Synthesis of Enantiopure Prolines via exo-Stereoselective 1,3-Dipolar ­Cycloadditions to Acetone-Derived Chiral Stabilised Azomethine Ylides

Abstract

The chiral stabilised azomethine ylide formed from condensation of the dimethyl acetal of acetone with (5S)-5-phenylmorpholinone undergoes stereoselective exo-cycloaddition reactions with a range of doubly and singly activated dipolarophiles when generated in the presence of excess MgBr₂·OEt₂. The cycloadducts can be degraded to yield enantiomerically pure proline derivatives.

ketone-derived azomethine ylide - 5,5-disubstituted prolines - Lewis acid - stereoselective cycloaddition

References and Notes

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Typical Experimental Procedure.
2,2-Dimethoxypropane (2 equiv) was added via syringe to a stirred solution of (5S)-5-phenylmorpholin-2-one (3, 1 equiv), dipolarophile (2 equiv), and MgBr·OEt₂ (10 equiv) in THF (10 mL per mmol substrate). The resulting mixture was stirred under nitrogen for 6 h, cooled to r.t., then quenched with aq NH₄Cl and extracted with CH₂Cl₂ (3 × 10 mL). The organic phase was washed with brine, the combined aqueous phases extracted with CH₂Cl₂ (3 × 10 mL) and the organic phases dried (MgSO₄) and concentrated in vacuo. The residue was then purified by flash column chromatography, gradient eluting with 3:1 hexane-EtOAc to pure EtOAc.

