 70 °C for 24 h and then allowed to cool
down to rt. The blue-purple suspension was diluted with EtOAc
(1 mL), filtered through a short pad of silica (previously deacti-
vated with Et3N) using EtOAc (10 mL) as eluent. The filtrate was
concentrated under vacuum to afford a crude green-yellow oil
which was purified by flash column chromatography (silica gel,
EtOAc/DCM/Et3N, 2.9:7.0:0.1) to afford the desired enamide 17 as
a white gum in 75% yield (10 mg, 33 lmol). Rf 0.42 (EtOAc/PE/
Et3N, 2.9:7.0:0.1); 1H NMR (500 MHz, acetone-d6): d 9.67 (1H, br
s), 8.13–8.08 (2H, m), 7.75 (1H, br s), 7.60–7.57 (1H, m), 7.53–
7.47 (2H, m), 7.02–6.98 (1H, m), 4.89 (1H, q, J = 8.2 Hz), 4.03 (2H,
d, J = 5.8 Hz), 3.66 (3H, s), 2.39–2.29 (4H, m), 1.82–1.75 (2H, qn,
J = 6.6 Hz); 13C NMR (125 MHz, acetone-d6): d 175.7, 171.8, 166.0,
135.8, 133.1, 129.8, 129.5, 125.2, 112.4, 52.9, 42.4, 34.8, 26.9,
26.1; mmax (film) 3304, 2953, 2923, 2854, 1745, 1646, 1515, 1484,
1457, 1437, 1375, 1281, 1207, 1030 and 708 cmꢀ1; HRMS (ESI)
calcd for C16H20N2O4 [M]+: 304.1423. Found: 304.1417.
3.8. Ethyl cis-3-iodoacrylate
A solution of ethyl propiolate (1.0 mL, 9.8 mmol) in glacial
acetic acid (5 mL) was treated with sodium iodide (1.5 g, 10 mmol)
and the reaction mixture was warmed up to 70 °C and stirred for
16 h. The reaction was quenched with H2O (5 mL) followed by
aq. NaOH (1 N, 5 mL) and extracted with diethyl ether
(3 ꢁ 5 mL). The combined organic phases were dried over Na2SO4,
filtered and concentrated under vacuum to afford the desired iodo-
acrylate as orange oil in a quantitative yield (2.23 g, 9.8 mmol). The
product was used without any further purification. Rf 0.59 (Et2O/
PE, 2.5:7.5); 1H NMR (500 MHz, CDCl3): d 7.31 (1H, dd, J = 8.8,
1.0 Hz), 6.74 (1H, dd, J = 8.9, 1.3 Hz), 4.06 (2H, qd, J = 7.2, 1.7 Hz),
1.14 (3H, td, J = 7.2, 1.6 Hz); 13C NMR (125 MHz, CDCl3): d 164.0,
129.6, 94.7, 60.4, 13.9; mmax (film) 1721, 1597, 1321, 1192, 1159,
3.6. Methyl 2-(6-(2-naphthamido)hex-5Z-enamido)acetate, 18
A suspension of 2-naphtamide 12 (30 mg, 175
l
mol), cesium
mol) and N,N’-
lmol) in degassed and dry THF
carbonate (57 mg, 175
methylenediamine (1.8
l
mol), CuI (1.7 mg, 8
l
l
L, 16
(1 mL) in a 2.0–5.0 mL microwave vial, was treated dropwise with
a solution of (Z)-methyl 2-(6-iodohex-5-enamido)acetate 9 (48 mg,
160 lmol) in degassed and dry THF (2 mL). The reaction mixture
1024 and 804 cmꢀ1
;
HRMS (ESI) calcd for C5H7IO2 [M]+:
225.9491. Found: 225.9494.
was stirred at 70 °C for 18 h and then allowed to cool down to rt.
The light-green suspension was diluted with EtOAc (3 mL), filtered
through a short pad of silica (previously deactivated with Et3N)
using EtOAc (15 mL) as eluent. The filtrate was concentrated under
vacuum to afford a crude green-yellow oil which was purified by
flash column chromatography (silica gel, EtOAc/DCM/Et3N,
3.9. Ethyl 3-(2-naphthamido)-Z-acrylate, 23
A suspension of 2-naphtamide 12 (50 mg, 292
l
mol), cesium
mol) and N,N’-methy-
lmol) in degassed and dry THF (2 mL) in a
carbonate (95 mg, 292
lmol), CuI (3 mg, 15 l
lenediamine (3.2 L, 30
l