Journal of Medicinal Chemistry
Page 10 of 18
60/40 EtOAc/hexanes gradient (Rf = 0.3). Tan oil, 924 mg,
= 0.4). Colorless oil, 67 mg, 0.23 mmol, 26% yield. 1H NMR
3.13 mmol, 54% yield. 1H NMR (400 MHz, chloroform-d) δ
7.83 – 7.75 (m, 3H), 7.58 – 7.51 (m, 1H), 7.49 – 7.43 (m, 2H),
5.65 (d, J = 9.5 Hz, 1H), 5.15 (ddd, J = 51.3, 5.1, 1.5 Hz, 1H),
4.52 – 4.41 (m, 1H), 4.32 (qd, J = 7.1, 2.4 Hz, 2H), 3.01 – 2.83
(m, 2H), 2.50 (dd, J = 24.0, 15.9 Hz, 1H), 2.27 (d, J = 15.4
Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz,
chloroform-d) δ 174.5, 166.6, 133.9, 132.3, 128.9, 127.1, 99.7
(d, J = 181.3 Hz), 77.0, 65.2, 63.0, 44.5, 40.87 (d, J = 21.9
(600 MHz, chloroform-d) δ 7.78 – 7.71 (m, 2H), 7.53 (t, J =
7.2 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.33 (s, 1H), 5.65 – 5.37
(m, 2H), 4.32 (q, J = 7.1 Hz, 2H), 2.88 – 2.71 (m, 2H), 2.58
1
2
3
4
5
6
7
8
(ddd, J = 18.8, 14.7, 5.5 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). 13
C
NMR (150 MHz, chloroform-d) δ 173.6, 167.3, 133.7, 132.3,
128.9, 127.0, 92.2 (dd, J = 188.7, 15.1 Hz), 63.1, 61.7 (t, J =
4.8 Hz), 40.3
– 40.1 (four-line multiplet, magnetic
inequivalence), 14.1. 19F NMR (376 MHz, chloroform-d,
fluorobenzene reference standard) δ -198.5 – -198.9 (m). IR
(neat, cm-1): 3312, 1739, 1632. HRMS (ESI) Calcd. for
C15H18O3NF2 (M+H)+: 298.12493. Found 298.12509.
Hz), 14.08.
19F NMR (376 MHz, chloroform-d,
9
trifluoroacetic acid reference standard) δ -179.6 (dddd, J =
51.0, 34.7, 23.8, 11.0 Hz). IR (neat, cm-1): 3354, 1728, 1636.
HRMS (ESI) Calcd. for C15H19O4NF (M+H)+: 296.12926.
Found: 296.12940.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1s,3R,4S)-1-Amino-3,4-difluorocyclopentane-1-
carboxylic acid hydrochloride (9). To a scintillation vial
open to air containing a stir bar and ethyl (1s,3R,4S)-1-
Racemic
ethyl-1-benzamido-3-fluoro-4-
(((trifluoromethyl)sulfonyl)oxy)cyclopentane-1-
carboxylate (7). A scintillation vial under N2 containing a stir
benzamido-3,4-difluorocyclopentane-1-carboxylate
(8)
(33 mg, 0.111 mmol), concentrated aqueous HCl (1 mL) was
added. The vial was sealed with a plastic cap and allowed to
stir at 90 °C for 10 hours. Upon cooling to room temperature,
colorless crystals formed spontaneously. These crystals were
collected by filtration, washed with diethyl ether, and freed of
residual solvent in vacuo. Colorless crystals, 20.1 mg, 0.100
bar
and
racemic
ethyl-1-benzamido-3-fluoro-4-
hydroxycyclopentane-1-carboxylate (6) (400 mg, 1.35
mmol, 1 equiv) and pyridine (240 µL, 2.97 mmol, 2.2 equiv)
in DCM (5 mL) was cooled to 0 °C. A separate vial containing
trifluoromethanesulfonic anhydride (385 µL, 2.70 mmol, 2.0
equiv) in DCM (1.5 mL) was cooled to 0 °C, and this mixture
was added dropwise to the fluorohydrin solution with
vigorous stirring. The mixture was stirred at 0 °C for 15
minutes, then diluted with hexanes (10 mL). A white powder
precipitated and was filtered away, and the supernatant was
concentrated at 0 °C. The crude residue was purified with a
silica plug, eluting the desired compound with a 30/70
EtOAc/hexanes gradient (Rf = 0.3). Colorless oil, 481 mg,
1.13 mmol, 83% yield. Note, these compounds are thermally
unstable. They should be isolated from the reaction mixture as
quickly as possible and used immediately, or stored as a
solution in benzene at < 0 °C. 1H NMR (400 MHz,
chloroform-d) δ 7.78 – 7.74 (m, 2H), 7.57 – 7.51 (m, 1H), 7.48
– 7.43 (m, 2H), 5.62 (ddd, J = 8.4, 6.3, 5.2 Hz, 1H), 5.50 (dtd,
J = 15.7, 7.8, 5.3 Hz, 1H), 4.34 (qd, J = 7.1, 4.7 Hz, 2H), 2.90
– 2.78 (m, 3H), 2.51 (ddd, J = 23.3, 15.0, 6.5 Hz, 1H), 1.34 (t,
J = 7.1 Hz, 3H). 13C NMR (100 MHz, chloroform-d) δ 172.8,
166.9, 133.5, 132.4, 129.0, 118.6 (q, J = 320 Hz), 94.1 (d, J =
188 Hz), 89.8 (d, J = 25 Hz), 63.3, 61.9 (d, J = 5.0 Hz), 39.5
(d, J = 22 Hz), 38.2 (d, J = 3.4 Hz), 14.1. 19F NMR (376 MHz,
chloroform-d, fluorobenzene reference standard) δ -74.5 (s,
3F), -184.7 (ddd, J = 53.6, 23.7, 12.4 Hz, 1F). IR (neat, cm-1):
3301, 1737, 1636. HRMS (ESI) Calcd. for C16H18O6NF4S
(M+H)+: 428.07855. Found: 428.07894.
