Y. Hu et al. / Bioorg. Med. Chem. 13 (2005) 6629–6644
6641
N-[(40-{[(3-methyl-1-benzofuran-2-yl)-carbonyl]oxy}-1,10-
biphenyl-4-yl)sulfonyl]-D-valine as a white solid in
71% yield (300 mg). 1H NMR (CDCl3): d 0.91 (d,
J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 1.21 (s, 9H),
2.10 (m, 1H), 2.70 (s, 3H), 3.73 (dd, J = 9.9, 4.4 Hz,
1H), 5.13 (d, J = 9.9 Hz, 1H), 7.41 (m, 3H), 7.52 (m,
1H), 7.63 (m, 3H), 7.71 (m, 3H), 7.94 (d, J = 8.3 Hz,
2H). Removal of tert-butyl ester (General synthesis 6)
gave compound 14 as a white solid in 96% yield
synthesis 7) gave compound 16 as a white solid in 88%
yield (54 mg). Mp: 178–180 ꢁC. H NMR (DMSO-d6):
1
d 0.79 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H),
2.03 (m, 1H), 2.41 (s, 3H), 3.51 (dd, J = 9.2, 5.9 Hz,
1H), 3.94 (s, 3H), 5.31 (s, 2H), 7.22 (d, J = 8.8 Hz,
2H), 7.41 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H),
7.72 (d, J = 9.1 Hz, 2H), 7.83 (m, 4H), 8.01 (d,
J = 9.2 Hz, 1H), 13.38 (br s, 1H). MS m/z: 600.1
(MꢀH)ꢀ, 1201.1 (2MꢀH)ꢀ. HRMS: calcd for
[C28H28BrNO7S + H]+: 602.0843. Found: 602.0826.
Anal. (C28H28BrNO7S): C, H, N. Chiral purity:
99.85% (13.4 min).19
1
(188 mg). H NMR (DMSO-d6): d 0.79 (d, J = 6.8 Hz,
3H), 0.82 (d, J = 6.8 Hz, 3H), 2.01 (m, 1H), 2.73 (s,
3H), 3.61 (dd, J = 9.2, 5.9 Hz, 1H), 7.42 (m, 1H), 7.52
(d, J = 8.8 Hz, 2H), 7.60 (m, 1H), 7.81 (d, J = 8.3 Hz,
1H), 7.91 (m, 7H), 8.10 (d, J = 9.2 Hz, 1H), 13.81 (br
s, 1H). HRMS: calcd for [C27H25NO7S + H]+:
508.14245. Found: 508.1424.
13.13. N-({40-[(5-Bromo-4-methoxy-3-methyl-1-benzo-
furan-2-yl)methoxy]-1,10-biphenyl-4-yl}sulfonyl)-L-valine
(17)
13.11. N-({40-[(3-Methyl-1-benzofuran-2-yl)-methoxy]-
Methyl N-({40-[(5-bromo-4-methoxy-3-methyl-1-benzo-
furan-2-yl)methoxy]-1,10-biphenyl-4-yl}sulfonyl)-L-vali-
nate, General synthesis 8, white solid, 35% yield
1,10-biphenyl-4-yl}sulfonyl)-D-valine (15)
1
Coupling of 34ii with 31ii was carried out according to
General synthesis 5 to give methyl N-({40-[(3-methyl-1-
benzofuran-2-yl)-methoxy]-l,10-biphenyl-4-yl}sulfonyl)-
(105 mg). Mp: 205–207 ꢁC. H NMR (CDCl3): d 0.89
(d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.96–2.16
(m, 1H), 2.39 (s, 3H), 3.43 (s, 3H), 3.78 (dd,
J = 10.07, 5.0 Hz, 1H), 3.90 (s, 3H), 5.09 (d,
J = 10.1 Hz, 1H), 5.16 (s, 2H), 7.14 (m, 3H), 7.43
(d, J = 8.81 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.66 (d,
J = 8.3 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H). MS m/z:
616.1 (M+H)+. Methyl ester hydrolysis (General synthe-
sis 7) gave compound 17 as a white solid in 96% yield
(76 mg). Mp: 180–182 ꢁC. 1H NMR (DMSO-d6): d
0.80 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H),
1.83–2.08 (m, 1H), 2.43 (s, 3H), 3.50 (s, 1H), 3.88 (s,
3H), 5.31 (s, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.37 (d,
J = 8.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.73 (d,
J = 8.8 Hz, 2H), 7.76–7.91 (m, 4H), 7.97 (s, 1H), 13.19
(br s, 1H). MS m/z: 600.0 (MꢀH)ꢀ. HRMS: calcd for
[C28H28BrNO7S + H]+: 602.0843. Found: 602.0828.
Anal. (C28H28BrNO7S): C, H, N.
