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20
Synthesis of (-)-Ethyl (2
E)-{(3aR,6aS)-5-[2-(Benzyloxy)-6-bromo-4-methoxy-3-methyphenyl]dihydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyrrol-6 (5H
)-ylidene}acetate (26)
: To a solution of ethyl bromoacetate (6.70 mL, 60.4 mmol, 5 equiv) in THF (250 mL) was added activated zinc powder (11.9 g, 181.9 mmol, 15 equiv) at r.t. After 5 min of stirring, iodine (2.15 g, 8.47 mmol, 0.7 equiv) was added in one portion, resulting in spontaneous reflux of the reaction mixture for a period of 5-10 min. The resulting greyish suspension was allowed to cool to r.t. over 1 h and then subjected to sonication for 1 h at 45 °C under an atmosphere of nitrogen. The mixture was allowed to cool to r.t. over 30 min, after which thiolactam 25 (rotameric mixture, 5.79 g, 12.1 mmol, 1 equiv) was added in one portion. The mixture was subsequently heated at reflux for 48 h, and then cooled to r.t. A further portion of organozinc reagent, prepared on the same scale as described above, was added, after which the mixture was heated again under reflux for 72 h. The reaction mixture was allowed to cool to r.t., and an ice-water mixture (200 mL) was added, which resulted in precipitation of inorganic solids. The organic material was extracted into Et2O, which was dried (MgSO4) and evaporated to yield a crude orange oil. Purification by column chromatography on silica gel using EtOAc-hexane (3:17, then 2:8) as eluent gave an inseparable mixture of vinylogous urethane rotamers 26 (5.62 g, 87%, 4:5 mixture of N-Ar rotamers by NMR spectroscopy; vide infra) as a viscous yellow oil-foam; R
f
0.41 (EtOAc-hexane 3:7); [α]D
23 -67.5 (c = 0.46, CHCl3). IR (CHCl3): 2981 (w), 1697 (s, C=O), 1476 (m), 1233 (w), 1134 (s), 735 (s) cm-1. HRMS (EI): m/z [M+] calcd for C26H30NO6
79Br: 531.1257; found: 531.1266.
Minor Rotamer: 1H NMR (300 MHz, CDCl3): δ = 7.26-7.44 (m, 5 H, CH2
Ph), 6.92 (s, 1 H, 5-H), 5.65 (d, J = 6.3 Hz, 1 H, 3a-H), 4.86 (d, J = 11.4 Hz, 1 H, OCH
aHbPh), 4.67 (d, J = 11.4 Hz, 1 H, OCHa
H
bPh), 4.56 (td, J ≈ 2.0, 6.2 Hz, 1 H, 6a-H), 4.38 (s, 1 H, =CHCO2Et), 4.13 (q, J = 7.0 Hz, 2 H, OCH
2CH3), 3.82 (s, 3 H, ArOCH
3), 3.77 (dd, J = 6.3, 10.8 Hz, 1 H, NCH
aHb), 3.50 (dd, J = 1.8, 10.8 Hz, 1 H, NCHa
H
b), 2.12 (s, 3 H, ArCH
3), 1.41, 1.56 (2 × s, 6 H, 2 × CH3), 1.22 (t, J = 7.0 Hz, 3 H, OCH2CH
3). 13C NMR (75 MHz, CDCl3): δ = 167.78 (C=O), 160.73 (C-4), 158.63, 156.40, 136.86, 128.57, 128.21, 127.97, 124.84, 121.45, 120.76 (arom C), 112.28 (O2
CMe2), 111.12 (arom C), 84.46 (=CHCO2Et), 80.29 (C-3a), 75.93 (OCH2Ph), 75.01 (C-6a), 58.79 (OCH2CH3), 57.61 (C-6), 55.96 (ArOCH3), 27.15, 25.33 (2 × CH3), 14.42 (OCH2
CH3), 9.59 (ArCH3).
Major Rotamer: 1H NMR (300 MHz, CDCl3): δ = 7.26-7.44 (m, 5 H, CH2
Ph), 6.90 (s, 1 H, arom H), 5.93 (d, J = 6.6 Hz, 1 H, H-3a), 5.07 (d, J = 11.1 Hz, 1 H, OCH
aHbPh), 4.94 (td, J = 2.4, 6.3 Hz, 1 H, H-6a), 4.71 (d, J = 11.1 Hz, 1 H, OCHa
H
bPh), 4.43 (s, 1 H, =CHCO2Et), 4.13 (q, J = 7.0 Hz, 2 H, OCH
2CH3), 3.83-3.89 (m, 2 H, NCH2), 3.84 (s, 3 H, ArOCH
3), 1.99 (s, 3 H, ArCH
3), 1.36, 1.44 (2 × s, 6 H, 2 × CH3), 1.22 (t, J = 7.0 Hz, 3 H, OCH2CH
3). 13C NMR (75 MHz, CDCl3): δ = 167.97 (C=O), 160.56 (C-4), 158.61, 156.21, 136.74, 128.31, 127.97, 127.48, 124.80, 121.47, 120.12 (arom C), 112.21 (O2
CMe2), 111.12 (arom C), 85.04 (=CHCO2Et), 80.03 (C-3a), 76.00 (OCH2Ph), 75.19 (C-6a), 58.82 (OCH2CH3), 57.68 (C-6), 55.93 (ArOCH3), 24.85, 26.75 (2 × CH3), 14.40 (OCH2
CH3), 9.45 (ArCH3).
21
Tietze LF.
Petersen S.
Eur. J. Org. Chem.
