Organocatalysis with a Fluorous Tag
chloride (EDCI; 374 mg, 1.95 mmol). The reaction mixture was
stirred at 0 °C for 1 h and then at room temperature for 20 h. The
mixture was then diluted with ethyl acetate (75 mL) and washed
successively with water (30 mL), cold 0.5 M HCl (2 × 30 mL),
saturated NaHCO3 (2 × 30 mL), and brine (30 mL), dried over
anhydrous MgSO4, filtered, and evaporated. Purification by column
chromatography on silica gel with a petroleum ether-ethyl acetate
mixture (24:1, Rf 0.21) afforded (S)-(-)-15c (413 mg, 71%) as an
off-white solid: mp 102-104 °C; [R]D -111.8 (c 0.5, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 0.92 (d, J ) 6.6 Hz, 3H), 1.03 (d, J )
6.4 Hz, 3H), 1.23 (d, J ) 6.9 Hz, 12H), 1.49 (s, 9H), 2.30-2.43
(m, 1H), 2.83 (s, 3H), 2.85 (hept, J ) 7.0 Hz, 2H), 4.13 (d, J )
10.9 Hz, 1H), 6.83 (s, 1H), 7.22 (s, 2H), 8.18 (br s, 1H); 13C NMR
δ 18.58 (CH3), 19.93 (CH3), 23.92 (CH3), 25.83 (CH3), 28.36 (CH3),
30.34 (CH), 34.20 (CH), 65.98 (CH), 80.60 (C), 115.28 (CH),
120.67 (CH), 137.99 (C), 149.79 (C), 157.46 (CO), 168.61 (CO);
IR (KBr) ν 3321, 2964, 1691, 1659, 1614, 1557, 1156, 883, 861
cm-1; MS (EI) m/z (%) 390 (M•+, 15), 177 (61), 130 (100), 86
(73), 57 (54); HRMS (EI) 390.2883 (C23H38O3N2 requires 390.2882).
Amide (S)-(-)-15d. Triethylamine (0.63 mL, 4.50 mmol) was
added to a solution of (S)-14 (694 mg, 3.0 mmol) and 3,5-di-tert-
butylaniline (739 mg, 3.60 mmol) in dry dichloromethane (30 mL)
at 0 °C. To the resulting clear solution were consecutively added
1-hydroxybenzotriazole hydrate (HOBt; 620 mg, ca. 3.9 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI;
747 mg, 3.90 mmol). The reaction mixture was stirred at 0 °C for
1 h and then at room temperature for 20 h. The mixture was then
diluted with ethyl acetate (150 mL) and washed successively with
water (60 mL), cold 0.5 M HCl (2 × 60 mL), saturated NaHCO3
(2 × 60 mL), and brine (60 mL), dried over anhydrous MgSO4,
filtered, and evaporated. Purification by column chromatography
on silica gel with a petroleum ether-ethyl acetate mixture (22:1,
Rf 0.26) afforded (S)-(-)-15d (1.197 g, 95%) as an off-white
(m, 2F), -126.64 (m, 2F); MS (CI) m/z (%) 669 ([MH]•+, 27),
668 (42), 613 (47), 569 (45), 456 (100), 455 (100), 131 (49), 88
(49), 59 (48); HRMS (CI) 669.1997 (C25H30O4N2F13 [MH]•+
requires 669.1998).
