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D. Ellis / Tetrahedron: Asymmetry 12 (2001) 1589–1593
1
ole C-6H), 6.89 (1H, d, J=1.47 Hz, benzodioxole C-
2H), 7.15–7.58 (13H, complex multiplets, aromatics),
8.0 (1H, s, indole C-7H); APCI-MS m/z: 444.6 (MH+,
100%). Anal. calcd for C34H32N2O6 (564.61): C, 72.32;
H, 5.71; N, 4.96. Found: C, 71.95; H 5.65; N, 4.92%.
7 as a foam (0.39 g, 0.62 mmol, 55%). H NMR (300
MHz, CDCl3): l 2.36 (3H, s, CH3-phenyl), 3.44 (3H, s,
N-CH3), 3.74 (3H, s, O-CH3), 5.04 (1H, s, CH6 -
CONHSO2), 5.40 (2H, s, PhCH2O), 5.91 (2H, br d,
J=3.29 Hz, O-CH2-O), 6.55 (1H, s, aromatic CH), 6.70
(3H, br s, aromatic CH), 6.86 (1H, d, J=7.69 Hz,
aromatic CH), 7.06 (1H, s, aromatic CH), 7.19 (1H, d,
J=8.42 Hz, aromatic CH), 7.3–7.5 (7H, complex multi-
plets, aromatics), 7.67 (1H, d, J=8.42 Hz, aromatic
CH), 7.92 (1H, d, J=8.05 Hz, aromatic CH), 8.04 (1H,
s, indole C-7H), 8.79 (1H, br s, CONHSO2); TSP-MS
m/z: 627.5 (MH+, 100%). Anal. calcd for
C34H30N2O8S·0.25CH2Cl2 (647.89): C, 63.49; H, 4.74;
N, 4.32. Found: C, 63.64; H, 4.71; N, 4.31%.
4.2. Preparation of benzyl 3-[(1S)-2-amino-1-(1,3-benzo-
dioxol-5-yl)-2-oxoethyl]-1-methyl-1H-indole-6-carboxy-
late 6
The (R)-a-methylbenzylamine salt of 3 (2.7 g, 4.8
mmol) was partitioned between ethyl acetate (200 mL)
and aqueous HCl (2 M, 100 mL). The organic phase
was separated and washed with further portions of
aqueous HCl (2 M, 2×50 mL), saturated aqueous
sodium chloride solution (50 mL), dried (MgSO4),
filtered and evaporated to give the free acid as a foam.
To a solution of the acid in CH2Cl2 (25 mL) at 0°C was
added HOAt (0.85 g, 6.2 mmol) followed by EDCI (1.4
g, 7.3 mmol) in portions over 5 min. After 90 min. the
solution was washed with aqueous citric acid solution
(10%, 3×10 mL) and saturated aqueous sodium chlo-
ride solution (10 mL), dried (MgSO4) and filtered. The
filtrate was cooled to 0°C and treated with concentrated
aqueous ammonia solution (SG 0.88, 0.7 mL, 14.3
mmol) dropwise over 2 min. After 10 min. the reaction
mixture was washed with aqueous citric acid solution
(10%, 2×10 mL), saturated aqueous sodium bicarbon-
ate solution (10 mL) and saturated aqueous sodium
chloride solution (5 mL), dried (MgSO4), filtered and
evaporated to give 6 as a solid (1.78 g, 84%, 98.7% e.e.);
4.4. Preparation of 3-((1S)-1-(1,3-benzodioxol-5-yl)-2-
{[(2-methoxy-4-methylphenyl)sulfonyl]amino}-2-
oxoethyl)-1-methyl-1H-indole-6-carboxylic acid A
A mixture of 7 (0.93 g, 1.5 mmol) and 5% Pd/C (0.15 g)
was hydrogenated at 60 psi and room temperature for
18 h. A further portion of catalyst (0.15 g) was then
added and the reaction continued for a further 4 h. The
reaction mixture was filtered and the filtrate was evapo-
rated. The residue was recrystallised from CH2Cl2/
CH3OH (9:1, ꢀ5 mL) to give A as a white solid (0.59
g, 1.1 mmol, 74%, >99% e.e.). H NMR: l 2.31 (3H, s,
CH3-phenyl), 3.58 (3H, s, N-CH3), 3.74 (3H, s, O-CH3),
5.19 (1H, s, CH6 CONH), 5.93 (2H, d, J=4.15 Hz,
1
O-CH2-O), 6.68 (2H, m, aromatics), 6.78 (1H, d, J=8.8
Hz, aromatic), 6.85 (1H, d, J=8.07 Hz, aromatic), 6.91
(1H, s, aromatic), 7.12 (1H, s, aromatic), 7.25 (1H, d,
J=8.31 Hz, aromatic), 7.52 (1H, dd, J=1.22, 8.31 Hz,
aromatic), 7.63 (1H, d, J=8.06 Hz, aromatic), 7.97
(1H, s, indole C-7H), 12.26 (1H, br s, NH), 12.53 (1H,
br s, COOH); APCI-MS m/z: 537.7 (MH+, 100%). Anal
calcd for C27H24N2O8S·0.9CH2Cl2 (612.99): C, 54.67;
H, 4.24; N, 4.57. Found: C, 54.67; H, 4.18; N, 4.53%.
1H NMR: l 3.79 (3H, s, N-CH3), 5.00 (1H, s, CH
6 -
CONH2), 5.32 (2H, s, PhCH2O), 5.90 (2H, q, J=0.98,
4.89 Hz, O-CH2-O), 6.76 (1H, d, J=7.82 Hz, benzodi-
oxole C-5H), 6.80 (1H, dd, J=1.23, 8.07 Hz, benzodi-
oxole C-6H), 6.86 (1H, d, J=1.47 Hz, benzodioxole
C-2H), 6.94 (1H, br s, amide NH), 7.26–7.62 (9H,
complex multiplets, aromatics+amide NH), 8.02 (1H, s,
indole C-7H); TSP+MS m/z: 443.0 (MH+, 100%). Anal
calcd for C26H22N2O5 (442.45): C, 70.57; H, 5.01; N,
6.33. Found: C, 70.11; H, 4.96; N, 6.29%.
Acknowledgements
4.3. Preparation of benzyl 3-((1S)-1-(1,3-benzodioxol-5-
yl)-2-{[(2-methoxy-4-methylphenyl)sulfonyl]amino}-2-
oxoethyl)-1-methyl-1H-indole-6-carboxylate 7
I would like to thank Dr D. J. Rawson for support
during this work and his help in the preparation of this
paper.
To a solution of 6 (0.5 g, 1.1 mmol) in THF (12 mL) at
−60°C (internal temperature) under nitrogen was added
NaHMDS (0.207 g, 1.1 mmol, 1.13 mL of 1 M solution
in THF) dropwise over 2 min. The pale yellow solution
was allowed to warm to −40°C and was treated with a
solution of 2-methoxy-4-methylbenzenesulfonyl chlo-
ride (0.25 g, 1.1 mmol) in THF (0.5 mL) dropwise over
2 min. After 30 min. the reaction was quenched with
saturated aqueous NH4Cl solution (5 mL) and allowed
to warm to room temperature. The THF was evapo-
rated and the aqueous residue was extracted with ethyl
acetate (3×10 mL). The combined organic extracts were
washed with aqueous HCl (1 M, 1×5 mL), saturated
aqueous sodium chloride solution (1×5 mL), dried
(MgSO4), filtered and evaporated. The residue was
purified by column chromatography (CH2Cl2:CH3OH
from 100:0 to 98:2 in 1% increments of CH3OH) to give
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