2000,
11:
1827
22
Synthesis of (-)-Ethyl (3a
R,10bS)-6-Benzyloxy-8-methoxy-2,2,7-trimethyl-3a,10b-dihydro-4H-[1,3]dioxolo-[4′,5′:3,4]pyrrolo[1,2-a
]indole-10-carboxylate (27)
: A solution of the vinylogous urethane 26 (N-Ar rotameric mixture, 5.62 g, 10.6 mmol, 1.0 equiv) in a mixture of DMF (70 mL), MeCN (70 mL) and H2O (15 mL) was thoroughly degassed with nitrogen for 10 min. Palladium(II) acetate (710 mg, 3.16 mmol, 0.3 equiv), P(o-tolyl)3 (5.15 g, 16.9 mmol, 1.6 equiv) and Et3N (14.7 mL, 105 mmol, 10 equiv) were added in succession and the resulting orange mixture was heated at reflux for 4 h. The dark brown reaction mixture was cooled to r.t., diluted with H2O (200 mL) and stirred vigorously for 1 h. The mixture was extracted with CH2Cl2, which was then dried (MgSO4) and evaporated to afford a dark brown oil. Purification by column chromatography on silica gel with EtOAc-hexane (1:9 then 2:8) as eluent gave the pyrrolo[1,2-a]indole 27 (3.92 g, 82%) as a pale yellow solid. Recrystallisation from EtOAc-hexane yielded a colourless crystalline solid; mp 90-91 °C; R
f
0.49 (EtOAc-hexane, 3:7); [α]D
23 -85.5 (c = 0.57, abs. EtOH). IR (CHCl3): 2982 (w), 1697 (s, C=O), 1570 (m), 1454 (m), 1433 (m), 1275 (s), 1206 (m), 1129 (s), 747 (w) cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.33-7.41 (m, 6 H, 9-H, CH2
Ph), 5.77 (s, J = 6.2 Hz, 1 H, 10b-H), 5.22 (br t, J ≈ 5.8 Hz, 1 H, 3a-H), 4.96 (d, J = 11.4 Hz, 1 H, OCH
aHbPh), 4.90 (d, J = 11.4 Hz, 1 H, OCHa
H
bPh), 4.40 (q, J = 7.1 Hz, 2 H, OCH
2CH3), 4.15-4.27 (m, 2 H, NCH2), 3.91 (s, 3 H, ArOCH
3), 2.27 (s, 3 H, ArCH
3), 1.26, 1.44 (2 × s, 6 H, 2 × CH3), 1.42 (t, J = 7.1 Hz, 3 H, OCH2CH
3). 13C NMR (75 MHz, CDCl3): δ = 164.82 (C=O), 155.28 (C-10), 146.45, 143.40, 136.70, 130.16, 128.65, 128.28, 127.74, 121.57, 115.68 (arom C), 112.61 (O2
CMe2), 101.73 (C-10a), 98.09 (C-9), 81.60 (C-3a), 76.92 (OCH2Ph), 76.41 (C-10b), 59.53 (OCH2CH3), 55.82 (ArOCH3), 53.30 (C-4), 26.97, 25.59 (2 ¥ CH3), 14.48 (OCH2
CH3), 9.61 (ArCH3). HRMS (EI): m/z calcd for C26H29NO6: 451.1995; found: 451.2006. Anal. Calcd for C26H29NO6·0.5H2O: C, 67.81; H, 6.57; N, 3.04. Found: C, 67.99; H, 6.56; N, 3.19.
23
Wiegerinck PHG.
Flucks L.
Hammink JB.
Mulders SJE.
de Groot FMH.
van Rozendaal HLM.
Scheeren HW.
J. Org. Chem.
1996,
61:
7092
24
{(1
R,2R)-(-)-1-Azido-2,3,5,8-tetrahydro-7-methoxy-6-methyl-2-methanesulfonyloxy-5,8-dioxo-1H-pyrrolo[1,2-a
]indol-9-yl}methyl Phenyl Carbonate (39)
: R
f
0.13 (EtOAc-hexane, 3:7); [α]D
23 -121.6 (c = 1.02, CHCl3). IR (CHCl3): 3018 (m), 2939 (m), 2108 (s, N3), 1761 (s, ester C=O), 1647 (s, quinone C=O), 1507 (m), 1365 (s), 1319 (s), 1246 (br s), 1210 (s), 1176 (s), 1106 (s), 960 (s) cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.18-7.41 (m, 5 H, arom H), 5.56 (d, J = 13.4 Hz, 1 H, CH
aHbOCO2Ph), 5.50 (d, J = 13.4 Hz, 1 H, CHa
H
bOCO2Ph), 5.47 (br dd, J ≈ 2.4, 4.2 Hz, 1 H, H-2), 5.28 (d, J = 1.2 Hz, 1 H, H-1), 4.50-4.64 (m, 2 H, NCH2), 4.06 (s, 3 H, OCH3), 3.07 (s, 3 H, OSO2CH3), 1.97 (s, 3 H, ArCH
3). 13C NMR (75 MHz, CDCl3): δ = 178.79, 178.63 (2 × quinone C=O), 157.46 (C-10), 153.47 (carbonate C=O), 150.99 (arom C), 135.95 (C-7), 129.50, 128.15, 127.51, 126.19, 124.22, 120.97 (3 × arom C, C-4, C-6, C-9), 114.53 (C-10), 84.25 (C-2), 61.99, 61.78 (C-1, CH2OCO2Ph), 61.29 (quinone OCH3), 51.71 (C-3), 38.71 (OSO2CH3), 8.49 (quinone CH3). LRMS (FAB): m/z = 517 [MH+].