Amide (S)-(-)-16b. Triethylamine (0.19 mL, 1.39 mmol) was
added to a solution of (S)-14 (217 mg, 0.94 mmol) in dry
dichloromethane (9 mL) at 0 °C. To the resulting clear solution
were consequently added aniline 13b (540 mg, 1.12 mmol),
1-hydroxybenzotriazole hydrate (HOBt; 190 mg, 1.22 mmol), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI;
234 mg, 1.22 mmol). The reaction mixture was stirred at 0 °C for
1 h and then at room temperature for 18 h. The mixture was then
diluted with ethyl acetate (50 mL) and washed successively with
water (20 mL), cold 0.5 M HCl (2 × 20 mL), saturated NaHCO3
(2 × 20 mL), and brine (20 mL) then dried over MgSO4 and
evaporated. The residue (540 mg) was purified by chromatography
on a column of silica gel (90 g) with a petroleum ether-ethyl acetate
mixture (12:1) to afford pure amide (S)-(-)-16b (380 mg, 58%)
as a yellowish oil: Rf 0.32 (petroleum ether-dichloromethane, 12:
1); [R]D -45.2 (c 0.5, EtOH); 1H NMR (400 MHz, CDCl3) δ 0.91
(d, J ) 6.6 Hz, 3H), 1.01 (d, J ) 6.3 Hz, 3H), 1.47 (s, 9H), 2.24
(s, 6H), 2.31-2.40 (m, 1H), 2.61 (tt, JH-H ) 6.5 Hz, JH-F ) 18.6
Hz, 2H), 2.84 (s, 3H), 3.99 (t, J ) 6.8 Hz, 2H), 4.10 (d, J ) 10.8
Hz, 1H), 7.18 (s, 2H), 8.21 (br s, 0.75H); 13C NMR δ 16.22 (CH3),
18.57 (CH3), 19.80 (CH3), 25.99 (CH3), 28.33 (CH3), 30.44 (CH),
31.78 (t, J ) 22 Hz, CH2), 63.73 (CH2), 65.91 (CH), 80.61 (C),
120.20 (CH), 131.28 (C), 134.03 (C), 151.61 (C), 157.40 (CO),
168.75 (CO); 19F NMR δ -81.28 (t, JF-F ) 10.3 Hz, 3F),
-113.75 (m, 2F), -122.34 (m, 2F), -123.30 (m, 2F), -124.05
(m, 2F), -126.60 (m, 2F); MS (CI) m/z (%) 719 ([MNa]•+, 56),
597 (38), 595 (16), 484 (100), 483 (100), 131 (100), 88 (100), 59
(94); HRMS (CI) 719.2124 (C27H33O4N2F13Na [MNa]•+ requires
719.2130).
Amide (S)-(-)-16c. Triethylamine (0.30 mL, 2.18 mmol) was
added to a solution of (S)-14 (350 mg, 1.51 mmol) in dry
dichloromethane (10 mL) at 0 °C. To the resulting clear solution
were consequently added aniline 13c (730 mg, 1.35 mmol),
1-hydroxybenzotriazole hydrate (HOBt; 270 mg, 1.75 mmol), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI;
330 mg, 1.72 mmol). The reaction mixture was stirred at 0 °C for
1 h and then at room temperature for 20 h. The mixture was then
diluted with ethyl acetate (60 mL) and washed successively with
water (30 mL), cold 0.5 M HCl (2 × 30 mL), saturated NaHCO3
(2 × 40 mL), and brine (30 mL) then dried over MgSO4 and
evaporated. The residue (1.05 g) was purified by chromatography
on a column of silica gel (50 g) with a petroleum ether-ethyl acetate
mixture (25:1 for the first 250 mL and then 19:1) to afford pure
amide (S)-(-)-16c (810 mg, 80%) as a white solid: Rf 0.60
(petroleum ether- thyl acetate, 9:1); mp 94-96 °C; [R]D -52.2
(c 0.5, EtOH); 1H NMR (400 MHz, CDCl3) δ 0.92 (d, J ) 6.6 Hz,
3H), 1.03 (d, J ) 6.4 Hz, 3H), 1.20-1.24 (m, 12 H), 1.49 (s, 9H),
2.32-2.42 (m, 1H), 2.65 (tt, JH-H ) 6.8 Hz, JH-F ) 18.6 Hz, 2H),
2.83 (s, 3H), 3.22 (hept, J ) 6.8 Hz, 2H), 3.98 (t, J ) 6.8 Hz, 2H),
4.12 (d, J ) 10.2 Hz, 1H), 7.25 (s, 2H), 8.19 (br s, 0.92H); 13C
NMR δ 18.61 (CH3), 19.97 (CH3), 23.86 (CH3), 25.84 (CH), 26.72
(CH), 28.35 (CH3), 30.38 (CH3), 31.92 (t, J ) 21.8 Hz, CH2), 66.11
(CH and CH2), 80.67 (C), 115.80 (CH), 135.06 (C), 142.31 (C),
148.98 (C), 157.52 (CO), 168.53 (CO); 19F NMR δ -81.27 (t,
JF-F ) 10.4 Hz, 3F), -113.79 (m, 2F), -122.37 (m, 2F), -123.38
(m, 2F), -124.06 (m, 2F), -126.62 (m, 2F); MS (EI) m/z (%) 752
(M•+, 35), 539 (92), 192 (66), 158 (65), 130 (100), 86 (62), 69
(60), 57 (55); HRMS (EI) 752.2853 (C31H41O4N2F13 requires
752.2859).
