C. Fäh, R. Mathys, L. A. Hardegger, S. Meyer, D. Bur, F. Diederich
910, 856, 818, 730, 717, 648 cm–1. MALDI-MS: m/z (%): calcd. for
FULL PAPER
[M + H]+); calcd. for C32H35F2NO2Na+ 526.2528; found 526.2524
(76, [M + Na]+); calcd. for C32H35F2NO2K+ 542.2267; found
542.2269 (69, [M + K]+).
C42H45F5NO4 722.3263; found 722.3269 (55, [M + H]+); calcd.
+
for C42H44F5NO4Na+ 744.3083; found 744.3075 (100, [M + Na]+);
calcd. for C42H44F5NO4K+ 760.2822; found 760.2820 (72,
[M + K]+).
(1S,4S)-4-({[4-(2-Cyclopentylethyl)phenyl][2-(2-naphthyl)ethyl]-
amino}carbonyl)-2,2-difluorocyclohexyl (2S)-3,3,3-Trifluoro-2-meth-
oxy-2-phenylpropanoate [(–)-20] and (1R,4R)-4-({[4-(2-Cyclopent-
(1S,4R)-4-({[4-(2-Cyclopentylethyl)phenyl][2-(2-naphthyl)ethyl]-
ylethyl)phenyl][2-(2-naphthyl)ethyl]amino}carbonyl)-2,2-difluoro- amino}carbonyl)-2,2-difluorocyclohexyl (2S)-3,3,3-Trifluoro-2-meth-
cyclohexyl (2S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate [(–)-
21]: To a solution of (–)-(R)-Mosher acid chloride (28 µL, 38 mg,
0.15 mmol) in THF (1 mL) under Ar at 0 °C, alcohol (Ϯ)-18
(50 mg, 0.10 mmol) and DMAP (15 mg, 0.12 mmol) were added,
and the mixture was stirred at 22 °C for 6 h. The solution was
treated with saturated aqueous NaHCO3 solution (2 mL) and the
aqueous phase extracted with CH2Cl2 (3ϫ4 mL). The combined
organic phases were dried with MgSO4, filtered, and concentrated
in vacuo. The resulting diastereoisomers were separated by HPLC
(Hibar, Si60; EtOAc/n-hexane, 1:4). The diastereoisomers (–)-20
(31 mg, 43%) and (–)-21 (31 mg, 43%) resulted as colorless wax,
eluting in the given order.
oxy-2-phenylpropanoate [(+)-22] and (1R,4S)-4-({[4-(2-Cyclopent-
ylethyl)phenyl][2-(2-naphthyl)ethyl]amino}carbonyl)-2,2-difluoro-
cyclohexyl (2S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate [(–)-
23]: To a solution of (–)-(R)-Mosher acid chloride (39 µL, 53 mg,
0.21 mmol) in THF (1 mL) under Ar at 0 °C, alcohol (Ϯ)-19
(70 mg, 0.14 mmol) and DMAP (25 mg, 0.21 mmol) were added,
and the mixture was stirred at 22 °C for 6 h. The solution was
treated with saturated aqueous NaHCO3 solution (2 mL) and the
aqueous phase extracted with CH2Cl2 (3ϫ4 mL). The combined
organic phases were dried with MgSO4, filtered, and concentrated
in vacuo. The resulting diastereoisomers were separated by HPLC
(Hibar, Si60; EtOAc/n-hexane, 1:4). The diastereoisomers (+)-22
(46 mg, 46%) and (–)-23 (46 mg, 46%) resulted as colorless wax,
eluting in the given order.
