E. Lenci, A. Angeli, L. Calugi et al.
European Journal of Medicinal Chemistry 214 (2021) 113260
0
4
.1.9. Synthesis of (2R,4S)-methyl 4-([1,1 -biphenyl]-4-
7.64e7.55 (m, 5H), 7.54e7.40 (m, 6H), 5.11e5.01 (m, 1H), 4.40 (dd,
J ¼ 9.4, 2.3 Hz, 1H), 3.79 (t, J ¼ 8.5 Hz, 1H), 3.74 (s, 3H), 3.63 (t,
J ¼ 8.5 Hz, 1H), 2.84 (dt, J ¼ 12.3, 9.8 Hz, 1H), 2.04 (ddd, J ¼ 12.2, 7.5,
ylsulfonamido)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2-
carboxylate (9)
According to the general procedure (A), compound 9 was ob-
tained as a brown oil in 73% yield (452 mg) from compound 8
13
3
2.1 Hz, 1H); C NMR (50 MHz, CDCl ) d 171.7, 147.2, 146.0, 138.7,
138.1, 129.1 (3C), 129.0 (2C), 128.9 (2C), 128.1 (3C), 127.8 (2C), 127.6
(
4
1
538 mg, 1.17 mmol), DMAP (142 mg, 1.17 mmol), TEA (651
.68 mmol), p-methoxy-benzenesulfonyl chloride (365 mg,
.76 mmol), after flash chromatography on silica gel (Petr. Et./EtOAc
m
L,
(2C), 127.4 (3C), 127.3 (2C), 58.7, 57.6, 52.7, 49.1, 33.6. MS (ESI) m/z
(%): 577.14 [100, (M þ H) ].
þ
2
2
1
0
4
.1.13. Synthesis of (2R,4S)-4-([1,1 -biphenyl]-4-ylsulfonamido)-N-
2
(
7
1
2
(
(
5
:1). ½
aꢂ
¼ ꢁ17.9 (CHCl
3
, c ¼ 1.1). H NMR (400 MHz, CDCl
3
) d 8.32
D
hydroxy-1-((4-methoxyphenyl) sulfonyl)pyrrolidine-2-carboxamide
13)
According to the general procedure (B), compound 13 was ob-
tained as a brown oil in 41% yield (72 mg) from compound 9
d, J ¼ 8.7 Hz, 2H), 8.00 (d, J ¼ 8.2 Hz, 4H), 7.77 (d, J ¼ 8.5 Hz, 4H),
(
.63 (d, J ¼ 7.4 Hz, 2H), 7.49 (dt, J ¼ 21.0, 7.0 Hz, 3H), 5.08e4.97 (m,
H), 4.51e4.41 (m, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.65e3.58 (m, 1H),
1
3
.88 (dt, J ¼ 22.2, 11.2 Hz, 1H), 2.09 (dt, J ¼ 18.4, 8.5 Hz, 1H). C NMR
(
(
2
180 mg, 0.33 mmol), NH OH*HCl (198 mg, 2.64 mmol) and KOH
221 mg, 3.96 mmol), after flash chromatography on silica gel
50 MHz, CDCl
3
)
d
171.8, 163.3, 147.2, 138.8, 138.1, 129.8, 129.1, 128.9
2C), 128.7 (3C), 127.8 (3C), 127.4 (2C), 114.2 (2C), 58.5, 57.6, 55.6,
þ
22
1
2.7, 49.1, 33.5. MS (ESI) m/z (%): 530.09 [(M þ Na) , 100].
(EtOAc). ½
aꢂ
¼ þ3.6 (MeOH, c ¼ 1). H NMR (400 MHz, CD
3
OD)
D
d
7.98e7.90 (m, 4H), 7.82e7.69 (m, 4H), 7.57e7.38 (m, 5H),
0
4
.1.10. Synthesis of (2R,4S)-methyl 4-([1,1 -biphenyl]-4-
7.10e7.08 (m, 2H), 5.05 (br s, 1H), 4.28 (d, J ¼ 9.2 Hz, 1H), 3.86 (d,
ylsulfonamido)-1-((4-nitrophenyl)sulfonyl)pyrrolidine-2-
carboxylate (10)
According to the general procedure (A), compound 10 was ob-
tained as a brown oil in 78% yield (442 mg) from compound 8
(
4
J ¼ 5.3 Hz, 1H), 3.81 (s, 3H), 3.63 (t, J ¼ 8.7 Hz, 1H), 3.51 (t, J ¼ 8.0 Hz,
13
1H), 2.75 (d, J ¼ 11.0 Hz, 1H), 1.99 (d, J ¼ 7.7 Hz, 1H); C NMR
3
(100 MHz, CD OD) d 163.6, 147.1, 138.6, 137.9, 129.7, 129.6, 128.8
(2C), 128.6 (2C), 128.5, 127.4 (2C), 127.1 (2C), 126.8 (2C), 114.1 (2C),
-
480 mg, 1.04 mmol), DMAP (127 mg, 1.04 mmol), TEA (580
.17 mmol), p-nitro-benzenesulfonyl chloride (344 mg, 1.56 mmol),
mL,
57.8, 54.8, 48.7, 33.3, 29.3. MS (ESI) m/z (%): 530.12 [100, (M ꢁ H) ].
