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S.-A. Poulsen, L. F. Bornaghi / Bioorg. Med. Chem. 14 (2006) 3275–3284
was purified by solid-phase extraction on normal-phase
silica sorbent (eluted with EtOAc/hexane, 1:2, v/v) to
give D in 53% yield (92 mg), as a white solid. 1H
NMR (200 MHz, CDCl3, ppm): d 7.98–7.56 (m, 2H,
ArH), 7.48–7.44 (m, 2H, ArH), 6.74 (dd, 1H,
(@CH2), 53.9, 53.7 (aCH, OCH3), 38.1 (CH2Ph); ESI
MS: m/z 310.1 [M+H]+, 332.5 [M+Na]+; HRMS (ESI)
332.1261. Calculated for C19H19N1O .Na+: 332.1258.
3
4.1.3. Synthesis of (2E)-4-(acyloxy)but-2-enyl-4-(amin-
osulfonyl)benzoate (1H). To a solution of (2E)-butene-
1,4-diol (0.5 g, 5.7 mmol) in pyridine (10 mL) was added
acetic anhydride (0.756 g, 7.4 mmol) dropwise over 6 h.
The reaction mixture was stirred at room temperature
for 24 h and then concentrated. The residue was redis-
solved in CH2Cl2 (25 mL), washed with 1 N HCl
(2 · 20 mL), saturated NaHCO3 (20 mL) and saturated
brine (20 mL). The organic phase was dried over MgSO4
and evaporated to afford the mono-acetyl intermediate
(0.70 g, yield 95%), which was used without further puri-
fication. To a mixture of this intermediate (100 mg,
0.77 mmol) in DMF (2.5 mL) were added 4-carboxyben-
zenesulfonamide (78 mg, 0.39 mmol), 1,3-dicyclohexyl-
carbodiimide (80 mg, 0.39 mmol) and DMAP (25 mg,
0.21 mmol). The solution was stirred at room tempera-
ture for 18 h. The reaction mixture was filtered through
Celite and the filtrate was diluted with EtOAc (25 mL),
washed with 1N HCl (2 · 25 mL) and saturated brine
(20 mL). The organic phase was dried over MgSO4
and evaporated. Purification by solid-phase extraction
on normal-phase silica sorbent (eluted with hexane/
EtOAc, 1:1, v/v) was carried out to generate 1H
(73 mg, 60% yield) as a white solid. 1H NMR
(400 MHz, CDCl3, ppm): d 8.16–8.13 (m, 2H, ArH),
7.99–7.96 (m, 2H, ArH), 5.90–5.78 (m, 2H, @CH),
5.16 (br s, 2H, NH2), 4.96–4.94 (m, 2H, CH2), 4.74–
4.72 (m, 2H, CH2), 2.06 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3, ppm): d 171.0 (CO), 165.0 (CO),
146.5 (OCH2CH@CH), 133.9 (OCH2CH@CH), 130.6,
129.0, 127.7, 126.7 (ArCH), 61.7 (CH2CH@), 60.2
(CH2CH@), 21.1 (CH3); ESI MS: m/z [MꢀH]ꢀ 311.9ꢀ1;
3
3Jma = 17.6 Hz, Jmx = 11.0 Hz, @CH), 6.69 (br s, 1H,
3
3
NH), 5.87–5.79 (m, 1H, Jam = 17.6 Hz, Jax = 0.8 Hz,
3
3
@CH2), 5.35 (dd, 1H, Jxm = 11.0 Hz, Jxa = 0.8 Hz,
@CH2), 4.78 (dd, 1H, J = 5.2 Hz, aCH), 3.77 (s, 3H,
OCH3), 2.35–2.22 (m, 1H, bCH), 1.02 (d, 3H,
J = 7.4 Hz, c0CH3), 0.98 (d, 3H, J = 7.4 Hz, cCH3);
13C NMR (50 MHz, CDCl3, ppm): d 172.8 (COCH3),
167.0 (CONH), 141.0, 136.1, 133.4, 127.6, 126.5 (ArCH,
@CH), 116.2 (@CH2), 57.7 (OCH3), 52.5 (aCH), 31.9
(bCH) 19.3, 18.3 (c,c0CH3); ESI MS: m/z 262.4
[M+H]+, 284.1 [M+Na]+; HRMS (ESI) 284.1249.
Calculated for C15H19N1O3ÆNa+: 284.1257.
