Asymmetric Michael Addition Reaction of α-Aryl-Substituted Lactams Catalyzed by Chiral Quaternary Ammonium Salts Derived from Cinchona Alkaloids: A New Short Synthesis of (+)-Mesembrine

Abstract

The enantioselective Michael addition reaction of α-aryl-substituted lactams with electron-deficient olefins was efficiently catalyzed using chiral quaternary ammonium salts derived from cinchona alkaloids. This method was highly useful for the construction of an all-carbon-substituted quaternary carbon stereogenic center at the α-position of lactams in good to high yields and with good enantiomeric excess and could be applied to the short synthesis of (+)-mesembrine.

Key words

asymmetric organocatalysis - lactams - Michael addition - cinchona alkaloids - mesembrine

• References and Notes

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• 11 General Procedure for the Asymmetric Michael Addition Reaction of Lactams The chiral ammonium catalyst was prepared by mixing a cinchona amine (0.06 mmol) and freshly distilled 4-methoxybenzyl bromide (0.06 mmol) in toluene (0.2 mL) at r.t. for 1 h. Then, Ag₂O (0.06 mmol) and EtOH (0.06 mmol) were added, and the mixture was stirred at r.t. for 20 min. After cooling to –15 °C, lactam (0.2 mmol) in toluene (0.8 mL) followed by the Michael acceptor (1.5 equiv) were added, and the reaction progress was monitored by TLC. After completion of the reaction, the mixture was directly purified by silica gel column chromatography (eluted with benzene–acetone, 12:1) to give the desired adduct. The ee of this compound was determined by chiral HPLC analysis. (R)-N-Boc-2-(3-oxobutyl)-2-phenyl-γ-butyrolactam (3a) Colorless needles; mp 97–99 °C (from hexane–Et₂O); R_f = 0.17 (hexane–acetone, 4:1). [α]_D ¹⁹ +83.2 (c 1.0, EtOH, 79% ee). FTIR (KBr): ν = 1773, 1715, 1365, 1313, 1164 cm^–1.¹H NMR (500 MHz, CDCl₃): δ = 1.53 (9 H, s), 2.03 (3 H, s), 2.10–2.16 (2 H, m), 2.19–2.29 (2 H, m), 2.41–2.45 (1 H, m), 2.53–2.62 (1 H, m), 3.48 (1 H, ddd, J = 10.0, 8.5, 8.0 Hz), 3.75 (1 H, ddd, J = 10.0, 8.0, 3.0 Hz), 7.26–7.41 (5 H, m). ¹³C NMR (125.8 MHz, CDCl₃): δ = 28.00 (3×), 29.91, 31.55, 32.17, 38.78, 42.95, 52.93, 83.02, 126.43 (2×), 127.37, 128.78 (2×), 139.04, 150.18, 175.56, 208.10. Anal. Calcd for C₁₉H₂₅NO₄: C, 68.86; H, 7.60; N, 4.23. Found: C, 68.76; H, 7.60; N, 4.09. The ee of the product was determined by chiral HPLC analysis (Chiralpak AD-H column, 0.46 × 25 cm, hexane–2-PrOH = 90:10, 0.3 cm³/min): t _R (major) = 39.4 min; t _R (minor) = 43.0 min.
• 12 We briefly examined the attachment on a quinuclidine nitrogen, but no improvements were observed using an anthracenylmethyl or 4-nitrobenzyl group.
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• 14 Unfortunately, the use of phenyl vinyl ketone as a Michael acceptor gave only a complex mixture of products.
• 15 In accordance with this observation, no reaction was observed for the 2-alkyl-substituted γ-butyrolactam even after prolonged reaction (r.t., 100 h).

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