A. M. Jordan et al. / Bioorg. Med. Chem. 9 (2001) 1549–1558
1555
6.0 Hz, CH2NH), 3.61 (2H, d, J=6.0 Hz, 2ÂNCH2),
3.68 (4H, d, J=6.0 Hz, 2ÂCH2Cl), 6.67 (1H, br t,
J=6.0 Hz, NH), 6.67 (2H, d, J=9.0 Hz, Ar), 6.77 (2H,
d, J=8.4 Hz, Ar), 6.99 (2H, d, J=9.0 Hz, Ar), 7.03 (2H,
d, J=8.4 Hz, Ar); 13C NMR (100 MHz, CDCl3) d 35.3
(CH2), 40.5 (CH2), 42.8 (CH2), 54.3 (CH2), 113.4 (CH),
115.8 (CH), 123.1 (CH), 130.2 (CH), 130.7 (C), 143.6
(C), 154.7(C), 155.8 (C and CO); (CI: found 397.1085
[M+H]+. C19H22Cl2N2O3 requires 397.1085); m/z
(CI) (397 [M+H]+, 45%), 234 (100), 184 (95), 107
(100).
30,40-Dihydroxybenzylamino-carbamic acid p-(bis-2-
chloroethylamino) phenyl ester (15). A solution of car-
bonate 6 (0.13 g, 0.32 mmol), 3,4-dihydroxybenzylamine
hydrobromide (0.14 g, 0.65 mmol) and triethylamine
(0.07 g, 0.09 mL, 0.65 mmol) in anhydrous dimethylfor-
mamide (2 cm3) was stirred at room temperature for
72 h. After this time, the mixture was concentrated to
dryness in vacuo. Column chromatography (silica gel,
dichloromethane/methanol 100:1 ! 9:1 v/v) gave car-
bamate 15 as a white powder (0.07 g, 52%); Rf 0.29
(silica, dichloromethane/methanol, 9:1, v/v); nmax (KBr
disc) 3322, 1689, 1616, 1507, 1427, 1281, 1215,
1037 cmÀ1. 1H NMR (400 MHz, CD3OD) d 3.65 (4H, d,
J=6.2 Hz, 2ÂNCH2), 3.71 (4H, d, J=6.2 Hz,
2ÂCH2Cl), 4.17 (2H, br d, J=7.3 Hz, CH2), 6.64 (1H,
br t, J=7.3 Hz, NH), 6.74–6.81 (5H, m, Ar), 6.96 (2H,
d, J=7.4 Hz, Ar); 13C NMR (100 MHz, CD3OD) d 41.6
(CH2), 45.3 (CH2), 54.6 (CH2), 113.9 (CH), 115.7 (CH),
116.2 (CH), 119.9 (CH), 123.7 (CH), 144.0 (C), 145.4
(C), 145.6 (C), 146.3 (C), 158.0 (C and CO); (CI: found
{20-(300,400-Dihydroxyphenyl)-ethyl} carbamic acid p-(bis-
2-chloroethylamino)phenyl ester (10). A solution of the
carbonate 6 (0.1 g, 0.26 mmol), 3-hydroxytyramine
hydrochloride (0.1 g, 0.53 mmol) and triethylamine
(0.05 g, 0.07 mL, 0.5 mmol) in anhydrous dimethylfor-
mamide (1.5 mL) was stirred for 3 days at ambient
temperature. After this time, the mixture was con-
centrated to dryness in vacuo. Column chromato-
graphy(silica gel, dichloromethane/methanol 100:1
!
[M+H]+,
399.0878); m/z (CI) ([M+H]+, 20%), 363 (10), 233
(70), 184 (100).
399.0870.
C18H20Cl2N2O4
requires
9:1 v/v) gave the carbamate 10 as a colourless viscous
oil (0.08 g, 73%); Rf 0.45 (silica, dichloromethane/
methanol, 9:1, v/v); nmax (KBr disc) 3421, 1718, 1653,
1
1507, 1218 cmÀ1. H NMR (400 MHz, CDCl3) d 2.60
(R)-3,4-Hydroxyphenylglycine methyl ester (14). To a
stirred solution of 3,4-hydroxyphenylglycine (0.5 g,
3.0 mmol) in 2,2-dimethoxypropane (30 mL) was added
concentrated hydrochloric acid (3 mL). After stirring
overnight at 20 ꢀC, the mixture was concentrated to
dryness in vacuo, and minimal methanol added to re-
dissolve the residues. Diethyl ether (75 mL) was added
and the resultant solid obtained byfiltration. Re-dis-
solution in methanol (30 mL) and addition of triethyla-
mine (0.3 g, 0.4 mL, 3 mmol), followed byconcentration
in vacuo and column chromatography(silica gel, di-
chloromethane/methanol 20:1 v/v) gave the free amine
14 as a white powder in quantitative yield; mp 172–
173 ꢀC (lit.12 178–180 ꢀC); [a]2D0 À114.4ꢀ (c 0.25, 10% aq
hydrochloric acid) (lit.13 [a]2D0 À121.1ꢀ (c 1, aq hydro-
chloric acid)); Rf 0.55 (silica, dichloromethane/metha-
nol, 10:1, v/v); nmax (KBr disc) 3447, 1734, 1559, 1517,
1465, 1281, 1255, 1220, 1167 cmÀ1; 1H NMR (400 MHz,
CDCl3) d 3.24 (2H, br s, NH2), 3.60 (3H, s, Me), 4.46
(1H, br s., CH), 6.70 (2H, d, J=8.6 Hz, Ar), 7.07 (2H, d,
J=8.6 Hz, Ar); 13C NMR (100 MHz, CDCl3) d 55.1
(CH), 61.3 (CH3), 118.9 (CH), 131.7 (CH), 134.0 (C),
161.0 (C), 178.2 (C); (CI: found [M+H]+, 182.0822.
