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ARTICLE
Journal Name
t-butanol (4 × 50 mL) followed by removal of solvent under CH2), 4.35 (s, 2H, CH2), 4.53-4.55 (m, 2H, 2xCH), 4.84-4.86 (m,
vacuum afforded relatively purified 5a-f
.
1H, CH), 5.07 (s, 2H, CH2), 7.21-7.27 (mD, O5IH: 1,0P.1h0-3H9/)C, 67R.A2095-878.33C5
(m, 5H, Ph-H), 7.38-7.40 (m, 1H, Im-H). 13C NMR (100.6 MHz,
Synthesis of and Boc-L-His(2-alkyl)-L-Arg-Lys-NHBzl (9a-f) and CD3OD): δ 20.5, 24.0, 24.2, 26.9, 28.3, 29.2, 29.9, 30.3, 42.5,
L-His(2-alkyl)-L-Arg-Lys-NHBzl (10a-f) 43.3, 58.6, 116.9, 126.2, 127.0, 128.2, 132.0. MS (APCI): m/z
To a solution of Boc-L-Lys(Z)-OH (
, 1 mmol) in DMF (3 mL), 805.39[MH]+ . [α]D25 = -8.3o (c =1.0, CH3OH)
benzyl amine (1.3 mmol), DIC (1.3 mmol) and HONB (1.3 4.1.2.4. Boc-His(2-cyclobutyl)-Arg-Lys(Z)-NHBzl (9d): Yield:
6
o
1
mmol) was added. The reaction mixture was stirred for 48 hrs 41%, off white solid, mp 190-192 C H NMR (CD3OD): δ 1.23-
at room temp followed by removal of solvent under vacuum. 1.25 (m, 2H, CH2), 1.38 (s, 9H, 3xCH3), 1.47-1.49 (m, 4H,
The reaction mixture was subjected to column 2xCH2), 1.69-1.71 (m, 4H, 2xCH2), 1.88-1.90 (m, 2H, CH2), 2.36-
chromatography yielding desired Boc-L-Lys(Z)-NHBzl (7). The 2.38 (m, 4H, 2xCH2), 2.61 (t, 2H, J=7.2 Hz, CH2), 3.11-3.13 (m,
obtained compound was then subjected to acidolysis for 15 2H, CH2), 3.18 (t, 2H, J=6.9 Hz, CH2), 3.24-3.26 (m, 1H, CH), 4.38
mins to afford L-Lys(Z)-NHBzl which was further coupled with (s, 2H, CH2), 4.55-4.57 (m, 2H, 2xCH), 4.83-4.85 (m, 1H, CH),
Boc-L-Arg-OH (1.3 mmol) in the presence of DIC (1.3 mmol), 5.10 (s, 2H, CH2), 7.21-7.28 (m, 5H, Ph-H), 7.41-7.43 (m, 1H,
HONB (1.3 mmol) and DMF(3ml). The reaction mixture was Im-H), 7.43-7.48 (m, 5H, Ph-H) . 13C NMR (100.6 MHz, CD3OD):
stirred for 48 hrs at room temp followed by purification using δ 18.19, 23.9, 25.0, 25.9, 27.0, 29.9, 31.8, 35.1, 41.9, 43.1,
column chromatography which yielded desired Boc-Arg-Lys(Z)- 53.2, 118.4, 119.9, 126.9, 127.6, 128.1, 131.5. MS (APCI): m/z
NHBzl (
25%TFA in DCM (5 mL) at 25 ˚C for 15 min followed by 4.1.2.5. Boc-His(2-adamantyl)-Arg-Lys(Z)-NHBzl (9e): Yield:
8
). The Boc group was further removed by using 817.21[MH]+ . [α]D25 = -14.0o (c =1.6, CH3OH)
o
1
neutralization with methanolic ammonia (5 ml). Finally, the 43%, off white solid, mp 205-207 C H NMR (CD3OD): δ 1.26-
resulting L-Arg-Lys(Z)-NHBzl (1 mmol) was coupled with Boc- 1.28 (m, 2H, CH2), 1.38 (s, 9H, 3xCH3), 1.66-1.68 (m, 4H,
His(2-alkyl)-OH (1.3 mmol) in the presence of HONB (1.3 2xCH2), 1.74-1.76 (m, 6H, 3xCH2), 1.84-1.86 (m, 4H, 2xCH2),
mmol), DIC (1.3 mmol) under constant stirring for 48 hrs at 2.02-2.04 (m, 6H, 3xCH2), 2.12-2.14 (m, 6H, 3xCH2), 2.71 (t, 2H,
room temp and purification using column chromatography to J=7.2 Hz, CH2), 3.18 (m, 2H, CH2), 3.21 (t, 2H, J=6.9 Hz, CH2),
afford desired Boc-His(2-alkyl)-Arg-Lys(Z)-NHBzl (9a-f). The Boc 4.39 (s, 2H, CH2), 4.48-4.50 (m, 2H, 2xCH), 4.93-4.95 (m, 1H,
and other orthogonal protection were removed using 33% HBr CH), 5.07 (s, 2H, CH2), 7.23-7.30 (m, 5H, Ph-H), 7.34-7.36 (m,
in acetic acid (5 mL) at 25 ˚C for 15 min resulting in the 1H, Im-H), 7.41-7.45 (m, 5H, Ph-H). 13C NMR (100.6 MHz,
formation of desired His(2-alkyl)-Arg-Lys-NHBzl (10a-f).
