Enantioselective Synthesis of Succinimides by Michael Addition
197.3, 176.6, 174.5, 136.9, 136.0, 129.8, 129.3, 126.7, 48.9, 45.2,
32.2, 26.8, 20.7, 20.1 ppm. MS (EI, 70 eV): m/z (%) = 303 (0.02)
[M]+, 259 (100). HRMS (EI): calcd. for C16H17NO5 303.1107;
found 303.1134. HPLC analysis (Chiralpak AS-H, λ = 210 nm, n-
hexane/2-propanol, 75:25, 1.0 mL/min): tR = 50.2 (minor) and tR
= 67.7 min (major).
Acknowledgments
The authors thank the Spanish Ministerio de Economía y Compet-
itividad (MEC) (projects CTQ2010-20387, CTQ2010-21263-C02,
and Consolider Ingenio 2010, CSD2007-00006), the Fondos
Europeos para el Desarrollo Regional (FEDER), the COST Action
CM0905 “Organocatalysis”, the Generalitat Valenciana (Prometeo/
2009/039), the Basque Government (GV grant IT-291-07), the Uni-
versity of Alicante, and the University of the Basque Country for
the financial support. The authors also thank SGI/IZO-SGIker
UPV/EHU for the allocation of computational resources and Dr.
Tatiana Soler from Research Technical Services at the University
of Alicante for carrying out the X-ray analysis.
(R)-2-(2,5-Dioxopyrrolidin-3-yl)-2-methylpropanal (8ai): Colorless
oil. IR (film): ν = 3235, 3077, 2973, 2938, 1779, 1698, 1353, 1290,
˜
1
1179, 804, 659 cm–1. H NMR (300 MHz, CDCl3): δ = 9.49 (s, 1
H), 8.73 (br. s, 1 H), 3.10 (dd, J = 9.4, 5.8 Hz, 1 H), 2.85 (dd, J =
18.4, 9.4 Hz, 1 H), 2.51 (dd, J = 18.4, 5.8 Hz, 1 H), 1.25 (s, 3 H),
1.23 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 202.9, 178.3,
176.2, 48.0, 46.3, 32.8, 20.1, 19.4 ppm. MS (EI, 70 eV): m/z (%) =
169 (0.66) [M]+, 69 (100). HRMS (EI): calcd. for C8H11NO3
169.0739; found 169.0738. HPLC analysis (Chiralpak AD-H, λ =
210 nm, n-hexane/2-propanol, 85:15, 1.0 mL/min): tR = 22.5
(major) and tR = 30.4 min (minor).
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(R)-2-[1-(4-Bromophenyl)-2,5-dioxopyrrolidin-3-yl]-2-methylprop-
anoic Acid (9ad): White solid; m.p. 186 °C (n-hexane/AcOEt).
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[α]2D0 = +1.6 (c = 1, CHCl ). IR (ATR): ν = 3000 (br.), 2986, 1706,
˜
3
1675, 1491, 1401, 1181, 781, 723 cm–1
.
1H NMR (300 MHz,
CDCl3): δ = 7.58 (m, 2 H), 7.15 (m, 2 H), 3.14 (dd, J = 9.5, 5.4 Hz,
1 H), 3.05–2.96 (dd, J = 18.1, 5.4 Hz, 1 H), 2.70 (dd, J = 18.1,
5.4 Hz, 1 H), 1.54 (s, 3 H), 1.39 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 180.5, 176.5, 174.5, 132.4, 130.8, 128.1, 122.6, 47.0,
32.6, 24.3, 23.6 ppm. MS (EI, 70 eV): m/z (%) = 338 (4.62) [M]+,
57 (100). HRMS (EI): calcd. for C14H14BrNO4 339.0106; found
339.0128.
One-Pot Michael Addition/Reductive Amination/Lactamization: To
a mixture of 1a (0.08 mmol, 19.2 mg), N-phenylmaleimide
(0.4 mmol, 69.2 mg), and imidazole (0.08 mmol, 4.8 mg) in DMF/
H2O (2:1, v/v, 0.5 mL) was added isobutyraldehyde (73 μL,
0.8 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 d, and the
solvent was evaporated to dryness (15 Torr). The crude residue was
dissolved in CHCl3 (3.5 mL), and benzylamine (1 m in CHCl3,
0.8 mL, 0.8 mmol) and sodium triacetoxyborohydride (211.9 mg,
1 mmol) were added. The mixture was stirred at room temp. for
6 h, and the solvent was evaporated in vacuo (15 Torr). To the
crude residue was added HCl (2 m solution, 5 mL), and the solution
was extracted with CHCl3 (3ϫ 2 mL). The combined organic ex-
tracts were dried with MgSO4, filtered, and evaporated (15 Torr).
The resulting crude residue was purified by flash chromatography
(n-hexane/AcOEt) to afford γ-lactam (R)-10aa (60.6 mg, 45%).
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(R)-2-(1-Benzyl-4,4-dimethyl-2-oxopyrrolidin-3-yl)-N-phenylacet-
amide (10aa): Yellow oil. [α]2D0 = +1.6 (c = 1, CHCl ). IR (film): ν
˜
3
= 3316, 3262, 2986, 1675, 1491, 1401, 1181, 781, 723 cm–1
.
1H
NMR (300 MHz, CDCl3): δ = 7.62 (m, 2 H), 7.41–7-18 (m, 7 H),
7.12–7.01 (m, 1 H), 4.60 (d, J = 14.6 Hz, 1 H), 4.38 (d, J = 14.6 Hz,
1 H), 3.09 (d, J = 9.7 Hz, 1 H), 2.86 (d, J = 9.7 Hz, 1 H), 2.81–
2.63 (m, 2 H), 2.30 (dd, J = 13.4, 0.8 Hz, 1 H), 1.15 (s, 3 H), 0.88
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 176.4, 170.2, 138.8,
135.7, 128.8, 128.2, 127.9, 123.6, 119.6, 58.9, 50.0, 46.9, 37.9, 34.6,
25.1, 21.8 ppm. MS (EI, 70 eV): m/z (%) = 336 (12.79) [M]+, 244
(100). HRMS (EI): calcd. for C21H24N2O2 336.1838; found
336.1851. HPLC analysis (Chiralpak AD, λ = 210 nm, n-hexane/2-
propanol, 80:20, 1.0 mL/min): tR = 8.6 (major) and tR = 9.9 min
(minor).
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Supporting Information (see footnote on the first page of this arti-
cle): Physical data, 1H and 13C NMR spectra and data, chiral
HPLC data, and description of computational methods and data
are included.
Eur. J. Org. Chem. 2013, 5085–5092
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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