M. Päiviö et al. / Tetrahedron: Asymmetry 23 (2012) 230–236
235
4.3. Preparative-scale solvent-free kinetic resolution of rac-1a–i
4.3.10. Compound (R)-2e
White solid in 37% yield {ee = 99%, ½a D25
ꢁ
¼ ꢀ30:0 (c 2, MeOH);
One of the amines rac-1a–i (2 mmol) and isopropyl methoxyac-
etate (2 mmol) were added into a reaction vessel containing
Novozym 435 (25 mg) and molecular sieves (4 Å, 50 mg). The reac-
tion mixture was shaken (170 rpm) at room temperature (23 °C) if
not otherwise stated. The reaction was stopped by filtering off the
enzyme at (50 0.5)% conversion. Isolation of the products was
performed by silica gel chromatography using a mixture of hexane
and ethylacetate and/or mixture of dichloromethane and methanol
as eluent.
lit.26
½
a 2D5
ꢁ
¼ þ30:8, ee = 99.1% (c 2, MeOH)}. HRMS [M+Na]+ found
([M+Na]+ calculated for C15H17NO2Na): 266.1161 (266.1152). The
NMR data identical with those reported in the literature.26
4.3.11. Compound (S)-1f
Light yellow oil in 41% yield {ee = 99%, ½a D25
¼ ꢀ9:4 (c 1, CHCl3);
ꢁ
lit.30
½aꢁD ¼ ꢀ6:7, ee >99% (c 0.5, CHCl3)}.
4.3.12. Compound (R)-2f
White solid in 45% yield {mp 69–70 °C, ee = 99%, ½a D25
¼ þ93:5
ꢁ
4.3.1. Compound (S)-1a
(c 1, CHCl3); ½a 2D5
ꢁ
¼ þ103 (c 2, MeOH); lit.26
½
a 2D5
ꢁ
¼ þ107:4 (c 2,
Clear oil in 35% yield {ee = 98%, ½a D25
ꢁ
¼ ꢀ30:6 (c 1, CHCl3); lit.27
MeOH)}. HRMS [M+Na]+ found ([M+Na]+ calculated for C12H17NO2-
Na): 230.1177 (230.1152); 1H NMR (DMSO, 500 MHz), d (ppm):
8.12 (d, J = 8.5 Hz, 1H, NH), 7.31 (m, 4H, ArH), 7.21 (tt, J = 7.0 Hz,
J = 2.0 Hz, 1H, ArH), 4.73 (q, J = 8.5 Hz, J = 6.5 Hz, 1H, CH), 3.82 (q,
J = 4.5 Hz, 2H, OCH2), 3.30 (s, 3H, OCH3), 1.74 (m, J = 6.5 Hz,
J = 7.0 Hz, 2H, CH2), 0.83 (t, J = 7.0 Hz, 3H, CH3); 13C NMR (DMSO,
126 MHz), d (ppm): 168.29 (CO), 143.52 (C(10)), 128.07, 126.57,
126.49 (C(20), C(30), C(40), C(50), C(60)), 71.41 (OCH2), 58.41
(OCH3), 53.70 (CH), 28.65 (CH2), 11.06 (CH3).
½
a 2D5
ꢁ
¼ ꢀ32:7, ee >99% (c 1.04, CHCl3)}.
4.3.2. Compound (R)-2a
White solid in 48% yield {ee = 97%, ½a D25
¼ þ101 (c 1, CHCl3);
ꢁ
lit.26
½
a 2D5
ꢁ
¼ þ110, ee = 99% (c 2, MeOH)}. HRMS [M+Na]+ found
([M+Na]+ calculated for C11H15NO2Na): 216.1028 (216.0995). The
NMR data identical with those reported in the literature.26
4.3.3. Compound (S)-1b
Light yellow oil in 37% yield {ee >99%, ½a D25
ꢁ
¼ ꢀ24:4 (c 1,
4.3.13. Compound (S)-1g
CHCl3)}.
Pale yellow semisolid in 39% yield {ee >99%, ½a D25
ꢁ
¼ þ20:8 (c 1,
CHCl3) lit.31
½
a 2D5
ꢁ
¼ þ20:0, ee = 96% (c 1.0, CHCl3)}.
4.3.4. Compound (R)-2b
White solid in 39% yield {mp 68–69 °C, ee = 97%, ½a D25
ꢁ
¼ þ84:7
4.3.14. Compound (R)-2g
(c 1, CHCl3)}. HRMS [M+Na]+ found ([M+Na]+ calculated for
White solid in 44% yield {mp 63 °C, ee = 95%, ½a D25
ꢁ
¼ þ62:2 (c 1,
C
11H14FNO2Na): 234.0921 (234.0901); 1H NMR (DMSO,
CHCl3), ½a 2D5
ꢁ
¼ þ105 (c 2, MeOH); lit.26
½
a 2D5
ꢁ
¼ þ112:4 (c 2, MeOH),
500 MHz), d (ppm): 8.20 (d, 1H, NH), 7.37 (2H, ArH), 7.13 (2H,
ArH), 4.99 (quint., J = 7.0 Hz, 1H, CH), 3, 1 (2H, CH2), 3.30 (s, 3H,
OCH3), 1.38 (d, J = 7.0 Hz, 3H, CH3); 13C NMR (DMSO, 126 MHz), d
(ppm): 167.97 (CO), 161.87, 159. 94 (d, arom C), 140.64 (arom C),
127.99, 127.92 (arom CH), 114.85, 114.68 (arom CH), 71.38 (CH2),
58.42 (OCH3), 46.73 (CH), 21.98 (CH3).