C9H11NO3 requires 182.0818); m/z (CI) 182 ([M+H]+,
15%), 165 (50), 122 (100), 107 (5).
(2H, br t, J=6.3 Hz, PhCH2), 3.32 (2H, br q, J=6.3 Hz,
CH2NH), 3.48 (4H, d, J=6.2 Hz, 2ÂNCH2), 3.55 (4H,
d, J=6.2 Hz, 2ÂCH2Cl), 5.17 (1H, br t, J=6.3 Hz,
NH), 6.50 (2H, d, J=7.9 Hz, Ar), 6.58 (2H, s, Ar), 6.64
(1H, d, J=7.7 Hz, Ar), 6.88 (2H, d, J=7.9 Hz, Ar); 13C
NMR (100 MHz, CDCl3) d 35.3 (CH2), 40.7 (CH2), 42.7
(CH2), 53.9 (CH2), 112.8 (CH), 115.6 (CH), 116.8 (CH),
120.9 (CH), 123.0 (CH), 130.9 (C), 142.5 (C), 143.0 (C),
144.1 (C), 144.4 (C), 156.1(C and CO); (CI: found
[M+H]+,
413.1034); m/z (CI) 413 ([M+H]+, 10%), 233 (50), 184
413.1045.
C19H22Cl2N2O4
requires
(100), 123 (35).
(R)-[20-Amino-30-(400-hydroxyphenyl)propionic
acid
methyl ester]-carbamic acid p-(bis-2-chloroethylamino)
phenyl ester (12). To a solution of the nitrophenyl car-
bonate 6 (0.20 g, 0.57 mmol) in chloroform (1 mL) was
added l-tyrosine methyl ester (0.127 g, 0.65 mmol) and
the mixture was heated under reflux for 4 h. After this
time, the reaction was cooled and concentrated in
vacuo. Column chromatography(silica gel, dichloro-
methane/methanol 100:1) afforded carbamate 12 as a
colourless oil (0.085 g, 62%); Rf 0.16 (silica, dichloro-
mehane/ethyl acetate 95:5); [a]2D0 +29.0ꢀ (c 0.9, chloro-
form); nmax (KBr disc) 3446, 1718, 1700, 1559, 1496,
1218 cmÀ1. 1H NMR (400 MHz, CDCl3) d 3.03 (2H, dq,
J=5.9 Hz, 14.2 Hz PhCH2), 3.54 (2H, d, J=6.2 Hz,
2ÂNCH2), 3.68 (2H, d, J=6.0 Hz, 2ÂCH2Cl), 3.69 (3H,
s, Me), 4.58 (2H, br d, J=6.6 Hz, CH), 5.41 (1H, d,
J=8.0 Hz, NH), 6.61 (2H, d, J=9.0 Hz, Ar), 6.68 (2H,
d, J=8.4 Hz, Ar), 6.92 (2H, d, J=9.1 Hz, Ar), 6.94 (2H,
d, J=9.1 Hz, Ar); 13C NMR (100 MHz, CDCl3) d 37.3
(CH2), 40.3 (CH2), 52.4 (CH3), 53.7 (CH2), 55.0 (CH),
112.6 (CH), 115.5 (CH), 122.7 (CH) 127.2 (C), 130.3
(CH), 142.3 (C), 143.8 (C), 154.7 (C), 155.0 (C), 172.0
(C); (CI: found 455.1148 [M+H]+. C21H24Cl2N2O5
requires 455.1141); m/z (CI) (455 [M+H]+, 10%), 234
(15), 184 (35), 107 (100).
(R)-[10-Amino-20-(3,400-hydroxyphenyl)ethanonic
acid
methyl ester]-carbamic acid p-(bis-2-chloroethylamino)
phenyl ester (16). A solution of the carbonate 6 (0.13 g,
0.32 mmol) and the amino acid methyl ester 14 (0.14 g,
0.65 mmol) in anhydrous dimethylformamide (2 mL)
was stirred at room temperature for 72 h. After this
time, the mixture was concentrated to dryness in vacuo.
Column chromatography(silica gel, dichloromethane/
ethyl acetate, 95:5, v/v) gave carbamate 16 as a colour-
less viscous oil (0.07 g, 54%); [a]2D0 À115.8ꢀ (c 0.85,
chloroform); Rf 0.14 (silica, dichloromethane/ethyl ace-
tate, 95:5, v/v); nmax (KBr disc) 3384, 1718, 1612, 1506,
1437, 1350, 1218, 1174, 1030 cmÀ1. 1H NMR (400 MHz,