0
after flash chromatography on silica gel (Petr. Et./EtOAc 1:1).
4.1.14. Synthesis of (2R,4S)-4-([1,1 -biphenyl]-4-ylsulfonamido)-N-
2
2
1
hydroxy-1-((4-nitrophenyl)sulfonyl)pyrrolidine-2-carboxamide
½
a
ꢂ
¼ -13.2 (CHCl
3
, c ¼ 1.2). H NMR (400 MHz, CDCl
3
) d 8.32 (d,
D
(
14)
According to the general procedure (B), compound 14 was ob-
tained as a brown oil in 38% yield (67 mg) from compound 10
175 mg, 0.32 mmol), NH OH*HCl (192 mg, 2.56 mmol), KOH
(216 mg, 3.85 mmol), after flash chromatography on silica gel
J ¼ 8.7 Hz,1H), 8.07e8.05 (m, 2H), 8.00 (d, J ¼ 8.2 Hz, 2H), 7.77e7.62
(
1
m, 4H), 7.63 (d, J ¼ 7.4 Hz, 2H), 7.53e7.49 (m, 3H), 5.11e4.96 (m,
H), 4.52e4.43 (m, 1H), 3.81 (t, J ¼ 8.6 Hz, 1H), 3.74 (s, 3H), 3.61 (t,
J ¼ 8.7 Hz, 1H), 2.90 (dd, J ¼ 22.4, 9.9 Hz, 1H), 2.09 (dt, J ¼ 17.3,
(
2
.9 Hz, 1H). 1 C NMR (100 MHz, CDCl
3
7
3
) d 171.4, 150.3, 147.4, 143.4,
2
2
¼ þ26.3 (MeOH, c ¼ 0.9). 1H NMR
1
1
(
38.6, 137.8, 129.2 (2C), 129.0 (2C), 128.7 (2C), 128.6 (3C), 127.9 (2C),
(EtOAc/Methanol 20:1). ½ ꢂ
a
D
27.4 (2C), 59.1, 57.6, 53.4, 52.9, 33.5. MS (ESI) m/z (%): 568.03 [100,
(400 MHz, DMSO)
d
8.33 (d, J ¼ 8.6 Hz, 1H), 8.01 (d, J ¼ 8.5 Hz, 2H),
þ
M þ Na) ].
7.93e7.57 (m, 7H), 7.51e7.37 (m, 4H), 4.09e4.07 (m, 1H), 3.76e3.70
(
13
m, 2H), 3.07e3.04 (m, 1H), 1.94e1.74 (m, 2H). C NMR (50 MHz,
0
4
.1.11. Synthesis of (2R,4S)-methyl 4-([1,1 -biphenyl]-4-
DMSO) 163.8, 150.0, 144.5, 142.1, 140.1, 139.7, 138.8, 129.6 (2C),
d
ylsulfonamido)-1-((4-(trifluoromethoxy)phenyl)sulfonyl)
pyrrolidine-2-carboxylate (11)
According to the general procedure (A), compound 11 was ob-
tained as a brown oil in 68% yield (376 mg) from compound 8
129.4 (2C), 128.3, 127.5 (2C), 127.3 (2C), 126.6 (2C), 124.6 (2C), 62.3,
52.9, 52.0, 36.8, 29.5. MS (ESI) m/z (%): 544.09 [(M ꢁ H) , 100].
