Journal of Medicinal Chemistry
Article
NMR (300 MHz, DMSO-d6): δ 8.68 (s, 3H), 7.59−7.45 (m, 2H),
7.44−7.13 (m, 6H), 7.08−6.98 (m, 2H), 6.73 (dd, JH−F = 21.2 Hz, JH−H
= 10.6 Hz, 1H), 4.27 (q, J = 7.8, 1H), 2.29−2.02 (m, 2H), 1.95−1.80
(m, 1H), 1.68−1.47 (m, 1H). 13C NMR (75 MHz, DMSO-d6): δ 148.3,
148.1 (d, JC−F = 288 Hz), 140.1, 130.6, 128.7, 128.4, 128.0, 126.1,
122.1, 120.6 (d, J = 16 Hz), 45.9 (d, JC−F = 6.7 Hz), 34.3, 30.2.
Phenyl (S,E)-3-Amino-5-phenylpent-1-ene-1-sulfonate Hydro-
chloride (14-(H)). Prepared following procedure F using 0.78 g of
compound 9-(H) in 14 mL 4 M HCl/dioxane. Yield: 0.34 g (51%). 1H
NMR (300 MHz, DMSO-d6): δ 8.64 (s, 3H), 7.50−7.41 (m, 2H),
7.41−7.34 (m, 2H), 7.34−7.24 (m, 3H), 7.24−7.17 (m, 1H), 7.16−
7.10 (m, 2H), 6.81 (dd, JH−H = 15.3, 6.8 Hz, 1H), 4.15−3.95 (m, 1H),
2.61−2.38 (m, 2H), 2.10−1.84 (m, 2H). 13C NMR (75 MHz, DMSO-
d6): δ 149.0, 145.3, 140.3, 130.1, 128.5, 128.2, 127.6, 127.6, 126.2,
122.6, 50.1, 33.3, 30.4.
Purification by column chromatography (petroleum ether/EtOAc 3:1).
Yield: 0.150 g (81%). 1H NMR (300 MHz, CDCl3): δ 7.46−7.08 (m,
13H), 6.97 (d, J = 6.8 Hz, 2H), 5.94−5.59 (m, 2H), 4.96 (s, 1H), 4.80
(q, J = 8.2 Hz, 1H), 4.25−4.11 (m, 1H), 3.14−2.87 (m, 2H), 2.44−2.17
(m, 2H), 1.82−1.61 (m, 1H), 1.53−1.42 (m, 1H), 1.41 (s, 9H). 13C
NMR (75 MHz, CDCl3): δ 171.0, 155.6, 149.2, 148.0 (d, JC−F = 289
Hz), 140.6, 136.7, 130.2, 129.5, 128.9, 128.6, 128.4, 128.1, 127.2, 126.3,
123.0, 123.0 (d, JC−F = 12 Hz), 80.6, 56.1, 46.1 (d, JC−F = 5.9 Hz), 38.5,
35.7, 31.8, 28.4.
tert-Butyl ((S)-1-(((S,E)-1-(Benzylsulfonyl)-1-fluoro-5-phenylpent-
1-en-3-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (20). Syn-
thesized following procedure C with 0.230 g compound 15, 0.165 g
boc-L-Phe-OH, 0.200 g TBTU, 0.095 g HOBt, and 0.325 mL DIEA.
Purification by column chromatography (petroleum ether/EtOAc 3:1).
1
Yield: 0.30 g (85%). H NMR (300 MHz, CDCl3): δ 7.42−7.15 (m,
(S,E)-1-(Benzylsulfonyl)-1-fluoro-5-phenylpent-1-en-3-amine Hy-
11H), 7.13−6.97 (m, 4H), 5.68 (d, J = 8.0 Hz, 1H), 5.53 (dd, JH−F = 33
Hz, JH−H = 8.9 Hz, 1H), 4.99 (br s, 1H), 4.68 (quint, J = 7.8 Hz, 1H),
4.35 (s, 2H), 4.18 (q, J = 7.9 Hz, 1H), 3.03 (dd, J = 13.5, 6.4 Hz, 1H),
2.91 (dd, J = 13.5, 8.0 Hz, 1H), 2.49−2.29 (m, 2H), 1.70−1.56 (m,
2H), 1.42 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 170.6, 155.6, 152.3
(d, JC−F = 301 Hz), 140.3, 136.6, 131.0, 129.5, 129.4, 129.2, 129.0,
128.7, 128.4, 127.3, 126.7, 126.5, 119.7 (d, JC−F = 4.0 Hz), 80.6, 58.8,
56.2, 44.7 (d, JC−F = 1.3 Hz), 38.6, 35.5 (d, JC−F = 1.4 Hz), 31.7, 28.4.
