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B. Evers et al. / Bioorg. Med. Chem. 13 (2005) 6748–6762
3H), 4.07 (d, 1H, J = 16.1 Hz), 3.38 (m, 1H), 3.17
(m, 1H), 3.04 (m, 2H), 1.42 (m, 12H), 0.89 (m, 3H). MS
m/z 631 (MH+).
(m, 3H), 4.02 (m, 1H), 3.88 (m, 1H), 1.44 (s, 9H). MS
m/z 295 (MÀÀ1).
5.4.57. N-tert-Butoxycarbonylamino-O-(3,5-dimethyl-iso-
xazol-4-ylmethyl)-D-serine (10d). The title compound was
prepared from 2 and 4-bromomethyl-3,5-dimethyl-isox-
5.4.51. 2-(R)-2-(2-Amino-2-methylpropionylamino)-3-(2-
chloro-3,6-difluorophenyl)methoxypropionic acid N-(5-
(4-chlorophenyl)-3,3-dimethyl-1,1-dioxo-2,3-dihydroisothia-
zol-4-ylmethyl)-N-ethylamide hydrochloride (9x). The title
compound was prepared from 3x as described in Methods
B and C (yield = 32%). 1H NMR (DMSO-d6) d 7.60–7.29
(m, 6H), 4.61 (m, 1H), 4.44 (s, 2H), 4.48 (d, 1H,
J = 16.2 Hz ), 4.07 (d, 1H, J = 16.2 Hz), 3.38 (m, 1H),
3.17 (m, 1H), 3.05 (m, 2H), 1.49–1.35 (m, 12H), 0.90
(m, 3H). MS m/z 647 (MH+).
1
azole by Method A (yield = 70%). H NMR (CDCl3) d
8.04 (br s, 1H), 5.38 (d, 1H, J = 8.6 Hz), 4.47 (m, 1H),
4.30 (m, 2H), 3.85 (m, 1H), 3.68 (m, 1H), 2.37 (s, 3H),
2.21 (s, 3H), 1.44 (s, 9H). MS m/z 313 (MÀÀ1).
5.4.58. N-tert-Butoxycarbonylamino-O-(2-methyl-thiazol-
4-ylmethyl)-D-serine (10e). The title compound was pre-
pared from 2 and 4-bromomethyl-2-methyl-thiazole by
1
Method A (yield = 51%). H NMR (CDCl3) d 9.30 (br s,
5.4.52. 2-(R)-2-(2-Amino-2-methylpropionylamino)-3-(2-
chloro-6-fluorophenyl)methoxypropionic acid N-(5-(4-
chlorophenyl)-3,3-dimethyl-1,1-dioxo-2,3-dihydroisothiazol-
4-ylmethyl)-N-ethylamide hydrochloride (9y). The title
compound was prepared from 3y as described in Methods
1H), 7.05 (m, 1H), 5.68 (d, 1H, J = 8.1 Hz), 4.63 (s,
2H), 4.47 (m, 1H), 4.02 (m, 1H), 3.78 (dd, 1H,
J1 = 3.6 Hz, J2 = 9.6 Hz), 2.71 (s, 3H), 1.45 (s, 9H). MS
m/z 315 (MÀÀ1).
1
B and C (yield = 50%). H NMR (DMSO-d6) d 7.58 (d,
5.4.59. N-tert-Butoxycarbonylamino-O-thiazol-4-ylmeth-
yl-D-serine (10f). The title compound was prepared from 2
and 4-bromomethyl-thiazole by Method A (yield = 41%).
1H NMR (CDCl3) d 8.88 (br s, 2H), 7.31 (s, 1H), 5.65 (d,
1H, J = 8.1 Hz), 4.73 (m, 2H), 4.48 (m, 1H), 4.03 (m, 1H),
3.80 (dd, 1H, J1 = 3.6 Hz, J2 = 9.7 Hz), 1.44 (s, 9H). MS
m/z 301 (MÀÀ1).
2H, J = 8.5 Hz), 7.50–7.20 (m, 5H), 4.61 (dd, 1H,
J1 = 5.4 Hz, J2 = 8.0 Hz), 4.53 (s, 2H), 4.50 (d, 1H,
J = 16.1 Hz), 4.05 (d, 1H, J = 16.2 Hz), 3.40 (dd, 1H,
J1 = 9.4 Hz, J2 = 8.9 Hz), 3.14 (dd, 1H, J1 = 4.9 Hz,
J2 = 9.9 Hz), 3.05 (m, 2H), 1.42 (m, 6H), 1.39 (s, 3H),
1.38 (s, 3H), 0.91 (t, 3H). MS m/z 629 (MH+).
