Synthetic strategy for side chain mono-N-alkylation
985
Na-(9-fluorenylmethoxycarbonyl)-Nd-benzyl–N0d-2-nitro-
benzensulfonyl-L-ornithine 3a HPLC: tR = 23.77 min
Na-(9-fluorenylmethoxycarbonyl)-Ne-3-phenylpropyl–N0e-
2-nitrobenzensulfonyl-L-lysine 4c, 4l HPLC: tR = 26.22 min
(gradient 2); 1H NMR (400 MHz, CDCl3): d 8.11 & 7.82 (2br,
2H, Ns–H3,6), 7.77 & 7.60 (2d, J = 7.6 Hz, 4H, Fmoc–
1
(gradient 2); H NMR (400 MHz, CDCl3): d 8.11 & 7.80
(2br, 2H, Ns–H3,6), 7.78 & 7.59 (2d, J = 7.6 Hz, 4H,
Fmoc–H1,4,5,8), 7.69 (m, 2H, Ns–H4,5), 7.41 & 7.32 (2t,
J = 7.2 Hz, 4H, Fmoc–H2,3,6,7), 7.37 (m, 5H, Ph–
H1,4,5,8), 7.70 (m, 2H, Ns–H4,5), 7.40 & 7.20 (2t, J = 7.2 Hz,
4H, Fmoc–H2,3,6,7), 7.29 (m, 5H, Ph–H2,3,4,5,6), 4.41 (d, 2H,
J = 6.8 Hz, 2H, Fmoc–CH2), 4.32 (m, 1H, Lys–CHa), 4.21
(t, 1H, J = 6.8 Hz, 1H, Fmoc–CH), 4.16 (m, 2H, CH2–CH2–
CH2–Ph) 3.09 (m, 2H, Lys–CHe2), 2.68 (t, 2H, J = 7.6 CH2–
CH2–CH2–Ph), 1.98 (m, 2H CH2–CH2–CH2–Ph), 1.79
(m, 1H, Lys–CHb2), 1.68–1.54 (m, 3H, Lys–CHb2 and Lys–
CH2c), 1.38 (m, 2H, Lys–CH2d); 13C NMR (100 MHz, CDCl3):
d 18.32; 22.55; 29.47; 30.52; 32.59; 43.90; 47.67; 54.01;
65.51; 67.56; 120.50; 125.61; 125.91; 126.65; 127.61;
128.25; 128.89; 129.03; 131.56; 133.24; 134.05; 141.36;
141.84; 144.28; 148.60; 156.53; 172.76. ES–MS: calcd
(M?H?), 671.23; found, m/z 671.11, calcd (M?Na?), 693.23;
found, m/z 693.81; HRMS (ESI) calcd for C36H37N3O8S,
671.2319; found, 671.2340. [a]2D5 = -5.7 (c = 1.1, CHCl3).
Na-(9-fluorenylmethoxycarbonyl)-Ne-propyl–N0e-2-nitro-
benzensulfonyl-L-lysine 4d HPLC: tR = 22.95 min (gradi-
ent 2); 1H NMR (400 MHz, CDCl3): d 8.11 & 7.82 (2br, 2H,
Ns–H3,6), 7.77 & 7.60 (2d, J = 7.6 Hz, 4H, Fmoc–H1,4,5,8),
7.71 (m, 2H, Ns–H4,5), 7.40 & 7.32 (2t, J = 7.2 Hz, 4H,
Fmoc–H2,3,6,7), 4.41 (d, J = 6.8 Hz, 2H, Fmoc–CH2), 4.33
(br, 1H, Lys–CHa), 4.21 (t, J = 6.8 Hz, 1H, Fmoc–CH),
4.10 (t, J = 6.4 Hz, 2H CH2–CH2–CH3) 3.95 (m, 2H, Lys–
CHe2), 1.83 (m, 1H, Lys–CHb), 1.73–1.50 (m, 5H, Lys–CHb,
CH2–CH2–CH3, Lys–CHc2) 1.38 (m, 2H Lys–CH2d),
0.94 (t, J = 7.2 Hz, CH2–CH2–CH3).13CNMR(100 MHz,
CDCl3): d 10.26; 22.25; 22.31; 29.74; 32.34; 45.51; 47.43;
54.49; 67.95; 68.56; 120.83; 125.31; 126.03; 127.45; 128.31;
131.84; 133.42; 134.79; 141.80; 144.23; 156.76; 170.26. ES–
MS: calcd (M?H?), 595.20; found, m/z 595.31, calcd
(M?Na?), 617.20; found, m/z 617.45; HRMS (ESI) calcd for
C30H33N3O8S, 595.2022; found, 595.2056. [a]2D5 = -7.4
(c = 0.5, CHCl3).
H
2,3,4,5,6), 5.18 (m, 2H, CH2–Ph), 4.41 (d, J = 6.8 Hz, 2H,
Fmoc–CH2), 4.37 (m, 1H, Orn–CHa), 4.20 (t, J = 6.8 Hz,
1H, Fmoc–CH), 3.08 (m, 2H, Orn–CHd2), 1.70 (m, 2H,
Orn–CHb2), 1.55 (m, 2H, Orn–CHc2); 13C NMR (100 MHz,
CDCl3): d 25.95; 30.22; 43.60; 47.66; 53.78; 67.52; 67.96;
1203.52; 125.57; 125.89; 127.62; 128.27; 128.94; 129.23;
131.53; 133.27; 134.07; 135.56; 141.84; 144.15; 144.32;
148.56; 156.43; 172.32. ES–MS: calcd (M?H?), 629.18;
found, m/z 629.52, calcd (M?Na?), 651.18; found, m/z
651.84; HRMS (ESI) calcd for C33H31N3O8S, 629.1812;
found, 629.1822. [a]2D5 = -1.3 (c = 0.8, CHCl3).
