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Synlett 2010(1): 119-122  
DOI: 10.1055/s-0029-1218539
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© Georg Thieme Verlag Stuttgart ˙ New York

Asymmetric Brønsted Acid Catalyzed Nucleophilic Addition to in situ Generated Chiral N-Acyliminium Ions

Magnus Rueping*a, Boris J. Nachtsheimb
a Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
e-Mail: Magnus.Rueping@rwth-aachen.de;
b Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA
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Publikationsverlauf

Received 15 September 2009
Publikationsdatum:
02. Dezember 2009 (online)

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Abstract

A new enantioselective Brønsted acid catalyzed nucleophilic substitution of γ-hydroxylactams with indole is presented. The reaction proceeds via an intermediary N-acyliminium ion and provides disubstituted γ-lactams in good yields and with high enantioselectivities.

Key words

organocatalysis - nucleophilic substitution - protonation - amino acid - quaternary stereocenter

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10

Typical Experimental Procedure Indole (0.1 mmol) and Brønsted acid catalyst (0.05 mmol) were dissolved in dry CH2Cl2 (1 mL), and the solution was cooled down to -65 ˚C. Hydroxylactam 1b (0.2 mmol) were dissolved in dry CH2Cl2 (0.3 mL) and slowly added to the cooled indole solution within 5 min. The reaction was stirred at -65 ˚C for 48 h, and the crude reaction mixture was purified by chromatography (hexane-EtOAc, 1:1) to yield 18 mg (54%) of 2b as a yellow oil which solidified upon standing.
Selected Data2b: ¹H NMR (250 MHz, CDCl3): δ = 8.49 (s, 1 H), 7.42-7.31 (m, 2 H), 7.20-7.14 (m, 1 H), 7.05-6.93 (m, 4 H), 6.66-6.60 (m, 2 H), 4.78 (d, J = 14.97 Hz, 1 H), 3.67 (s, 3 H), 3.55 (d, J = 14.90 Hz, 1 H), 2.65-2.42 (m, 3 H), 2.03-1.92 (m, 1 H), 1.39 (s, 3 H). ¹³C NMR (63 MHz, CDCl3): δ = 175.1, 158.6, 137.2, 131.1, 129.5, 124.9, 122.4, 122.4, 120.1, 119.8, 119.7, 113.6, 111.6, 63.5, 55.2, 43.4, 34.7, 30.1, 26.4. IR (neat): ν = 3271, 2967, 2930, 1652, 1511, 1436, 1409, 1246, 1030, 743 cm-¹. MS (EI): m/z (%) = 334.2 (31) [M] +, 157.2 (76) [M - C10H11NO2] +.
2d: Yellow oil. ¹H NMR (250 MHz, CDCl3): δ = 8.29 (s, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.18-6.99 (m, 4 H), 6.88 (d, J = 2.50 Hz, 1 H), 6.83-6.74 (m, 1 H), 6.65 (d, J = 8.2 Hz, 1 H), 4.67 (d, J = 16.1 Hz, 1 H), 3.99 (d, J = 16.1 Hz, 1 H), 3.58 (s, 3 H), 2.67-2.42 (m, 3 H), 2.13-1.98 (m, 1 H), 1.50 (s, 3 H). ¹³C NMR (63 MHz, CDCl3):
δ = 175.6, 156.6, 137.2, 128.8, 127.9, 126.5, 124.9, 122.3, 122.1, 120.3, 119.9, 119.8, 111.5, 109.9, 63.7, 55.0, 38.5, 34.8, 30.2, 26.1. IR (neat): ν = 3270 (br), 2967, 1654, 1491, 1460, 1434, 1408, 1240, 1162, 1113, 1021, 749 cm-¹.
MS (EI): m/z (%) = 334.2 (23) [M] +, 157.1 (61) [M - C10H11NO2] +.