5.4.53. 2-(R)-2-(2-Amino-2-methylpropionylamino)-3-(2,6-
difluoro-3-methylphenyl)methoxypropionic acid N-(5-(4-
chlorophenyl)-3,3-dimethyl-1,1-dioxo-2,3-dihydroisothiazol-
4-ylmethyl)-N-ethylamide hydrochloride (9z). The title
compound was prepared from 3z as described in Methods
5.4.60. N-tert-Butoxycarbonylamino-O-thien-3-ylmethyl-
D-serine (10g). The title compound was prepared from 2
and 3-bromomethyl-thiophene by Method A (yield =
30%). 1H NMR (CDCl3) d 8.83 (br s, 1H), 7.33–7.00 (m,
3H), 5.40 (d, 1H, J = 8.1 Hz), 4.72–4.53 (m, 2H), 4.47 (m,
1H), 3.91 (m, 1H), 3.70 (dd, 1H, J1 = 3.3 Hz, J2 =
9.3 Hz), 1.44 (s, 9H). MS m/z 300 (MÀÀ1).
1
B and C (yield = 37%). H NMR (DMSO-d6) d 7.54 (m,
2H), 7.41 (m, 2H), 7.31 (m, 1H), 6.99 (m, 1H), 4.59–
4.45 (m, 4H), 4.04 (d, 1H, J = 16.3 Hz), 3.37 (m, 1H),
3.13 (m, 1H), 3.04 (m, 2H), 2.20 (s, 3H), 1.42 (m, 12H),
0.90 (m, 3H). MS m/z 627 (MH+).
5.4.61. N-tert-Butoxycarbonylamino-O-thien-2-ylmethyl-
D-serine (10h). The title compound was prepared from 2
and 2-bromomethyl-thiophene by Method A (yield =
45%). 1H NMR (CDCl3) d 8.85 (br s, 1H), 7.28 (m, 1H),
6.95 (m, 2H), 5.40 (d, 1H, J = 8.1 Hz), 4.73 (m, 2H), 4.47
(m, 1H), 3.91 (m, 1H), 3.70 (dd, 1H, J1 = 3.3 Hz,
J2 = 9.3 Hz), 1.44 (s, 9H). MS m/z 300 (MÀÀ1).
5.4.54. N-tert-Butoxycarbonylamino-O-pyridin-2-ylmeth-
yl-D-serine (10a). The title compound was prepared from
2 and 2-bromomethyl-pyridine by Method A (yield =
1
62%). H NMR (CDCl3) d 8.94 (br s, 2H), 8.60 (d, 1H,
J = 4.6 Hz), 7.78 (m, 1H), 7.42 (d, 1H, J = 7.9 Hz), 7.30
(m, 1H), 5.72 (d, 1H, J = 7.6 Hz), 4.76 (m, 2H), 4.46 (m,
1H), 4.03 (dd, 1H, J1 = 3.4 Hz, J2 = 10.0 Hz), 3.88 (dd,
1H, J1 = 4.6 Hz, J2 = 10.0 Hz), 1.44 (s, 9H). MS m/z 295
(MÀÀ1).
5.4.62. N-tert-Butoxycarbonylamino-O-(1-phenylethyl)-D-
serine (10i). The title compound was prepared from 2 and
(1-bromoethyl)-benzene by Method A (yield = 50%). H
1
NMR (DMSO-d6) d 12.60 (br s, 1H), 7.30 (m, 5H),
6.85 (d, 1H, J = 8.3 Hz), 4.45 (m, 1H), 3.37 (m, 1H),
3.63 (m, 2H), 1.38 (s, 9H), 1.32 (d, 3H, J = 6.4 Hz). MS
m/z 308 (MÀÀ1).
5.4.55. N-tert-Butoxycarbonylamino-O-pyridin-3-ylmeth-
yl-D-serine (10b). The title compound was prepared from
2 and 3-bromomethyl-pyridine by Method A (yield =
67%). 1H NMR (CDCl3) d 8.60 (br s, 1H), 8.42 (m, 2H),
7.90–7.70 (m, 1H), 7.40 (m, 1H), 7.30 (m, 1H), 5.61 (d,
1H, J = 7.5 Hz), 4.77–4.28 (m, 3H), 4.01 (dd, 1H,
J1 = 2.4 Hz, J2 = 9.2 Hz), 3.82 (m, 1H), 1.44 (s, 9H). MS
m/z 295 (MÀÀ1).
5.4.63. 2-(R)-2-(2-Amino-2-methylpropionylamino)-3-(pyri-
din-2-yl)methoxypropionic acid N-(5-(4-chlorophenyl)-3,3-
dimethyl-1,1-dioxo-2,3-dihydroisothiazol-4-ylmethyl)-N-
ethylamide hydrochloride (11a). The title compound was
prepared from 10a as described in Methods B and C
(yield over all steps = 30%). 1H NMR (DMSO-
d6 + D2O) d 8.73 (m, 1H), 8.35 (m, 1H), 7.79 (m, 2H),
7.56 (m, 2H), 7.43 (m, 2H), 4.72 (m, 3H), 4.44 (d, 1H,
J = 16.1 Hz), 4.05 (d, 1H, J = 16.1 Hz), 3.48 (m, 1H),
3.27 (m, 1H), 3.09 (m, 2H), 1.53–1.37 (m, 12H), 0.95
(m, 3H). MS m/z 578 (MH+).
5.4.56. N-tert-Butoxycarbonylamino-O-pyridin-4-ylmeth-
yl-D-serine (10c). The title compound was prepared from
2 and 4-bromomethyl-pyridine by Method A (yield =
1
34%). H NMR (CDCl3) d 9.57 (br s, 2H), 8.49 (m,
2H), 7.35 (m, 2H), 5.60 (d, 1H, J = 7.5 Hz), 4.80–4.42