V. M. Shahani et al. / Bioorg. Med. Chem. 19 (2011) 1823–1838
1831
Ar-OH (Tyr)), 7.17–7.25 (m, 3H, 3 CH (Ar)), 7.37–7.47 (m, 4H, 4 CH
(Ar)), 7.67–7.69 (m, 2H, 2 CONH2), 7.86–7.95 (m, 6H, 6 CH (Ar-CN
and CH (Ar)), 8.03 (s, 1H, CH (Ar)), 8.35 (d, J = 7.7 Hz, 1H, CONH),
8.61 (t, J = 6.0 Hz, 1H, NHBn), 8.80 (d, J = 8.4 Hz, 1H, CONH), 9.16
(s, 1H, Ar-OH (Tyr)), 10.23 (s, 1H, NHAr); dC (100 MHz, DMSO-d6)
21.6, 23.0, 24.3, 36.2, 40.7, 42.4, 52.2, 55.3, 113.7, 114.9, 117.8,
118.3, 120.24, 126.6, 127.1, 127.4, 128.1, 128.2, 128.2, 129.6,
130.0, 132.0, 132.4, 133.0, 138.0, 139.2, 139.4, 139.7, 143.2,
155.7, 165.0, 167.6, 168.6, 171.4, 171.4; LRMS (MS ES), calcdfor
Crude material was purified by flash chromatography (92:7:1
CH2Cl2/MeOH/NH4OH) and yielded final product 12ad as a white
solid (59 mg, 0.078 mmol, 39%): dH (400 MHz, DMSO-d6) 0.91
(dd, J = 16.2 and 6.4 Hz, 6H, 2 CH3 (Leu)), 1.52–1.73 (m, 3H, CH2CH
(Leu)), 2.83–2.89 (m, 1H, CH2 (Tyr)), 3.02–3.06 (m, 1H, CH2 (Tyr)),
4.27 (d, J = 6.0 Hz, 2H, CH2Ph), 4.46–4.51 (m, 1H, CH (Leu)), 4.66–
4.71 (m, 1H, CH (Tyr)), 6.61 (d, J = 6.8 Hz, 2H, Ar-OH (Tyr)), 7.07
(m, 2H, 2 CH (Ar)), 7.14 (d, J = 8.4 Hz, 1H, CH (Ar)), 7.20–7.27 (m,
3H, 3 CH (Ar)), 7.37–7.48 (m, 4H, 4 CH (Ar)), 7.66–7.67 (m, 2H, 2
CH (Ar)), 7.69–7.72 (m, 1H, CH (Ar)), 7.87 (d, J = 7.4 Hz, 1H, CH
(Ar)), 7.91–7.95 (m, 5H, Ar-CN and Ar), 8.03 (s, 1H, CH (Ar)), 8.33
(d, J = 7.5 Hz, 1H, CONH), 8.59 (t, J = 6.0 Hz, 1H, NHBn), 8.80 (d,
J = 8.4 Hz, 1H, CONH), 9.14 (s, 1H, Ar-OH (Tyr)), 10.22 (s, 1H,
NHAr)); dC (100 MHz, DMSO-d6) 21.6, 23.0, 24.3, 36.2, 40.7, 42.4,
52.2, 55.3, 113.7, 114.9, 117.6, 118.3, 120.5, 126.2, 126.5, 127.0,
127.7, 127.9, 128.2, 128.2, 128.7, 128.7, 128.8, 130.0, 131.1,
131.4, 131.5, 131.9, 132.4, 134.3, 138.0, 139.7, 139.8, 140.5,
155.7, 165.0, 167.7, 168.6, 171.4. LRMS (MS ES), calcd for
C44H42N6O6 [M+Na] m/z = 773.31, found 773.33.
4.2.12. N-Benzyl-40-cyano-5-((S)-2-((S)-2-(4-cyanobenzamido)-
3-(4-hydroxyphenyl)propanamido)-4-methylpentanamido)-
[1,10-biphenyl]-2-carboxamide (12ab)
Compound 11a (142 mg, 0.2 mmol) was coupled to 4-cya-
nophenylboronic-acid according to general procedure G. Crude
material was purified by flash chromatography (2:1 CH2Cl2:(92:7:1
CH2Cl2/MeOH/NH4OH)) and yield final product 12ab as white solid
(81 mg, 0.11 mmol, 55%): dH (400 MHz, DMSO-d6)) 0.91 (dd,
C44H42N6O6Na [M+Na] m/z = 773.32, found 773.23.
