244
S. Butini et al. / European Journal of Medicinal Chemistry 70 (2013) 233e247
amorphous solid (yield 82%). 1H NMR (300 MHz, CDCl3)
d
ꢀ0.05 (s,
2H), 4.30e4.47 (m, 2H), 4.79e4.91 (m, 2H), 5.05e5.16 (m, 2H), 5.38
(br s, 1H), 6.15 (br s, 1H), 7.22e7.60 (m, 22H), 8.56 (br s, 1H), 11.43
3H), 0.10 (s, 3H), 0.95 (s, 9H), 1.49 (m, 9H), 3.01e3.08 (m, 1H), 3.39e
3.59 (m, 1H), 4.30e4.38 (m, 1H), 4.69e4.79 (m, 1H), 5.05e5.17 (m,
3H), 5.41 (br s, 1H), 6.20 (br s, 1H), 7.05e7.67 (m, 22H), 8.67 (m, 1H),
11.47 (m, 1H); MS (ESI) m/z: 867 (M þ K)þ; 850 (M þ Na)þ.
(br s, 1H); 13C NMR (75 MHz, CDCl3)
d 28.6, 53.0, 55.6, 60.7, 67.4,
74.3, 81.5, 118.7, 120.1, 122.4, 127.6, 127.7, 128.3, 128.5 (2C), 128.7,
128.9 (2C), 129.4 (2C), 129.9, 132.5, 134.4, 136.4, 137.6, 137.9, 138.8,
140.4, 149.9, 155.8, 158.5, 169.1, 199.5; MS (ESI) m/z: 736 (M þ Na)þ;
20
4.1.37. (2S)-2-(Benzyloxycarbonylamino)-N-(2-benzoyl-5-(((R)-1-
(tert-butyldimethylsilyl)oxy)-2-(benzyl(tert-butoxycarbonylamino))
ethyl)phenyl)-2-phenylacetamide ((2S-10R)-15a)
[a
]
¼ ꢀ33.9 (c ¼ 0.9, CHCl3). Anal. (C43H43N3O7), C, H, N.
436
4.1.42. (2R)-2-(Benzyloxycarbonylamino)-N-(3-(((S)-1-hydroxy)-2-
(benzyl(tert-butoxycarbonylamino))ethyl)phenyl)-2-phenylacetamide
(5c)
Starting from
same procedure reported for 4a, title compound was obtained as an
amorphous solid (yield 71%). 1H NMR (300 MHz, CDCl3)
L-Cbz-Phg-OH and (R)-14a, and following the
d
ꢀ0.07 (s,
Starting from (2R-10S)-15b, and following the same procedure
reported for 5a title compound was obtained as an amorphous solid
3H), 0.09 (s, 3H), 0.95 (s, 9H), 1.46 (m, 9H), 3.00e3.11 (m, 1H), 3.38e
3.59 (m, 1H), 4.31e4.37 (m, 1H), 4.68e4.77 (m, 1H), 5.04e5.16 (m,
3H), 5.40 (br s, 1H), 6.18 (br s, 1H), 7.04e7.63 (m, 22H), 8.65 (m, 1H),
11.44 (m, 1H); MS (ESI) m/z: 867 (M þ K)þ; 850 (M þ Na)þ.
(yield 29%). 1H NMR (400 MHz, CDCl3)
d 1.43 (s, 9H), 2.89 (br s, 1H),
3.18e3.43 (m, 2H), 4.44e4.75 (m, 2H), 4.96 (s, 1H), 5.10 (m, 2H),
5.51 (m, 1H), 6.23 (br s, 1H), 7.05 (m, 2H), 7.23e7.40 (m, 13H), 7.56e
7.68 (m, 4H), 9.51 (s, 1H). 1H NMR (300 MHz, CDCl3)
d 1.46 (s, 9H),
4.1.38. (2R)-2-(Benzyloxycarbonylamino)-N-(3-(((S)-1-(tert-
butyldimethylsilyl)oxy)-2-(benzyl(tert-butoxycarbonylamino))
ethyl)phenyl)-2-phenylacetamide ((2R-10S)-15b)
3.23e3.47 (m, 2H), 4.17 (m, 1H), 4.42e4.78 (m, 2H), 4.81 (m, 1H),
5.09 (s, 2H), 5.41 (m, 1H), 6.20 (m, 1H), 6.97 (m, 2H), 7.15e7.61 (m,
17H), 8.02 (br d, 1H); 13C NMR (75 MHz, CDCl3)
d 28.6, 52.8, 55.8,
Starting from
procedure reported for 4a, title compound was obtained as an
amorphous solid (yield 85%). 1H NMR (300 MHz, CDCl3)
3H), 0.05 (s, 3H), 0.90 (s, 9H), 1.46 (m, 9H), 2.90e3.08 (m, 1H), 3.25e
3.48 (m, 1H), 4.27e4.34 (m, 1H), 4.49e4.68 (m, 1H), 4.92e5.15 (m,
3H), 5.40 (br s, 1H), 6.22 (br s, 1H), 7.02e7.49 (m, 19H), 7.87e8.00
(m, 1H); MS (ESI) m/z: 746 (M þ Na)þ.
