ꢀ
O. Sanchez-Antonio et al. / Tetrahedron 75 (2019) 130594
8
1315, 1273, 1254, 1181, 1094, 1035, 1018, 900, 763, 695, 558, 512.
HRMS (ESI-TOF): m/z calculated for C18H21NO6 þ H: 348.1442;
[M þ Hþ]; found: 348.1446.
m, Har), 7.53e7.55 (2H, m, Har), 7.72e7.75 (2H, m, Har), 7.79e7.82
(2H, m, Har) 13C NMR (100.5 MHz, CDCl3) 14.1 (CH3), 29.3 (CH2), 29.8
(CH2), 53.0 (OCH3), 60.5 (OCH2), 66.7 (Cq), 123.4 (2 ꢂ CHar), 127.0
(2 ꢂ CHar), 128.1 (CHar), 128.2 (2 ꢂ CHar), 131.5 (Cipso), 134.3 (2 ꢂ
CHar), 136.3 (Cipso), 167.9 (NC]O), 170.0 (OC]O), 172.6 (OC]O). FT-
3.2.7. Triethyl (1R,2S,3S,10bS)-10b-hydroxy-6-oxo-1,2,3,4,6,10b-
hexahydropyrido[2,1-a]isoindole-1,2,3-tricarboxylate, (rac-7)
IR/ATR n
cmꢁ1: 3435, 3387, 2993, 2953, 1783, 1728, 1711, 1470, 1434,
The procedure described above was followed with 2 (250 mg,
1.01 mmol), diethyl fumarate (0.25 mL, 1.51 mmol), and LiHMDS
solution 1 M (1.3 mL, 1.3 mmol). The crude product was purified by
column chromatography (hexane/EtOAc 7:3 v/v) to afford 280 mg
(66% yield) of rac-7 as a colorless solid mp ¼ 138e140 ꢀC, Rf ¼ 0.25
(hexane/EtOAc 1:1 v/v). 1H NMR (400 MHz, CDCl3) 1.21 (3H, t,
J ¼ 7.1 Hz, CH3), 1.27 (3H, t, J ¼ 7.1 Hz, CH3), 1.28 (3H, t, J ¼ 7.1 Hz,
CH3), 2.56 (1H, d, J ¼ 12.1 Hz, CHax), 2.81 (1H, td, J ¼ 5.2, 11.9 Hz,
CHax), 3.23 (1H,dd, J ¼ 12.3, 13.2 Hz, NCHaxH), 3.57 (1H, t,
J ¼ 12.0 Hz, CHax), 4.01e4.26 (5H, m, OCH2), 4.29e4.37 (1H, m,
OCH2), 4.47 (1H, dd, J ¼ 5.2, 13.2 Hz, NCHHeq), 5.30 (br s, 1H, OH),
7.36e7.39 (1H, m, Har), 7.45e7.54 (2H, m, Har), 7.71e7.74 (1H, m,
Har). 13C NMR (100.5 MHz, CDCl3) 13.9 (2 ꢂ CH3), 14.0 (CH3), 35.7
(NCH2), 43.6 (CH), 43.7 (CH), 51.2 (CH), 61.4 (2 ꢂ OCH2), 62.2
(OCH2), 84.8 (CeOH), 121.9 (CHar), 123.9 (CHar), 130.0 (CHar), 130.4
(Cipso), 132.3 (CHar),145.8 (Cipso), 164.5 (NC]O),170.5 (OC]O),171.3
1375, 1247, 1226, 1114, 973, 902, 850, 720, 698, 649, 614. HRMS (ESI-
TOF) calculated for C22H21NO6 þ Hþ: 396.1442; [M þ Hþ]; found:
396.1443.
The rest of the fractions afforded 88 mg (33% yield) of a mixture
of diastereoisomeric products (rac-3a as the main component and
two more polar compounds).
