A. G. M. Barrett et al. / Tetrahedron Letters 42 (2001) 5579–5581
5581
CO2Me
R1
NH
CO2Me
R1
NH
(i) MeO2CCH(R1)NH2 4
O
O
O
H
H
Ph
Ph
Ph
R2CHO 5, NEt3,
50% TFA
N
N
HN
MgSO4, AgOAc,
toluene, 20 °C, 3 d
Ph
H
H
O
O
R2
O
R2
(ii) extensive washing
7
2
1
CO2Me
NH
CO2Me
Me
CO2Me
Ph
NH
CO2Me
O
O
O
O
H
H
H
H
H
H
S
15
16
17
18
NH
NH
HN
HN
HN
HN
H
H
C6H4-4-Cl
C6H4-4-OMe
C6H4-3-OH
c-C6H11
O
O
O
O
Scheme 3.
USA 1997, 94, 2805; (e) Costero, A. M.; Pitarch, M.;
Cano, M. L. J. Chem. Res. (S) 1994, 316.
Acknowledgements
6. Henkel, B.; Stenzel, W.; Schotten, T. Bioorg. Med.
Chem. Lett. 2000, 10, 975.
We thank Aventis Pharma for the most generous sup-
port of our programmes on parallel and combinatorial
syntheses (to R.J.B and R.S.R.) under the auspices of
the TeknoMed project and the Norwegian Research
Council (M.U.F) for predoctoral fellowship support. In
addition we thank GlaxoSmithKline for their endow-
ment (to A.G.M.B.) and the Wolfson Foundation for
establishing the Wolfson Centre for Organic Chemistry
in Medical Science at Imperial College.
7. Hollinshead, S. P. Tetrahedron Lett. 1996, 37, 9157.
8. Mumper, M. W.; Aurenge, C.; Hosmane, R. S. Bioorg.
Med. Chem. Lett. 1993, 3, 2847.
9. For example, see: Aly, M. F.; Younes, M. I.; Metwally,
S. A. M. Tetrahedron 1994, 50, 3159.
10. Peyronel, J.-F.; Grisoni, S.; Carboni, B.; Courgeon, T.;
Carrie´, R. Tetrahedron 1994, 50, 189.
11. Schwartz, A. L.; Lerner, L. M. J. Org. Chem. 1974, 39,
21.
12. Grigg, R.; Montgomery, J.; Somasunderam, A. Tetra-
hedron 1992, 48, 10431.
13. Typical procedure: Alanine methyl ester (92 mg, 0.66
mmol) in toluene (2 mL) was added to a slurry of
maleimide resin (7) (200 mg, ca. 0.22 mmol), AgOAc
(110 mg, 0.66 mmol), MgSO4 (100 mg, 0.66 mmol),
NEt3 (0.11 mL, 0.78 mmol), 4-chlorobenzaldehyde (93
mg, 0.66 mmol) and toluene (3 mL). The resultant sus-
pension was agitated at ambient temperature (56 h),
whereupon it was filtered and washed sequentially with
toluene, THF, DMSO, water, THF, CH2Cl2 and
methanol and dried in vacuo. The bicyclic succinimide
resin (i.e. 2) was added to a solution of 50% TFA–
CH2Cl2 (10 mL) and agitated for 4 h. The resin was
filtered, and washed with CH2Cl2 and methanol. The
filtrate was concentrated, then dissolved in acetone and
filtered through a small pad of Celite and the resultant
filtrate was concentrated in vacuo to reveal essentially
pure desired bicyclic imide 15. Flash column chromatog-
raphy (1:1 EtOAc:hexane) afforded analytically pure
product: 1H NMR (300 MHz, CDCl3) 8.11 (bs, 1H),
7.34 (s, 4H), 4.76 (dd, 1H, J=8.0, 6.5), 3.87 (s, 3H),
3.54 (dd, 1H, J=8.0, 7.5), 3.34 (d, 1H, J=7.5), 2.52 (d,
1H, J=6.5), 1.61 (s, 3H); HRMS (CI) calcd for
C15H16ClN2O4; 323.0799; found 323.0797.
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