D
-Cbz-Phg-OH and (S)-14b and following the same
59.6, 67.5, 74.1, 81.3,117.5,119.4,122.2,127.5,128.3,128.4 (2C),128.7,
128.8 (2C), 129.2, 129.4 (2C), 136.0, 137.6, 137.7, 138.1, 143.5, 156.2,
158.3, 168.4; MS (ESI) m/z: 632 [M þ Na]þ; [
a]
¼ þ24.6 (c ¼ 0.7,
20
d
ꢀ0.13 (s,
436
CHCl3). Anal. (C36H39N3O6) C, H, N.
4.1.43. (2S)-2-(Benzyloxycarbonylamino)-N-(3-(((S)-1-hydroxy)-2-
(benzyl(tert-butoxycarbonylamino))ethyl)phenyl)-2-phenylacetamide
(5d)
4.1.39. (2S)-2-(Benzyloxycarbonylamino)-N-(3-(((S)-1-(tert-
butyldimethylsilyl)oxy)-2-(benzyl(tert-butoxycarbonylamino))
ethyl)phenyl)-2-phenylacetamide ((2S-10S)-15b)
Starting from (2S-10S)-15b, and following the same procedure
reported for 5a, title compound was obtained as an amorphous
solid (yield 33%). 1H NMR (400 MHz, CDCl3)
d 1.46 (s, 9H), 2.88 (br s,
Starting from
procedure reported for 4a, title compound was obtained as an
amorphous solid (yield 32%). 1H NMR (300 MHz, CDCl3)
3H), 0.05 (s, 3H), 0.91 (s, 9H), 1.46 (m, 9H), 2.90e3.09 (m, 1H), 3.25e
3.48 (m, 1H), 4.28e4.35 (m, 1H), 4.49e4.68 (m, 1H), 4.92e5.14 (m,
3H), 5.44 (br s, 1H), 6.27 (br s, 1H), 7.02e7.45 (m, 19H), 7.83e7.93
(m, 1H); MS (ESI) m/z: 746 (M þ Na)þ.
L
-Cbz-Phg-OH and (S)-14b and following the same
1H), 3.19e3.45 (m, 2H), 4.44e4.80 (m, 2H), 4.96 (s, 1H), 5.10 (m,
2H), 5.53 (m, 1H), 6.25 (br s, 1H), 7.16 (m, 2H), 7.21e7.42 (m, 13H),
d
ꢀ0.12 (s,
7.57e7.67 (m, 4H), 9.50 (s, 1H). 1H NMR (300 MHz, CDCl3)
d 1.45 (s,
9H), 3.24e3.47 (m, 2H), 4.10 (m, 1H), 4.42e4.78 (m, 2H), 4.81 (m,
1H), 5.09 (s, 2H), 5.41 (m, 1H), 6.20 (m, 1H), 6.97 (m, 2H), 7.15e7.61
(m,17H), 8.02 (br d,1H); 13C NMR (75 MHz, CDCl3)
d 28.6, 52.8, 55.8,
59.6, 67.5, 74.1, 81.3,117.5,119.4,122.2,127.5,128.3,128.4 (2C),128.7,
128.8 (2C), 129.2, 129.4 (2C), 136.0, 137.6, 137.7, 138.1, 143.5, 156.2,
20
4.1.40. (2S)-2-(Benzyloxycarbonylamino)-N-(2-benzoyl-5-(((R)-1-
hydroxy)-2-(benzyl(tert-butoxycarbonylamino))ethyl)phenyl)-2-
phenylacetamide (5a)
158.3, 168.4; MS (ESI) m/z: 632 (M þ Na)þ; [
a]
¼ þ46.0 (c ¼ 0.1,
436
CHCl3). Anal. (C36H39N3O6), C, H, N.