4.1.2.1. Methyl-4-methyl-2-[(4-vinylbenzoyl)amino]-
pentanoate (E). Preparation from L-leucine methyl ester
hydrochloride. Yield 18%. 1H NMR (200 MHz, CDCl3,
ppm): d 7.77–7.73 (m, 2H, ArH), 7.45–7.39 (m, 2H,
ArH), 6.82–6.79 (br s, 1H, NH), 6.79–6.65 (dd, 1H,
3
3Jma = 17.4 Hz, Jmx = 10.4 Hz, @CH), 5.81 (d, 1H,
3
3Jam = 17.4 Hz, @CH2), 5.34 (d, 1H, Jxm = 10.4 Hz,
@CH2), 4.91–4.80 (m, 1H, aCH), 3.76 (s, 3H, OCH3),
1.79–1.62 (m, 3H, bCH2, cCH), 0.99 (d, 3H,
J = 7.4 Hz, d0CH3), 0.95 (d, 3H, J = 7.4 Hz, dCH3);
13C NMR (50 MHz, CDCl3, ppm): d 174.0 (COCH3),
166.9 (CONH), 141.0, 136.1, 133.1, 127.6, 126.4,
(ArCH, @CH), 116.2 (@CH2), 52.6, 51.4 (aCH,
OCH3), 42.0 (bCH2), 25.3 (cCH), 23.1, 22.3 (d,d0CH3);
ESI MS: m/z 276.1 [M+H]+, 298.7 [M+Na]+; HRMS
(ESI) 298.1396. Calculated for C16H21N1O3ÆNa+:
298.1404.
4.1.2.2. Methyl-phenyl[(4-vinylbenzoyl)amino]acetate
(F). Preparation from L-phenylglycine methyl ester
hydrochloride. Yield 27%. 1H NMR (200 MHz, CDCl3,
ppm): d 7.83–7.79 (m, 2H, ArH), 7.51–7.33 (m, 7H,
ArH), 7.30–7.27 (br s, 1H, NH), 6.74 (dd, 1H,
HRMS (ESI) 312.0544. Calculated for C13H14N1O6S1
312.0547.
:
4.1.4. Synthesis of (2E)-4-(biphenyloxy)but-2-enyl-4-
(aminosulfonyl)benzoate (1J). Biphenylcarbonyl chloride
(0.125 g, 0.575 mmol) was added portionwise over 2 h to
a solution of (2E)-butene-1,4-diol (1.20 g, 2.3 mmol) in
pyridine (5 mL). The solution was stirred at room tem-
perature for 72 h and then concentrated. The residue
was redissolved in CH2Cl2 (25 mL), washed with 1 N
HCl (2 · 20 mL), saturated NaHCO3 (20 mL) and satu-
rated brine (20 mL). The organic phase was dried over
MgSO4 and evaporated to afford the mono-biphenyl
intermediate (0.142 g, yield 92%), which was used
in the next step without purification. To a mixture of
this intermediate (0.142 g, 0.53 mmol) in DMF (5 mL)
were added 4-carboxybenzenesulfonamide (0.230 g,
1.15 mmol), 1,3-dicyclohexylcarbodiimide (0.237 g,
1.15 mmol) and DMAP (25 mg, 0.17 mmol). The reac-
tion was stirred at room temperature for 8 h, then fil-
tered through Celite and the filtrate was concentrated
to give a clear oil. Purification by solid-phase extraction
on normal-phase silica sorbent (eluted with CH2Cl2/
methanol, 20:1, v/v) was carried out to generate 1J
(29 mg, yield 11%) as a white solid. 1H NMR
(400 MHz, DMSO-d6, ppm): d 8.13–8.11 (m, 2H,
ArH), 8.03–8.01 (m, 2H, ArH), 7.94–7.92 (m, 2H,
3
3Jma = 17.6 Hz, Jmx = 10.8 Hz, @CH), 5.84 (d, 1H,
3Jam = 17.6 Hz, @CH2), 5.81 (d, 1H, J = 7 Hz, aCH),
3
5.37 (d, 1H, Jxm = 10.8 Hz, @CH2), 3.77 (s, 3H,
OCH3); 13C NMR (50 MHz, CDCl3, ppm): d 171.7
(COCH3), 166.5 (CONH), 141.2, 136.7, 136.1, 132.8,
130.6, 129.2, 128.8, 127.8, 127.6, 126.5 (ArCH, @CH),
116.4 (@CH2), 57.1 (OCH3), 53.7 (aCH); ESI MS: m/z
296.7 [M+H]+, 318.4 [M+Na]+; HRMS (ESI)
318.1091. Calculated for C18H17N1O3ÆNa+: 318.1101.
4.1.2.3.
Methyl-3-phenyl-2-[(4-vinylbenzoyl)amino]-
propanoate (G). Preparation from L-phenylalanine
methyl ester hydrochloride. Yield 32%. 1H NMR
(200 MHz, CDCl3, ppm): d 7.73–7.69 (m, 2H, ArH),
7.45–7.41 (m, 2H, ArH), 7.31–7.14 (m, 5H, ArH),
3
6.82–6.78 (br s, 1H, NH), 6.73 (dd, 1H, Jma = 17.6 Hz,
3
3Jmx = 11.0 Hz, @CH), 5.84 (d, 1H, Jam = 17.4 Hz,
3
@CH2), 5.50 (d, 1H, Jxm = 10.8 Hz, @CH2), 5.15–5.06
(m, 1H, aCH), 3.76 (s, 3H, OCH3), 3.30–3.24 (m, 2H,
CH2Ph); 13C NMR (50 MHz, CDCl3, ppm): d 172.3
(COCH3), 166.7 (CONH), 141.1, 136.1, 133.1, 129.5,
128.8, 127.6, 127.4, 126.5, (ArCH, @CH), 116.3