3.3.3. Methyl (1R,3S,9bR)- and (1S,3R,9bS)-1-cyano-9b-hydroxy-5-
oxo-3-phenyl-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindole-3-
carboxylate, (rac-4a)
A mixture of rac-1 (200 mg, 0.677 mmol), acrylonitrile (67 mL,
1.02 mmol), and cesium carbonate (242 mg, 0.74 mmol) was milled
in a stainless-steel milling vial with two 11 mm diameter balls at
25 Hz for 90 min. After the milling was complete, the resulting
reaction mixture was extracted with EtOAc (3 ꢂ 20 mL) and the
combined organic extracts were washed with brine (30 mL) and
dried over anhydr. Na2SO4. The solvent was evaporated under
vacuum and the residue was purified by column chromatography
(hexane-EtOAc 8:2 v/v). TLC (hexane-EtOAc 7:3, eluted three times)
of the reaction crude showed four components with Rf ¼ 0.70, 0.38,
0.25, 0.20. The fraction with Rf ¼ 0.70 corresponded to starting
material rac-1 (60 mg was recovered). The fraction with Rf ¼ 0.38
was isolated and recrystallized from hexane-EtOAc (2:1 v/v) to
afford 70 mg (30% yield) of rac-4a as a colorless solid with mp
245e246 ꢀC. 1H NMR (400 MHz, CDCl3): 2.95 (1H, br s, OH), 3.40
(1H, dd, J ¼ 7.5, 12.1 Hz, CHH), 3.45 (1H, t, J ¼ 11.7 Hz, CHH), 3.55
(1H, dd, J ¼ 7.6, 11.1 Hz, CH), 3.69 (3H, s, OCH3), 7.33e7.46 (5H, m,
Har), 7.64 (1H, t, J ¼ 7.5 Hz, Har), 7.73 (1H, t, J ¼ 7.5 Hz, Har), 7.83 (1H,
d, J ¼ 7.2 Hz, Har), 7.84 (1H, d, J ¼ 7.4 Hz, Har). 13C NMR (100.5 MHz,
CDCl3) 36.2 (CH), 45.6 (CH2), 53.5 (OCH3), 69.0 (C), 95.0 (CeOH),
116.2 (CN), 122.7 (CHar), 124.7 (CHar), 126.9 (2 ꢂ CHar), 128.1 (CHar),
128.3 (2 ꢂ CHar), 131.2 (Cipso), 131.4 (CHar), 134.1 (CHar), 139.8 (CHar),
143.8 (CHar), 168.6 (NC]O), 171.5 (OC]O). HRMS (ESI-TOF): m/z
calculated for C20H16N2O4 þ Hþ: 349.1183; [M þ Hþ]; found:
349.1187.
(OC]O), 172.5 (OC]O). FT-IR/ATR n
cmꢁ1: 3268, 2986, 2936, 2910,
1738, 1723, 1677, 1470, 1426, 1396, 1375, 1314, 1213, 1178, 1113, 1091,
1011, 769, 697, 669, 567. HRMS (ESI-TOF): m/z calculated for
C
21H25NO8 þ Hþ: 420.1653; found: 420.1649.
3.3. Preparation of compounds rac-3a-b, rac-4a,d and rac-6a-c
under solvent-free ball-milling conditions
3.3.1. 1-Ethyl-3-methyl-(1S,3S,9bR)- and (1R,3R,9bS)-9b-hydroxy-
5-oxo-3-phenyl-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindole-
1,3-dicarboxylate, (rac-3a)
A mixture of phthalimide rac-1 (200 mg, 0.677 mmol), ethyl
acrylate (110 mL, 1.02 mmol), and cesium carbonate (242 mg,
0.74 mmol) was milled in a stainless-steel milling vial with two
11 mm diameter balls at 25 Hz for 90 min. The resulting reaction
mixture was extracted with EtOAc (3 ꢂ 20 mL) and the combined
organic extracts were washed with brine (30 mL) and dried over
anhydr. Na2SO4. The solvent was evaporated under vacuum and the
residue was purified by column chromatography (hexane-EtOAc
8:2 v/v). TLC (hexane-EtOAc 7:3, eluted twice) of the reaction crude