J = 16.4 and 6.4 Hz, 6H,
2 CH3 (Leu)), 1.59–1.71 (m, 3H,
CH2CH(Leu)), 2.81–2.89 (m, 1H, CH2 (Tyr)), 3.00–3.05 (m, 1H, CH,
CH2 (Tyr)), 4.26 (d, J = 6.0 Hz, 2H, CH2Ph), 4.43–4.50 (m, 1H, CH
(Leu)), 4.65–4.71 (m, 1H, CH (Tyr)), 6.61 (d, J = 8.5 Hz, 2H, Ar-OH
(Tyr)), 7.06–7.08 (m, 2H, 2 CH (Ar)), 7.13 (d, J = 8.5 Hz, 2H, Ar-OH
(Tyr)), 7.23–7.29 (m, 3H, 3 CH (Ar)), 7.45 (d, J = 8.4 Hz, 2H, 2 CH
(Ar)), 7.49–7.20 (m, 1H, CH (Ar)), 7.69–7.71 (m, 2H, 2 CH (Ar)),
7.76–7.78 (m, 2H, 2 CH (Ar)), 7.90–7.96 (m, 4H, 4 CH(Ar-CN)),
8.33 (d, J = 7.7 Hz, 1H, CONH), 8.66 (t, J = 6.0 Hz, 1H, NHBn), 8.78
(d, J = 8.4 Hz, 1H, CONH), 9.14 (s, 1H, Ar-OH (Tyr)), 10.25 (s, 1H,
NHAr); dC (100 MHz, DMSO-d6) 21.6, 23.0, 24.3, 36.2, 40.6, 42.4,
52.2, 55.3, 110.0, 113.7, 114.9, 118.3, 118.8, 120.1, 126.7, 127.3,
128.1, 128.2, 128.2, 128.8, 129.2, 130.0, 131.8, 132.0, 132.4,
138.0, 138.6, 139.0, 139.9, 145.1, 145.1 155.7, 165.0, 168.1, 171.4,
4.2.15 N-Benzyl-30-cyano-5-((S)-2-((S)-2-(4-cyanobenzamido)-
3-(4-hydroxyphenyl)propanamido)-4-methylpentanamido)-
[1,10-biphenyl]-2-carboxamide (12ae) Compound 11a
(142 mg, 0.2 mmol) was coupled to 3-cyanophenylboronic-acid
according to general procedure G. Crude material was purified by
flash chromatography (2:1 CH2Cl2:(92:7:1 CH2Cl2/MeOH/NH4OH))
and yielded final product 12ae as a white solid (51 mg, 0.070
mmol, 35%): dH (400 MHz, DMSO-d6) 0.91 (dd, J = 16.4 and 6.3 Hz,
6H, 2 CH3 (Leu)), 1.51–1.71 (m, 3H, CH2CH (Leu)), 2.82–2.89 (m, 1H,
CH2 (Tyr)), 3.00–3.05 (m, 1H, CH2 (Tyr)), 3.86 (s, 3H, COOCH3), 4.27
(d, J = 5.9 Hz, 2H, CH2Ph), 4.44–4.50 (m, 1H, CH (Leu)), 4.65–4.70
(m, 1H, CH (Tyr)), 6.61 (d, J = 8.4 Hz, 2H, Ar-OH (Tyr)), 7.06–7.07
(m, 2H, 2 CH (Ar)), 7.13 (d, J = 8.4 Hz, 2H, Ar-OH (Tyr)), 7.20–7.29
(m, 3H, 3 CH (Ar)), 7.50–7.60 (m, 3H, 3 CH (Ar)), 7.66–7.67 (m, 1H,
CH (Ar)), 7.70–7.72 (m, 2H, 2 CH (Ar)), 7.82 (d, J = 8.2 Hz, 1H, 1 CH
(Ar)), 7.90–7.95 (m, 4H, 4 CH (Ar-CN)), 8.36 (d, J = 7.7 Hz, 1H,
CONH), 8.69 (t, J = 6.1 Hz, 1H, NHBn), 8.80 (d, J = 8.2 Hz, 1H, CONH),
9.16 (s, 1H, Ar-OH (Tyr)), 10.26 (s, 1H, NHAr); dC (100 MHz, DMSO-
d6) 21.6, 23.0, 24.3, 36.2, 40.6, 42.4, 52.3, 55.3, 111.3, 113.7, 114.9,
118.2, 118.3, 118.7, 120.4, 126.7, 127.1, 128.2, 128.2, 128.2, 128.8,
129.4, 130.0, 131.0, 131.6, 131.7, 132.4, 133.2, 138.0, 138.2, 139.1,
139.9, 141.6, 155.7, 165.0, 168.2, 171.4, 171.4; LRMS (MS ES), calcd
for C44H40N6O5Na [M+Na] m/z = 755.31, found 755.15.
171.4;LRMS (MS ES), calcd for
z = 755.31, found 755.15.
C44H40N6O5Na [M+Na] m/
4.2.13. Methyl 20-(benzylcarbamoyl)-50-((S)-2-((S)-2-(4-cyano-
benzamido)-3-(4-hydroxyphenyl)propanamido)-4-methylpen-
tanamido)-[1,10-biphenyl]-3-carboxylate (12ac)
Compound 11a (142 mg, 0.2 mmol) was coupled to 4-meth-
oxycarboxyphenylboronic-acid according to general procedure G.
