Chiral Amine-Triggered Triple Cascade Reactions: A New Approach to Functionalized Decahydroquinolines

Abstract

A chiral amine-triggered highly enantio- and diastereoselective synthesis yielding 69-94% of cis-decahydroquinolines is reported. The synthetic protocol involves a [2+2+2]-annulation via (S)-diphenylprolinol trimethylsilyl ether catalyzed Michael addition of cyclohexanone to nitroalkenes followed by aza-Henry-hemiaminalization reaction cascade. The process stereoselectively installs five contiguous chiral centers into the quinoline structure.

organocatalysis - quinolines - nitroalkenes - cascade ­reactions - stereoselective synthesis

References and Notes

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35

General Procedure for the Synthesis of cis -Decahydro-quinolines 5: To a solution of ketone 1 (0.4 mmol) and the catalyst diphenylprolinol trimethylsilyl ether 4a (20 mol%) in 1,4-dioxane (1 mL) was added nitroalkene 2 (0.4 mmol) under stirring. The reaction mixture was stirred at r.t. for 8 h followed by addition of aldimine 3 (0.4 mmol) along with K₂CO₃ (0.2 mmol) in 1,4-dioxane (2 mL) and stirring at r.t. until complete consumption of aldimine 3 (11-18 h) as indicated by TLC. The reaction mixture was concentrated under reduced pressure and the residue was directly purified by silica gel column chromatography (EtOAc-hexane as eluent) to afford an analytically pure sample of cis-decahydroquinolines 5 (Table  [²] ).
Characterization Data of Representative Compounds cis -5:
Compound cis- 5a: white solid; yield: 78%; mp 178-179 ˚C. IR (KBr): 3589, 2964, 1554, 1534, 1408, 1348, 1174, 1092, 856, 797, 745, 702, 605 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.10-1.33 (m, 4 H), 1.60-1.76 (m, 5 H), 1.92 (br s, 1 H, exch. D₂O), 2.34 (s, 3 H), 3.34 (dd, 1 H, J = 11.7, 11.6 Hz), 5.06 (d, 1 H, J = 11.1 Hz), 5.91 (dd, 1 H, J = 11.7, 11.1 Hz), 7.34 (d, 2 H, J = 8.1 Hz), 7.45-7.75 (m, 10 H), 7.72 (d, 2 H, J = 8.5 Hz). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 17.1, 18.7, 23.6, 24.3, 25.1, 30.4, 37.9, 42.7, 75.1, 84.8, 124.8, 126.0, 127.4, 128.1, 129.3, 130.6, 131.7, 134.6, 137.9, 140.1, 141.5, 142.7. EIMS: m/z = 506 [M⁺]. Anal. Calcd for C₂₈H₃₀N₂O₅S: C, 66.38; H, 5.97; N, 5.53. Found: C, 66.10; H, 5.61; N, 5.83. [α]_D ^²0 +22 (c = 0.60, THF). The enantiomeric excess was determined to be 97% by HPLC on a chiral Eurocel column (250 × 4.6 mm, 5 µm): λ = 225 nm; i-PrOH-hexane (10:90), flow rate: 1 mL/min; t _R = 5.8 min (minor), t _R = 6.8 min (major).
Compound cis- 5e: white solid; yield: 90%; mp 189-190 ˚C. IR (KBr): 3598, 2952, 1557, 1532, 1402, 1345, 1161, 1090, 854, 799, 741, 710, 606 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.06-1.30 (m, 4 H), 1.61-1.79 (m, 5 H), 1.94 (br s, 1 H, exch. D₂O), 2.36 (s, 3 H), 3.35 (dd, 1 H, J = 11.8, 11.6 Hz), 5.05 (d, 1 H, J = 11.2 Hz), 5.93 (dd, 1 H, J = 11.8, 11.2 Hz), 7.30 (d, 2 H, J = 8.1 Hz), 7.65-7.70 (m, 2 H), 7.66-7.71 (m, 5 H), 7.72 (d, 2 H, J = 8.3 Hz), 8.10-8.17 (m, 2 H). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 18.9, 20.1, 21.8, 22.7, 25.2, 27.6, 34.9, 39.3, 75.4, 84.5, 125.1, 126.9, 127.8, 128.6, 129.5, 131.1, 132.9, 134.4, 137.0, 138.3, 140.4, 141.6. EIMS: m/z = 540 [M⁺]. Anal. Calcd for C₂₈H₂₉ClN₂O₅S: C, 62.16; H, 5.40; N, 5.18. Found: C, 62.52; H, 5.58; N, 4.86. [α]_D ^²0 +19 (c = 0.80, THF). The enantiomeric excess was determined to be 91% by HPLC on a chiral Eurocel column (250 × 4.6 mm, 5 µm): λ = 225 nm; i-PrOH-hexane (10:90), flow rate: 1 mL/min; t _R = 5.9 min (minor), t _R = 7.1 min (major).
Compound cis- 5m: white solid; yield: 71%; mp 187-188 ˚C. IR (KBr): 3592, 2815, 2910, 1559, 1531, 1410, 1340, 1169, 1095, 852, 796, 741, 708, 601 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.09-1.34 (m, 4 H), 1.59-1.76 (m, 5 H), 1.91 (br s, 1 H, exchangeable with D₂O), 2.33 (s, 3 H), 3.34 (dd, 1 H, J = 11.6, 11.4 Hz), 3.85 (s, 3 H), 5.09 (d, 1 H, J = 11.2 Hz), 5.95 (dd, 1 H, J = 11.6, 11.2 Hz), 7.31 (d, 2 H, J = 8.0 Hz), 7.61-7.69 (m, 5 H), 7.66-7.68 (m, 2 H), 7.74 (d, 2 H,
J = 8.2 Hz), 8.01-8.03 (m, 2 H). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 17.6, 18.8, 21.5, 24.3, 25.6, 28.9, 37.5, 42.1, 49.5, 75.4, 84.2, 114.8, 126.7, 127.9, 128.8, 130.0, 131.7, 132.5, 134.7, 136.7, 138.1, 141.6, 156.6. EIMS: m/z = 536 [M⁺]. Anal. Calcd for C₂₉H₃₂N₂O₆S: C, 64.91; H, 6.01; N, 5.22. Found: C, 65.11; H, 5.77; N, 4.93. [α]_D ^²0 +25 (c = 0.90, THF). The enantiomeric excess was determined to be 94% by HPLC on a chiral Eurocel column (250 × 4.6 mm, 5 µm): λ = 225 nm; i-PrOH-hexane (10:90), flow rate: 1 mL/min; t _R = 6.7 min (minor), t _R = 7.8 min (major).