ee = 98.2%}. HRMS [M+Na]+ found ([M+Na]+ calculated for
C
12H15NO2Na): 228.1002 (228.0995). The NMR data identical with
those reported in the literature.26
4.3.15. Compound (S)-1h
Pale yellow semisolid in 34% yield {ee = 98%, ½a D25
ꢁ
¼ þ34:7 (c 1,
CHCl3); lit.33
½
a 2D5
ꢁ
¼ þ27:9 (c 0.51, MeOH), ee>99.5%}.
4.3.5. Compound (S)-1c
Pale yellow oil in 46% yield {ee >99%, ½a D25
ꢁ
¼ ꢀ28:4 (c 1, CHCl3);
4.3.16. Compound (R)-2h
lit.28
½
a 2D5
ꢁ
¼ ꢀ23:7, ee >99% (c 2, MeOH)}.
Solid in 45% yield (mp 87 °C, ee = 99%, ½a D25
ꢁ
¼ þ75:7 (c 1,
CHCl3)}. HRMS [M+Na]+ found ([M+Na]+ calculated for C12H15NO2-
Na): 242.1179 (242.1152); 1H NMR (DMSO, 500 MHz), d (ppm):
8.01 (d, J = 9.0 Hz, 1H, NH), 7.14 (arom., m, 3H), 7.08 (arom., m,
1H), 5.03 (m, 1H, CHNH2), 3.87 (s, 2H, CH2), 3.30 (s, 3H, OCH3),
2.67–79 (m, 2H), 2.87 (m, 2H), 1.67–1.78 (m, 2H); 13C NMR
4.3.6. Compound (R)-2c
White solid in 47% yield {mp 79–80 °C, ee = 98%, ½a D25
¼ þ102 (c
ꢁ
1, CHCl3)}. HRMS [M+Na]+ found ([M+Na]+ calculated for
C
11H14ClNO2Na): 250.0597 (250.0605); 1H NMR (DMSO,
500 MHz), d (ppm): 8.23 (d, J = 8.0 Hz, 1H, NH), 7.36 (4H, ArH),
4.98 (quint., J = 7.0 Hz, 1H, CH), 3.81 (2H, CH2), 3.30 (s, 3H,
OCH3), 1.37 (d, J = 7.0 Hz, 3H, CH3); 13C NMR (DMSO, 126 MHz), d
(ppm): 168.06 (CO), 143.51 (arom C), 131.05 (arom C), 128.04
(arom CH), 127.94 (arom CH), 71.37 (CH2), 58.43 (OCH3), 46.83
(CH), 21.79 (CH3).
(126 MHz, DMSO): d 168.35 (CO), 137.33, 137.02 (arom C),
128.62, 127.67, 126.55, 125.72 (arom CH), 71.33 (CH2), 58.41
(OCH3), 46.05 (CHNH2), 29.57 (C(2)), 28.67 (C(2)), 20.20 (C(3)).
4.3.17. Compound (S)-1i
Pale yellow oil in 45% yield {ee >99%, ½a D25
ꢁ
¼ þ4:1 (c 1, CHCl3);
lit.32
½
a 2D5
ꢁ
¼ þ6:4 (c 0.47, CHCl3), ee = 98%}.
4.3.7. Compound (S)-1d
Light yellow oil in 45% yield {ee >99%, ½a D25
ꢁ
¼ ꢀ30:5 (c 1,
4.3.18. Compound (R)-2i
CHCl3)}.
White solid in 48% yield (ee = 98%, ½a D25
ꢁ
¼ þ34:1 (c 1, CHCl3)}.
HRMS [M+Na]+ found ([M+Na]+ calculated for C12H15NO2Na):
244.1328 (244.1308). The NMR data were identical with those re-
ported in the literature.26
4.3.8. Compound (R)-2d
White solid in 45% yield {ee = 98%, ½a D25
ꢁ
¼ þ105 (c 1, CHCl3),
½
a 2D5
ꢁ
¼ þ119:7 (c 2, MeOH); lit.26
½
a 2D5
ꢁ
¼ þ124 (c 2, MeOH),
ee = 99.1%}. HRMS [M+Na]+ found ([M+Na]+ calculated for
4.4. Preparation of a sol–gel CAL-B catalyst
C
11H14ClNO2Na): 230.1182 (230.1152). The NMR data identical
with those reported in the literature.26
Phosphate buffer (0.1 M, pH 7.5, 390 lL producing gel/water
with a ratio of 1:10) and possible additives (Celite 50 mg, Celite
50 mg together with sucrose 5 mg or 18-crown-6 (0.5 mmol,
132 mg), 18-crown-6 (0.5 mmol, 132 mg) together with Celite
4.3.9. Compound (S)-1e
Yellow oil in 35% yield {ee >99%, ½a D25
ꢁ
¼ ꢀ59:2 (c 2, MeOH); lit.29
½
a 2D5
ꢁ
¼ ꢀ18:0, ee = 90% (c 1.0, EtOH)}.
50 mg) were added to a vial containing the CAL-B powder