Example 27 (3aα,4α.7α,7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-lH-isoindole- l,3(2H)-dione (27D)
A. (endo, endo)-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (27A)
Compounds 27A, 27B and 27C were synthesized in accordance with the
approaches described in Sprague et al, J. Med. Chem. 28, 1580-1590
(1985). A mixture of furan (100 mL, 1.38 mol, 1 eq) and maleic acid
(159.6 g, 1.38 mol, 1 eq) in H
2O (340 mL) was stiπed at room
temperature for 5 days. The mixture was placed in a separatory funnel
and the aqueous layer was separated from the layer containing the
unreacted furan. The aqueous layer was treated with charcoal, filtered
tlirough celite and placed in the refrigerator. The desired product
crystallized from solution upon seeding, was filtered, washed with cold
water and dried over P
2O
5 to give 70 g (0.38 mol, 28%) of compound 27A as a white solid.
B. (endo, endo)-7-Oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid (27B)
To a solution of compound 27A (69 g, 0.375 mol, 1 eq)
in EtOH (700 mL) was added 10% Pd/C (4.5 g, cat.) and the mixture was
shaken under a hydrogen atmosphere at 55 psi until gas uptake ceased.
The mixture was filtered through celite and concentrated in vacuo to
give 66 g (0.355 mol, 95%) of compound 27B as a white solid.
C. (3aα,4α,7α,7aα)-Hexahydro-4,7-epoxyisobenzofuran-l,3-dione (27C)
A solution of compound 27B (66 g, 355 mol) in acetyl
chloride (300 mL) was refluxed for 1 h. The reaction solution was
concentrated in vacuo and the resulting residue was recrystallized from
benzene to give 49.2 g (0.292 mol, 82%o) of compound 27C as a white
solid (>99% endo by 'H NMR).
D. (3aα,4α,7α,7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-lH-isoindole-
l,3(2H)-dione (27D)
Compound 27C (45 mg, 0.30 mmol, 1 eq) was combined with
2- naphthalenamine (47 mg, 0.33 mmol, 1.1 eq) in acetic acid (1 mL) and
heated at 115°C overnight. After the reaction was cooled to rt, a drop
of water was added, and the resulting precipitate was filtered. The
material was washed with methanol and dried to provide 65.7 mg (74.5%)
of compound 27D as a white crystalline solid. HPLC: 99% at 2.68 min
(retention time) (YMC S5 ODS column 4.6 x 50 mm, 10- 90% aqueous
methanol over 4 minutes containing 0.2%> phosphoric acid, 4 mL/min,
monitoring at 220 nm), MS (ESI): m/z 294.0 [M+H]
+.
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