7428 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23
Sharma et al.
1.35 (s, 9H), 1.50 (m, 2H), 2.31 (m, 4H), 2.95 (m, 2H), 3.04 (m,
1H), 3.19 (m, 2H), 3.61 (s, 3H), 3.81 (t, 1H, J=6.8 Hz), 4.35 (t,
1H, J=6.9 Hz), 6.73 (s, 1H), 7.04-7.08 (m, 3H), 7.31-7.33 (m,
2H). 13C NMR (75 MHz, CD3OD): δ 18.91, 25.23, 27.61, 28.02,
28.47, 29.67, 31.98, 42.18, 51.92, 52.31, 54.89, 79.83, 107.67,
111.72, 112.56, 117.34, 118.70, 119.89, 120.56, 125.23, 128.13,
134.39, 141.90, 157.36, 171.67, 176.28. MS (APCI): m/z 510.9
[MH]þ.
25.71, 25.98, 27.19, 28.86, 30.12, 31.24, 36.44, 43.29, 51.70,
52.78, 63.70, 107.18, 111.80, 117.16, 118.10, 119.66, 120.04,
122.24, 125.26, 129.03, 134.94, 170.82, 170.75. MS (APCI): m/
z 438.4 [MH]þ. [R]D25=-13.9° (c=1.5, CH3OH).
L-Trp-L-His[2-(adamantan-1-yl)]-OMe 2HCl (9e). Yield:
3
85%, colorless semisolid. 1H NMR (CD3OD): δ 1.58-1.65
(m, 12H), 2.07 (m, 3H), 2.89 (m, 2H), 3.31 (m, 2H), 3.65 (s,
3H), 3.74 (t, 1H, J=7.1 Hz), 4.17 (t, 1H, J=6.8 Hz), 6.78 (s, 1H),
7.07-7.13 (m, 3H), 7.28-7.30 (m, 2H). 13C NMR (75 MHz,
CD3OD): δ 25.39, 28.58, 28.91, 30.12, 31.34, 36.29, 43.27, 51.67,
52.02, 67.54, 108.43, 111.88, 116.86, 118.30, 119.82, 121.29,
122.61, 125.92, 128.42, 134.92, 171.02, 174.75. MS (APCI): m/
z 490.3 [MH]þ. [R]D25=-25.4° (c=2.0, CH3OH).
N-r-Boc-L-Trp-L-His(2-cyclohexyl)-OMe (8d). Yield: 61%,
colorless solid; mp 211-214 °C. 1H NMR (CD3OD): δ 1.25 (m,
6H), 1.39 (s, 9H), 1.65 (m, 4H), 1.90 (m, 1H), 2.93 (m, 2H), 3.20
(m, 2H), 3.59 (s, 3H), 3.69 (t, 1H, J=7.1 Hz), 4.35 (t, 1H, J=6.8
Hz), 6.49 (s, 1H), 7.05-7.10 (m, 3H), 7.33-7.35 (m, 2H). 13C
NMR (75 MHz, CD3OD): δ 23.94, 26.14, 26.45, 28.33, 28.79,
30.21, 31.98, 37.10, 43.18, 51.91, 53.01, 56.51, 80.83, 109.97,
112.09, 118.90, 119.81, 122.36, 124.15, 128.02, 128.86, 134.77,
153.48, 156.47, 171.60, 172.75. MS (APCI): m/z 538.2 [MH]þ.
N-r-Boc-L-Trp-L-His[2-(adamantan-1-yl)]-OMe (8e). Yield:
L-Trp-L-His-OMe 2HCl (9f). Yield: 88%, colorless semiso-
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1
lid. H NMR (CD3OD): δ 2.90 (m, 2H), 3.21 (m, 2H), 3.55 (s,
3H), 3.64 (t, 1H, J=7.0 Hz), 3.74 (t, 1H, J=6.8 Hz), 6.93 (s, 1H),
7.12-7.15 (m, 3H), 7.27 (m, 2H), 7.42 (s, 1H).; 13C NMR (75
MHz, CD3OD): δ 27.12, 30.12, 52.58, 63.67, 67.55, 111.81,
118.19, 118.60, 119.72, 120.04, 124.53, 128.69, 134.94, 171.75,
174.97. MS (APCI): m/z 356.1 [MH]þ. [R]D25=-18.4° (c=1.3,
CH3OH).
