860
W. N. Draffin, L. M. Harwood
LETTER
2b-H), 4.06 (1 H, dd, J = 1.6 Hz, J¢ = 8.5 Hz, 7b-H), 4.00 (1
H, dd, J = 5.7 Hz, J¢ = 11.6 Hz, 3a-H), 3.08 (3 H, s, NCH3),
3.06 (1 H, d, J = 8.5 Hz, 8b-H), 1.19 (3 H, s, CH3), 1.00 (3
H, s, CH3). 13C NMR (62.5 MHz, CDCl3): d = 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 (2S,6S,7S,8R)-9,9-Dimethyl-2-phenyl-1-aza-4-
oxa[4.3.01,6]bicyclononan-5-one-7,8-dicarboxylate (5c).
Colourless oil (41%); [a]D25 –71.3 (c 0.35, CHCl3). 1H NMR
(250 MHz, CDCl3): d = 7.46–7.25 (5 H, m, Ar-H), 4.79 (1 H,
d, J = 6.4 Hz, 6a-H), 4.27–4.10 (3 H, m, 2b-3a-3b-H), 3.93
(1 H, dd, J = 6.4 Hz, J¢ = 7.8 Hz, 7b-H), 3.72 (3 H, CO2Me),
3.68 (3 H, CO2Me), 3.13 (1 H, d, J = 7.8 Hz, 8b-H), 1.11 (3
H, s, CH3) 0.71 (3 H, s, CH3). 13C NMR (62.5 MHz, CDCl3):
d = 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 (2S,6S,7S,8R)-9,9-Dimethyl-2-phenyl-1-aza-4-
oxa[4.3.01,6]bicyclononan-5-one-7,8-dicarboxylate (5d).
Colourless crystals (60%); mp 105–107 °C [a]d25 –38.0 (c
0.5, CHCl3). 1H NMR (250 MHz, CDCl3): d = 7.46–7.29 (5
H, m, Ar-H), 4.43 (1 H, d, J = 5.4 Hz, 6a-H), 4.31–4.07 (4
H, m, 2b-3a-3b-7aH), 3.77 (3 H, CO2Me), 3.74 (3 H,
CO2Me), 3.12 (1 H, d, J = 10.8 Hz, 8b-H), 1.11 (3 H, s, CH3),
0.71 (3 H, s, CH3). 13C NMR (62.5 MHz, CDCl3): d = 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+].
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.
(1S,3aR,6aS)-3,3-Dimethyl-4,6-dioxo-5-phenylocta-
hydropyrrolo[3,4-c]pyrrole-1-carboxylic Acid (6b).
Colourless powder; mp 168–170 °C; [a]D25 +51.3 (c 0.30,
H2O). 1H NMR (250 MHz, MeOH-d4): d = 7.56–7.29 (5 H,
m, Ar-H), 4.70 (1 H, d, J = 4.2 Hz, 2a-H), 4.31 (1 H, dd, J =
4.2 Hz, J¢ = 9.3 Hz, 3b-H), 3.59 (1 H, d, J = 9.3 Hz, 4b-H),
1.61 (6 H, s, CH3). 13C NMR (62.5 MHz, MeOH-d4): d =
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+].
(2R,3R,4S)-3,4-Bis(methoxycarbonyl)-5,5-dimethyl-
pyrrolidine-2-carboxylic Acid (6c).
Colourless powder; mp 168–170 °C; [a]D25 +10.0 (c 0.05,
H2O). 1H NMR (250 MHz, MeOH-d4): d = 4.85 (1 H, d, J =
8.2 Hz, 2a-H), 4.08 (1 H, t, J = 7.0 Hz, 3b-H), 3.76 (3 H
CO2Me), 3.74 (3 H CO2Me), 3.51 (1 H, d, J = 8.1 Hz, 4b-H),
1.51 (3 H, s, CH3) 1.48 (3 H, s, CH3). 13C NMR (62.5 MHz,
MeOH-d4): d = 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+].
(2R,3S,4S)-3,4-Bis(methoxycarbonyl)-5,5-dimethyl-
pyrrolidine-2-carboxylic Acid (6d).
Colourless powder; [a]D25 –2.5 (c 0.25, H2O). 1H NMR (250
MHz, MeOH-d4): d = 4.49 (1 H, d, J = 7.4 Hz, 2a-H), 3.98
(1 H, dd, J = 7.4 Hz, J¢ = 10.3 Hz, 3b-H), 3.79 (3 H CO2Me),
3.79 (3 H s CO2Me), 3.31 (1 H, d, J = 10.3 Hz, 4a-H), 1.64
(3 H, s, CH3) 1.30 (3 H, s, CH3). 13C NMR (62.5 MHz,
MeOH-d4): d = 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+].
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®
(17) Isolated as an inseparable mixture of exo-regioisomers,
configuration was assigned by 2D NMR (COSY)
experiments and comparison with the known endo adduct.
Synlett 2006, No. 6, 857–860 © Thieme Stuttgart · New York