D. L. Whitehouse et al./Bioorg. Med. Chem. 6 (1998) 1273±1282
1281
column chromatography (hexanes/EtOAc, 3/1) as a
crystalline white solid (2.10 g, 5.9 mmol, 81%). IR (KBr,
white solid; mp 105±106 ꢀC; yield: 50 mg (88%); IR
(KBr, cm
(300 MHz, CDCl3) d 2.43 (s, 3H), 2.56 (s, 3H), 3.89 (s,
3H), 4.34 (s, 2H); 13C NMR (75 MHz, CDCl3) d 16.8,
25.5, 53.1, 53.2, 125.2, 163.1, 166.7, 169.1, 171.0.
1
)
2954, 1701, 1627, 1330; 1H NMR
1
cm 1) 2959, 2361, 1734; H NMR (300 MHz, CDCl3) d
0.88 (dd, J=6.6, 20.1 Hz, 6H), 1.93 (m, 1H), 1.99 (s,
3H), 2.99 (d, J=7.5 Hz, 2H), 3.82 (s, 3H), 3.87 (s, 3H),
3.93 (s, 3H); 13C NMR (75 MHz, CDCl3) d 15.81, 19.85,
20.07, 28.61, 49.57, 52.93, 53.17, 53.61, 90.25, 98.96,
144.88, 147.09, 161.50, 162.30, 171.18.
Synthesis of methyl 2-methyl-1,3-dioxo-1,2,3,3a-tetra-
hydrocyclohepta[c]pyrrole-3a-carboxylate (12). Diazo
imide 10 (32 mg, 0.12 mmol) was added to a solution
containing rhodium (II) acetate (1 mg) and dimethyl
acetylenedicarboxylate (DMAD) (23 mL, 0.18 mmol) in
benzene-d6 (0.6 mL). The reaction mixture was allowed
to stand at room temperature until 1H NMR showed
complete disappearance of the diazo compound. Flash
column chromatography aorded methyl 2-methyl-
1,3-dioxo-1,2,3,3a-tetrahydrocyclohepta[c]pyrrole-3a-
carboxylate (12) as a viscous yellow oil; yield: 12 mg
(42%); IR (neat, cm 1) 3028, 2954, 1775, 1750, 1706,
Synthesis of trimethyl 5-methyl-2,3,4-furantricarboxylate
(17). Compound 4 (70 mg, 0.29 mmol) was added to a
solution containing rhodium (II) per¯uorobutyramidate
(1 mg) and dimethyl acetylenedicarboxylate (50 mL,
0.43 mmol) in benzene-d6 (0.6 mL). The reaction mixture
was allowed to stand at room temperature for 5 h until
1H NMR showed disappearance of the diazo com-
pound. The mixture was heated to re¯ux for 20 min to
ensure complete cycloreversion. Flash column chroma-
tography aorded trimethyl 5-methyl-2,3,4-furantri-
carboxylate (17) as a white solid; mp 94±95 ꢀC; yield:
70 mg (95%), IR (KBr, cm 1) 3006, 2956, 1715, 1608,
1
1650, 1434, 1379, 1283; H NMR (300 MHz, CDCl3) d
3.14 (s, 3H), 3.63 (s, 3H), 5.90 (d, J=10 Hz, 1H), 6.51±
6.79 (m, 3H), 7.31 (d, J=6 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 25.7, 53.2, 58.1, 124.4, 127.7, 128.0, 129.4,
135.8, 166.2, 167.4, 172.3.
1
1559, 1443, 1288, 1224; H NMR (300 MHz, CDCl3) d
2.63 (s, 3H), 3.81 (s, 3H), 3.86 (s, 3H), 3.92 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 14.2, 52.1, 52.6, 53.1, 114.0,
126.2, 138.9, 157.6, 162.0, 162.3, 163.6.