To a solution of (2S-10R)-15a (60 mg, 0.07 mmol) in dry THF
(5 mL), 1 M solution of tetrabutylammonium fluoride in THF
4.1.44. (3-(((R)-1-(tert-Butyldimethylsilyl)oxy))-2-(((1S)-1-phenyl-
(2-hydroxy)ethyl)(amino))ethyl)-1-nitrobenzene (16a)
(100
m
L, 0.09 mmol) was added and the reaction was stirred for
A mixture of (R)-12a (174 mg, 0.38 mmol), (S)-2-amino-2-
phenylethanol (105 mg, 0.771 mmol), DMSO (5 mL), and DIPEA
12 h. The solvent was removed under reduced pressure and the
residue was taken up in DCM. The organic phase was washed with
brine, dried over Na2SO4, filtered and evaporated. The residue was
purified by flash chromatography (1:2, EtOAc/n-hexane) to afford
title compound as an amorphous solid (yield 61%). 1H NMR
(67 m
L, 0.38 mmol), was heated at 75 ꢁC for 20 h. To the reaction
mixture was added to EtOAc (20 mL) and water (20 mL) and stirred
for 15 min. Agitation was stopped, and the layers were allowed to
separate. The organic layer was washed with water (20 mL) and
concentrated. The residue was purified by flash chromatography
(1:1, EtOAc/n-hexane) to afford title compound as colorless oil
(300 MHz, CDCl3)
d 1.49 (s, 9H), 3.38e3.61 (m, 2H), 4.29e4.52 (m,
2H), 4.87e4.92 (m, 2H), 5.04e5.16 (m, 2H), 5.36 (br s,1H), 6.15 (br d,
1H), 7.23e7.62 (m, 22H), 8.55 (br s, 1H), 11.42 (br s, 1H); 13C NMR
(yield 50%). 1H NMR (300 MHz, CDCl3)
d
ꢀ0.10 (s, 3H), 0.11 (s, 3H),
(75 MHz, CDCl3)
d
29.9, 53.0, 55.7, 60.7, 67.4, 74.4, 81.6, 118.7, 120.1,
0.93 (s, 9H), 2.40 (br s, 2H), 2.59e2.77 (m, 2H), 3.49 (t, J ¼ 9.6 Hz,
1H) 3.65e3.84 (m, 2H), 4.89e4.93 (m, 1H), 7.18e7.62 (m, 7H), 8.10
122.3, 127.6, 127.7, 128.4 (2C), 128.5, 128.7, 128.9 (2C), 129.5 (2C),
130.0, 132.6, 134.4, 136.4, 137.6, 137.8, 138.8, 140.5, 149.9, 155.8,
(d, J ¼ 7.9 Hz, 1H), 8.16 (s, 1H); MS (ESI) m/z:439 (M þ Na)þ;
20
20
158.6, 169.1, 199.5; MS (ESI) m/z: 736 (M þ Na)þ; [
(c ¼ 0.9, CHCl3). Anal. (C43H43N3O7), C, H, N.
a
]
¼ ꢀ49.2
[a
]
¼ ꢀ55.4 (c ¼ 0.2, CHCl3).
436
436
4.1.45. (3-(((R)-1-(tert-Butyldimethylsilyl)oxy))-2-(((1S)-1-benzyl-
(2-hydroxy)ethyl)(amino))ethyl)-1-nitrobenzene (16b)
4.1.41. (2R)-2-(Benzyloxycarbonylamino)-N-(2-benzoyl-5-(((R)-1-
hydroxy)-2-(benzyl(tert-butoxycarbonylamino))ethyl)phenyl)-2-
phenylacetamide (5b)
Following the same procedure described for 16a and using (S)-2-
amino-3-phenylpropan-1-ol, title compound was obtained as color-
Starting from (2R-10R)-15a, and following the same procedure
reported for 5a title compound was obtained as an amorphous solid
less oil (yield 46%). 1H NMR (300 MHz, CDCl3)
d
ꢀ0.15 (s, 3H), 0.13 (s,
3H), 0.84 (s, 9H), 2.17 (br s, 2H), 2.73e2.88 (m, 5H), 3.30 (dd, J ¼ 10.2,
(yield 57%). 1H NMR (300 MHz, CDCl3)
d 1.49 (s, 9H), 3.39e3.64 (m,
4.9 Hz,1H), 3.57 (dd, J ¼ 10.6, 2.0 Hz, 1H), 4.81e4.84 (m,1H) 7.14e7.31