J. L. Viveros-Ceballos et al. / Tetrahedron: Asymmetry 22 (2011) 1479–1484
1483
reaction was monitored by TLC. The crude product was analyzed
by 1H and 31P NMR spectroscopy. Finally, the crude product was
purified by column chromatography.
(CH3O)2P), 3.60 (d, J = 10.8 Hz, 3H, (CH3O)2P), 3.61⁄ (d, J = 11.2 Hz,
3H, (CH3O)2P), 3.73⁄ (d, J = 11.2 Hz, (CH3O)2P), 4.03 (d, J = 13.6,
Hz, 1H, CHP(OCH3)2), 4.83⁄ (d, J = 12.4, Hz, 1H, CHP(OCH3)2),
6.27⁄ (q, J = 7.6 Hz, 1H, NCHCH3), 6.35 (q, J = 7.2 Hz, 1H, CH–CH3),
7.26–7.62 (m, 13H, Harom), 7.75–8.29 (m, 9H, Harom). 13C NMR
(100 MHz, CDCl3) d: 18.3 (CH3–CH), 19.7⁄ (CH3–CH), 49.4 (CH–
CH3), 52.2⁄(CH–CH3), 53.6 (d, J = 6.0 Hz, (CH3O)2P), 53.8 (d,
J = 7.5 Hz, (CH3O)2P), 54.3⁄ (d, J = 6.0 Hz, (CH3O)2P), 56.6 (d,
J = 154.7 Hz, CH-P), 58.7⁄ (d, J = 154.7 Hz, CH-P), 122.5, 122.8⁄,
124.0⁄, 124.1, 124.9, 125.0, 125.2, 125.6⁄, 125.8, 126.7⁄, 126.9,
127.3, 128.3, 128.9, 129.0, 129.1, 129.2, 131.2, 131.6⁄, 131.8⁄,
131.9⁄, 133.7, 134.0⁄,134.1, 137.5, 139.4, 169.7, 170.3⁄. 31P NMR
(81 MHz, CDCl3) d: 21.6⁄, 21.8. HRMS [FAB+]: Calcd C22H23NO4P
396.1365. Found 396.1367.
4.2.1. Dimethyl (3R,10S)-2-(10-methylbenzyl)isoindolin-1-one-3-
yl)phosphonate (3R,10S)-3a
2-Formylbenzoic acid (2.5 g, 17 mmol), (S)-a-methylbenzyl-
amine (2.2 g, 2.5 mL, 18 mmol) and dimethyl phosphite (2.3 g,
3.0 mL, 21 mmol) were stirred at 80 °C for 1.0 h. The product
(R,S)-3a was obtained (4.3 g, 75%) as a white solid in a 95:05 dr.
The major diastereoisomer was crystallized in a methanol–dichlo-
romethane mixture. Mp 193–194 °C. [
a]
D = ꢀ19.2 (c 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3) d: 2.05 (d, J = 7.6 Hz, 3H, CH3CH), 3.52 (d,
J = 10.6 Hz, 3H, (CH3O)2P), 3.61 (d, J = 10.6 Hz, 3H, (CH3O)2P), 4.91
(d, J = 12.8 Hz, 1H, CHP(OMe)2), 5.35 (q, J = 7.2 Hz, 1H, NCHCH3),
7.20–7.86 (m, 9H, Harom). 13C NMR (100 MHz, CDCl3) d: 18.6
(CH3CH), 53.8 (d, J = 7.6 Hz, (CH3O)2P), 54.0 (d, J = 7.6 Hz,
(CH3O)2P), 55.5 (CHCH3), 58.3 (d, J = 156.2 Hz, CHP(OMe)2), 124.0,
124.5, 127.3, 127.5, 128.6, 129.1, 131.8, 133.3, 138.6, 141.8, 169.8
(C@O). 31P NMR (81 MHz, CDCl3) d: 21.4. HRMS [CI+]: Calcd
4.2.5. Dimethyl (3S,20R)- and (3R,20R)-2-(20-phenyl-ethanol)iso-
indolin-1-one-3-yl)phosphonate 3d
2-Formylbenzoic acid (200 mg, 1.33 mmol), (R)-2-phenylglycin-
ol (192 mg, 1.40 mmol), and dimethyl phosphite (154 mg, 0.13 mL,
1.40 mmol) were stirred at 80 °C for 2 h. The diastereoisomeric
mixture 3d was obtained (337 mg, 70%) as a white solid in 53:47
dr, which was purified by flash column chromatography (AcOEt/
hexane = 1:1).