CD3OD): δ 21.4, 22.9, 26.8, 29.2, 31.7, 32.0, 36.2, 41.9, 42.6,
4.1.2.1. Boc-His(2-t-butyl)-Arg-Lys(Z)-NHBzl (9a): Yield: 60%, 43.2, 58.9, 66.2, 79.1, 119.1, 126.2, 126.4, 128.5, 137.5, 155.6.
o
1
off white solid, mp 187-189 C, H NMR (CD3OD): δ 1.28-1.30 MS (APCI): m/z 898.21[MH]+ . [α]D25 = -6.9o (c =1.2, CH3OH)
(m, 2H, CH2), 1.35 (s, 9H, 3xCH3), 1.38 (s, 9H, 3xCH3), 1.56-1.58 4.1.2.6. Boc-His-Arg-Lys(Z)-NHBzl (9f): Yield: 52%, off white
o
1
(m, 4H, 2xCH2), 1.61-1.63 (m, 4H, 2xCH2), 2.71 (t, 2H, J=7.1 Hz, solid, mp 179-181 C, H NMR (CD3OD): δ 1.29-1.31 (m, 2H,
CH2), 3.19-3.21 (m, 2H, CH2), 3.22 (t, 2H, J=7.3 Hz, 2xCH2), 4.42 CH2), 1.39 (s, 9H, 3xCH3), 1.54-1.56 (m, 4H, 2xCH2), 1.74-1.76
(s, 2H, CH2), 4.56-4.58 (m, 2H, 2xCH), 4.90-4.92 (m, 1H, CH), (m, 4H, 2xCH2), 2.87 (t, 2H, J=7.1 Hz, CH2), 3.09-3.11 (m, 2H,
7.23-7.30 (m, 5H, Ar-H), 7.34-7.36 (m, 1H, Im-H), 7.38-7.45 (m, CH2), 3.18 (t, 2H, J=7.3 Hz, CH2), 4.36 (s, 2H, CH2), 4.61-4.63 (m,
5H, Ar-H). 13C NMR (100.6 MHz, CD3OD): δ 23.3, 24.2, 28.4, 2H, 2xCH), 4.89-4.91 (m, 1H, CH), 7.25-7.31 (m, 5H, Ar-H), 7.38-
28.5, 31.0, 42.1, 43.3, 53.8, 57.2, 118.3, 126.3, 126.9, 128.0, 7.40 (m, 1H, Im-H), 7.42-7.48 (m, 5H, Ar-H). 13C NMR (100.6
25
137.2. MS (APCI): m/z 819.00 [MH]+ . [α]D = -12.5o (c =1.3, MHz, CD3OD): δ 27.3, 112.4, 115.3, 118.2, 121.1, 127.1, 127.3,
CH3OH)
127.6, 128.1, 161.3, 161.6, 161.9. MS (APCI): m/z 763.32 [MH]+
4.1.2.2. Boc-His(2-cyclohexyl)-Arg-Lys(Z)-NHBzl (9b): Yield: . [α]D25 = -10.4o (c =1.1, CH3OH)
55%, off white solid, mp 195-197 oC, H NMR (CD3OD): δ 1.25- 4.1.2.7. His(2-t-butyl)-Arg-Lys-NHBzl (10a): Yield: 68%, off
1
o
1
1.27 (m, 2H, CH2), 1.38 (s, 9H, 3xCH3), 1.45-1.47 (m, 2H, CH2), white solid, mp 235-237 C, H NMR (CD3OD): δ 1.22-1.24 (m,
1.49-1.51 (m, 4H, 2xCH2), 1.54-1.56 (m, 4H, 2xCH2), 1.74-1.77 2H, CH2), 1.36 (s, 9H, 3xCH3), 1.58-1.60 (m, 4H, 2xCH2), 1.71-
