BAJAJ ET AL.
2-((S)-2-((tert-Butoxycarbonyl)amino)-3-(1-tosyl-1H-imidazol-
4-yl)propanamido)-3-phenylpropanoic acid (Boc-His(Tos)-DL-
Phe-OH, 5a+5a0)
(6S,12S)-12-Isopropyl-2,2-dimethyl-4,7,10-trioxo-6-((1-tosyl-
1H-imidazol-4-yl)methyl)-3-oxa-5,8,11-triazatridecan-13-oic
acid (Boc-L-His(Tos)-Gly-L-Val-OH, 5e)
White microcrystals (72%); mp 175–177 ꢀC; 1H NMR (CDCl3) d
8.97–8.96 (d, J = 4.4 Hz, 1H), 8.16–8.07 (m, 1H), 7.50–7.47 (m, 2H),
7.27–6.98 (m, 8H), 4.51–4.43 (m, 1H), 4.32–4.25 (m, 1H), 3.19–
2.64 (m, 4H), 2.29 (s, 3H), 1.32 (s, 9H).13C NMR (CDCl3) d 172.6,
170.3, 170.1, 155.1, 145.5, 137.7, 137.3, 133.7, 129.5, 129.5, 129.2,
128.2, 128.1, 126.5, 125.5, 116.8, 116.6, 78.5, 53.3, 53.0, 36.8,
36.6, 28.1, 27.1, 20.8; Anal. calcd for C27H32N4O7S: C, 58.36; H,
5.79; N, 10.07; found: C, 57.87; H, 6.02; N, 9.83.
White microcrystals (68%); mp 113–115 ꢀC; 1H NMR (CDCl3) d 8.02–
8.00 (m, 1H), 7.87–7.74 (m, 3H), 7.45–7.14 (m, 5H), 5.95–5.87 (m, 1H),
4.49–4.39 (m, 1H), 4.11–3.78 (m, 2H), 3.08–2.93 (m, 2H), 2.42 (s, 3H),
2.42–2.13 (m, 1H), 1.33 (s, 9H), 0.94–0.90 (m, 6H); 13C NMR (CDCl3) d
174.7, 172.6, 169.8, 155.8, 146.8, 139.9, 136.8, 134.6, 130.7, 127.7,
126.0, 115.4, 80.3, 58.3, 58.1, 54.2, 43.4, 30.7, 28.4, 21.9, 19.4, 18.1.
Anal. calcd for C25H35N5O8S: C, 53.08; H, 6.24; N, 12.38; found: C,
52.68; H, 6.43; N, 12.32.
(6S,15S)-15-((S)-sec-Butyl)-2,2-dimethyl-4,7,10,13-tetraoxo-6-
((1-tosyl-1H-imidazol-4-yl)methyl)-3-oxa-5,8,11,14-tetraaza-
hexadecan-16-oic acid (Boc-L-His(Tos)-Gly-Gly-L-Ile-OH, 5f)
(S)-2-((S)-3-(1-Benzyl-1H-imidazol-4-yl)-2-(tert-butoxycarbony-
lamino)propanamido)-3-methylbutanoic acid (Boc-His(Tos)-
L-Val-OH, 5b)
1
White microcrystals (60%); mp 140–142 ꢀC; H NMR (DMSO-d6) d
Oil (72%); 1H NMR (CDCl3) d 8.04 (s, 1H), 7.82 (d, J =8.1 Hz, 2H), 7.35
(d, J = 8.1Hz, 1H), 7.11 (s, 1H), 5.52 (d, J = 8.7 Hz, 1H), 4.58–4.49
(m, 2H), 3.13 (d, J = 14.1 Hz, 1H), 2.61–2.50 (m, 1H), 2.43 (s, 3H),
2.25–2.19 (m, 1H), 1.31 (s, 9H), 0.98–0.92 (m, 6H). 13C NMR (CDCl3)
d 174.4, 171.5, 155.4, 146.9, 139.9, 136.6, 134.6, 130.8, 130.7, 127.8,
115.6, 79.7, 57.8, 53.9, 32.4, 31.8, 28.4, 22.0, 18.8, 18.1. HRMS (+ESI-
TOF): m/z for C23H32N4O5 [M+ H]+ calcd 507.1919, found 507.1926.