Crude material was purified by flash chromatography (2:1
CH2Cl2:(92:7:1 CH2Cl2/MeOH/NH4OH)) and yielded final product
12ac as a white solid (66 mg, 0.086 mmol, 43%): dH (400 MHz,
DMSO-d6) 0.91 (dd, J = 16.4 and 6.3 Hz, 6H, 2 CH3 (Leu)), 1.52–
1.75 (m, 3H, CH2CH (Leu)), 2.82–2.88 (m, 1H, CH2 (Tyr)), 3.01–
3.08 (m, 1H, CH, CH2 (Tyr)), 3.86 (s, 3H, COOCH3), 4.25 (d,
J = 6.0 Hz, 2H, CH2Ph), 4.40–4.50 (m, 1H, CH(Leu)), 4.65–4.71 (m,
1H, CH (Tyr)), 6.61 (d, J = 8.4 Hz, 2H, Ar-OH (Tyr)), 7.05–7.06 (m,
2H, 2 CH (Ar)), 7.14 (d, J = 8.4 Hz, 2H, Ar-OH), 7.20–7.22 (m, 3H, 3
CH (Ar)), 7.42–7.44 (m, 2H, 2 CH (Ar)), 7.47–7.49 (m, 1H, CH
(Ar)), 7.68–7.70 (m, 2H, 2 CH (Ar)), 7.88–7.94 (m, 6H, Ar-CN and
Ar), 8.36 (d, J = 7.7 Hz, 1H, CONH), 8.64 (t, J = 6.0 Hz, 1H, NHBn),
8.80 (d, J = 8.4 Hz, 1H, CONH), 9.19 (s, 1H, Ar-OH (Tyr)), 10.26 (s,
1H, NHAr); dC (100 MHz, DMSO-d6) 21.7, 23.0, 24.4, 36.3, 40.7,
42.5, 52.2, 52.3, 55.4, 113.7, 114.9, 118.1, 118.3, 120.2, 126.7,
127.3, 128.1, 128.2, 128.3, 128.4, 128.7, 128.8, 129.1, 130.0,
132.0, 132.4, 138.0, 139.0, 139.1, 139.9, 145.2, 155.8, 165.1,
166.2, 168.5, 171.5, 171.5; LRMS (MS ES), calcd for C45H43N5O7Na
[M+Na] m/z = 788.32, found 788.28.
4.2.16. Methyl 20-(benzylcarbamoyl)-50-((S)-2-((S)-2-(4-cyano-
benzamido)-3-(4-hydroxyphenyl)propan-amido)-4-methyl-
pentanamido)-[1,10-biphenyl]-3-carboxylate (12af)
Compound 11a (142 mg, 0.2 mmol) was coupled to 3-meth-
oxycarboxyphenylboronic-acid according to general procedure G.
Crude material was purified by flash chromatography (2:1
CH2Cl2:(92:7:1 CH2Cl2/MeOH/NH4OH)) and yielded final product
12af as a white solid (81 mg, 0.11 mmol, 53%): dH (400 MHz,
DMSO-d6) 0.91 (dd, J = 16.4 and 6.3 Hz, 6H, 2 CH3 (Leu)), 1.53–
1.72 (m, 3H, CH2CH (Leu)), 2.83–2.89 (m, 1H, CH2 (Tyr)), 3.02–
3.06 (m, 1H, CH2 (Tyr)), 3.86 (s, 3H, COOCH3), 4.25 (d, J = 6.0 Hz,
2H, CH2Ph), 4.45–4.50 (m, 1H, CH (Leu)), 4.65–4.71 (m, 1H, CH
(Tyr)), 6.61 (d, J = 8.4 Hz, 2H, Ar-OH (Tyr)), 7.03–7.05 (m, 2H, 2
CH (Ar)), 7.14 (d, J = 8.4 Hz, 2H, Ar-OH), 7.17–7.24 (m, 3H, 3 CH
(Ar)), 7.47–7.51 (m, 2H, 2 CH (Ar)), 7.55–7.58 (m, 1H, CH (Ar)),
7.68–7.72 (m, 2H, 2 CH (Ar)), 7.92–7.95 (m, 6H, Ar-CN and Ar),
8.36 (d, J = 7.7 Hz, 1H, CONH), 8.62 (t, J = 6.0 Hz, 1H, NHBn), 8.81
(d, J = 8.4 Hz, 1H, CONH), 9.15 (s, 1H, Ar-OH (Tyr)), 10.25 (s, 1H,
NHAr): dC (100 MHz, DMSO-d6) 21.6, 23.0, 24.3, 36.2, 40.7, 42.4,
52.2, 52.3, 55.3, 113.7, 114.9, 117.8, 118.3, 120.2, 126.6, 127.1,
128.0, 128.1, 128.2, 128.7, 128.8, 128.9, 129.6, 130.0, 131.8,
132.3, 133.1, 138.0, 139.0, 139.1, 139.9, 140.8, 155.7, 165.0,
4.2.14. N2-Benzyl-5-((S)-2-((S)-2-(4-cyanobenzamido)-3-(4-hydr-
oxyphenyl)propanamido)-4-methylpentanamido)-[1,10-biphenyl]-
2,30-dicarboxamide (12ad)
Compound 11a (142 mg, 0.2 mmol) was coupled to 3-amid-
ocarboxyphenylboronic-acid according to general procedure G.