(–)-20: [α]2D0 = –27.2 (c = 1.00, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.03–1.09 (m, 2 H), 1.20–1.31 (m, 1 H), 1.40–1.47 (m,
2 H), 1.50–1.59 (m, 4 H), 1.62–1.66 (m, 2 H), 1.67–1.74 (m, 3 H),
1.81–1.86 (m, 1 H), 2.03–2.08 (m, 1 H), 2.03–2.17 (m, 1 H), 2.37–
2.45 (m, 1 H), 2.56 (t, J = 8.0 Hz, 2 H), 2.93–2.97 (m, 2 H), 3.47
(d, J = 1.0 Hz, 3 H), 3.84–3.96 (m, 2 H), 5.04–5.14 (m, 1 H), 6.84,
7.10 (AAЈBBЈ, J = 8.3 Hz, 4 H), 7.23 (dd, J = 1.7, 8.4 Hz, 1 H),
7.26–7.30 (m, 3 H), 7.33–7.39 (m, 2 H), 7.41–7.43 (m, 2 H), 7.53
(s, 1 H), 7.65–7.68 (m, 2 H), 7.71–7.73 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.20, 26.42, 26.99 (d, J = 5.8 Hz), 32.68,
(+)-22: [α]2D0 = +25.8 (c = 1.00, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.12–1.17 (m, 2 H), 1.40–1.45 (m, 1 H), 1.49–1.58 (m,
4 H), 1.55–1.68 (m, 4 H), 1.75–1.87 (m, 4 H), 1.93–1.99 (m, 1 H),
2.17–2.34 (m, 1 H), 2.44–2.50 (m, 1 H), 2.66 (t, J = 7.9 Hz, 2 H),
2.95–3.07 (m, 2 H), 3.56 (s, 3 H), 3.87–4.02 (m, 2 H), 5.21 (s, 1 H),
6.96, 7.19 (AAЈBBЈ, J = 8.3 Hz, 4 H), 7.29 (dd, J = 1.7, 8.4 Hz, 1
H), 7.40–7.46 (m, 5 H), 7.52–7.55 (m, 2 H), 7.59 (s, 1 H), 7.71–7.74
(m, 2 H), 7.78–7.80 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
34.06, 34.72, 36.20 (t, J = 22.7 Hz), 37.47 (d, J = 9.2 Hz), 37.74, δ = 22.02, 25.23, 26.85 (d, J = 5.4 Hz), 32.66 (t, J = 22.9 Hz),
39.80, 50.98, 55.54, 72.67 (t, J = 20.3 Hz), 84.75 (d, J = 28.0 Hz), 32.70, 34.06, 34.75, 37.79, 39.79, 51.08, 55.44, 70.06 (dd, J = 22.3,
119.83 (dd, J = 245.7, 247.2 Hz), 123.14 (d, J = 288.8 Hz), 125.43,
40.6 Hz), 84.86 (d, J = 18.1 Hz), 120.26 (dd, J = 238.3, 252.2 Hz),
126.04, 127.15, 127.20, 127.32, 127.41, 127.55, 127.62, 128.03, 123.27 (d, J = 288.5 Hz), 125.38, 125.99, 127.15, 127.30, 127.36,
128.34, 129.58, 129.85, 132.04, 132.23, 133.54, 136.05, 139.33, 127.42, 127.61, 127.65, 127.99, 128.52, 129.76, 129.80, 131.83,
143.70, 165.65, 172.45 ppm. 19F NMR (376 MHz, CDCl3): δ =
–115.92 (d, J = 239.9 Hz, 1 F), –102.83 (d, J = 239.3 Hz, 1 F),
132.22, 133.55, 136.13, 139.49, 143.54, 165.33, 172.55 ppm (one sig-
nal in the aromatic region is not visible due to overlap). 19F NMR
(376 MHz, CDCl3): δ = –105.88 (d, J = 255.7 Hz, 1 F), –101.34 (d,
–71.90 (s, 3 F) ppm. IR (neat): ν = 2946, 2863, 1753, 1652, 1603,
˜
1510, 1451, 1409, 1363, 1330, 1241, 1168, 1096, 1045, 1000, 955,
J = 255.7 Hz, 1 F), –71.44 (s, 3 F) ppm. IR (neat): ν = 2845, 2862,
1758, 1655, 1510, 1439, 1408, 1363, 1318, 1238, 1170, 1123, 1102,
˜
856, 818, 744, 716, 696 cm–1. MALDI-MS: m/z (%): calcd. for
C42H45F5NO4 722.3263; found 722.3271 (100, [M + H]+); calcd. 1018, 948, 909, 855, 818, 730, 717, 697 cm–1. MALDI-MS: m/z (%):
+
for C42H45F5NO4Na+ 744.3083; found 744.3082 (86, [M + Na]+);
calcd. for C42H45F5NO4 722.3263; found 722.3261 (74,
+
calcd. for C42H45F5NO4K+ 760.2822; found 760.2833 (57, [M + H]+); calcd. for C42H44F5NO4Na+ 744.3083; found 744.3071
[M + K]+).
(90, [M + Na]+); calcd. for C42H44F5NO4K+ 760.2822; found
760.2810 (100, [M + K]+).
