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The Journal of Organic Chemistry
2H), 3.16 (t, J = 16.0 Hz, 2H), 2.45 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H);
J = 251.6 Hz), 114.8, 112.2, 112.0, 101.4, 99.5, 62.86, 55.5, 34.8 (t, J
= 24.6 Hz), 31.5, 13.6, 13.2. 19F NMR (376 MHz, DMSO-d6) δ -99.5.
HRMS (ESI) m/z Calcd for C25H23F2NO7Na+ 510.1335; found
510.1329.
13C NMR {1H} (101 MHz, Chloroform-d) δ 173.7, 164.4, 163.8 (t, J =
32.5 Hz), 144.2, 142.8, 129.7, 128.9, 127.8, 114.5 (t, J = 253.0 Hz),
97.8, 63.1, 35.0 (t, J = 25.0 Hz), 21.6, 13.9. 19F NMR (376 MHz,
Chloroform-d) δ -105.7; Melting Point: 144~146 °C; HRMS (ESI) m/z
Calcd for C16H17F2NO5Na+ 364.0967; found 364.0962.
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(Z)-2-(((R)-3-((5S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-
3,7,12-trioxohexadecahydro-1H-cyclopenta[a]phenanthren-17-
yl)butanamido)methylene)-5-ethoxy-4,4-difluoro-5-oxopentanoic
acid (1F): yellow solid, 43% yield, (0.2 mmol, 51 mg), column
chromatography using petroleum ether/EtOAc/acetic acid (100/100/1);
1H NMR (400 MHz, Chloroform-d) δ 10.42 (d, J = 11.6 Hz, 1H), 7.64
(d, J = 11.6 Hz, 1H), 4.31 – 4.29 (m, 2H), 3.06 (t, J = 16.0 Hz, 1H),
2.94 – 2.85 (m, 3H), 2.34 – 2.33 (m, 4H), 2.25 – 2.21 (m, 3H), 2.15 –
2.12 (m, 2H), 2.05 – 2.02 (m, 4H), 1.87 – 1.85 (m, 3H), 1.67 – 1.62 (m,
1H), 1.41 (s, 3H), 1.34 (t, J = 7.2 Hz, 6H), 1.07 (s, 3H), 0.86 (d, J = 6.8
Hz, 3H); 13C NMR {1H} (101 MHz, Chloroform-d) δ 212.2, 209.4,
208.8, 177.1, 172.6, 171.5, 164.1 (t, J = 32.9 Hz), 140.1, 114.8 ( t, J =
253.0 Hz ), 102.2, 63.0, 56.9, 51.8, 48.9, 46.8, 45.5, 44.9, 42.7, 38.6,
(Z)-5-ethoxy-4,4-difluoro-2-((5-(4-fluorophenyl)-5-
oxopentanamido)methylene)-5-oxopentanoic acid (1A): yellow
solid, 48% yield, (0.2 mmol, 40 mg), column chromatography using
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petroleum ether/EtOAc/acetic acid (100/20/1); H NMR (400 MHz,
Chloroform-d) δ 10.34 (d, J = 11.6 Hz, 1H), 8.01 – 7.98 (m, 2H), 7.68
(d, J = 11.6 Hz, 1H), 7.15 – 7.11 (m, 2H), 4.31 (q, J = 7.2 Hz, 2H), 3.11
– 3.03 (m, 4H), 2.54 (t, J = 7.2 Hz, 2H), 2.18 – 2.11 (m, 2H), 1.34 (t, J
= 7.2 Hz, 3H); 13C NMR {1H} (101 MHz, Chloroform-d) δ 197.8,
172.8, 170.7, 165.8 (d, J = 249.8 Hz), 163.8 (t, J = 32.8 Hz), 141.4,
133.1 (d, J = 3.1 Hz), 130.7 (d, J = 9.3 Hz), 115.7 (d, J = 21.9 Hz),
114.5 (t, J = 252.4 Hz), 97.5, 63.1, 37.0, 35.5, 34.9 (t, J = 24.5 Hz),
19.0, 13.9. 19F NMR (376 MHz, Chloroform-d) δ -105.0, -105.8;
Melting Point: 124~126 °C; HRMS (ESI) m/z Calcd for
C19H20F3NO6Na+ 438.1135; found 438.1127.
