Molecules 2017, 22, 2210
6 of 10
1
2,5-Bis(morpholinomethyl)furan (
8
). Yield 1.04 g, 98% [27]. H-NMR (500 MHz, CDCl3)
δ
= 6.13 (s, 2H),
3.70 (m, 8H), 3.51 (s, 4H), 2.45 (m, 8H). 13C-NMR (126 MHz, CDCl3)
δ = 150.9, 109.7, 66.8, 55.3, 53.2.
HRMS (ESI) Calcd. for C14H22N2O3 [M + H]: 267.1703. Found 267.1703.
3.3. General Method for One-Pot Synthesis of Norcantharimide Derivatives
To a solution of 2,5-bis(aminomethyl)furans
6
–
8
(0.6 mmol) in 2 mL of THF, maleimide (0.12 g,
◦
1.2 mmol, 2 eq.) was added. The reaction mixture was stirred for 24 h at 24 C. Approximately
20 mg of 10% Pd/C was added, and the reaction mixture was placed under a hydrogen atmosphere
(1 atm) for 8 h at 24 ◦C. The catalyst was filtered off and washed thoroughly with hot THF (3 × 4 mL).
The filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography
(ethyl acetate as eluent). Target compounds 10–12 were obtained as pale-yellow oils. Diastereomeric
products 10-endo and 10-exo were formed in a ratio of 4:1 and separated using column chromatography.
endo-4,7-Bis((phenylamino)methyl)-2-propylhexahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione(endo-4,7-bis-(phe
1
nylamino)-2-propyl-norcantharimide) (10-endo). Yield 133 mg, 53%. H-NMR (500 MHz, CDCl3)
δ = 7.22
(t, J = 7.8 Hz, 8H), 6.77 (t, J = 7.4 Hz, 12H), 4.37 (br. s, 2H), 3.70 (d, J = 13.3 Hz, 2H), 3.59 (d, J = 13.3 Hz,
2H), 3.53–3.41 (m, 4H), 1.89 (d, J = 7.6 Hz, 2H), 1.76 (d, J = 7.7 Hz, 2H), 1.63 (m, 1H), 0.97 (t, J = 7.4 Hz,
1H). 13C-NMR (126 MHz, CDCl3)
δ = 176.2, 148.0, 129.4, 118.1, 113.2, 88.6, 53.4, 47.3, 40.7, 30.0, 21.1,
11.5. HRMS (ESI) Calcd. for C25H29N3O3 [M + Na]: 442.2101. Found 442.2114.
exo-4,7-Bis((phenylamino)methyl)-2-propylhexahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione(exo-4,7-
1
bis(phe-nylamino)-2-propyl-norcantharimide) (10-exo). Yield 33 mg, 13%. H-NMR (400 MHz, CDCl3)
δ
= 7.19 (t, J = 7.9 Hz, 4H), 6.72 (dd, J = 12.5, 7.6 Hz, 6H), 4.21 (s, 2H), 3.69 (q, J = 14.0 Hz, 4H), 3.49
t, J = 7.1 Hz, 2H), 3.10 (s, 2H), 2.06 (d, J = 7.2 Hz, 2H), 1.76 (d, J = 7.2 Hz, 2H), 1.61 (m, 2H), 0.88
t, J = 7.4 Hz, 3H). 13C-NMR (126 MHz, CDCl3)
= 176.1, 148.2, 129.4, 117.9, 113.4, 88.2, 52.1, 45.4, 40.7,
(
(
δ
34.2, 21.1, 11.3. HRMS (ESI) Calcd. for C25H29N3O3 [M + Na]: 442.2101. Found 442.2111.
endo-4,7-Bis((diethylamino)methyl)hexahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione(endo-4,7-bis(diethyla-
1
mino)norcantharimide) (11). Yield 103 mg, 51% [27]. H-NMR (500 MHz, CD3OD) δ = 3.66 (s, 2H), 2.99
(m, 4H), 2.76–2.89 (m, 8H), 1.76–1.85 (m, 4H), 1.12 (t, 12H, J = 7.1 Hz). 13C-NMR (126 MHz, CD3OD)
δ = 177.8, 88.6, 54.5, 53.6, 48.4, 29.1, 10.3.
endo-4,7-Bis(morpholinomethyl)hexahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione(endo-4,7-bis(morpholino-
methyl)norcantharimide) (12). Yield 93 mg, 42% [27]. 1H-NMR (500 MHz, CD3OD)
(
δ
= 3.58–3.65
m, 10H), 2.72 (m, 4H), 2.48–2.66 (m, 8H), 1.69–1.83 (m, 4H). 13C-NMR (126 MHz, CD3OD)
δ
= 178.2,
89.1, 66.7, 59.8, 54.6, 53.7, 28.9.
3.4. General Method for One-Pot Synthesis of Norcantharidin Derivatives
To a solution of compounds 14–16 (1 mmol) in 2 mL of THF, maleic anhydride (196 mg, 2 mmol,
2 eq.) was added, and the reaction mixture was stirred for 24 h at 24 ◦C. Approximately 30 mg of 10%
Pd/C was added, and the reaction mixture was placed under a hydrogen atmosphere (1 atm) for 12 h
◦
at 24 C. The catalyst was filtered off and washed thoroughly with hot THF (3
×
4 mL). The filtrate was
evaporated under reduced pressure, and the resulting mixture was treated by column chromatography.
Target compounds 17–19 were obtained as white solids or light yellow oils.
endo-4,7-Bis(methoxymethyl)hexahydro-4,7-epoxyisobenzofuran-1,3-dione(endo-4,7-bis(methoxymethyl)-nor
1
cantharidin) (17). Yield 43 mg, 17% (33% based on reacted substrate). H-NMR (500 MHz, CDCl3)
δ = 3.86 (d, J = 10.6 Hz, 2H), 3.76 (d, J = 10.6 Hz, 2H), 3.42 (s, 6H), 3.31 (s, 2H), 2.06 (d, J = 7.4 Hz, 2H),
1.71 (d, J = 7.5 Hz, 2H). 13C-NMR (126 MHz, CDCl3)
δ = 169.3, 88.1, 70.8, 59.7, 52.5, 32.0. HRMS (ESI)
Calcd. for C12H16O6 [M + Na]: 279.0839. Found 279.0836.
endo-4,7-Bis(ethoxymethyl)hexahydro-4,7-epoxyisobenzofuran-1,3-dione(endo-4,7-bis(ethoxymethyl)nor-canth
1
aridin) (18). Yield 77 mg, 27% (59% based on reacted substrate). H-NMR (500 MHz, CDCl3)
δ
= 3.92