showed five products with Rf ¼ 0.55, 0.45, 0.33, 0.25, 0.20. The
fraction with Rf ¼ 0.55 corresponded to starting material rac-1
(28 mg was recovered). The fraction with Rf ¼ 0.25 was isolated and
recrystallized from hexane-EtOAc (2:1 v/v) to give 42 mg (16%
yield) of rac-3a as a colorless solid with mp 160e162 ꢀC. 1H NMR
(400 MHz, CDCl3) 1.36 (3H, t, J ¼ 7.2 Hz, CH3), 3.27 (1H, dd, J ¼ 7.2,
13.0 Hz, CHH), 3.35 (br s, 1H, OH), 3.41 (1H, t, J ¼ 12.7 Hz, CHH), 3.58
(1H, dd, J ¼ 7.2, 12.4 Hz, CH), 3.66 (3H, s, OCH3), 4.25e4.37 (2H, m,
OCH2), 7.29e7.39 (3H, m, Har), 7.50e7.58 (3H, m, Har), 7.65 (1H, t,
J ¼ 7.5 Hz, Har), 7.80 (1H, d, J ¼ 7.5 Hz, Har), 7.85 (1H, d, J ¼ 7.5 Hz,
Har). 13C NMR (100.5 MHz, CDCl3) 14.2 (CH3), 44.6 (CH2), 49.2 (CH),
53.1 (OCH3), 61.6 (OCH2), 68.5 (C), 95.8 (CeOH), 123.8 (CHar), 124.1
(CHar), 127.1 (2 ꢂ CHar), 127.7 (CHar), 128.0 (2 ꢂ CHar), 130.3 (CHar),
131.6 (Cipso), 133.3 (CHar), 140.7 (Cipso), 145.6 (Cipso), 169.1 (NC]O),
169.9 (OC]O), 172.0 (OC]O).
3.3.4. Methyl (1R,3R,9bS)- and (1S,3S,9bR)-1-cyano-9b-hydroxy-5-
oxo-3-phenyl-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindole-3-
carboxylate, (rac-4d)
The fractions with Rf ¼ 0.25, and 0.20 afforded 70 mg (30% yield)
of a mixture of diastereoisomers rac-4b and rac-4d. This mixture
was recrystallized from hexane-EtOAc (2:1 v/v) to yield 15 mg (6%
yield) of rac-4d (the more polar diastereoisomer) as colorless
crystals with mp 234e236 ꢀC. 1H NMR (400 MHz, Acetone-d6) 3.47
(1H, dd, J ¼ 8.0, 13.9 Hz, CHH), 3.59 (3H, s, OCH3), 3.62 (1H, d,
J ¼ 13.8 Hz, CHH), 4.01 (1H, d, J ¼ 7.8 Hz, CH), 6.04 (1H, br s, 1H, OH),
7.28e7.44 (3H, m, Har), 7.49e7.61 (3H, m, Har), 7.75e7.90 (1H, m,
Har), 7.75e7.82 (3H, m, Har). 13C NMR (100.5 MHz, Acetone-d6): 36.2
(CH), 45.6 (CH2), 53.5 (OCH3), 68.9 (C), 95.0 (CeOH), 116.5 (CN),
124.27 (CHar), 124.3 (CHar), 128.16 (2 ꢂ CHar), 128.18 (CHar), 128.4
(2 ꢂ CHar), 131.4 (CHar), 133.4 (Cipso), 134.2 (CHar),142.0 (Cipso), 144.6
(Cipso), 166.9 (NC]O), 171.5 (OC]O). HRMS (ESI-TOF) calculated for
3.3.2. Ethyl 1-methyl-(RS)-2-(1,3-dioxoisoindolin-2-yl)-2-
phenylpentanedioate (rac-3b)
C
20H16N2O4 þ Hþ: 349.1183; [M þ Hþ]; found: 349.1187.
The fraction with Rf ¼ 0.45 of the chromatographic profile of rac-
3a was isolated to give 94 mg (35% yield) of rac-3b as a colorless
solid with mp 97e99 ꢀC. 1H NMR (400 MHz, CDCl3) 1.19 (3H, t,
J ¼ 7.1 Hz, CH3), 2.39e2.58 (2H, m, CH2), 2.98e3.17 (2H, m, CH2),
3.72 (3H, s, OCH3), 4.03 (2H, qd, J ¼ 2.1, 7.1 Hz, OCH2), 7.29e7.43 (3H,
3.3.5. Diethyl (1R,3S,10bS)- and (1S,3R,10bR)-10b-hydroxy-6-oxo-
1,2,3,4,6,10b-hexahydropyrido[2,1-a]isoindole-1,3-dicarboxylate,
(rac-6a)
A mixture of phthalimide (200 mg, 1.36 mmol), ethyl acrylate
(0.59 mL, 5.44 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene