304 K. Yang et al.
hydrochloride (2b) following the general procedure as
described above (preparation of 5a), yield: 84.5%, mp
4.372–4.335 (m, 1H, CH), 4.287–4.256 (m, 1H, CH), 3.088
(dd, J= 12.6 Hz, J= 8.4 Hz, 1H, CH), 2.778 (dd, J= 12.6 Hz,
J= 8.4 Hz, 1H, CH), 1.7–1.594 (m, 2H, CH2), 1.567–1.522
(m, 1H, CH), 0.882 (d, J= 6.6 Hz, 3H, CH3), 0.839 (d, J= 6.6
Hz, 3H, CH3); HRMS (FAB) calcd for C16H24N2O4 309.1809;
found: 309.1807 (M+H)+.
1
95–97°C; [α]25D =-9.72° (c 1, MeOH); H-NMR (DMSO-d6)
δ 7.921 (d, J=7.8 Hz, 1H, -CONH-), 7.287–7.362 (m, 2H,
Ar-H), 7.177–7.166 (m, 3H, NH3), 6.526 (s, 1H, OH), 5.801
(d, J=5.4 Hz, 1H, -CONH-), 4.604–4.567 (m, 1H, CH),
3.889–3.869 (m, 1H, CH), 3.627 (s, 3H, -OCH3), 3.173–3.135
(m, 1H, Ar-CH2- ), 3.075 (dd, J=13.8 Hz, J=8.4 Hz, 1H,
CH2), 3.032 (dd, J=13.8 Hz, J=8.4 Hz, 1H, CH2), 2.817–2.77
(m, 1H, Ar-CH2-),1.435 (s, 9m, CH3); HRMS (FAB) calcd
for C18H26N2O6 389.1683; found: 389.167 [M+Na]+.
L-Isoseryl-L-leucyl-L-phenylalanine methyl ester
hydrochloride (13a)
A white solid, yield: 64.3%, mp 65–68°C; [α]25D = -33.2°
(c 1, H2O); 1H-NMR (DMSO-d6) δ 8.588 (d, J= 7.8 Hz,
1H, -CONH-), 8.12 (s, 3H, NH3), 7.843 (d, J= 7.8 Hz, 1H,
-CONH-), 7.298–7.2 (m, 5H, Ar-H), 6.485 (s, 1H, OH),
4.486–4.499 (m, 1H, CH), 4.368–4.329 (m, 1H, CH), 4.12–
4.199 (m, 1H, CH), 3.579 (s, 3H, -OCH3), 3.102–3.093 (m,
1H, Ar-CH2-), 3.055 (dd, J= 13.80 Hz, J= 8.4 Hz, 1H, CH2),
2.977 (dd, J= 13.8 Hz, J= 8.4 Hz, 1H, CH2), 2.798–2.752 (m,
1H, Ar-CH2-), 1.528–1.494 (m, 1H, CH), 1.483–1.359 (m,
2H, CH2), 0.861 (d, J= 6.6 Hz, 3H, CH3), 0.831 (d, J= 6.6
Hz, 3H, CH3); HRMS (FAB) calcd for C19H29N3O5 380.2180;
found: 380.2174 (M+H)+.
Compound 11a was obtained through the deprotec-
tion of compound 9a in the saturated HCl/EtOAc solu-
tion as the preparation of 6a, yield: 77.7%, mp 138–140°C;
1
[α]25D = -19.8° (c 1, H2O). H-NMR (DMSO-d6) δ 8.25 (d,
J= 7.8 Hz, 1H, -CONH-), 8.094 (s, 3H, NH3), 7.294–7.27
(m, 2H, Ar-H), 7.23–7.197 (m, 3H, Ar-H), 6.541 (s, 1H,
OH), 4.6–4.563 (m, 1H, CH), 4.203–4.173 (m, 1H, CH),
3.107 (s, 3H, -OCH3), 3.101 (dd, J= 13.8 Hz, J= 8.4 Hz, 1H,
CH2), 3.05 (dd, J= 13.8 Hz, J= 8.4 Hz, 1H, CH2), 2.927 (dd,
J= 13.2 Hz, J= 9 Hz, 1H, Ar-CH2-), 2.569 (dd, J= 13.2 Hz,
J= 9 Hz, 1H, Ar-CH2-); HRMS (FAB) calcd for C13H18N2O4
267.1339; found: 267.1335 [M+H]+.
L-Isoseryl-L-phenylalanyl-L-leucine methyl ester
Compounds 9c–9d were prepared from N protected
L-Isoserine and amino acid methyl/benzyl ester hydro-
chlorides (2a,4a and 4b) and compounds 10a–10d were
prepared from N protected L-Isoserine and dipeptide
methyl/benzyl ester hydrochlorides(6a, 6b, 6c and 6d).
