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15
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.
16
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+].
17 Isolated as an inseparable mixture of exo-regioisomers, configuration was assigned by 2D NMR (COSY) experiments and comparison with the known endo adduct.