Kinetic evaluation of the cycloreversion of trimethyl 2-
isobutyl-1-methyl-3-oxo-7-oxa-2-azabicyclo[2.2.1]hept-5-
ene-4,5,6-tricarboxylate (5). This reaction was con-
ducted in a number of solvents and monitored by 1H
NMR spectroscopy. A sample of the cycloadduct was
dissolved in the appropriate deuterated solvent and
placed in an incubator set to the desired temperature.
Periodically the samples were removed and proton
spectra were acquired. The samples were then placed
Synthesis of trimethyl 5-phenyl-2,3,4-furantricarboxylate
from cycloadduct (11). As described for 17 trimethyl 5-
phenyl-2,3,4-furantricarboxylate was prepared and iso-
lated as a white solid (92%), mp 63±64 ꢀC; IR (KBr,
cm 1) 3005, 2954, 1733, 1606, 1446, 1235; 1H NMR
(300 MHz, CDCl3) d 3.81 (s, 3H), 3.93 (s, 3H), 3.99 (s,
3H), 7.42±7.52 (m, 3H), 7.90±7.99 (m, 2H); 13C NMR
(75 MHz, CDCl3) d 52.4, 52.7, 53.2, 127.4, 127.9, 128.2,
124.4, 129.1, 131.0, 139.7, 157.7, 159.7, 161.8, 163.5.
1
back in the incubator. H NMR of trimethyl 5-methyl-
2,3,4-furantricarboxylate (17) (300 MHz, CDCl3) d 2.67
(s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 3.96 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 14.18, 52.12, 52.55, 53.05,
114.02, 126.15, 138.93, 157.59, 162.01, 162.29, 163.58;
IR (neat, cm 1) 3005, 2956, 2850, 2362, 2338, 1749.
Synthesis of trimethyl 5-isopropyl-2,3,4-furantricarboxy-
late from cycloadduct (8). As described for 17 trimethyl
5-isopropyl-2,3,4-furantricarboxylate was prepared and
isolated as a clear thick oil (89%); IR (neat, cm 1) 2955,
2878, 1728, 1607, 1558, 1443; 1H NMR (300 MHz,
CDCl3) d 1.30 (d, J=7 Hz, 6H), 3.78 (m, 1H) 3.81 (s,
3H), 3.86 (s, 3H), 3.93 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 20.4, 27.7, 52.1, 52.5, 53.1, 112.2, 126.1, 138.9,
157.7, 162.0, 163.9, 170.1.
Solid-phase synthesis of trimethyl 5-methyl-2,3,4-furan-
tricarboxylate (17). Wang resin (1.0 g, 0.80 mmol/g
loading) was combined with 6-(acetylamino)hexanoic
acid (0.26 g, 1.48 mmol), benzotriazole-1-yl-oxy-tris-
(dimethylamino)-phosphonium
hexa¯uorophosphate
(BOP) (0.66 g, 1.48 mmol), N-hydroxybenzotriazole
monohydrate (HOBt) (0.20 g, 1.48 mmol) and N,N0-di-
isopropylethylamine (DIPEA) (0.39 mL, 2.22 mmol) in
methylene chloride (5 mL). The resin mixture was agi-
tated for 8 h at 25 ꢀC. The resin was washed with DMF,
Synthesis of methyl 1-acetyl-4-methyl-2-oxo-2,5-dihydro-
1H-3-pyrrolecarboxylate (15). Diazo imide 13 (56 mg,
0.25 mmol) was added to a solution of rhodium (II)
acetate (1 mg) and dimethylacetylene dicarboxylate
(DMAD) (46 mL, 0.38 mmol) in benzene-d6 (0.6 mL).
The reaction mixture was allowed to stand at room
temperature for 2 days until 1H NMR showed complete
disappearance of the diazo compound. Flash column
chromatography aorded methyl 1-acetyl-4-methyl-
2-oxo-2,5-dihydro-1H-3-pyrrolecarboxylate (15) as a
methylene chloride yielding 1.21 g of air dried Wang
1
resin 6-(acetylamino)hexanoate (19); IR (KBr, cm
3291, 1733, 1653.
)
As described in the solution phase synthesis of compound
4, Wang resin 6-[acetyl(3-methoxy-3-oxopropanoyl)-