C
C
18H21NO4P 346.1208. Found 346.1209. Anal. Calcd for
18H20NO4P: C, 62.60; H, 5.84; N, 4.06. Found: C, 62.96; H, 5.54;
N, 4.25.
Less polar diastereoisomer (3S,20R): Mp 106–108 °C. [
a]D = +64
4.2.2. Dimethyl (3S,10R)-2-(10-methylbenzyl)isoindolin-1-one-3-
yl)phosphonate (3S,10R)-3a
(c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) d: 3.65 (d, J = 10.3 Hz,
3H, (CH3O)2P), 3.76 (d, J = 11.3 Hz, 3H, (CH3O)2P), 4.18 (dd,
J = 12.8, 3.6 Hz, 1H, CH2CH), 4.54 (dd, J = 12.8, 8.0 Hz, 1H, CHCH2),
4.71 (d, J = 13.6 Hz, 1H, CHP(OCH3)2), 5.38 (dd, J = 8.0, 3.6 Hz, 1H,
CH2CH), 7.24–7.34 (m, 5H, Harom), 7.53–7.65 (m, 3H, Harom), 7.91
(d, J = 7.6 Hz, 1H, Harom). 13C NMR (100 MHz, CDCl3) d: 53.8 (d,
J = 7.6 Hz, (CH3O)2P), 54.5 (d, J = 7.6 Hz, (CH3O)2P), 59.0 (d,
J = 153.2 Hz, CHP(OCH3)2), 64.6 (CHCH2), 64.7 (CH2CH), 124.3,
124.5, 127.4, 128.2, 129.0, 129.3, 132.3, 132.5, 137.7, 139.0,
170.6. 31P NMR (81 MHz, CDCl3) d: 20.9. HRMS [FAB+]: Calcd
2-Formylbenzoic acid (2.5 g, 17 mmol), (R)-a-methylbenzyl-
amine (2.2 g, 2.5 mL, 18 mmol) and dimethyl phosphite (2.3 g,
3.0 mL, 21 mmol) were stirred at 80 °C for 1.0 h. The product
(R,S)-3a was obtained (4.2 g, 73%) as a white solid in 95:05 dr.
The major diastereoisomer was crystallized in a methanol–dichlo-
romethane mixture. Mp 193–194 °C. [a]D = +19.2 (c 1.0, CHCl3).
Spectroscopy data for (S,R)-3a were identical to (R,S)-3a.
4.2.3. Dimethyl (3R,10S)- and (3S,20S)-2-(10-methyl-p-methoxy-
benzyl)isoindolin-1-one-3-yl)phosphonate 3b
C
18H21NO5P 362.1157. Found 362.1170.
More polar diastereoisomer (3R,20R): Mp 165–168 °C. [
a]D = +32
2-Formylbenzoic acid (200 mg, 1.33 mmol), (S)-4-methoxy-
a
-
(c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) d: 3.42 (d, J = 11.2 Hz, 3H,
(CH3O)2P), 3.45 (d, J = 11.0 Hz, 3H, (CH3O)2P), 4.13 (dd, J = 11.2,
4.4 Hz, 1H, CH2CH), 4.66 (dd, J = 11.2, 9.6 Hz, 1H, CHCH2), 4.92 (d,
J = 13.6, Hz, 1H, CHP(OCH3)2), 5.29 (dd, J = 9.6, 4.4 Hz, 1H, CH2CH),
7.24–7.84 (m, 9H, Harom). 13C NMR (100 MHz, CDCl3) d: 53.8 (d,
J = 6.1 Hz, (CH3O)2P), 53.8 (d, J = 7.6 Hz, (CH3O)2P), 60.0 (d,
J = 156.3 Hz, CHP(OCH3)2), 63.2 (CHCH2), 63.4 (CH2CH), 124.0,
124.5, 127.7, 128.3, 128.5, 129.2, 132.1, 132.3, 137.3, 139.0, 170.9
31P NMR (81 MHz, CDCl3) d: 21.4. HRMS [FAB+]: Calcd C18H21NO5P
362.1157. Found 362.1169. Anal. Calcd for C18H20NO5P: C, 59.83;
H, 5.58; N, 3.88. Found C, 59.67; H, 5.38; N, 3.91.
