8
Tetrahedron
1
concentrated under reduced pressure to give a crude material,
afford amide 23 (582 mg, 906 μmol, 87%). A white foam; H
1
which was purified by silica gel column chromatography
(hexanes:EtOAc = 5:1) to afford amide hemiaminal 21g (16.6
mg, 63.2 μmol, 92%). A colorless oil; 1H NMR (400 MHz,
CDCl3, mixture of rotamers): δ 7.36–7.22 (5H, m), 4.86 (2H, br),
4.86–4.65 (2H, br), 3.69 (0.7H, br), 2.64–2.49 (0.9H, m), 2.31
(1.4H, t, J = 8.0 Hz), 1.71–1.61 (m, 2H), 1.25 (br, 8H), 0.88–0.84
(m, 3 H); 13C NMR (100 MHz, CDCl3, mixture of rotamers):
δ 175.9, 174.2, 138.0, 136.9, 128.9, 128.7, 128.1, 127.6, 127.5, 1
26.4, 72.2, 71.7, 51.5, 48.2, 33.4, 33.1, 31.7, 31.6, 29.4, 29.2, 29.
1, 29.0, 25.4, 24.9, 22.6, 14.0 (Two signals are missing due to
overlap.); IR (film): 3371, 3087, 3063, 3030, 2954, 2926, 2870,
2855, 1636, 1629, 1453, 1423, 1041, 1029, 699 cm–1; HRMS
(ESI) m/z: calcd. for C16H26N2O2 [M+H+] 264.1958, Found
264.1946.
NMR (400 MHz, CDCl3, mixture of rotamers): H NMR (400
MHz, CDCl3, mixture of rotamers): δ 7.49–7.28 (8.8H, m), 7.12–
7.09 (1.2H, m), 6.48–6.37 (2.4H, m), 6.11 (0.6H, d, J = 8.4 Hz),
5.37–5.13 (3H, m), 5.05–4.76 (3H, m), 4.50 (1H, ddd, J = 8.4,
8.4, 2.8 Hz), 3.81 (1.2H, s), 3.72 (1.8H, s), 3.26–3.04 (3H, m),
2.76 (0.4H, d, J = 15.2 Hz), 2.64 (0.6H, d, J = 15.2 Hz), 0.940
(9H, s), 0.120 (3H, s), 0.054 (3H, s); 13C NMR (100 MHz,
CDCl3, mixture of rotamers): δ 171.6, 171.5, 171.4, 171.2, 154.7,
153.9, 145.5, 145.2, 136.1, 135.7, 135.4, 135.0, 129.4, 129.1,
128.5, 128.5, 128.4, 128.3, 128.1, 128.1, 127.9, 127.1, 127.0,
120.3, 118.7, 105.9, 105.5, 67.6, 67.3, 67.1, 65.9, 65.0, 64.4,
61.8, 61.4, 53.0, 52.5, 52.2, 52.1, 37.8, 37.7, 33.3, 32.0, 25.6,
17.8, −4.5, −4.6, −5.0, −5.1 (Five signals are missing due to
overlap.); IR (film): 3325, 3031, 2953, 2928, 2895, 2855, 1746,
1713, 1639, 1526, 1437, 1408, 1350, 1318, 1252, 1210, 1142,
4.28 amide 19g
1113, 1085, 959, 836, 777, 748, 698 cm−1; [α]D = −175 (c =
27
1.20, CHCl3); HRMS (ESI) m/z: calcd. for C33H42N2NaO7Si
To a mixture of hemiaminal 21g (19.1 mg, 72.7 μmol) and
NaI (76.3 mg, 509 μmol) in MeCN (0.36 mL) was added TMSCl
(46.0 µL, 495 μmol) at 0 °C. After stirred for 24 h at room
temperature, the reaction was quenched with sat. aq. Na2CO3, and
the aqueous phase was extracted with EtOAc (x3). The combined
organic extracts were dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure to give a crude
material, which was purified by preparative TLC
(hexanes:EtOAc = 1:1) to afford amide 19g (17.0 mg, 72.3 μmol,
quant).
[M+Na+] 629.2653, found 629.2624.
