Synthesis of Anticancer Compounds, I
521
NaH (60% dispersion in oil; washed with hexane) in 13cm3
dry DMF. After stirring for 0.5 h at 0ꢁC a solution of
2.57 g 4-[tert-butoxycarbonyl)amino]benzyl methansulfonate
(8.54 mmol) in 14.2cm3 dry DMF was added and stirring
was continued for 14 h. The reaction was quenched with water
and extracted with ethyl acetate. The combined organic layers
were dried (Na2SO4), filtered, and concentrated. The resulting
crude product was purified by column chromatography (silica
gel, EtOAc=LP ¼ 1=1 þ 0.5% triethyl amine) to afford 2.37g
1a (92%) as yellow crystals. Mp 191–193ꢁC; 1H NMR
(200 MHz, d6-DMSO): ꢁ ¼ 1.44 (s, 9H), 4.62 (d, J ¼ 5.3 Hz,
2H), 5.13 (s, 2H), 5.22 (dd, J ¼ 1.5, 10.5Hz, 1H), 5.40
(dd, J ¼ 1.6, 17.2 Hz, 1H), 5.84–6.03 (m, 1H), 6.98 (s, 1H),
7. 29 (d, J ¼ 8.5 Hz, 2H), 7.44 (d, J ¼ 8.5Hz, 2H), 7.56 (d,
J ¼ 1.6 Hz, 1H), 7.78 (d, J ¼ 1.6 Hz, 1H), 8.78 (s, 1H), 9.38 (s,
1H) ppm; 13C NMR (50 MHz, d6-DMSO): ꢁ ¼ 28.1, 52.7,
65.7, 79.1, 115.4, 117.96, 118.3, 118.6, 120.8, 124.3, 126.3,
128.7, 130.1, 132.4, 139.6, 142.5, 152.4, 175.3, 181.6 ppm; IR
(KBr): ꢂꢀ¼ 1162, 1523, 1632, 1671, 1703, 1738, 3291,
3362 cmꢂ1; MS: m=z (%) ¼ 451 (Mþ, 3), 395 (2), 150 (18),
106 (100), 57 (90), 56 (19), 44 (17), 41 (39).
2H), 4.71 (t, J ¼ 5.3Hz, 2H), 5.03 (s, 2H), 5.23 (dd, J ¼ 1.4,
10.4Hz, 1H), 5.39 (dd, J ¼ 1.6, 17.2Hz, 1H), 5.84–6.03 (m,
1H), 6.64 (d, J ¼ 8.8 Hz, 2H), 6.96 (s, 1H), 7.21 (d, J ¼ 8.8 Hz,
2H), 7.53 (d, J ¼ 1.8 Hz, 1H), 7.75 (d, J ¼ 1.8 Hz, 1H), 8.77
(s, 1H) ppm; 13C NMR (50 MHz, d6-DMSO): ꢁ ¼ 52.8, 53.2,
58.1, 65.7, 111.2, 115.4, 117.98, 118.5, 120.7, 122.7, 124.1,
126.0, 129.5, 132.4, 142.5, 147.9, 152.4, 175.3, 181.4ppm; IR
(KBr): ꢂꢀ¼ 1049, 1194, 1517, 1615, 1636, 1738, 3355cmꢂ1
;
MS: m=z (%) ¼ 439 (Mþ, 0.05), 176 (7), 162 (14), 118 (17),
58 (14), 57 (71), 44 (100), 41 (29).
4. To a solution of 210 mg (0.48 mmol) of the diol obtainded
above in 2.2 cm3 dry CH2Cl2 and 0.17 cm3 triethyl amine
(1.2mmol) were added under Ar at 0ꢁC 0.08 cm3 methaneslu-
fonic acid chloride (1.07 mmol). After 15min the reaction mix-
ture was washed with H2O, dried (MgSO4), filtered, and
concentrated. The resulting crude product was purified by col-
umn chromatography (silica gel, EtOAc=LP¼ 1=1) to afford
193 mg 1e (85%) as yellow crystals. Mp 185–187ꢁC; 1H
NMR (200MHz, CDCl3): ꢁ ¼ 3.64 (m, 4H), 3.72 (m, 4H),
4.68 (d, J ¼ 5.8 Hz, 2H), 4.98 (s, 2H), 5.25–5.41 (m, 2H),
5.85–6.05 (d, J ¼ 5.8 Hz, 2H), 6.66 (d, J ¼ 8.7 Hz, 2H), 7.13
(d, J ¼ 8.7 Hz, 2H), 7.19 (d, J ¼ 1.9 Hz, 1H), 7.21 (s, 1H), 7.30
(d, J ¼ 1.9 Hz, 1H), 7.87 (s, 1H) ppm; 13C NMR (50 MHz,
CDCl3): ꢁ ¼ 40.2, 53.3, 54.0, 66.5, 112.2, 115.9, 118.9, 119.1,
121.98, 122.95, 123.5, 124,95, 129.96, 131.7, 141.7, 146.5,
152.1, 176.1, 182.6ppm; IR (KBr): ꢂꢀ¼ 1190, 1512, 1615,
1643, 1735, 3333 cmꢂ1; MS: m=z (%) ¼ 475 (Mþ, 10), 428
(17), 426 (47), 232 (55), 230 (74), 118 (100), 63 (17), 41 (46).