1
solid: mp 138-140 °C; [R]D -118.7 (c 1.0, CHCl3); H NMR
(400 MHz, CDCl3) δ 0.92 (d, J ) 6.6 Hz, 3H), 1.04 (d, J ) 6.4
Hz, 3H), 1.31 (s, 18H), 1.49 (s, 9H), 2.31-2.44 (m, 1H), 2.83 (s,
3H), 4.14 (d, J ) 11.2 Hz, 1H), 7.17 (s, 1H), 7.37 (s, 2H), 8.19 (br
s, 1H); 13C NMR δ 18.60 (CH3), 19.97 (CH3), 25.80 (CH3), 28.36
(CH3), 30.91 (CH), 34.89 (C), 65.97 (CH), 80.59 (C), 114.22 (CH),
118.28 (CH), 137.50 (C), 151.60 (C), 157.49 (CO), 168.59 (CO);
IR ν 3339, 2964, 1692, 1666, 1612, 1558, 1155 cm-1; MS (EI)
m/z (%) 418 (M•+, 14), 205 (78), 158 (16), 130 (100), 86 (76), 57
(61); HRMS (EI) 418.3198 (C25H42O3N2 requires 418.3195).
Amide (S)-(-)-16a. Triethylamine (0.45 mL, 3.27 mmol) was
added to a solution of (S)-14 (0.5 g, 2.16 mmol) in dry CH2Cl2 (15
mL) at 0 °C. To the resulting clear solution were consequently
added aniline 13a (890 mg, 1.95 mmol), 1-hydroxybenzotriazole
hydrate (HOBt; 430 mg, 2.75 mmol), and 1-(3-dimethylaminopro-
pyl)-3-ethylcarbodiimide hydrochloride (EDCI; 530 mg, 2.76
mmol). The reaction mixture was stirred at 0 °C for 1 h and then
at room temperature for 24 h. The mixture was then diluted with
ethyl acetate (110 mL) and washed successively with water (45
mL), cold 0.5 M HCl (2 × 45 mL), saturated NaHCO3 (2 × 45
mL), and brine (45 mL), dried over MgSO4, filtered, and evaporated.
The residue (1.18 g) was purified by chromatography on a column
of silica gel (50 g) with a hexane-ethyl acetate mixture (19:1, 600
mL), which eluted impurities. Continued elution with the same
mixture in 14:1 ratio afforded pure (S)-(-)-16a (880 mg, 68%) as
a slightly yellowish oil: Rf 0.3 (petroleum ether-ethyl acetate, 9:1);
[R]D -59.6 (c 0.5, EtOH); 1H NMR (400 MHz, CDCl3) δ 0.91 (d,
J ) 6.6 Hz, 3H), 1.02 (d, J ) 6.3 Hz, 3H), 1.48 (s, 9H), 2.33-
2.42 (m, 1H), 2.61 (tt, JH-H ) 6.8 Hz, JH-F ) 18.5 Hz, 2H), 2.83
(s, 3H), 4.09 (d, J ) 11.4 Hz, 1H), 4.25 (t, J ) 6.8 Hz, 2H), 6.85
(d, J ) 9.0 Hz, 2H), 7.43 (d, J ) 9.0 Hz, 2H), 8.20 (br s, 1H); 13
C
Amide (S)-(-)-16d. Triethylamine (0.30 mL, 2.18 mmol) was
added to a solution of (S)-14 (370 mg, 1.60 mmol) in dry
dichloromethane (7 mL) at 0 °C. To the resulting clear solution
were consequently added aniline 13d (440 mg, 1.44 mmol) in DCM
(3 mL), 1-hydroxybenzotriazole hydrate (HOBt; 280 mg, 1.83
mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hy-
NMR δ 18.57 (CH3), 19.83 (CH3), 25.96 (CH3), 28.33 (CH3), 30.89
(CH), 31.20 (t, J ) 21.5 Hz, CH2), 60.31 (CH2), 65.95 (CH), 80.65
(C), 114.90 (CH), 121.37 (CH), 131.99 (C), 154.55 (C), 157.43
(CO), 168.61 (CO); 19F NMR (CCl3F) δ -81.27 (t, JF-F ) 9.7 Hz,
3F), -113.82 (m, 2F), -122.37 (m, 2F), -123.37 (m, 2F), -124.07
J. Org. Chem, Vol. 72, No. 4, 2007 1323