1
63%, colorless solid; mp 233-235 °C. H NMR (CD3OD): δ
1.36 (s, 9H), 1.52-1.55 (m, 12H), 1.99 (m, 3H), 3.01 (m, 2H),
3.22 (m, 2H), 3.65 (s, 3H), 3.73 (t, 1H, J=7.0 Hz), 4.32 (t, 1H, J=
6.8 Hz), 6.83 (s, 1H), 7.01-7.08 (m, 3H), 7.31-7.33 (m, 2H). 13
C
General Method for the Synthesis of N-r-Boc-L-His(2-alkyl)-
L-Arg-NHBzl (11a-f, Scheme 3). HONB (1.2 mmol) was added
to N-R-Boc-L-His(2-alkyl)-OH (1a-f, 1 mmol) in water-free
DMF (10 mL). At -10 °C, DIC (1.2 mmol) was added, and
after 5 min stirring, L-Arg-NHBzl (10, 1 mmol) was added. After
stirring for 36 h at 4 °C, the solvent was removed and the crude
product chromatographed on neutral alumina using CH3OH:
CHCl3 (1:9) to afford N-R-Boc-L-His(2-alkyl)-L-Arg-NHBzl
(11a-f).
NMR (75 MHz, CD3OD): δ 26.53, 26.62, 27.35, 28.91, 35.15,
39.63, 41.66, 43.47, 51.23, 54.89, 78.52, 108.71, 110.15, 115.95,
117.16, 119.89, 120.23, 122.51, 126.68, 129.14, 133.30, 135.85,
155.38, 158.19, 170.34, 173.63. MS (APCI): m/z 591.0 [MH]þ.
N-r-Boc-L-Trp-L-His-OMe (8f). Yield: 67%, white solid; mp
171-173 °C. 1H NMR (300 MHz, CD3OD): δ 1.36 (s, 9H), 3.05
(m, 2H), 3.23 (m, 2H), 3.64 (s, 3H), 3.77 (t, 1H, J=7.1 Hz), 4.35
(t, 1H, J=6.9 Hz), 6.85 (s, 1H), 7.07 (m, 3H), 7.31 (m, 2H), 7.59
(s, 1H). 13C NMR (75 MHz, CD3OD): δ 22.97, 27.69, 29.09,
51.68, 53.20, 56.36, 110.31, 111.69, 118.03, 119.19, 121.54,
124.11, 128.25, 134.88, 155.62, 172.14, 175.37. MS (APCI): m/
z 455.9 [MH]þ.
N-r-Boc-L-His(2-isopropyl)-L-Arg-NHBzl (11a). Yield: 58%,
1
colorless solid; mp 182-183 °C. H NMR (CDCl3): δ 1.18 (d,
6H, J=7.0 Hz), 1.37 (s, 9H), 1.63 (m, 2H), 1.84 (m, 2H), 2.67 (t,
2H, J=7.1 Hz), 3.03 (m, 2H), 3.29 (m, 1H), 4.46 (s, 2H), 4.68 (t,
1H, J=6.7 Hz), 4.93 (t, 1H, J=6.9 Hz), 6.90 (s, 1H), 7.26-7.31
(m, 5H). 13C NMR (75 MHz, CDCl3): δ 21.4, 23.11, 28.08, 29.5,
29.84, 30.12, 41.89, 44.81, 54.27, 58.1, 75.7, 116.06, 124.88,
126.12, 127.8, 128.95, 129.26, 131.83, 139.53, 151.37, 157.99,
172.92.; MS (APCI): m/z 543.3 [MH]þ.