tert-Butyl ((S)-1-(((S,E)-1-Fluoro-5-phenyl-1-(phenylsulfonyl)-
pent-1-en-3-yl)amino)-1-oxo-3-(m-tolyl)propan-2-yl)carbamate
(21). Synthesized following procedure C with 0.220 g compound 13,
0.173 g boc-L-Phe(3-Me)-OH, 0.198 g TBTU, 0.095 g HOBt, and
0.330 mL DIEA. Purification by column chromatography (petroleum
ether/EtOAc 3:1). Yield: 0.28 g (77%). 1H NMR (300 MHz, CDCl3):
δ 8.00−7.88 (m, 2H), 7.76−7.65 (m, 1H), 7.64−7.53 (m, 2H), 7.31−
7.12 (m, 4H), 7.11−6.88 (m, 5H), 6.04 (dd, JH−F = 32.1 Hz, JH−H = 8.4
Hz, 1H), 5.93 (d, J = 8.0 Hz, 1H), 4.92 (s, 1H), 4.78−4.59 (m, 1H),
4.21 (q, J = 7.3 Hz, 1H), 3.01 (dd, J = 13.8, 6.6 Hz, 1H), 2.92 (dd, J =
13.8, 7.5 Hz, 1H), 2.58−2.46 (m, 2H), 2.31 (s, 3H), 1.93−1.77 (m,
2H), 1.41 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 170.9, 155.62, 154.9
(d, JC−F = 303 Hz), 140.4, 138.7, 137.1, 136.5, 134.8, 130.1, 129.7,
128.9, 128.8, 128.7, 128.4, 128.1, 126.4, 126.4, 117.4 (d, JC−F = 3.6 Hz),
80.6, 56.2, 45.2, 38.2, 35.8, 31.8, 28.4, 21.5.
drochloride (15). Prepared following procedure F using 0.46 g of
1
compound 10 in 10 mL 4 M HCl/dioxane. Yield: 0.37 g (95%). H
NMR (300 MHz, DMSO-d6): δ 8.66 (s, 3H), 7.48−7.27 (m, 7H),
7.26−7.09 (m, 3H), 6.13 (dd, JH−F = 33 Hz, JH−H = 9.9 Hz, 1H), 4.87 (s,
2H), 4.04 (td, J = 9.3, 5.0 Hz, 1H), 2.39 (t, J = 8.1 Hz, 2H), 2.13−1.97
(m, 1H), 1.91−1.74 (m, 1H). 13C NMR (75 MHz, DMSO-d6): δ 154.1
(d, JC−F = 304 Hz), 140.2, 131.2, 129.0, 128.7, 128.5, 128.2, 127.0,
126.2, 115.7 (d, JC−F = 2.9 Hz), 57.6, 45.0 (d, JC−F = 2.2 Hz), 33.5, 30.4.
(S,E)-1-Fluoro-5-(methylthio)-1-(phenylsulfonyl)pent-1-en-3-
aminium 2,2,2-Trifluoroacetate (16). Prepared following procedure G
with 0.88 g compound 11. Yield: 0.60 g (65%). 1H NMR (300 MHz,
DMSO-d6): δ 7.89−7.82 (m, 2H), 7.82−7.63 (m, 1H), 7.57−7.52 (m,
2H), 6.21 (d, JH−F = 32 Hz, 1H), 4.46 (m, 1H), 2.69−2.41 (m, 2H),
2.06 (s, 3H), 2.05−1.75 (m, 2H).