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36.4, 36.0, 35.4, 33.7, 30.2, 27.6, 25.1, 21.8, 21.1, 18.6, 13.9, 11.8. 19
F
NMR (376 MHz, Chloroform-d) δ -105.3. HRMS (ESI) m/z Calcd for
C31H41F2NO8Na+ 616.2692; found 616.2688.
(R,Z)-5-ethoxy-4,4-difluoro-2-((2-(4-
isobutylphenyl)propanamido)methylene)-5-oxopentanoic
(Z)-5-ethoxy-4,4-difluoro-5-oxo-2-
acid
(palmitamidomethylene)pentanoic acid (1B): yellow solid, 40%
yield, (0.2 mmol, 37 mg), column chromatography using petroleum
ether/EtOAc/acetic acid (100/20/1); 1H NMR (400 MHz, Chloroform-
d) δ 10.30 (d, J = 11.6 Hz, 1H), 7.69 (d, J = 11.6 Hz, 1H), 4.32 (q, J =
7.2 Hz, 2H), 3.07 (t, J = 16.0 Hz, 2H), 2.39 (t, J = 7.6 Hz, 2H), 1.71 –
1.67 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.25 (s, 24H), 0.88 (t, J = 6.8
Hz, 3H); 13C NMR {1H} (101 MHz, Chloroform-d) δ 173.2, 171.4,
163.8 (t, J = 32.7 Hz), 141.9, 114.5 (t, J = 253.0 Hz), 97.2, 63.0, 36.9,
34.9 (t, J = 24.9 Hz), 31.9, 29.7, 29.6, 29.6, 29.6, 29.4, 29.3, 29.2, 29.1,
24.8, 22.7, 14.1, 13.8. 19F NMR (376 MHz, Chloroform-d) δ -105.9;
Melting Point: 74~76 °C; HRMS (ESI) m/z Calcd for C24H41F2NO5Na+
484.2845; found 484.2834.
(1G): yellow oil, 32% yield, (0.4 mmol, 52 mg), column
chromatography using petroleum ether/EtOAc/acetic acid (100/50/1);
1H NMR (400 MHz, Chloroform-d) δ 10.25 (d, J = 11.6 Hz, 1H), 7.60
(d, J = 11.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H),
4.29 (q, J = 7.2 Hz, 2H), 3.68 (q, J = 7.2 Hz, 1H), 3.03 (td, J = 15.6,
4.8 Hz, 2H), 2.45 (d, J = 7.2 Hz, 2H), 1.84 (dp, J = 13.6, 6.8 Hz, 1H),
1.57 (d, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 0.88 (s, 3H), 0.86 (s,
3H); 13C NMR {1H} (101 MHz, Chloroform-d) δ 173.1, 172.7, 163.7
(t, J = 32.6 Hz), 141.9, 141.5, 136.3, 129.9, 127.4, 114.6 (t, J = 252.7
Hz), 97.4, 63.0, 47.1, 45.0, 34.8 (t, J = 25.3 Hz), 30.1, 22.3, 17.6, 13.8.
19F NMR (376 MHz, Chloroform-d) δ -105.6. HRMS (ESI) m/z Calcd
for C21H27F2NO5Na+ 434.1750; found 434.1742.