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Representative Analytical Data. N -Methyl (2 S ,6 S ,7 S ,8 R )-9,9-Dimethyl-2-phenyl-1-aza-4-oxa[4.3.0 ^¹,6 ]bicyclononan-5-one-7,8-dicarboximide ( 5b).
Colourless crystals (61%), mp 160-163 °C; [α]_D ²⁵ -24.0 (c 0.35, CHCl₃). ¹H NMR (250 MHz, CDCl₃): δ = 7.36-7.23 (5 H, m, Ar-H), 4.43 (1 H, t, J = 5.7 Hz, 3β-H), 4.38 (1 H, d, J = 1.7 Hz, 6α-H), 4.21 (1 H, dd, J = 5.7 Hz, J′ = 11.6 Hz, 2β-H), 4.06 (1 H, dd, J = 1.6 Hz, J′ = 8.5 Hz, 7β-H), 4.00 (1 H, dd, J = 5.7 Hz, J′ = 11.6 Hz, 3α-H), 3.08 (3 H, s, NCH₃), 3.06 (1 H, d, J = 8.5 Hz, 8β-H), 1.19 (3 H, s, CH₃), 1.00 (3 H, s, CH₃). ¹³C NMR (62.5 MHz, CDCl₃): δ = 178.6, 172.1 (C=O), 139.0, 129.3, 128.5, 126.9 (C-aromatic), 71.2 (C₃), 66.1 (C₉), 60.8 (C₆), 55.2 (C₂), 54.7 (C₈), 44.9 (C₇), 26.2 (CH₃), 25.7 (NCH₃), 23.4 (CH₃). HRMS: m/z calcd for C₁₈H₂₀N₂O₄: 329.1501; found: 329.1499 [MH⁺].
Dimethyl (2 S ,6 S ,7 S ,8 R )-9,9-Dimethyl-2-phenyl-1-aza-4-oxa[4.3.0 ^¹,6 ]bicyclononan-5-one-7,8-dicarboxylate ( 5c).
Colourless oil (41%); [α]_D ²⁵ -71.3 (c 0.35, CHCl₃). ¹H NMR (250 MHz, CDCl₃): δ = 7.46-7.25 (5 H, m, Ar-H), 4.79 (1 H, d, J = 6.4 Hz, 6α-H), 4.27-4.10 (3 H, m, 2β-3α-3β-H), 3.93 (1 H, dd, J = 6.4 Hz, J′ = 7.8 Hz, 7β-H), 3.72 (3 H, CO₂Me), 3.68 (3 H, CO₂Me), 3.13 (1 H, d, J = 7.8 Hz, 8β-H), 1.11 (3 H, s, CH₃) 0.71 (3 H, s, CH₃). ¹³C NMR (62.5 MHz, CDCl₃): δ = 174.7, 172.2 (C=O), 140.8, 129.0, 128.4, 127.3 (C-aromatic), 71.5 (C₃), 65.8 (C₉), 57.8 (C₆), 57.5 (C₂), 56.7 (C₈), 52.9 (C₇), 52.0 (CO₂Me), 45.5 (CO₂Me), 26.2 (CH₃), 21.9 (CH₃). HRMS: m/z calcd for C₁₉H₂₄NO₆: 362.1603; found: 362.1613 [MH⁺].
Dimethyl (2 S ,6 S ,7 S ,8 R )-9,9-Dimethyl-2-phenyl-1-aza-4-oxa[4.3.0 ^¹,6 ]bicyclononan-5-one-7,8-dicarboxylate ( 5d).
Colourless crystals (60%); mp 105-107 °C [α]_d ²⁵ -38.0 (c 0.5, CHCl₃). ¹H NMR (250 MHz, CDCl₃): δ = 7.46-7.29 (5 H, m, Ar-H), 4.43 (1 H, d, J = 5.4 Hz, 6α-H), 4.31-4.07 (4 H, m, 2β-3α-3β-7αH), 3.77 (3 H, CO₂Me), 3.74 (3 H, CO₂Me), 3.12 (1 H, d, J = 10.8 Hz, 8β-H), 1.11 (3 H, s, CH₃), 0.71 (3 H, s, CH₃). ¹³C NMR (62.5 MHz, CDCl₃): δ = 173.7, 173.5 (C=O), 140.2, 129.0, 128.4, 127.3 (C-aromatic), 71.2 (C₃), 65.6 (C₉), 59.3 (C₆), 57.9 (C₈), 56.4 (C₂), 53.7 (C₇), 52.6 (CO₂Me), 44.7 (CO₂Me), 28.8 (CH₃), 16.8 (CH₃): HRMS: m/z calcd for C₁₉H₂₄N₂O₆: 362.1541; found: 362.1559 [MH⁺].
General Procedure for Hydrogenolysis. The cycloadduct (1 equiv) was dissolved in aq MeOH (2 mL MeOH, 0.1 mL H₂O per mmol substrate) containing TFA (1 equiv). Pearlman’s catalyst was added and the suspension was degassed then subjected to H₂ (5 bar) with stirring at r.t. for 48 h. The solution was filtered through a pad of Celite^® then the solvent removed in vacuo and the crude material purified by dry flash column chromatography (MeOH-H₂O, 1:1) or by trituration with Et₂O.
(1 S ,3a R ,6a S )-3,3-Dimethyl-4,6-dioxo-5-phenylocta-hydropyrrolo[3,4- c ]pyrrole-1-carboxylic Acid ( 6b). Colourless powder; mp 168-170 °C; [α]_D ²⁵ +51.3 (c 0.30, H₂O). ¹H NMR (250 MHz, MeOH-d ₄): δ = 7.56-7.29 (5 H, m, Ar-H), 4.70 (1 H, d, J = 4.2 Hz, 2α-H), 4.31 (1 H, dd, J = 4.2 Hz, J′ = 9.3 Hz, 3β-H), 3.59 (1 H, d, J = 9.3 Hz, 4β-H), 1.61 (6 H, s, CH₃). ¹³C NMR (62.5 MHz, MeOH-d ₄): δ = 178.6, 176.8, 174.8 (C=O), 133.6, 130.5, 130.3, 128.3 (C-aromatic), 67.9 (C₂), 62.5 (C₅), 54.9 (C₄), 49.0 (C₃), 28.4 (CH₃) 22.8 (CH₃): HRMS: m/z calcd for C₁₅H₁₆N₂O₄: 289.1188; found: 289.1193 [MH⁺].
(2 R ,3 R ,4 S )-3,4-Bis(methoxycarbonyl)-5,5-dimethyl-pyrrolidine-2-carboxylic Acid ( 6c). Colourless powder; mp 168-170 °C; [α]_D ²⁵ +10.0 (c 0.05, H₂O). ¹H NMR (250 MHz, MeOH-d ₄): δ = 4.85 (1 H, d, J = 8.2 Hz, 2α-H), 4.08 (1 H, t, J = 7.0 Hz, 3β-H), 3.76 (3 H CO₂Me), 3.74 (3 H CO₂Me), 3.51 (1 H, d, J = 8.1 Hz, 4β-H), 1.51 (3 H, s, CH₃) 1.48 (3 H, s, CH₃). ¹³C NMR (62.5 MHz, MeOH-d ₄): δ = 173.6, 171.9, 170.0 (C=O), 66.9 (C₂), 60.0 (C₅), 56.4 (CO₂Me), 48.0 (CO₂Me), 24.4 (CH₃) 20.9 (CH₃): HRMS: m/z calcd for C₁₁H₁₈NO₆: 260.1134; found: 260.1123 [MH⁺].
(2 R ,3 S ,4 S )-3,4-Bis(methoxycarbonyl)-5,5-dimethyl-pyrrolidine-2-carboxylic Acid ( 6d).
Colourless powder; [α]_D ²⁵ -2.5 (c 0.25, H₂O). ¹H NMR (250 MHz, MeOH-d ₄): δ = 4.49 (1 H, d, J = 7.4 Hz, 2α-H), 3.98 (1 H, dd, J = 7.4 Hz, J′ = 10.3 Hz, 3β-H), 3.79 (3 H CO₂Me), 3.79 (3 H s CO₂Me), 3.31 (1 H, d, J = 10.3 Hz, 4α-H), 1.64 (3 H, s, CH₃) 1.30 (3 H, s, CH₃). ¹³C NMR (62.5 MHz, MeOH-d ₄): δ = 173.3, 171.9, 170.0 (C=O), 66.8 (C₂), 60.0 (C₅), 56.4 (CO₂Me), 48.0 (CO₂Me), 24.6 (CH₃), 20.9 (CH₃). HRMS: m/z calcd for C₁₁H₁₈NO₆: 260.1134; found: 260.1126 [MH⁺].

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Isolated as an inseparable mixture of exo-regioisomers, configuration was assigned by 2D NMR (COSY) experiments and comparison with the known endo adduct.