Q.H. Sodji et al. / European Journal of Medicinal Chemistry 96 (2015) 340e359
357
4.7.7.49. (S)-Tert-butyl
2-azido-5-((8-((2-((tert-butoxycarbonyl)
3.20e3.07 (m, 2H), 2.99e2.75 (m, 2H), 2.35 (t, J ¼ 7.1 Hz, 2H), 2.25
(t, J ¼ 14.4 Hz, 2H), 2.04 (dd, J ¼ 20.4, 9.4 Hz, 1H), 1.84e1.72 (m, 1H),
amino)-5-(thiophen-2-yl)phenyl)amino)-8-oxooctyl)amino)-5-
oxopentanoate (21c). Compound 1 (0.11 g, 0.49 mmol) was coupled
to 20c (0.15 g, 0.35 mmol) with EDCI (0.093 g, 0.49 mmol) and
HOBT (0.066 g, 0.49 mmol) as described for 21a to give 21c (0.23 g,
1.70e1.61 (m, 2H), 1.47 (s, 9H), 1.40 (s, 9H), 1.34e1.18 (m, 6H). 13
C
NMR (101 MHz, CDCl3) d 172.9,154.1,143.3,131.2,130.4,130.1, 128.0,
125.0, 123.5, 123.1, 122.6, 82.0, 80.7, 77.4, 77.1, 76.8, 50.4, 39.4, 36.9,
32.7, 29.2, 28.7, 28.4, 28.3, 28.0, 26.4, 25.4.
quantitative yield). 1H NMR (400 MHz, CDCl3)
d 7.53e7.41 (m, 2H),
7.39e7.30 (m, 1H), 7.18 (t, J ¼ 3.8 Hz, 2H), 6.99 (dd, J ¼ 4.9, 3.8 Hz,
1H), 3.76 (dd, J ¼ 9.0, 4.8 Hz, 1H), 3.13 (dd, J ¼ 13.4, 6.7 Hz, 2H), 2.32
(t, J ¼ 7.3 Hz, 2H), 2.21 (t, J ¼ 7.2 Hz, 2H), 2.15e2.03 (m, 1H), 1.89
(ddd, J ¼ 15.6, 13.9, 6.9 Hz, 1H), 1.71e1.57 (m, 2H), 1.46 (s, 9H), 1.44
(s, 9H), 1.42e1.37 (m, 2H), 1.31e1.22 (m, 6H). 13C NMR (101 MHz,
4.7.7.54. (S)-Tert-butyl
2-amino-5-((9-((2-((tert-butoxycarbonyl)
amino)-5-(thiophen-2-yl)phenyl)amino)-9-oxononyl)amino)-5-
oxopentanoate (22d). Compound 21d (0.20 g, 0.30 mmol) was
reduced in the presence of NH4Cl (0.073 g, 1.36 mmol) and zinc
powder (0.089 g) as described for 22a yielding 22d (0.17 g, 88%
CDCl3)
d 172.8, 171.5, 169.2, 154.0, 143.3, 131.1, 130.4, 129.9, 128.0,
124.7, 124.5, 123.4, 123.1, 122.5, 83.0, 80.7, 61.8, 39.4, 36.9, 32.1, 29.3,
28.8, 28.6, 28.3, 28.0, 27.1, 26.5, 25.4.
yield). 1H NMR (400 MHz, CDCl3)
d
7.58 (s, 1H), 7.44 (t, J ¼ 11.0 Hz,
1H), 7.32 (dd, J ¼ 8.4, 1.6 Hz, 1H), 7.22e7.13 (m, 2H), 7.04e6.92 (m,
1H), 3.18e3.03 (m, 2H), 2.34 (t, J ¼ 7.3 Hz, 2H), 2.31e2.20 (m, 2H),
2.10e1.94 (m, 1H), 1.87e1.70 (m, 1H), 1.71e1.60 (m, 2H), 1.46 (s, 9H),
4.7.7.50. (S)-Tert-butyl
2-azido-5-((9-((2-((tert-butoxycarbonyl)
amino)-5-(thiophen-2-yl)phenyl)amino)-9-oxononyl)amino)-5-
oxopentanoate (21d). Compound 1 (0.087 g, 0.38 mmol) was
coupled to 20d (0.15 g, 0.27 mmol) with EDCI (0.072 g, 0.38 mmol)
and HOBT (0.051 g, 0.38 mmol) as described for 21a to give 21d
1.41 (m, 10H), 1.36e1.15 (m, 9H). 13C NMR (101 MHz, CDCl3)
d 173.0,
154.1,143.3,131.1,130.5,130.0,128.0,124.7,124.5, 123.4,123.1,122.5,
81.9, 80.6, 39.4, 36.9, 32.7, 29.3, 28.8, 28.7, 28.3, 28.0, 26.5, 25.5.