2. Allyl [2-(4-aminobenzyl)-4,7-dioxo-4,7-dihydro-
2H-isoindol-5-yl]carbamate
To a solution of 2.37g (5.25 mmol) of the product obtainded
above in 24 cm3 of dry CH2Cl2 were added dropwise under Ar
4.8 cm3 trifluoroacetic acid (62 mmol). After stirring for 2 h
at room temperature the reaction mixture was concentrated.
The residue was dissolved in ethyl acetate and the organic lay-
er washed with sat. NaHCO3-solution and brine. The organic
layer was dried (MgSO4), filtered, and concentrated. The re-
sulting crude product was purified by column chromatography
(aluminum oxide, EtOAc=LP¼ 7=3) to afford 1.19 g (65%) of
the product as yellow crystals. Mp 194–196ꢁC; 1H NMR
(200 MHz, d6-DMSO): ꢁ ¼ 4.62 (d, J ¼ 5.3 Hz, 2H), 4.99 (s,
2H), 5.15 (s, 2H), 5.22 (dd, J ¼ 1.4, 10.4Hz, 1H), 5.38 (dd,
J ¼ 1.8, 17.3 Hz, 1H), 6.53 (d, J ¼ 8.4Hz, 2H), 6.96 (s, 1H),
7.08 (d, J ¼ 8.4 Hz, 2H), 7.50 (d, J ¼ 1.8 Hz,1H), 7.71, d,
J ¼ 1.8 Hz, 1H), 8.75 (s, 1H) ppm; 13C NMR (50 MHz,
d6-DMSO): ꢁ ¼ 53.1, 65.8, 113.8, 115.4, 118.0, 118.5, 120.7,
123.3, 124.1, 126.1, 129.3, 132.4, 142.5, 148.8, 152.4, 175.3,
181.7ppm; IR (KBr): ꢂꢀ¼ 1155, 1201, 1519, 1629, 1664,
1728, 3348, 3433 cmꢂ1; MS: m=z (%) ¼ 351 (Mþ, 4), 107 (8),
106 (100), 61 (12), 45 (11), 44 (8), 43 (63), 41 (16).
General Procedure for the Cleavage of the Alloc-
Protecting Group
A portion of 1.1 equ. of tributyltin hydride was added under
Ar to a suspension of 1 equivalent of 1a, or 1c–1e, respec-
tively, 0.02 equ. of bis(triphenylphosphin)palladium chloride,
2 equ. of H2O, and 0.3 equ. of CH2Cl2. After stirring for
15min at room temperature the reaction mixture was concen-
trated and subsequently purified.
5-Amino-2-(oxiran-2-ylmethyl)-2H-isoindole-4,7-dione
(2a, C11H10N2O3)
Column chromatography (aluminum oxide; EtOAc=MeOH¼
9=1) afforded 51% yield of 2a as orange crystals. Mp 210ꢁC;
1H NMR (200MHz, CDCl3): ꢁ ¼ 2.55 (m, 1H), 2.80 (t,
J ¼ 4.5Hz,1H), 3.32 (s, 1H), 4.01 (dd, J ¼ 6.2, 14.4Hz, 1H),
4.32 (dd, J ¼ 3.5, 14.3Hz, 1H), 5.46 (s, 1H), 6.78 (s, 2H), 7.24
(d, J ¼ 1.6 Hz, 1H), 7.55 (d, J ¼ 1.6Hz, 1H) ppm; 13C NMR
(50 MHz, d6-DMSO): ꢁ ¼ 45.0, 50.5, 51.3, 102.4, 122.6, 123.2,
125.98, 152.0, 177.5, 180.9 ppm; IR (KBr): ꢂꢀ¼ 1169, 1205,
1537, 1597, 1618, 3376 cmꢂ1; MS: m=z (%) ¼ 218 (Mþ, 100),
161 (7), 69 (42), 65 (43), 57 (100), 55 (71), 51 (43), 45 (40).
3. Allyl [2-[4-[bis(2-hydroxyethyl)amino]benzyl]-
4,7-dioxo-4,7-dihydro-2H-isoindol-5-yl]carbamate
To a solution of 1.19 g (3.39 mmol) of the product obtained
above in 64 cm3 EtOH=H2O (3=1) were added 1.5cm3 ethy-
lene oxide at 0ꢁC. After refluxing for 24 h a portion of 1 cm3
ethylene oxide was added and refluxing was continued for
further 15h. In the following the reaction mixture was con-
centrated and the residue was dissolved in ethyl acetate. The
organic layer was dried (MgSO4), filtered, and concentrated.
The resulting crude product was purified by column chroma-
tography (silica gel, EtOAc) to afford 1.15g (77%) of the prod-
2-(5-Amino-4,7-dioxo-4,7-dihydro-2H-isoindol-2-yl)ethyl
methanesulfonate (2c, C11H12N2O5S)
Column chromatography (aluminum oxide; EtOAc=MeOH¼
9=1) afforded 59% yield of 2c as orange crystals. Mp 179–
1
1
181ꢁC; H NMR (200 MHz, CDCl3): ꢁ ¼ 3.13 (s, 3H), 4.33
uct as yellow crystals. Mp 184–186ꢁC; H NMR (200MHz,
(t, J ¼ 4.6 Hz, 2H), 4.53 (t, J ¼ 4.6Hz, 2H), 5.45 (d, J ¼ 0.7 Hz,
d6-DMSO): ꢁ ¼ 3.38 (m, 4H), 3.49 (m, 4H), 4.62 (d, J ¼ 5.3 Hz,