-
0
4.1.15. Synthesis of (2R,4S)-4-([1,1 -biphenyl]-4-ylsulfonamido)-N-
(
3
440 mg, 0.95 mmol), DMAP (115 mg, 0.95 mmol), TEA (528
.80 mmol), p-trifluoromethoxybenzenesulfonyl chloride (371 mg,
m
L,
hydroxy-1-((4 (trifluoromethoxy)phenyl) sulfonyl)-pyrrolidine-2-
carboxamide (15)
1
.43 mmol), after flash chromatography on silica gel (Petr. Et./EtOAc
According to the general procedure (B), compound 15 was ob-
tained as a brown oil in 45% yield (47 mg) from compound 11
22
1
3
:2). ½aꢂ
¼ ꢁ22.5 (CHCl
3
, c ¼ 1.1). H NMR (400 MHz, CDCl
3
) d 8.08
D
(
(
2
109 mg, 0.19 mmol), NH OH*HCl (114 mg, 1.52 mmol) and KOH
(
7
7
1
d, J ¼ 8.3 Hz, 1H), 8.01 (d, J ¼ 8.5 Hz, 1H), 7.88 (d, J ¼ 8.8 Hz, 2H),
128 mg, 2.28 mmol), after flash chromatography on silica gel
.79 (dd, J ¼ 16.4, 8.5 Hz, 3H), 7.66e7.57 (m, 3H), 7.57e7.40 (m, 3H),
2
2
1
.33 (s, 1H), 5.03 (dd, J ¼ 18.0, 8.4 Hz, 1H), 4.39 (dd, J ¼ 10.0, 1.8 Hz,
(EtOAc). ½
aꢂ
¼ þ23.6 (MeOH, c ¼ 1.3). H NMR (400 MHz, DMSO)
D
H), 3.77 (dd, J ¼ 10.0, 3.5 Hz, 1H), 3.72 (s, 3H), 3.59 (t, J ¼ 8.6 Hz,
H), 2.85 (dd, J ¼ 22.2, 10.0, 1H), 2.05 (ddd, J ¼ 12.1, 7.6, 1.8 Hz, 1H);
d 7.92e7.43 (m, 14H), 4.12e4.06 (m, 1H), 3.72e3.70 (m, 1H),
13
1
3.04e3.02 (m, 2H), 1.98e1.67 (m, 2H). C NMR (100 MHz, DMSO)
163.4, 151.5, 145.4, 144.5, 142.1, 139.6, 138.8, 129.6 (2C), 129.4 (2C),
1
3
C NMR (50 MHz, CDCl
3
)
d
171.6, 147.3, 138.7, 137.9, 135.9 (2C),
d
1
29.7, 129.2 (2C), 129.0 (2C), 128.7 (2C), 128.6 (2C), 127.8 (2C), 127.4
127.9 (2C), 127.5 (2C), 127.2, 126.5 (2C), 121.6 (2C), 61.2, 52.8, 51.9,
36.5. MS (ESI) m/z (%): 584.09 [100, (M ꢁ H) ].
-
(
2C), 120.9, 58.8, 57.6, 52.7, 49.2, 33.5. MS (ESI) m/z (%): 585.10 [100,
þ
(
M þ H) ].
0
4
.1.16. Synthesis of (2R,4S)-4-([1,1 -biphenyl]-4-ylsulfonamido)-1-
0
0
4.1.12. Synthesis of (2R,4S)-methyl 4-([1,1 -biphenyl]-4-
([1,1 -biphenyl]-4-ylsulfonyl)-N-hydroxypyrrolidine-2-carboxamide
(16)
0
ylsulfonamido)-1-([1,1 -biphenyl]-4-ylsulfonyl)pyrrolidine-2-
carboxylate (12)
According to the general procedure (A), compound 12 was ob-
tained as a brown oil in 58% yield (344 mg) from compound 8
According to the general procedure (B), compound 16 was ob-
tained as a brown oil in 42% yield (22 mg) from compound 12
(50 mg, 0.09 mmol), NH OH*HCl (51 mg, 0.69 mmol), KOH (58 mg,
2
(
4
1
477 mg, 1.03 mmol), DMAP (125 mg, 1.03 mmol), TEA (575
.17 mmol), p-phenyl-benzenesulfonyl chloride (389 mg,
.55 mmol), after flash chromatography on silica gel (Petr. Et./EtOAc
m
L,
1.04 mmol), after flash chromatography on silica gel (EtOAc).
2
2
1
½
a
ꢂ
¼ þ14.8 (MeOH, c ¼ 1.1). H NMR (400 MHz, DMSO)
d 8.10 (br
D
s, 1H), 7.88e7.78 (m, 7H), 7.73e7.71 (m, 4H), 7.50e7.42 (m, 7H),
4.07-4-00 (m, 1H), 3.85e3.78 (m, 1H), 2.99e2.90 (m, 2H), 1.76e1.69
2
2
, c ¼ 0.9). 1H NMR (400 MHz, CDCl
4
d
:1). ½
aꢂ
¼ ꢁ18.9 (CHCl
3
3
)
D
13
8.04e7.98 (m, 2H), 7.89 (d, J ¼ 8.4 Hz, 2H), 7.78e7.68 (m, 4H),
(m, 2H). C NMR (100 MHz, DMSO) d 167.6, 144.9, 144.5, 139.7,
8