(0.20 g, quantitative yield). 1H NMR (400 MHz, CDCl3)
d
7.43 (dd,
4.7.7.55. (S)-Tert-butyl 2-(4-(((2-amino-4-oxo-3,4-dihydropteridin-
6-yl)methyl)amino)benzamido)-5-((4-((2-((tert-butoxycarbonyl)
amino)-5-(thiophen-2-yl)phenyl)amino)-4-oxobutyl)amino)-5-
oxopentanoate (23a). Compound 22a (0.12 g, 0.21 mmol) was
coupled to pteroyl azide (0.19 g, 0.41 mmol) in the presence of TMG
(0.071 g, 0.62 mmol) in DMSO as described for the synthesis of 5 to
J ¼ 15.0, 9.4 Hz, 2H), 7.34 (dd, J ¼ 8.4, 2.0 Hz, 1H), 7.20 (dd, J ¼ 4.1,
2.9 Hz, 2H), 7.00 (dd, J ¼ 4.9, 3.7 Hz, 1H), 3.77 (dd, J ¼ 9.0, 4.8 Hz,
1H), 3.16 (dd, J ¼ 13.6, 6.5 Hz, 2H), 2.34 (t, J ¼ 7.4 Hz, 2H), 2.22 (t,
J ¼ 7.1 Hz, 2H), 2.17e2.07 (m, 1H), 1.97e1.85 (m, 1H), 1.71e1.61 (m,
2H), 1.47 (s, 9H), 1.45 (s, 9H), 1.43e1.39 (m, 2H), 1.30e1.18 (m, 8H).
13C NMR (101 MHz, CDCl3)
d
172.8, 171.4, 169.2, 154.0, 143.3, 131.2,
yield 23a (0.045 g, 26% yield). 1H NMR (500 MHz, DMSO-d6)
d 8.66
130.4, 130.0, 128.0, 124.7, 124.5, 123.5, 123.1, 122.5, 83.1, 80.7, 61.8,
39.5, 37.0, 32.1, 29.4, 28.9, 28.8, 28.3, 28.0, 27.1, 26.6, 25.5.
(s, 1H), 7.75 (d, J ¼ 1.9 Hz, 1H), 7.67 (d, J ¼ 8.8 Hz, 2H), 7.62 (d,
J ¼ 8.5 Hz, 1H), 7.52 (dd, J ¼ 5.1, 1.0 Hz, 1H), 7.48e7.38 (m, 2H), 7.12
(dd, J ¼ 5.0, 3.6 Hz, 1H), 6.66 (dd, J ¼ 14.6, 8.9 Hz, 2H), 4.49 (d,
J ¼ 6.0 Hz, 2H), 4.24 (dd, J ¼ 12.3, 9.4 Hz, 1H), 3.15e3.08 (m, 2H),
2.38 (t, J ¼ 7.3 Hz, 2H), 2.21 (dt, J ¼ 14.2, 7.1 Hz, 2H), 2.09e1.99 (m,
1H), 1.97e1.87 (m, 1H), 1.74 (dd, J ¼ 16.3, 9.0 Hz, 2H), 1.46 (s, 9H),
1.40 (s, 9H). HRMS (ESI) calcd for C42H51N10O8S [MþH]þ 855.3607
found 855.3607.
4.7.7.51. (S)-Tert-butyl
2-amino-5-((4-((2-((tert-butoxycarbonyl)
amino)-5-(thiophen-2-yl)phenyl)amino)-4-oxobutyl)amino)-5-
oxopentanoate (22a). To a solution of 21a (0.21 g, 0.37 mmol) in
EtOH (9 mL) and H2O (3 mL) was added NH4Cl (0.049 g, 0.91 mmol)
and zinc powder (0.06 g) and the resulting mixture was stirred
under reflux for 3 h. After completion of the reaction, the mixture
was filtered through a cilite pad. The crude product was purified by
preparative TLC with DCM:MeOH (10:1) yielding 22a (0.13 g, 63%
4.7.7.56. (S)-Tert-butyl 2-(4-(((2-amino-4-oxo-3,4-dihydropteridin-
6-yl)methyl)amino)benzamido)-5-((7-((2-((tert-butoxycarbonyl)
amino)-5-(thiophen-2-yl)phenyl)amino)-7-oxoheptyl)amino)-5-
oxopentanoate (23b). Compound 22b (0.12 g, 0.20 mmol) was
coupled to pteroyl azide (0.18 g, 0.41 mmol) in the presence of TMG
(0.07 g, 0.61 mmol) in DMSO as described for the synthesis of 5 to
yield). 1H NMR (400 MHz, CDCl3)
d
7.72 (s, 1H), 7.55 (d, J ¼ 8.3 Hz,
1H), 7.38 (d, J ¼ 8.4 Hz, 1H), 7.23 (dd, J ¼ 8.9, 8.1 Hz, 2H), 7.06e6.98
(m, 1H), 3.36e3.20 (m, 3H), 2.39 (t, J ¼ 6.2 Hz, 2H), 2.32e2.24 (m,
2H), 2.14e2.06 (m,1H),1.93e1.83 (m, 2H),1.79e1.70 (m,1H),1.49 (s,
9H), 1.43 (s, 9H). 13C NMR (101 MHz, CDCl3)
d
172.3, 154.0, 143.4,
yield 23b (0.038 g, 21% yield). 1H NMR (500 MHz, DMSO-d6)
d 8.66
131.1, 130.4, 129.8, 128.0, 124.7, 123.6, 123.1, 122.4, 81.5, 80.6, 38.6,
34.3, 33.0, 28.3, 28.0, 26.1.