4.31 Amide 24
To a suspension of amide 23 (398 mg, 657 μmol) and
Pd(OAc)2 (57.8 mg, 257 μmol) in CH2Cl2 (12.0 mL) was added
Et3N (300 μL, 2.16 mmol) at room temperature. After stirring for
30 min at reflux, Et3SiH (1.10 mL, 6.90 mmol) was added, and
the mixture. was stirred for 40 min at reflux. The reaction
mixture was diluted by CH2Cl2 and the reaction was quenched
with sat. aq. NaHCO3. The separated aqueous phase was
extracted with CH2Cl2 (x4). The combined organic extracts were
dried over anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure to give a crude material, which was
purified by silica gel column chromatography (hexanes:EtOAc =
6:1 to 2:1) to afford amine 24 (347 mg, quant). A colorless oil;
1H NMR (400 MHz, CDCl3): δ 7.90 (1H, d, J = 8.4 Hz), 7.22–
7.16 (3H, m), 7.03 (2H, d, J = 6.8 Hz), 6.25 (1H, d, J = 2.0 Hz),
6.22 (1H, d, J = 8.0 Hz), 4.80 (1H, ddd, J = 10.8, 3.2, 3.2 Hz),
4.71 (1H, dd, J = 8.0, 7.8 Hz), 4.27 (1H, dd, J = 7.8, 2.2 Hz),
3.79 (1H, dd, J = 7.2, 5.6 Hz), 3.70 (3H, s), 3.55 (1H, s), 3.19
(1H, dd, J = 14.0, 5.8 Hz), 3.01 (1H, dd, J = 14.0, 6.6 Hz), 2.73–
2.71 (2H, m), 2.28 (1H, s), 0.82 (9H, s), 0.033 (3H, s), 0.022 (3H,
s); 13C NMR (100 MHz, CDCl3): δ 173.0, 171.9, 145.5, 135.8,
133.1, 129.1, 128.3, 126.9, 120.5, 105.6, 67.9, 63.9, 60.9, 52.5,
52.1, 37.6, 35.0, 25.6, 17.9, -3.8, -4.7; IR (film): 3349, 3029,
2952, 2928, 2893, 2855, 2360, 2341, 1745, 1677, 1644, 1508,
1437, 1360, 1344, 1254, 1200, 1079, 961, 837, 779, 702 cm–1;
4.29 amide 22g
To a mixture of amide 20g (17.3 mg, 57.0 μmol) and
Pd(PPh3)4 (6.6 mg, 5.67 μmol) and 1,3-dimethylbarbituric acid
(17.8 mg, 114 μmol) was added MeOH (0.2 mL) at room
temperature. The resulting suspension was stirred for 16.5 h at 40
°C. Then, the reaction was quenched with sat. aq. Na2CO3, and
the mixture was extracted with EtOAc (x3). The combined
organic extracts were washed with 1 M aq. HCl and brine, dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to give a crude material, which was purified by
preparative TLC (hexanes:EtOAc = 3:1) to afford amide 19g (0.7
mg, 3.00 μmol, 5.3%), 21g (3.2 mg, 12.1 μmol, 21%), and 22g
1
(6.1 mg, 22.0 μmol, 39%). A colorless oil; H NMR (400 MHz,
CDCl3, mixture of rotamers): δ 7.37–7.18 (5H, m), 4.85 (0.8H,
s), 4.67 (1.2H, s), 4.61 (2H, s), 3.33 (1.2H, s), 3.28 (1.8H, s), 2.46
(1.2H, t, J = 7.6 Hz), 2.35 (0.8H, t, J = 7.6 Hz), 2.48–1.64 (2H,
m), 1.32–1.25 (8H, m), 0.88–0.84 (3H, m); 13C NMR (100 MHz,
CDCl3, mixture of rotamers): δ 175.0, 174.2, 137.8, 136.9, 128.8,
128.5, 128.1, 127.5, 127.3, 126.3, 78.9, 76.0, 56.1, 55.3, 49.1,
48.3, 33.4, 33.0, 31.7, 31.6, 29.3, 29.2, 29.1, 29.0, 25.2, 25.1,
22.57, 22.55, 14.0 (One signal is missing due to overlap.); IR
(film): 3087, 3063, 3031, 2953, 2927, 2871, 2855, 1663, 1453,
1420, 1389, 1095, 1077, 699 cm–1; HRMS (ESI) m/z: calcd. for
C17H27NNaO2 [M+Na+] 300.1934, Found 300.1921.
26
[α]D = –195 (c = 1.65, CHCl3); HRMS (ESI) m/z: calcd. for
C25H37N2O5Si+ [M+H+] 473.2466, found 473.2451.
4.32 Dithiodiketopiperazine 25
To a solution of amine 24 (447 mg, 945 μmol) in MeOH (250
mL) was added 25% aq. NH3 (15.0 mL) at room temperature.
After stirring for 2.7 days at room temperature, the reaction was
concentrated under reduced pressure to give a crude material,
which was purified by silica gel column chromatography
(hexanes:EtOAc = 2:1) to afford diketopiperazine 25 (202 mg,
4.30 amide 23
To a solution of carboxylic acid 9 [9] (491 mg, 1.10 mmol)
and L-phenylalanine methyl ester 10 (497 mg, 2.78 mmol) in dry
1
459 μmol, 48%). A colorless oil; H NMR (400 MHz, CDCl3): δ
7.33–7.18 (5H, m), 6.41 (1H, s), 6.29 (1H, d, J = 8.0 Hz), 5.90
(1H, s), 5.00 (1H, d, J = 7.6 Hz), 4.88 (1H, dd, J = 8.0, 7.6 Hz),
4.77 (1H, s), 4.23–4.16 (2H, m), 3.51 (1H, dd, J = 14.0, 3.6 Hz),
2.89–2.79 (2H, m), 2.52 (1H, dd, J = 13.0, 13.0 Hz), 0.79 (9H, s),
0.011 (3H, s), 0.006 (3H, s); 13C NMR (100 MHz, CDCl3): δ
168.5, 163.9, 145.0, 135.6, 135.1, 129.3, 128.9, 127.3, 112.4,
106.4, 66.9, 63.1, 57.9, 56.2, 37.3, 33.4, 25.7, 17.8, −4.3, −4.5;
IR (film): 3381, 3228, 3220, 2952, 2928, 2895, 2855, 2359,
2341, 1684, 1663, 1444, 1422, 1294, 1256, 1202, 1139, 1083,
CH2Cl2 (15.0 mL) was added Et3N (612 μL, 4.40 mmol) at room
temperature. After stirring for 10 min, BOP-Cl (576 mg, 2.26
mmol) was added, and the mixture was stirred for 2.7 h at room
temperature. The reaction was quenched with sat. aq. NaHCO3,
and the mixture was extracted with EtOAc (x3). The combined
organic extracts were washed with 1 M aq. HCl and brine, dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to give a crude material, which was purified by
silica gel column chromatography (hexanes:EtOAc = 2:1) to