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D-valinate as a white solid in 75% yield (616 mg). H
NMR (MeOH-d4): d 0.81 (m, 6H), 1.93 (m, 1H), 2.21
(s, 3H), 3.23 (s, 3H), 3.50 (d, J = 6.6 Hz, 1H), 5.11 (s,
2H), 7.01 (d, J = 9.1 Hz, 2H), 7.14 (m, 1H), 7.21 (m,
1H), 7.33 (m, 1H), 7.41 (m, 1H), 7.52 (d, J = 9.1 Hz,
2H), 7.61 (d, J = 8.8 Hz, 2H), 7.71 (m, 2H). Methyl ester
hydrolysis (General synthesis 7) gave compound 15 as a
1
white solid in 89% yield (354 mg). Mp: 178–180 ꢁC. H
NMR (MeOH-d4): d 0.76 (d, J = 6.8 Hz, 3H), 0.84 (d,
J = 6.8 Hz, 3H), 2.00 (m, 1H), 2.21 (s, 3H), 3.53 (d,
J = 5.3 Hz, 1H), 5.11 (s, 2H), 7.11 (d, J = 9.1 Hz, 2H),
7.14 (m, 1H), 7.21 (m, 1H), 7.32 (d, J = 8.3 Hz, 1H),
7.52 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 9.1 Hz, 2H), 7.61
(d, J = 8.6 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H). HRMS:
calcd for [C27H27NO6S + H]+: 494.1632. Found:
494.164. Anal. (C27H27NO6SÆ0.2H2O): C, H, N.
13.14. N-({40-[(5-Chloro-4-methoxy-3-methyl-1-benzo-
furan-2-yl)methoxy]-1,10-biphenyl-4-yl}sulfonyl)-L-valine
(18)
13.12. N-({40-[(5-Bromo-4-methoxy-3-methyl-1-benzo-
furan-2-yl)methoxy]-1,10-biphenyl-4-yl}sulfonyl)-D-valine
(16)
Methyl N-({40-[(5-chloro-4-methoxy-3-methyl-1-benzo-
furan-2-yl)methoxy]-1,10-biphenyl-4-yl}sulfonyl)-L-vali-
nate, General synthesis 8, off-white solid, 57% yield
General synthesis 8, alkylation: a mixture of 35ii
(155 mg, 0.43 mmol), 29iii (120 mg, 0.42 mmol), and
K2CO3 (137 mg, 0.99 mmol) in 8 mL DMF under nitro-
gen was stirred at room temperature. After 12 h, the
mixture was diluted with EtOAc (150 mL) and washed
with H2O (3 · 50 mL) and brine (3 · 50 mL). The organ-
ic layer was dried over MgSO4, filtered, and concentrat-
ed in vacuo. Column chromatography of the residue
eluting with EtOAc/hexane (1:5, v/v) gave D-2-[40-(5-
bromo-4-methoxy-3-methylbenzofuran-2-ylmethoxy)-bi-
phenyl-4-sulfonylamino]-3-methyl-butyric acid methyl
ester (102 mg) as a white solid in 40% yield. Mp: 196–
1
(410 mg). H NMR (DMSO-d6): d 0.80 (d, J = 6.8 Hz,
3H), 0.84 (d, J = 6.8 Hz, 3H) 1.84–1.99 (m, 1H), 2.43
(s, 3H), 3.34 (s, 3H), 3.57 (dd, J = 9.3, 7.3 Hz, 1H),
3.90 (s, 3H), 5.30 (s, 2H), 7.15–7.26 (m, 2H), 7.40 (m,
2H), 7.68–7.90 (m, 6H), 8.27 (d, J = 9.3 Hz, 1H). MS
m/z: 572.1 (MꢀH)ꢀ. Methyl ester hydrolysis (General
synthesis 7) gave compound 18 as an off-white solid in
79% yield (320 mg). Mp: 174–177 ꢁC. 1H NMR
(DMSO-d6): d 0.82 (d, J = 6.8 Hz, 3H), 0.85 (d,
J = 6.8 Hz, 3H), 1.84–2.04 (m, 1H), 2.43 (s, 3H), 3.55
(dd, J = 9.3, 6.0 Hz, 1H), 3.90 (s, 3H), 5.30 (s, 2H),
7.11–7.27 (m, 2H), 7.37–7.42 (m, 2H), 7.68–7.78 (m,
2H), 7.82 (m, 4H), 8.03 (d, J = 9.3 Hz, 1H), 13.54 (br
s, 1H). MS m/z: 556.1 (MꢀH)ꢀ, 1113.2 (2MꢀH)ꢀ.
HRMS: calcd for [C28H28ClNO7S + H]+: 558.13478.
Found: 558.1345. Anal. (C28H28ClNO7SÆ0.2H2O): C,
H, N.
1
198 ꢁC. H NMR (CDCl3): d 0.86 (d, J = 6.8 Hz, 3H),
0.94 (d, J = 6.8 Hz, 3H), 2.11 (m, 1H), 2.51 (s, 3H),
3.40 (s, 3H), 3.82 (dd, J = 10.2, 5.2 Hz, 1H), 3.92 (s,
3H), 5.11 (d, J = 10.2 Hz, 1H), 5.23 (s, 2H), 7.10 (m,
3H), 7.41 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H),
7.71 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 8.6 Hz, 2H). MS
m/z: 616.1 (M+H)+. Methyl ester hydrolysis (General