Enantioselective Synthesis of Wieland-Miescher Ketone through Bimorpholine-Catalyzed Organocatalytic Aldol Condensation

Abstract

Novel bimorpholine-derived organocatalysts have been used for highly enantioselective intramolecular aldol reaction affording Wieland-Miescher ketone in high yield and enantioselectivity (up to 92% and 95%, respectively).

Key words

asymmetric catalysis - organocatalysis - diamines - ­stereoselective synthesis - aldol reactions

References and Notes

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17

General Method for the Organocatalytic Aldol Condensation of Ketones 5 and 6.
Organocatalyst 3 or 4 (0.05 mmol) was added to a stirred solution of triketone 5 or 6 (1.0 mmol) in anhyd MeCN (2.0 mL). The reaction mixture was refluxed for an appropriate time. The reaction was monitored by capillary GC. After completion of the reaction, toluene (5 mL) was added, the mixture was concentrated under vacuum and the crude product was purified by chromatography on silica gel (30% EtOAc in PE). The obtained ketones 1 and 2 are known compounds and our spectroscopic and chromatographic data are in agreement with published data. The ee was determined by HPLC (Daicel Chiralcel OD-H (250 × 4.6 mm), detection at λ = 254 nm, eluent: 4% of i-PrOH in hexane, flow rate 0.8 mL/min); t _R (S)-1 = 19.4 min, t _R (R)-1 = 21.6 min, t _R (S)-2 = 25.6 min, t _R (R)-2 = 28.3 min.

19

(4a S *,8a S *)-6,8a-Dimethylhexahydro-2 H -chromene-2,5 (3 H )-dione (7).
A 2:1 mixture of two isomers with differing orientations of the 6-methyl group. Main isomer with 6R* configuration: ¹H NMR (500 MHz, CDCl₃): δ = 2.73 (m, 1 H, H-3), 2.54 (m, 1 H, H-4a), 2.49 (m, 1 H, H-3), 2.43 (m, 1 H, H-6), 2.42 (m, 1 H, H-4), 2.15 (m, 1 H, H-8), 1.97 (m, 1 H, H-8), 1.94 (m, 1 H, H-7), 1.93 (m, 1 H, H-4), 1.71 (m, 1 H, H-7), 1.54 (s, 3 H, 8a-Me), 1.03 (d, J = 6.5 Hz, 3 H, 6-Me). ¹³C NMR (125 MHz, CDCl₃): δ = 209.33 (C-5), 171.24 (C-2), 86.19 (C-8a), 49.52 (C-4a), 44.32 (C-6), 37.48 (C-8), 29.83 (C-7), 28.39 (C-8a-Me), 25.54 (C-3), 15.69 (C-4), 14.19 (C-6 Me).
Minor isomer with 6S* configuration: ¹H NMR (500 MHz, CDCl₃,): δ = 2.68 (m, 1 H, H-3), 2.66 (m, 1 H, H-4a), 2.57 (m, 1 H, H-6), 2.45 (m, 1 H, H-3), 2.27 (m, 1 H, H-4), 2.10 (m, 2 H, H-7), 2.08 (m, 2 H, H-8), 1.95 (m, 1 H, H-4), 1.44 (s, 3 H, 8a-Me), 1.13 (d, J = 6.5 Hz, 3 H, 6-Me). ¹³C NMR (125 MHz, CDCl₃): δ = 211.33 (C-5), 169.97 (C-2), 85.27 (C-8a), 51.49 (C-4a), 41.53 (C-6), 33.14 (C-8), 27.90 (C-7), 27.81 (C-8a-Me), 27.56 (C-3), 19.53 (C-4), 15.23 (C-6 Me). MS (EI): m/z (%) = 196 (3) [M⁺], 181 (2), 168 (4), 112 (86), 84 (29), 43 (100).