(R,E)-1-(Benzylthio)-4-fluoro-4-(phenylsulfonyl)but-3-en-2-ami-
nium 2,2,2-Trifluoroacetate (17). Prepared following procedure G
with 0.44 g compound 12. Yield: 0.37 g (81%). 1H NMR (300 MHz,
DMSO-d6): δ 8.04 (s, 3H), 7.95−7.84 (m, 2H), 7.77−7.55 (m, 4H),
7.25−7.19 (m, 4H), 6.44 (dd, JH−F = 30 Hz, JH−H = 9.1 Hz, 1H), 4.20−
4.01 (m, 1H), 3.71 (s, 2H), 2.91−2.62 (m, 2H). 13C NMR (75 MHz,
DMSO-d6): δ 161.4, 160.8, 155.5, 136.6, 135.5, 135.0, 129.9, 129.7,
129.2, 129.1, 128.9, 127.9, 117.3, 113.5, 111.1, 77.2, 46.2, 36.2, 33.3.
tert-Butyl ((S)-1-(((S,E)-1-Fluoro-5-phenyl-1-(phenylsulfonyl)-
pent-1-en-3-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
(18). Synthesized following procedure C with 0.180 g compound 13,
0.135 g boc-L-Phe-OH, 0.162 g TBTU, 0.078 g HOBt, and 0.265 mL
DIEA. Purification by column chromatography (petroleum ether/
Phenyl (S,E)-3-((S)-2-((tert-Butoxycarbonyl)amino)-3-(m-tolyl)-
propanamido)-1-fluoro-5-phenylpent-1-ene-1-sulfonate (22). Syn-
thesized following procedure C with 0.280 g compound 14, 0.210 g
boc-L-Phe(3-Me)-OH, 0.242 g TBTU, 0.115 g HOBt, and 0.40 mL
DIEA. Purification by column chromatography (petroleum ether/
EtOAc 3:1). Yield: 0.34 g (75%). 1H NMR (300 MHz, CDCl3): δ 7.40
(t, J = 7.3 Hz, 2H), 7.35−7.08 (m, 7H), 7.08−7.00 (m, 3H), 6.91 (s,
1
EtOAc 3:1). Yield: 0.21 g (73%). H NMR (300 MHz, CDCl3): δ
8.00−7.89 (m, 2H), 7.79−7.68 (m, 1H), 7.67−7.55 (m, 2H), 7.39−
7.12 (m, 8H), 7.10−7.00 (m, 2H), 6.00 (dd, JH−F = 32 Hz, JH−H = 8.5
Hz, 1H), 5.82 (d, J = 8.0 Hz, 1H), 4.91 (s, 1H), 4.69 (quint, J = 7.7 Hz,
1H), 4.20 (q, J = 7.5 Hz, 1H), 3.04 (dd, J = 13.7, 6.6 Hz, 1H), 2.95 (dd, J
= 13.7, 7.6 Hz, 1H), 2.52 (t, J = 7.2 Hz, 2H), 1.96−1.75 (m, 2H), 1.40
1H), 6.80 (d, J = 7.3 Hz, 1H), 5.78 (d, J = 7.7 Hz, 1H), 5.65 (dd, JH−F
=
31.4 Hz, JH−H = 8.3 Hz, 1H), 5.04 (s, 1H), 4.70 (quint, J = 8.2, 7.0 Hz,
1H), 4.18 (quint, J = 8.7, 8.0 Hz, 1H), 3.01 (dd, J = 13.3, 6.1 Hz, 1H),
2.83 (dd, J = 13.3, 8.6 Hz, 1H), 2.55−2.37 (m, 2H), 2.28 (s, 3H), 1.81−
1.65 (m, 2H), 1.42 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 170.9,
155.6, 149.4, 149.0 (d, JC−F = 297 Hz), 140.2, 138.7, 136.5, 130.2,
130.0, 128.9, 128.8, 128.4, 128.1, 128.0, 126.5, 126.4, 122.4, 121.3 (d,
(s, 9H). 13C NMR (75 MHz, CDCl3): δ 170.8, 155.6, 154.8 (d, JC−F
=
301 Hz), 140.4, 137.1, 136.6, 134.8, 129.7, 129.4, 129.0, 128.8, 128.7,
128.4, 127.3, 126.4, 117.3 (d, JC−F = 4.7 Hz), 80.6, 56.2, 45.0, 38.4, 35.7,
31.8, 28.4.