Na-(9-fluorenylmethoxycarbonyl)-Ne-benzyl–N0e-2-nitro-
benzensulfonyl-L-lysine 4a, 4k HPLC: tR = 24.20 min
1
(gradient 2); H NMR (400 MHz, CDCl3): d 8.11 & 7.82
(2br, 2H, Ns–H3,6), 7.77 & 7.60 (2d, J = 7.6 Hz, 4H,
Fmoc–H1,4,5,8), 7.70 (m, 2H, Ns–H4,5), 7.40 & 7.31 (2t,
J = 7.2 Hz, 4H, Fmoc–H2,3,6,7), 7.35 (m, 5H, Ph–
H
2,3,4,5,6), 5.18 (m, 2H, CH2–Ph), 4.41 (d, J = 6.8 Hz, 2H,
Fmoc–CH2), 4.38 (br, 1H, Lys–CHa), 4.22 (t, J = 6.8 Hz,
1H, Fmoc–CH), 3.04 (m, 2H, Lys–CHe2), 1.82 & 1.65 (2m,
Lys–CHba,b), 1.52 (m, 2H, Lys–CHac,b) 1.32 (m, 2H, Lys–
CHda,b). 13C NMR (100 MHz, CDCl3): d 22.40; 29.40;
32.60; 43.87; 47.64; 53.97; 67.59; 67.84; 120.49; 125.59;
125.90; 127.59; 128.23; 128.93; 129.19; 131.56; 133.22;
134.02; 141.82; 144.24; 156.46;172.56. ES–MS: calcd
(M?H?), 643.20; found, m/z 643.11, calcd (M?Na?),
665.20; found, m/z 665.81; HRMS (ESI) calcd for
C34H33N3O8S, 643.2031; found, 643.2048. [a]2D5 = -6.1
(c = 0.4, CHCl3).
Na-(9-fluorenylmethoxycarbonyl)-Ne-2-phenylethyl–N0e-
2-nitrobenzensulfonyl-L-lysine 4b HPLC: tR = 24.73 min
1
(gradient 2); H NMR (400 MHz, CDCl3): d 8.11 & 7.83
(2br, 2H, Ns–H3,6), 7.77 & 7.60 (2d, J = 7.6 Hz, 4H, Fmoc–
Na-(9-fluorenylmethoxycarbonyl)-Ne-diphenylmethyl–
N0e-2-nitrobenzensulfonyl-L-lysine 4f HPLC: tR =
27.25 min (gradient 2); 1H NMR (400 MHz, CDCl3):
d 8.08 & 7.79 (2br, 2H, Ns–H3,6), 7.76 & 7.58 (2d,
J = 7.6 Hz, 4H, Fmoc–H1,4,5,8), 7.68 (m, 2H, Ns–H4,5),
7.39 & 7.39–7.30 (m, 9H, Fmoc–H2,3,6,7, CH–(Ph)2),
6.88 (s, 1H, CH–(Ph)2), 4.46 (m, 1H, Lys–CHa), 4.40
(d, J = 6.8 Hz, 2H, Fmoc–CH2), 4.19 (t, J = 6.8 Hz, 1H,
Fmoc–CH), 2.99 (m, 2H, Lys–CHe2), 1.66–1.26 (4m, Lys–
H
1,4,5,8), 7.70 (m, 2H, Ns–H4,5), 7.40 & 7.21 (2t, J = 7.2 Hz,
4H, Fmoc–H2,3,6,7), 7.30 (m, 5H, Ph–H2,3,4,5,6), 4.48–4.28
(m, 5H, Lys–CHa, Fmoc–CH2, CH2–CH2–Ph), 4.21 (t, 1H,
J = 6.8 Hz, 1H, Fmoc–CH), 3.03 (m, 2H, Lys–CHe2), 2.96
(t, 2H, J = 6.8 CH2–CH2–Ph), 1.72 (m, 1H, Lys–CHb2),
1.55–1.44 (m, 3H, Lys–CHb2 and Lys–CH2c), 1.24 (m, 2H,
Lys–CHd2). 13C NMR (100 MHz, CDCl3): d 22.33; 29.41;
32.57; 35.41; 43.87; 47.64; 53.94; 66.40; 67.52; 120.50;
125.60; 125.93; 127.24; 127.59; 128.25; 129.07; 129.39;
131.57; 133.25; 134.05; 137.83; 141.82; 144.26; 148.60;
156.41; 172.61. ES–MS: calcd (M?H?), 657.21; found,
m/z 657.61, calcd (M?Na?), 679.21; found, m/z 679.81;
HRMS (ESI) calcd for C35H35N3O8S, 657.2162; found,
657.2182. [a]2D5 = -6.8 (c = 0.3, CHCl3).
CHba,b
,
Lys–CHc2, Lys–CHd2). 13C NMR (100 MHz,
CDCl3): d 22.27; 29.44; 32.54; 43.89; 47.62; 54.00;
67.59; 66.40; 78.71; 120.48; 125.58; 125.90; 127.45;
127.59; 127.78; 128.23; 128.68; 128.85; 129.14; 131.57;
133.21; 134.02; 139.70; 141.80; 144.25; 156.73; 171.80.
ES–MS: calcd (M?H?), 719.23; found, m/z 719.57, calcd
(M?Na?), 741.23; found, m/z 741.66; HRMS (ESI) calcd
123