(s, 1H), 7.73 (d, J ¼ 1.9 Hz, 1H), 7.66 (d, J ¼ 8.8 Hz, 2H), 7.61 (d,
J ¼ 8.4 Hz, 1H), 7.52 (dd, J ¼ 5.1, 1.1 Hz, 1H), 7.47e7.40 (m, 2H), 7.13
(dd, J ¼ 4.5, 3.0 Hz, 1H), 6.65 (d, J ¼ 8.8 Hz, 2H), 4.49 (d, J ¼ 5.9 Hz,
2H), 4.24e4.16 (m, 1H), 3.03 (dd, J ¼ 12.9, 6.7 Hz, 2H), 2.40e2.35 (m,
2H), 2.24e2.12 (m, 2H), 2.06e1.97 (m, 1H), 1.94e1.85 (m, 1H),
1.65e1.54 (m, 2H), 1.47 (s, 10H), 1.42e1.36 (m, 12H), 1.35e1.27 (m,
4H). HRMS (ESI) calcd for C45H57N10O8S [MþH]þ 897.4076 found
897.4072.
4.7.7.52. (S)-Tert-butyl
2-amino-5-((7-((2-((tert-butoxycarbonyl)
amino)-5-(thiophen-2-yl)phenyl)amino)-7-oxoheptyl)amino)-5-
oxopentanoate (22b). Compound 21b (0.22 g, 0.34 mmol) was
reduced in the presence of NH4Cl (0.046 g, 0.86 mmol) and zinc
powder (0.056 g) as described for 22a yielding 22b (0.14 g, 68%
yield). 1H NMR (400 MHz, CDCl3)
7.29e7.18 (m, 2H), 7.10e6.94 (m, 1H), 3.29e3.07 (m, 2H), 2.37 (t,
J ¼ 5.5 Hz, 2H), 2.32e2.19 (m, 2H), 2.15e1.99 (m, 1H), 1.85e1.63 (m,
4H), 1.61e1.39 (m, 20H), 1.39e1.27 (m, 4H). 13C NMR (101 MHz,
d
7.42 (dd, J ¼ 31.0, 8.4 Hz, 3H),
4.7.7.57. (S)-Tert-butyl2-(4-(((2-amino-4-oxo-3,4-dihydropteridin-
6-yl)methyl)amino)benzamido)-5-((8-((2-((tert-butoxycarbonyl)
amino)-5-(thiophen-2-yl)phenyl)amino)-8-oxooctyl)amino)-5-
oxopentanoate (23c). Compound 22c (0.17 g, 0.28 mmol) was
coupled to pteroyl azide (0.25 g, 0.56 mmol) in the presence of TMG
(0.097 g, 0.84 mmol) in DMSO as described for the synthesis of 5 to
CDCl3)
d 172.5, 143.3, 131.5, 130.2, 128.0, 124.8, 123.6, 123.2, 122.6,
81.4, 80.8, 39.2, 36.8, 33.1, 29.3, 28.3, 28.0, 26.2, 25.3.
4.7.7.53. (S)-Tert-butyl
2-amino-5-((8-((2-((tert-butoxycarbonyl)
yield 23c (0.070 g, 28% yield). 1H NMR (400 MHz, DMSO-d6)
d 8.58
amino)-5-(thiophen-2-yl)phenyl)amino)-8-oxooctyl)amino)-5-
oxopentanoate (22c). Compound 21c (0.23 g, 0.36 mmol) was
reduced in the presence of NH4Cl (0.086 g, 1.61 mmol) and zinc
powder (0.11 g) as described for 22a yielding 22c (0.20 g, 90% yield).
(s, 1H), 7.71 (s, 1H), 7.62 (d, J ¼ 8.6 Hz, 2H), 7.58 (d, J ¼ 8.7 Hz, 1H),
7.49 (d, J ¼ 4.5 Hz,1H), 7.44e7.37 (m, 2H), 7.12e7.08 (m,1H), 6.61 (d,
J ¼ 8.5 Hz, 2H), 4.44 (d, J ¼ 6.0 Hz, 2H), 4.23e4.12 (m,1H), 3.03e2.94
(m, 2H), 2.34 (t, J ¼ 7.5 Hz, 2H), 2.20e2.11 (m, 2H), 2.02e1.94 (m,
1H), 1.91e1.82 (m, 1H), 1.62e1.54 (m, 2H), 1.42 (s, 9H), 1.37 (s, 9H),
1.32e1.20 (m, 8H). HRMS (ESI) calcd for C46H59N10O8S [MþH]þ
1H NMR (400 MHz, CDCl3)
d
7.59 (s, 1H), 7.45 (d, J ¼ 8.4 Hz, 1H), 7.34
(d, J ¼ 8.3 Hz, 1H), 7.20 (d, J ¼ 4.3 Hz, 2H), 7.06e6.93 (m, 1H),