Asymmetric Organocatalytic Michael/Michael/Henry Sequence to Construct Cyclohexanes with Six Vicinal Stereogenic Centers

Abstract

An efficient, asymmetric, catalytic, triple-cascade reaction between α-keto esters and nitroalkenes to construct cyclohexanes with six vicinal stereogenic centers in good yields and with high enantioselectivities has been established. A bifunctional guanidine–amide organocatalyst proved to be useful for the Michael/Michael/Henry sequence through Brønsted base and hydrogen-bonding cooperative catalysis.

Key words

asymmetric catalysis - cascade reaction - cyclohexanes - organocatalysis - keto esters - nitroalkenes

• References and Notes


For reviews on asymmetric organocatalysis, see:
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• 9 Hexasubstituted Cyclohexanes 3aa–3ik; General Procedure Guanidine G-5 (10 mol%), α-keto ester 1 (0.1 mmol), and 4 Å MS (20 mg) were weighed into a test tube under N₂. THF (0.5 mL) was added and the solution was stirred for 0.5 h at 0 °C. Nitroalkene 2 (0.3 mmol) was then added at 0 °C, and the resulting mixture was stirred for 3 d at 0 °C to give the product 3, which was purified by flash chromatography.
• 10 tert-Butyl (1R,2R,3R,4S,5R,6S)-2-Benzyl-1-hydroxy-4,6-dinitro-3,5-diphenylcyclohexanecarboxylate (3aa) White solid; yield: 51.7 mg (93%, 90% ee, >20:1 dr); mp 162 °C; [α]_D ²⁹ +45.3 (c 0.47, CH₂Cl₂); HPLC: [Daicel CHIRALCEL IA; hexane–i-PrOH (85:15); flow rate = 1.0 mL/min; λ = 210 nm]: t _R = 7.33 min (minor), 12.59 min (major). ¹H NMR (400 MHz, CDCl₃): δ = 7.35–7.08 (m, 13 H), 6.78 (d, J = 7.2 Hz, 2 H), 5.22–5.16 (m, 1 H), 5.10 (dd, J = 12.4, 6.4 Hz, 1 H), 4.49 (t, J = 12.4 Hz, 1 H), 4.18 (s, 1 H), 3.54 (t, J = 6.4 Hz, 1 H), 2.95 (s, 1 H), 2.54–2.36 (m, 2 H), 1.59 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.5, 137.4, 134.9, 132.1, 129.0, 128.9, 128.6, 128.5, 128.4, 128.3 127.0, 92.7, 90.3, 86.6, 77.7, 47.1, 45.7, 40.3, 33.7, 27.9. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₃₀H₃₂N₂NaO₇ ⁺: 555.2102; found: 555.2101. tert-Butyl (1R,2R,3R,4S,5R,6S)-2-Benzyl-1-hydroxy-4,6-dinitro-3,5-bis(2-tolyl)cyclohexanecarboxylate (3ah) White solid; yield: 53.0 mg (91%, 95% ee, >20:1 dr); mp 140 °C; [α]_D ²⁶ +72.6 (c 1.26, CH₂Cl₂); HPLC: [Daicel CHIRALCEL IA; hexane–i-PrOH (85:15); flow rate = 1.0 mL/min; λ = 210 nm]: t _R = 10.21 min (minor), 16.58 min (major). ¹H NMR (400 MHz, CDCl₃): δ = 8.53 (d, J = 7.6 Hz, 1 H), 7.33 (d, J = 7.6 Hz, 1 H), 7.24–7.08 (m, 8 H), 6.97 (d, J = 7.6 Hz, 1 H), 6.74 (d, J = 6.0 Hz, 2 H), 5.27 (t, J = 12.0 Hz, 2 H), 4.88 (t, J = 12.0 Hz, 1 H), 4.35 (s, 1 H), 4.16 (t, J = 6.4 Hz, 1 H), 3.26 (s, 1 H), 2.65–2.53 (m, 1 H), 2.50 (s, 3 H), 2.49–2.32 (m, 1 H), 1.64 (s, 9 H), 1.32 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.6, 140.0, 139.3, 137.0, 133.2, 131.7, 131.3, 131.2, 131.1, 129.0, 128.8, 128.1, 128.0, 126.9, 126.3, 126.2, 124.0, 93.1, 90.8, 86.5, 77.8, 45.2, 39.8, 34.8, 33.5, 27.9, 19.5, 19.3. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₃₂H₃₆N₂NaO₇ ⁺ : 583.2415; found: 583.2415.