12.62 (s, 1H), 8.28 (s, 1H), 8.22–8.10 (m, 2H), 7.92 (d, J = 8.1 Hz,
2H), 7.49 (d, J = 8.4 Hz, 2H), 7.37 (s, 1H), 6.88 (d, J = 8.1 Hz, 1H),
4.23–4.16 (m, 2H), 3.79 (t, J = 5.7 Hz, 2H), 3.66 (d, J = 5.4 Hz, 2H),
2.92–2.80 (m, 1H), 2.75–2.65 (m, 1H), 2.40 (s, 3H), 1.82–1.70 (m,
1H), 1.30 (s, 9H), 1.24–1.11 (m, 2H), 0.85–0.78 (m, 6H); 13C NMR
(DMSO-d6) d 172.8, 171.5, 168.9, 168.6, 155.1, 146.3, 140.7, 136.7,
134.4, 130.6, 127.2, 114.7, 78.3, 56.2, 53.5, 42.2, 41.6, 36.4, 30.3,
28.1, 24.6, 21.2, 15.5, 11.3. Anal. calcd for C28H40N6O9S: C, 52.82;
H, 6.33; N, 13.20; found: C, 52.88; H, 6.70; N, 13.09.
2-((S)-3-(1-Benzyl-1H-imidazol-4-yl)-2-(tert-butoxycarbonyla-
mino)propanamido)-3-methylbutanoic acid (Boc-His(Tos)-DL-
Val-OH, 5b+5b0)
1
Procedure for Preparation of Compound 7
Oil (70%); H NMR (CDCl3) d 8.03 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H),
7.36 (d, J = 8.1 Hz, 2H), 7.21–7.14 (m, 1H), 5.86–5.84 (m, 1H),
5.65–5.62 (m, 1H), 4.68–4.50 (m, 2H), 3.18–3.05 (m, 1H), 2.74–
2.64 (m, 1H), 2.43 (s, 3H), 2.28–2.19 (m, 1H), 1.31 (d, J = 12.0 Hz,
9H), 0.96–0.90 (m, 6H). 13C NMR (CDCl3) d 174.6, 174.3, 171.6,
171.4, 155.6, 155.4, 146.8, 139.9, 136.5, 134.6, 130.7, 127.7, 115.6,
79.8, 79.7, 66.0, 57.7, 57.3, 53.9, 31.7, 31.6, 28.4, 21.9, 18.9, 18.8,
18.0, 17.9, 15.4. HRMS (+ESI-TOF): m/z for C23H32N4O5 [M + H]+
calcd 507.1919, found 507.1932.
To a solution of compound 3b (1.0 eq.) in acetonitrile, a solution
of D-H-Phe-OMe (1.0 eq.) and Et3N (1.2 eq.) in water was added
dropwise, and the reaction mixture was stirred at room tempera-
ture for 3 h. After complete consumption of compound 3b (TLC),
the solution was concentrated under reduced pressure. The
residue was extracted with ethyl acetate, dried over anhydrous
MgSO4, and evaporated under reduced pressure to afford the
desired product as an oil.