(–)-21: [α]2D0 = –2.8 (c = 1.00, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 1.04–1.10 (m, 2 H), 1.38–1.48 (m, 3 H), 1.52–1.60 (m, 4 H), (–)-23: [α]2D0 = –46.6 (c = 1.00, CHCl3). 1H NMR (400 MHz,
1.64–1.75 (m, 5 H), 1.93–1.98 (m, 1 H), 2.02–2.09 (m, 1 H), 2.03–
2.16 (m, 1 H), 2.39–2.47 (m, 1 H), 2.57 (t, J = 7.9 Hz, 2 H), 2.92–
2.99 (m, 2 H), 3.39 (d, J = 0.7 Hz, 3 H), 3.90 (dt, J = 4.0, 7.9 Hz,
CDCl3): δ = 1.03–1.10 (m, 2 H), 1.42–1–50 (m, 3 H), 1.53–1.60 (m,
4 H), 1.63–1.76 (m, 5 H), 1.80–1–87 (m, 2 H), 2.03–2.19 (m, 1 H),
2.38–2.44 (m, 1 H), 2.58 (t, J = 7.9 Hz, 2 H), 2.90–2.98 (m, 2 H),
2 H), 5.05–5.15 (m, 1 H), 6.85, 7.11 (AAЈBBЈ, J = 8.3 Hz, 4 H), 3.48 (d, J = 0.9 Hz, 3 H), 3.81–3.94 (m, 2 H), 5.17 (s, 1 H), 6.85,
7.23 (dd, J = 1.7, 8.4 Hz, 1 H), 7.27–7.33 (m, 3 H), 7.33–7.39 (m, 7.12 (AAЈBBЈ, J = 8.3 Hz, 4 H), 7.21 (dd, J = 1.8, 8.4 Hz, 1 H),
2 H), 7.41–7.43 (m, 2 H), 7.53 (s, 1 H), 7.65–7.68 (m, 2 H), 7.71– 7.31–7.37 (m, 5 H), 7.44–7.47 (m, 2 H), 7.52 (s, 1 H), 7.63–7.67 (m,
7.73 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.23, 26.48, 2 H), 7.69–7.72 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
27.28 (d, J = 1.7 Hz), 32.69, 34.06, 34.73, 36.20 (t, J = 22.8 Hz), 22.29, 25.23, 26.95 (d, J = 5.3 Hz), 32.56 (t, J = 23.0 Hz), 32.70,
37.48 (d, J = 9.0 Hz), 37.76, 39.80, 50.99, 55.29, 72.79 (t, J =
34.08, 34.75, 37.45 (d, J = 9.4 Hz), 37.80, 39.79, 51.07, 55.46, 69.92
20.4 Hz), 84.88 (d, J = 28.3 Hz), 119.67 (dd, J = 245.5, 247.6 Hz), (dd, J = 22.8, 40.4 Hz), 84.88 (d, J = 28.2 Hz), 120.08 (dd, J =
123.10 (d, J = 288.2 Hz), 125.43, 126.04, 127.15, 127.33, 127.41, 238.5, 253.0 Hz), 123.23 (d, J = 288.4 Hz), 125.39, 126.00, 127.15,
127.56, 127.62, 128.04, 128.33, 129.64, 129.86, 131.64, 132.24, 127.35, 127.41, 127.49, 127.61, 127.64, 128.00, 128.45, 129.74,
133.55, 136.06, 139.35, 143.70, 165.60, 172.46 ppm (one signal in
the aromatic region is not visible due to overlap). 19F NMR
(376 MHz, CDCl3): δ = –116.35 (d, J = 240.6 Hz, 1 F), –103.66 (d,
129.82, 131.65, 132.22, 133.56, 136.12, 139.48, 143.57, 165.22,
172.62 ppm. 19F NMR (376 MHz, CDCl3): δ = –105.78 (d, J =
255.2 Hz, 1 F), –102.26 (d, J = 255.2 Hz, 1 F), –71.79 (s, 3 F) ppm.
J = 240.7 Hz, 1 F), –72.41 (s, 3 F) ppm. IR (neat): ν = 2946, 2863,
IR (neat): ν = 2944, 2862, 1759, 1655, 1510, 1451, 1439, 1408, 1383,
˜
˜
1755, 1652, 1510, 1451, 1409, 1270, 1242, 1168, 1098, 1045, 955,
1363, 1318, 1239, 1170, 1103, 1018, 947, 909, 855, 818, 731, 717,
4626
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Eur. J. Org. Chem. 2010, 4617–4629