(Z)-2-(((Z)-docos-13-enamido)methylene)-5-ethoxy-4,4-
(Z)-5-ethoxy-4,4-difluoro-5-oxo-2-((2-(4-((2-
difluoro-5-oxopentanoic acid (1C): yellow solid, 43% yield, (0.2
mmol, 47 mg), column chromatography using petroleum
ether/EtOAc/acetic acid (100/20/1); 1H NMR (400 MHz, Chloroform-
d) δ 10.28 (d, J = 11.6, 1H), 7.69 (d, J = 11.6, 1H), 5.39 – 5.31 (m, 2H),
4.32 (q, J = 7.2, 2H), 3.07 (t, J = 16.0, 2H), 2.39 (t, J = 7.5, 2H), 2.03
– 1.99 (m, 2H), 1.69 (p, J = 7.6, 2H), 1.37 – 1.27 (m, 31H), 0.88 (t, J =
7.2, 3H); 13C NMR {1H} (101 MHz, Chloroform-d) δ 172.8, 171.3,
163.8 (t, J = 32.8 Hz), 142.0, 129.9, 114.5 (t, J = 250.6 Hz), 96.9, 63.0,
36.9, 35.0 (t, J = 25.0 Hz), 31.9, 29.8, 29.7, 29.6, 29.6, 29.6, 29.5, 29.4,
29.3, 29.3, 29.1, 27.2, 24.8, 22.7, 14.1, 13.9. 19F NMR (376 MHz,
Chloroform-d) δ -105.8; Melting Point: 66~68 °C; HRMS (ESI) m/z
Calcd for C30H51F2NO5Na+ 566.3628; found 566.3622.
(S,Z)-2-((1-benzylpyrrolidine-2-carboxamido)methylene)-5-
ethoxy-4,4-difluoro-5-oxopentanoic acid (1D): yellow solid, 32%
yield, (0.2 mmol, 26 mg), column chromatography using petroleum
ether/EtOAc/acetic acid (50/100/1); 1H NMR (400 MHz, DMSO-d6) δ
11.48 (d, J = 11.6 Hz, 1H), 7.41 – 7.39 (m, 2H), 7.30 – 7.23 (m, 3H),
4.23 (q, J = 7.2 Hz, 2H), 3.82 (d, J = 12.8 Hz, 1H), 3.52 (d, J = 12.8
Hz, 1H), 3.29 – 3.25 (m, 1H), 3.08 (t, J = 16.0 Hz, 2H), 2.94 – 2.90 (m,
2H), 2.36 – 2.30 (m, 1H), 2.24 – 2.16 (m, 1H), 1.77 – 1.74 (m, 2H),
1.67 – 1.62 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H);13C NMR {1H} (101 MHz,
DMSO-d6) δ 173.1, 168.8, 163.4 (t, J = 32.9 Hz), 138.3, 137.6, 128.8,
128.2, 127.1, 115.2 (t, J = 250.5 Hz), 100.1 (t, J = 5.2 Hz), 66.9, 62.9,
59.4, 53.5, 35.1 (t, J = 25.0 Hz), 30.3, 23.7, 13.6. 19F NMR (376 MHz,
DMSO-d6) δ -104.1. HRMS (ESI) m/z Calcd for C20H24F2N2O5Na+
433.1545; found 433.1534.