(S)-2-((S)-2-((tert-Butoxycarbonyl)amino)-3-(1-tosyl-1H-imida-
zol-4-yl)propanamido)-4-methylpentanoic acid (Boc-L-His
(Tos)-L-Leu-OH, 5c)
Methyl 2-((S)-3-(1-benzyl-1H-imidazol-4-yl)-2-(tert-butoxy-
carbonylamino)propanamido)-3-phenylpropanoate (Boc-His
(Bzl)-Phe-OMe, 7)
White microcrystals (89%); mp 121–123 ꢀC [lit. mp 146–148 ꢀC]16;
1H NMR (CDCl3) d 8.02 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.75
(d, J = 7.5 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.15 (s, 1H), 5.60
(d, J = 9.0 Hz, 1H), 4.64–4.52 (m, 2H), 3.14–3.05 (m, 1H), 2.68–2.56
(m, 1H), 2.43 (s, 3H), 1.78–1.56 (m, 3H), 1.32–1.22 (m, 9H), 0.96
(d, J = 6.3 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3) d
175.6, 171.4, 155.4, 146.8, 139.9, 136.5, 134.6, 130.7, 127.7, 115.7,
79.7, 53.7, 51.5, 42.6, 32.3, 31.8, 28.3, 25.0, 22.8, 22.6, 21.9, 14.3.
Oil (69%); 1H NMR (CDCl3) d 7.42–7.38 (m, 1H), 7.34–7.16 (m, 7H),
7.13–7.06 (m, 3H), 6.96–6.94 (m, 1H), 6.71–6.63 (m, 1H), 6.39–6.27
(m, 1H), 4.97 (s, 2H), 4.79–4.75 (m, 1H), 3.69 (s, 1H), 3.63 (s, 1H),
3.59 (s, 1H), 3.06–2.84 (m, 4H), 1.40 (d, J = 4.0 Hz, 9H). 13C NMR
(CDCl3) d 175.4, 171.6, 171.5, 171.4, 155.6, 138.5, 138.2, 136.7,
136.0, 135.8, 129.2, 128.9, 128.5, 128.4, 128.3, 128.2, 127.4, 127.3,
126.9, 126.8. HRMS (+ESI-TOF): m/z for C28H34N4O5 [M + H]+ calcd
507.2602, found 507.2604.
2-((S)-2-(tert-Butoxycarbonylamino)-3-(1-tosyl-1H-imidazol-4-
yl)propanamido)propanoic acid (Boc-L-His(Tos)-L-Ala-OH, 5d)
Procedure for Preparation of Compound 8a
White microcrystals (92%); mp 151–153 ꢀC; 1H NMR (CDCl3) d 8.02
(s, 1H), 7.84–7.82 (d, J = 8.1 Hz, 2H), 7.38–7.35 (d, J = 8.1 Hz, 2H),
7.12 (s, 1H), 5.66–5.63 (d, J = 8.2 Hz, 1H), 5.46–5.44 (d, J = 7.9 Hz,
1H), 4.63–4.50 (m, 1H), 3.19–3.10 (m, 1H), 2.70–2.48 (m, 2H), 2.44
(s, 3H), 1.51–1.27 (m, 12H); 13C NMR (CDCl3) d 157.9, 171.3,
155.3, 146.9, 139.8, 136.5, 134.5, 130.8, 127.8, 115.7, 79.7, 53.6,
49.2, 48.8, 32.5, 28.3, 22.0, 18.9. HRMS (+ESI-TOF): m/z for
C21H28N4O7S [M + Na]+ calcd 503.1571, found 503.1571.
N-(3-Aminopropyl)-imidazole (1.0eq.) was dissolved in THF and
Et3N (1.5eq.). Na-Boc-Nim-4-toluenesylfonyl-histidylbenzotriazole
3a (1.0 eq.) was added to the solution, and the mixture was stirred at
room temperature for 3 h. The mixture was acidified with 4N HCl, con-
centrated and then diluted with ethyl acetate. The organic layer was
washed with 10% Na2CO3 solution, water and dried over anhydrous
MgSO4, filtered, and evaporated to give a white solid, which was
further washed with diethyl ether to give the desired compound.
wileyonlinelibrary.com/journal/jpepsci Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd. J. Pept. Sci. 2013; 19: 110–117