(m, 4H, 2xCH2), 1.85-1.87 (m, 4H, 2xCH2), 2.87 (t, 2H, J=6.8 Hz, 1.73 (m, 4H, 2xCH2), 2.61 (t, 4H, J=7.1 Hz, 2xCH2), 3.17-3.19 (m,
CH2), 3.00 (m, 1H, CH), 3.20 (t, 2H, J=7.0 Hz, CH2), 3.23-3.25 (m, 2H, CH2), 3.86-3.88 (m, 1H, CH), 4.40 (s, 2H, CH2), 4.56-4.58 (m,
2H, CH2), 4.40 (s, 2H, CH2), 4.57-4.59 (m, 2H, 2xCH), 4.92-4.94 2H, 2xCH), 7.21-7.29 (m, 5H, Ar-H), 7.37-7.39 (m, 1H, Im-H). 13
C
(m, 1H, CH), 5.05 (s, 2H, CH2), 7.23-7.29 (m, 5H, Ar-H), 7.38- NMR (100.6 MHz, CD3OD): δ 22.9, 24.3, 27.9, 29.3, 30.0, 41.9,
7.40 (m, 1H, Im-H), 7.40-7.48 (m, 5H, Ar-H). 13C NMR (100.6 42.7, 54.0, 58.2, 117.3, 126.4, 127.5, 128.1, 138.0. MS (APCI):
MHz, CD3OD): δ 11.8, 15.9, 17.4, 24.9, 25.1, 27.2, 27.4, 29.4, m/z 585.76 [MH]+ . [α]D25 = -20.0o (c =1.0, CH3OH)
30.3, 30.4, 35.7, 42.4, 53.2, 53.5, 54.4, 79.4, 116.0, 129.3, 4.1.2.8. His(2-cyclohexyl)-Arg-Lys-NHBzl (10b): Yield: 70%, off
25
o
1
151.2. MS (APCI): m/z 846.23 [MH]+ . [α]D = -18.2o (c =1.1, white solid, mp 243-245 C, H NMR (CD3OD): δ 1.25-1.27 (m,
CH3OH)
2H, CH2), 1.48-1.50 (m, 2H, CH2), 1.51-1.53 (m, 4H, 2xCH2),
4.1.2.3. Boc-His(2-i-propyl)-Arg-Lys(Z)-NHBzl (9c): Yield: 39%, 1.57-1.59 (m, 4H, 2xCH2), 1.71-1.73 (m, 4H, 2xCH2), 1.83-1.85
o
1
off white solid, mp 183-185 C H NMR (CD3OD): δ 1.22-1.24 (m, 4H, 2xCH2), 2.68 (t, 4H, J=6.7 Hz, 2xCH2), 3.03-3.05 (m, 1H,
(m, 6H, 2xCH3), 1.28-1.30 (m, 2H, CH2), 1.40 (s, 9H, 3xCH3), CH), 3.30-3.32 (m, 2H, CH2), 3.86-3.88 (m, 1H, CH), 4.45 (s, 2H,
1.44-1.46 (m, 4H, 2xCH2), 1.64-1.66 (m, 4H, 2xCH2), 2.71 (t, 2H, CH2), 4.52-4.54 (m, 2H, 2xCH), 7.21-7.28 (m, 5H, Ar-H), 7.34-
J=6.8 Hz, CH2), 3.09-3.11 (m, 2H, CH2), 3.18 (t, 2H, J=6.9 Hz, 7.36 (m, 1H, Im-H). 13C NMR (100.6 MHz, CD3OD): δ 20.9, 24.2,
8 | J. Name., 2012, 00, 1-3
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