1
mmol, 90% yield. H NMR (400 MHz, Deuterium Oxide) δ
5.40 – 5.17 (m, 2H), 2.81 (ddt, J = 18.4, 15.9, 5.1 Hz, 1H),
2.40 (ddd, J = 18.5, 14.2, 5.4 Hz, 2H). 13C NMR (125 MHz,
deuterium oxide) δ 173.3, 91.3 (dd, J = 186.9, 15.6 Hz), 60.3
(t, J = 4.2 Hz), 37.7 – 37.4 (four-line multiplet, magnetic
inequivalence). 19F NMR (376 MHz, deuterium oxide,
trifluoroacetic acid reference standard) δ -201.3 – -201.6 (m).
IR (neat, cm-1): 3196, 3067, 1712. HRMS (ESI) Calcd. for
C6H9O2NClF2 (M-H)-: 200.02954. Found 200.03002. Melting
point: 242-244 °C (decomposes).
Racemic 1-amino-3-fluoro-4-
hydroxycyclopentane-1-carboxylic acid hydrochloride
(10). To a mixture of racemic ethyl-1-benzamido-3-fluoro-
4-hydroxycyclopentane-1-carboxylate (3.06) (800 mg,
2.71 mmol) in a scintillation vial with a magnetic stir bar and
open to air, concentrated aqueous HCl was added (3.0 mL).
The vial was sealed with a plastic cap and heated to 90 °C
overnight. The reaction was removed from heat,
concentrated in vacuo and washed with ether. A white solid
(519 mg) was obtained that was carried forward without
further purification. 1H NMR (600 MHz, deuterium oxide) δ
5.12 (d, J = 49.8 Hz, 1H), 4.59 – 4.45 (m, 1H), 2.77 – 2.46
(m, 3H), 2.12 (d, J = 14.8 Hz, 1H). 13C NMR (125 MHz,
deuterium oxide) δ 173.7, 97.1 (d, J = 179.9 Hz), 74.8 (d, J =
26.7 Hz), 63.3, 40.5 (d, J = 23.5), 40.5.
Ethyl
(1s,3R,4S)-1-benzamido-3,4-
difluorocyclopentane-1-carboxylate (8). To a scintillation
vial under N2 containing a stir bar and a mixture of racemic
ethyl-1-benzamido-3-fluoro-4-
Racemic ethyl (1S,3R,4R)-1-amino-3-fluoro-4-
hydroxycyclopentane-1-carboxylate (11).
To a round-bottomed flask under N2 fitted with a reflux
condenser and stir bar and containing a crude mixture of
(((trifluoromethyl)sulfonyl)oxy)cyclopentane-1-
carboxylate (7) (370 mg, 1.09 mmol, 1 equiv) in THF (10
mL, 0.1 M), triethylamine trihydrofluoride (0.60 mL, 10.9
mmol, 10.0 equiv) was added at once and the reaction was
stirred overnight at room temperature. The reaction was
diluted with DCM (20 mL) and washed with two portions of
saturated aqueous sodium bicarbonate (10 mL), then brine (10
mL). The organic phase was dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The crude residue was
purified by silica gel flash chromatography, eluting the
desired compound with a 20/80 EtOAc/hexanes gradient (Rf
racemic
1-amino-3-fluoro-4-hydroxycyclopentane-1-
carboxylic acid hydrochloride (10) (519 mg) in dry ethanol,
H2SO4 (0.1 mL) was added, and the reaction was heated to
reflux for 10 hours. Ethanol was removed in vacuo and the
crude residue was taken up in water (10 mL) and washed with
three portions of DCM (10 mL). The organic layers were
discarded, and the aqueous phase was treated with 30 mL of
saturated aqueous sodium bicarbonate, then extracted with
three portions of DCM (30 mL). The organics were collected,
dried over anhydrous Na2SO4, filtered, and concentrated in
9
ACS Paragon Plus Environment