Compounds11c–11dand13a–13dwereobtainedthrough
the deprotection of compounds 9c–9d and 10a–10d.
hydrochloride (13b)
A white solid, yield: 50.9%, mp 77–80°C; [α]25D = -26.7°
(c 1, H2O); 1H-NMR (DMSO-d6) δ 8.631(d, J= 7.8 Hz,
1H, -CONH-), 8.1 (s, 3H, NH3), 7.862 (d, J= 7.8 Hz, 1H,
-CONH-), 7.298–7.195 (m, 5H, Ar-H), 6.512 (s, 1H, OH),
4.633–4.596 (m, 1H, CH), 4.33–4.269 (m, 1H, CH), 4.166–
4.145 (m, 1H, CH), 3.639 (s, 3H, -OCH3), 3.077 (dd, J= 13.8
Hz, J= 8.4 Hz, 1H, CH2), 2.918 (dd, J= 13.8 Hz, J= 8.4 Hz,
1H, CH2), 2.895–2.55 (m, 1H, Ar-CH2-), 2.568–2.521 (m,
1H, Ar-CH2-), 1.656–1.597 (m, 2H, CH2), 1.544–1.497 (m,
1H, CH), 0.894 (d, J= 6.6 Hz, 3H, CH3), 0.847 (d, J= 6.6 Hz,
3H, CH3); HRMS (FAB) calcd for C19H29N3O5 380.2180;
found: 380.2179 (M+H)+.
L-Isoseryl-L-leucine methyl ester hydrochloride (11b)
A white solid, yield: 63.1%, mp 120–123°C; [α]25D = -36.1°
(c 1, H2O); 1H-NMR (DMSO-d6) δ 8.054 (d, J= 7.8 Hz, 1H,
-CONH-), 7.903 (s, 3H, NH3), 6.427 (s, 1H, OH), 4.607–
4.593 (m, 1H, CH), 4.186–4.152 (m, 1H, CH), 3.218 (s, 3H,
-OCH3), 3.106 (dd, J= 13.8 Hz, J= 8.4 Hz, 1H, CH2), 3.023
(dd, J= 13.8 Hz, J= 8.4 Hz, 1H, CH2), 1.523–1.704 (m, 3H,
CH2CH), 0.926–0.947 (m, 6H, CH3); HRMS (FAB) calcd for
C10H20N2O4 233.1496; found: 233.1493 [M+H]+.
L-Isoseryl-L-leucyl-L-phenylalanine benzyl ester
hydrochloride (13c)
A white solid, yield: 52.2%, mp 135–137°C; [α]25D = -30.5°
(c 1, H2O); 1H-NMR (DMSO-d6) δ 8.631(d, J = 7.8 Hz,
1H, -CONH-), 8.134 (s, 3H, NH3), 7.827 (d, J = 7.8 Hz,
1H, -CONH-), 7.368–7.311 (m, 3H, Ar-H), 7.27–7.202
(m, 7H, Ar-H), 6.493 (s, 1H, -OH), 5.088–5.033 (m, 2H,
Ar-CH2-O-), 4.547–4.51 (m, 1H, CH), 4.381–4.341 (m,
1H, CH), 4.216–4.201 (m, 1H, CH), 3.084–3.074 (m, 1H,
Ar-CH2-), 3.067 (dd, J = 13.8 Hz, J = 8.4 Hz, 1H, CH2),
2.993 (dd, J = 13.8 Hz, J = 8.4 Hz, 1H, CH2), 2.782–2.63 (m,
1H, Ar-CH2-),1.512-1.35 (m, 3H, CH2CH), 0.844 (d, J = 6.6
Hz, 3H, CH3), 0.797 (d, J = 6.6 Hz, 3H, CH3); HRMS (FAB)
calcd for C25H33N3O5 456.2493; found: 456.2490 (M+H)+.
L-Isoseryl-L- phenylalanine benzyl ester hydrochloride (11c)
A white solid, yield: 76.6%, mp 177–179°C; [α]25D = −23.3°
1
(c 1, H2O); H-NMR (DMSO-d6) δ 8.285 (d, J = 7.8 Hz,
1H, -CONH-), 8.032 (s, 3H, NH3), 7.391–7.303 (m, 5H,
Ar-H), 7.274–7.177 (m, 5H, Ar-H), 6.511 (s, 1H, OH),
5.14–5.097 (m, 2H, Ar-CH2-O-), 4.644–4.607 (m, 1H,
CH), 4.195–4.164 (m, 1H, CH), 3.126 (dd, J = 13.8 Hz,
J = 8.4 Hz, 1H, CH2), 3.028 (dd, J = 13.8 Hz, J = 8.4 Hz, 1H,
CH2), 2.95–2.93 (m, 1H, Ar-CH2-), 2.601–2.566 (m, 1H,
Ar-CH2-); HRMS (FAB) calcd for C19H22N2O4 343.1652;
found: 343.1650 (M+H)+.
L-Isoseryl-L-phenylalanyl-L-leucine benzyl ester
L-Isoseryl-L-leucine benzyl ester hydrochloride (11d)
hydrochloride (13d)
A white solid, yield: 84.6%, mp 98–103°C; [α]25D = -25.7°
(c 1, H2O); 1H-NMR (DMSO-d6) δ 8.387 (d, J= 7.8 Hz,
1H, -CONH-), 8.189 (s, 3H, NH3), 7.405–7.324 (m, 5H,
Ar-H), 6.48 (s, 1H, OH), 5.187–5.13 (m, 2H, Ar-CH2-O-),
A white solid, yield: 58.1%, mp 140–142°C; [α]25D = -28.6°
(c 1, H2O); 1H-NMR (DMSO-d6) δ 8.644 (d, J= 7.8 Hz,
1H, -CONH-), 8.037 (s, 3H, NH3), 7.852 (d, J= 7.8 Hz, 1H,
-CONH-), 7.377–7.319 (m, 3H, Ar-H), 7.242–7.171 (m, 5H,
Journal of Enzyme Inhibition and Medicinal Chemistry