methylbenzylamine (212 mg, 0.21 mL, 1.40 mmol), and dimethyl
phosphite (154 mg, 0.13 mL, 1.40 mmol) were stirred at 80 °C for
1 h. The diastereoisomeric mixture 3b was obtained (365 mg,
73%) as a white solid in 56:44 dr. Asterik denotes minor diastereo-
isomer. 1H NMR (400 MHz, CDCl3), d: 1.86⁄ (d, J = 7.4 Hz, 3H,
CH3CH), 2.03 (d, J = 7.0 Hz, 3H, CH3CH), 3.46–3.70 (m, 12H,
(CH3O)2P), 3.76 (s, 3H, CH3OPh), 3.80⁄ (s, 3H, CH3OPh), 4.61⁄ (d,
J = 13.6 Hz, 1H, CHP(OCH3)2), 4.90 (d, J = 13.2, Hz, 1H, CH-P), 5.27
(q, J = 7.6 Hz, 1H, NCHCH3), 5.57⁄ (q, J = 7.2 Hz, 1H, CHCH3), 6.81–
6.89 (m, 4H,
H
arom), 7.37–7.88 (m, 12H, Harom). 13C NMR
(100 MHz, CDCl3) d: 18.0⁄ (CH3), 18.8 (CH3), 53.3 (CH3–O), 53.7⁄
(d, J = 6.1 Hz, (CH3O)2P), 53.8 (d, J = 7.6 Hz, (CH3O)2P), 55.2⁄ (CH–
CH3), 55.4 (CH–CH3), 57.2⁄ (d, J = 156.2 Hz, CHP(OCH3)2), 58.4 (d,
J = 156.3 Hz, CHP(OCH3)2), 123.9, 124.5, 124.8⁄, 128.6, 129.0,
129.5, 131.7, 132.0⁄, 132.6⁄, 133.5⁄, 134.0⁄, 138.6, 139.2⁄, 158.9,
159.0⁄, 169.6. 31P NMR (81 MHz, CDCl3) d: 21.5, 21.9⁄. HRMS
[FAB+]: Calcd C19H23NO5P 376.1314. Found 376.1304. Anal. Calcd
for C19H22NO5P: C, 60.80; H, 5.91; N, 3.73. Found C, 60.45; H,
5.68; N, 3.79.
4.2.6. Dimethyl (3R,20S)-2(20-(3,3-dimethylbuthyl)isoindolin-1-
one-3-yl)phosphonate 3e
2-Formylbenzoic acid (200 mg, 1.33 mmol), (S)-3,3-dimethyl-2-
butylamine (142 mg, 0.2 mL, 1.40 mmol), and dimethyl phosphite
(154 mg, 0.15 mL, 1.40 mmol) were stirred at 80 °C for 3 h. Com-
pound 3e was obtained (170 mg, 40%) as a white solid in a
>98:02 dr. Mp 144–147 °C. [a]
D = +9.2 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 1.02 (s, 9H, (CH3)3), 1.72 (d, J = 6.8 Hz, 3H,
CH3CH), 3.55 (d, J = 10.4 Hz, 3H, (CH3O)2P), 3.72 (d, J = 10.8 Hz,
3H, (CH3O)2P), 3.76 (q, J = 7.2 Hz, 1H, NCHCH3), 4.91 (d,
J = 12.8 Hz, 1H, CHP(OMe)2), 7.48–7.83 (m, 4H, Harom). 13C NMR
(100 MHz, CDCl3) d: 13.6 (CH3CH), 28.3 ((CH3)3), 53.8 (d,
J = 7.6 Hz, (CH3O)2P), 53.9 (d, J = 6.1 Hz, (CH3O)2P), 61.7 (d,
J = 151.7 Hz, CHP(OMe)2), 62.8 (NCHCH3), 123.7, 124.4, 129.0,
131.3, 134.1, 138.0, 169.1 31P NMR (81 MHz, CDCl3) d: 21.9. HRMS
[FAB+]: Calcd C16H25NO4P 326.1521. Found 326.1530. Anal. Calcd
for C16H24NO4P: C, 59.07; H, 7.44; N, 4.31. Found C, 59.42; H,
7.12; N, 4.48.
4.2.4. Dimethyl (3R,10S)- and (3S,10S)-2-(10-(naphthalen-1-yl)
ethyl)isoindolin-1-one-3-yl)phosphonate 3c
2-Formylbenzoic acid (200 mg, 1.33 mmol), (S)-1-(1-naph-
thyl)ethylamine (240 mg, 0.23 mL, 1.40 mmol), and dimethyl
phosphite (154 mg, 0.13 mL, 1.40 mmol) were stirred at 80 °C for
2 h. The diastereoisomeric mixture 3c was obtained (362 mg,
70%) as a yellow oil in 75:25 dr. Asterik denotes minor diastereo-
isomer. 1H NMR (400 MHz, CDCl3), d: 2.09 (d, J = 7.2 Hz, 3H,
CH3CH), 2.24⁄ (d, J = 7.2 Hz, 3H, CH3CH), 3.43 (d, J = 10.8 Hz, 3H,