General Method for the Synthesis of L-Trp-2-alkyl-L-His-
OMe 2HCl (9a-f, Scheme 2). A solution of N-R-Boc-L-Trp-L-
3
His(2-alkyl)-OMe (8a-f, 1 mmol) in 3 N HCl in 1,4-dioxane (15
mL) was stirred at ambient temperature for 15 min. The solvent
was evaporated under reduced pressure to afford L-Trp-2-alkyl-
L-His-OMe 2HCl (9a-f).
L-Trp-L-His(2-isopropyl)-OMe 2HCl (9a). Yield: 90%, col-
N-r-Boc-L-His(2-tert-butyl)-L-Arg-NHBzl (11b). Yield: 53%,
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1
colorless solid; mp 197-200 °C. H NMR (CDCl3): δ 1.35 (s,
3
1
orless semisolid. H NMR (CD3OD): δ 1.32 (d, 6H), 2.93 (m,
2H), 3.24 (m, 1H), 3.34 (m, 2H), 3.57 (s, 3H), 3.76 (t, 1H, J=6.9
Hz), 4.07 (t, 1H, J=6.6 Hz), 6.88 (s, 1H), 7.02-7.04 (m, 3H),
7.22 (m, 2H). 13C NMR (75 MHz, CD3OD): δ 20.11, 27.43,
28.56, 30.13, 51.67, 54.40, 63.69, 114.58, 117.20, 118.57, 120.41,
122.23, 124.53, 127.52, 134.92, 170.50, 174.76. MS (APCI): m/z
398.2 [MH]þ. [R]D25=-13.0° (c=1.0, CH3OH).
9H), 1.46 (s, 9H), 1.70 (m, 2H), 1.84 (m, 2H), 2.71 (t, 2H, J=6.9
Hz), 3.04 (m, 2H), 4.34 (s, 2H), 4.51 (t, 1H, J=6.7 Hz), 4.85 (t,
1H, J=6.8 Hz), 6.78 (s, 1H), 7.24-7.27 (m, 5H). 13C NMR (75
MHz, CDCl3): δ 23.78, 28.72, 29.36, 29.79, 40.12, 43.92, 55.7,
58.86, 73.2, 119.61, 125.11, 126.6, 127.44, 128.72, 137.85, 148.17,
154.31, 158.63, 174.8. MS (APCI): m/z 557.3 [MH]þ.
N-r-Boc-L-His(2-cyclobutyl)-L-Arg-NHBzl (11c). Yield: 50%,
colorless solid; mp 213-215 °C. 1H NMR (CDCl3): δ 1.34 (s, 9H),
1.57(m, 2H), 1.87 (m, 2H), 1.93(m, 2H), 2.14 (m, 4H), 2.56 (t, 2H,
J=7.1 Hz), 3.12 (m, 2H), 3.27 (m, 1H), 4.37 (s, 2H), 4.58 (t, 1H,
J=6.9 Hz), 4.80 (t, 1H, J=6.8 Hz), 6.94 (s, 1H), 7.27-7.32 (m,
5H). 13C NMR (75 MHz, CDCl3): δ 19.57, 24.73, 26.2, 27.84,
28.3, 29.45, 31.92, 35.56, 40.9, 44.6, 56.76, 59.44, 78.3, 119.52,
125.4, 126.55, 127.78, 129.6, 136.48, 146.2, 155.0, 158.28, 178.4.
MS (APCI): m/z 555.3 [MH]þ.