Phenyl (S,E)-3-((S)-2-((tert-Butoxycarbonyl)amino)-3-phenylpro-
panamido)-1-fluoro-5-phenylpent-1-Ene-1-sulfonate (19). Synthe-
sized following procedure C with 0.160 g compound 14, 0.114 g boc-
Phe-OH, 0.138 g TBTU, 0.066 g HOBt, and 0.225 mL DIEA.
Purification by column chromatography (petroleum ether/EtOAc 3:1).
J
C−F = 4.9 Hz), 80.6, 56.2, 44.9 (d, JC−F = 1.2 Hz), 38.5, 35.4 (d, JC−F
=
0.9 Hz), 31.7, 28.4, 21.4.
tert-Butyl ((S)-1-(((S,E)-1-(Benzylsulfonyl)-1-fluoro-5-phenylpent-
1-en-3-yl)amino)-1-oxo-3-(m-tolyl)propan-2-yl)carbamate (23).
Synthesized following procedure C with 0.230 g compound 15, 0.174
g boc-L-Phe(3-Me)-OH, 0.200 g TBTU, 0.095 g HOBt, and 0.325 mL
DIEA. Purification by column chromatography (petroleum ether/
1
Yield: 0.20 g (78%). H NMR (300 MHz, CDCl3): δ 7.47−7.35 (m,
2H), 7.35−7.10 (m, 9H), 7.08−6.95 (m, 4H), 5.65 (d, J = 7.9 Hz, 1H),
5.60 (dd, JH−F = 32 Hz, JH−H = 8.3 Hz, 1H), 5.02 (d, J = 7.1 Hz, 1H),
4.68 (q, J = 7.4 Hz, 1H), 4.18 (dd, J = 8.6, 5.6 Hz, 1H), 3.04 (dd, J =
13.4, 6.2 Hz, 1H), 2.85 (dd, J = 13.4, 8.4 Hz, 1H), 2.55−2.35 (m, 2H),
1.83−1.60 (m, 2H), 1.41 (s, 9H). 13C NMR (75 MHz, CDCl3): δ
170.8, 155.8, 149.4, 149.0 (d, JC−F = 297 Hz), 147.0, 140.1, 136.5,
130.2, 129.3, 129.0, 128.8, 128.4, 128.0, 127.4, 126.6, 122.5, 121.3 (d,
1
EtOAc 3:1). Yield: 0.28 g (69%). H NMR (300 MHz, CDCl3): δ
7.41−7.12 (m, 9H), 7.04 (d, J = 7.3 Hz, 3H), 6.94 (s, 1H), 6.85 (d, J =
7.3 Hz, 1H), 5.73 (d, J = 7.8 Hz, 1H), 5.56 (dd, JH−F = 32.8 Hz, JH−H
=
8.8 Hz, 1H), 4.99 (s, 1H), 4.69 (quint, J = 8.3, 7.8 Hz, 1H), 4.34 (s, 2H),
4.18 (q, J = 8.7 Hz, 1H), 3.01 (dd, J = 13.6, 6.5 Hz, 1H), 2.87 (dd, J =
13.6, 7.9 Hz, 1H), 2.49−2.33 (m, 2H), 2.30 (s, 3H), 1.72−1.57 (m,
2H), 1.42 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 170.7, 155.6, 152.3
(d, JC−F = 301 Hz), 140.4, 138.7, 136.5, 131.1, 130.1, 129.5, 129.2,
128.9, 128.7, 128.4, 128.1, 126.7, 126.5, 119.8 (d, JC−F = 4.2 Hz), 80.6,
58.8, 56.2, 44.8 (d, JC−F = 1.3 Hz), 38.4, 35.6, 31.7, 28.4, 21.5.
J
C−F = 5.1 Hz), 80.6, 56.2, 44.8, 38.7, 35.3, 31.7, 28.4.
Phenyl (S,Z)-3-((S)-2-((tert-Butoxycarbonyl)amino)-3-phenylpro-
panamido)-1-fluoro-5-phenylpent-1-ene-1-sulfonate (19-(Z)). Syn-
thesized following procedure C with 0.128 g compound 14-(Z), 0.091 g
boc-L-Phe-OH, 0.110 g TBTU, 0.053 g HOBt, and 0.204 mL DIEA.
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J. Med. Chem. 2021, 64, 12322−12358