(Z)-5-ethoxy-4,4-difluoro-5-oxo-2-((2-(12-oxo-7,12-dihydro-
6H-dibenzo[b,e]oxocin-2-yl)acetamido)methylene)pentanoic acid
(1E): yellow solid, 25% yield, (0.4 mmol, 48 mg), column
chromatography using petroleum ether/EtOAc/acetic acid (100/100/1);
1H NMR (400 MHz, DMSO-d6) δ 10.68 (d, J = 11.2 Hz, 1H), 7.72 (d,
J = 8.4 Hz, 2H), 7.66 (d, J = 8. Hz, 2H), 7.49 (d, J = 11.2 Hz, 1H), 7.09
(d, J = 2.0 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.73 (dd, J = 8.8, 2.0 Hz,
1H), 4.19 (q, J = 7.2 Hz, 2H), 3.76 (s, 2H), 3.33 (s, 2H), 3.04 (t, J =
16.0 Hz, 2H), 2.25 (s, 2H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR {1H}
(101 MHz, DMSO-d6) δ 169.3, 168.5, 168.0, 163.3 (t, J = 32.7 Hz),
155.8, 138.8, 137.8, 136.1, 134.1, 131.2, 130.5, 130.3, 129.2, 115.2 (t,
oxocyclopentyl)methyl)phenyl)propanamido)methylene)pentanoic
acid (1H): yellow oil, 28% yield, (0.4 mmol, 46 mg), column
chromatography using petroleum ether/EtOAc/acetic acid (100/30/1);
1H NMR (400 MHz, Chloroform-d) δ 10.35 (d, J = 11.6 Hz, 1H), 7.54
(d, J = 11.2 Hz, 1H), 7.22 – 7.15 (m, 4H), 4.26 (q, J = 7.2 Hz, 2H), 3.66
(q, J = 7.2 Hz, 1H), 3.10 – 2.96 (m, 3H), 2.59 – 2.53 (m, 1H), 2.35 –
2.29 (m, 2H), 2.13 – 2.06 (m, 3H), 1.99 – 1.92 (m, 1H), 1.80 – 1.68 (m,
1H), 1.55 (d, J = 7.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR {1H}
(101 MHz, Chloroform-d) δ 220.8, 172.5, 172.5, 164.1 (t, J = 32.6 Hz),
140.2, 139.5, 137.2, 129.6, 127.8, 114.7 (t, J = 251.6 Hz), 99.2, 63.0,
50.7, 47.0, 38.1, 35.2, 30.9, 29.3, 20.5, 17.6, 13.8. 19F NMR (376 MHz,
Chloroform-d) δ -105.7. HRMS (ESI) m/z Calcd for C23H27F2NO6Na+
474.1699; found 474.1690.
Ethyl
2,2-difluoro-3-(6-oxo-2-phenyl-6H-1,3-oxazin-5-
yl)propanoate (2a): yellow solid, 65% yield, (0.2 mmol, 40 mg),
column chromatography using petroleum ether/EtOAc (30/1);1H NMR
(400 MHz, Chloroform-d) δ 8.23 – 8.18 (m, 2H), 7.84 (s, 1H), 7.65 –
7.56 (m, 1H), 7.54 – 7.46 (m, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.31 (t, J
= 16.0 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H); 13C NMR {1H} (101 MHz,
Chloroform-d) δ 164.0, 163.2 (t, J = 32.3 Hz), 159.3, 154.4, 133.6,
129.3, 128.9, 128.5, 114.0 (t, J = 253.8 Hz), 113.3 (t, J = 4.0 Hz), 63.4,
32.4 (t, J = 25.8 Hz), 13.8. 19F NMR (376 MHz, Chloroform-d) δ -
104.6; Melting Point: 80~82 °C; HRMS (ESI) Calcd for
C15H13F2NO4H+ 310.0885; found 310.0892.
Ethyl
2,2-difluoro-3-(6-oxo-2-(p-tolyl)-6H-1,3-oxazin-5-
yl)propanoate (2b): yellow solid, 50% yield, (0.2 mmol, 32 mg),
column chromatography using petroleum ether/EtOAc (30/1);1H NMR
(400 MHz, Chloroform-d) δ 8.10 (d, J = 8.0 Hz, 2H), 7.82 (s, 1H), 7.30
(d, J = 8.4 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.30 (t, J = 16.0 Hz, 2H),
2.44 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); 13C NMR {1H} (101 MHz,
Chloroform-d) δ 164.3, 163.2 (t, J = 32.1 Hz), 159.5, 154.7, 144.7,
129.7, 128.6, 126.4, 115.2 (t, J = 253.7 Hz), 112.7 (t, J = 4.1 Hz), 63.4,
32.4 (t, J = 25.8 Hz), 21.8, 13.8. 19F NMR (376 MHz, Chloroform-d) δ
-104.6; Melting Point: 88~90 °C; HRMS (ESI) m/z Calcd for
C16H15F2NO4H+ 324.1042; found 324.1046.
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