N-r-Boc-L-His(2-cyclohexyl)-L-Arg-NHBzl (11d). Yield: 52%,
colorless solid; mp 220 °C. 1H NMR (CDCl3): δ 1.33-1.36 (m,
6H), 1.40 (s, 9H), 1.73 (m, 2H), 1.80(m, 4H), 1.92(m, 2H), 2.67(t,
2H, J=7.2 Hz), 3.03 (m, 2H), 4.39 (s, 2H), 4.55 (t, 1H, J=6.9 Hz),
4.81 (t, 1H, J=6.8 Hz), 6.68 (s, 1H), 7.28-7.31 (m, 5H). 13C
NMR (75 MHz, CDCl3): δ 25.57, 26.42, 26.66, 28.10, 29.86,
30.14, 32.47, 38.60, 41.29, 43.47, 53.76, 56.72, 72.13, 119.80,
126.18, 127.61, 128.93, 130.16, 137.71, 147.74, 154.62, 158.63,
177.52. MS (APCI): m/z 583.3 [MH]þ.
N-r-Boc-L-His[2-(adamantan-1-yl)]-L-Arg-NHBzl (11e). Yield:
45%, colorless solid; mp 268-270 °C. 1H NMR (CDCl3): δ 1.31
(s, 9H), 1.58-1.62 (m, 12H), 1.72 (m, 2H), 1.85 (m, 2H), 2.01 (m,
3H), 2.59 (t, 2H, J=7.0 Hz), 3.08 (m, 2H), 4.30 (s, 2H), 4.54 (t, 1H,
J = 6.8 Hz), 4.86 (t, 1H, J = 6.7 Hz), 6.67 (s, 1H), 7.24-7.28
L-Trp-L-His(2-tert-butyl)-OMe 2HCl (9b). Yield: 92%, col-
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1
orless semisolid. H NMR (CD3OD): δ 1.44 (s, 9H), 2.76 (m,
2H), 3.16 (m, 2H), 3.67 (s, 3H), 3.73 (t, 1H, J=7.0 Hz,), 4.43 (t,
1H, J=6.7 Hz), 6.91 (s, 1H), 7.09-7.12 (m, 3H), 7.21-7.23 (m,
2H). 13C NMR (75 MHz, CD3OD): δ 27.16, 28.17, 29.53, 30.13,
43.26, 51.66, 52.69, 54.36, 111.80, 117.24, 118.58, 119.67, 120.04,
122.24, 125.22, 129.48, 134.92, 170.89, 174.75. MS (APCI): m/z
412.2 [MH]þ. [R]D25=-22.9° (c=1.7, CH3OH).
L-Trp-L-His(2-cyclobutyl)-OMe 2HCl (9c). Yield: 86%, col-
3
orless semisolid. 1H NMR (CD3OD): δ 1.49 (m, 2H), 2.33 (m,
4H), 2.87 (m, 2H), 3.21 (m, 1H), 3.29 (m, 2H), 3.54 (s, 3H), 3.73
(t, 1H, J=6.7 Hz), 4.32 (t, 1H, J=6.8 Hz), 6.94 (s, 1H), 7.10-
7.13 (m, 3H,), 7.28 (m, 2H). 13C NMR (75 MHz, CD3OD): δ
18.74, 27.17, 28.18, 29.46, 31.43, 52.55, 52.78, 54.44, 107.19,
112.014, 117.25, 118.64, 119.65, 119.99, 122.22, 125.15, 128.56,
134.93, 169.67, 170.82. MS (APCI): m/z 410.3 [MH]þ. [R]D25=-
16.7° (c=1.0, CH3OH).
L-Trp-L-His(2-cyclohexyl)-OMe 2HCl (9d). Yield: 95%, col-
3
orless semisolid. 1H NMR (CD3OD): δ 1.28 (m, 6H), 1.74 (m,
4H), 2.02 (m, 1H), 2.98 (m, 2H), 3.30 (m, 2H), 3.64 (s, 3H), 3.73
(t, 1H, J=6.9 Hz), 4.24 (t, 1H, J=6.8 Hz), 6.88 (s, 1H), 7.03-
7.08 (m, 3H), 7.25 (m, 2H). 13C NMR (75 MHz, CD3OD): δ