6600
K. Hayamizu et al. / Tetrahedron 71 (2015) 6594e6601
4.6.1. 1-Fluoro-2-oxo-N-(tert-butyl)cyclopentanecarboxamide
1.84 (d, JHeF¼23.3 Hz, 3H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3):
(8c). White solid; 72%, 90% ee; [
a
]
22 þ96.4 (c 0.90, CHCl3) >99% ee;
d
192.9 (d, JCeF¼23.9 Hz), 167.5 (d, JCeF¼20.1 Hz), 134.1, 133.6, 129.6
D
1H NMR (400 MHz, CDCl3):
d
6.21 (br s, 1H), 2.71e2.61 (m, 1H),
(d, JCeF¼3.8 Hz, 2C), 128.6 (2C), 99.0 (d, JCeF¼194.7 Hz), 52.0, 28.7
2.52e2.37 (m, 2H), 2.26e2.02 (m, 3H), 1.37 (s, 9H); 13C NMR
(100 MHz, CDCl3):
210.0 (d, JCeF¼16.2 Hz), 166.9 (d, JCeF¼21.0 Hz),
(3C), 21.8 (d, JCeF¼22.9 Hz); 19F NMR (376 MHz, CDCl3):
ꢁ148.3 (q,
d
d
J¼23.3 Hz); HRMS (ESI) calcd for C14H18FNO2 [MþNa]þ 274.1214;
found 274.1214. HPLC (DAICEL CHIRALPAK AD-H, n-hexane/
IPA¼99:1, 0.8 mL/min, 254 nm) tR (major)¼15.7 min, tR (minor)¼
18.7 min.
96.4 (d, JCeF¼201.4 Hz), 51.9, 36.1, 33.3 (d, JCeF¼20.0 Hz), 28.7 (3C),
18.4 (d, JCeF¼3.8 Hz); 19F NMR (376 MHz, CDCl3):
d
ꢁ158.5 (dd,
J¼22.9, 22.9 Hz); HRMS (ESI) calcd for C10H16FNO2 [MþNa]þ
224.1057; found 224.1058; HPLC (DAICEL CHIRALPAK AD-H, n-
hexane/IPA¼99:1, 0.8 mL/min, 254 nm) tR (major)¼12.5 min, tR
(minor)¼16.3 min.
4.6.7. 2-Fluoro-2-methyl-3-oxo-3-phenyl-N-phenylpropanamide
25
(10d). White solid; >99%, 56% ee; [
a
]
ꢁ45.0 (c 0.50, CHCl3) 56%
D
ee; 1H NMR (400 MHz, CDCl3):
d
8.20 (br s, 1H), 8.04 (d, J¼8.4 Hz,
4.6.2. 1-Fluoro-2-oxo-N-phenylcyclopentanecarboxamide
2H), 7.58 (d, J¼8.0 Hz, 2H), 7.58 (t, J¼7.8 Hz, 1H), 7.45 (dd, J¼8.4,
7.8 Hz, 2H), 7.36 (dd, J¼8.0, 7.6 Hz, 2H), 7.18 (t, J¼7.6 Hz, 1H), 1.99 (d,
(8d). White solid; 86%, 66% ee; [
a
]
25 þ53.1 (c 0.43, CHCl3) 66% ee;
D
1H NMR (400 MHz, CDCl3):
d
8.07 (br s, 1H), 7.54 (d, J¼8.8 Hz, 2H),
JHeF¼25.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 192.7 (d,
7.34 (dd, J¼8.8, 7.2 Hz, 2H), 7.16 (t, J¼7.2 Hz, 1H), 2.85e2.74 (m, 1H),
JCeF¼23.9 Hz), 166.5 (d, JCeF¼21.0 Hz), 136.6, 134.0, 133.8 (d,
JCeF¼2.9 Hz), 129.7 (d, JCeF¼3.9 Hz, 2C),129.4 (2C),128.8 (2C), 125.4,
120.2 (2C), 99.4 (d, JCeF¼195.7 Hz), 22.2 (d, JCeF¼22.9 Hz); 19F NMR
2.63e2.45 (m, 2H), 2.37e2.23 (m, 2H), 2.19e2.07 (m, 1H); 13C NMR
(100 MHz, CDCl3):
d
209.0 (d, JCeF¼16.1 Hz), 165.6 (d, JCeF¼21.9 Hz),
136.5, 129.2 (2C), 125.4, 120.2 (2C), 96.8 (d, JCeF¼201.4 Hz), 36.1,
(376 MHz, CDCl3):
d
ꢁ149.5 (q, J¼25.0 Hz); HRMS (ESI) calcd for
33.4 (d, JCeF¼20.0 Hz), 18.4 (d, JCeF¼3.8 Hz); 19F NMR (376 MHz,
C
16H14FNO2 [MþNa]þ 294.0901; found 294.0904. HPLC (DAICEL
CDCl3):
C
d
ꢁ159.5 (dd, J¼22.9, 22.9 Hz); HRMS (ESI) calcd for
CHIRALPAK AD-H, n-hexane/IPA¼95:5, 1.0 mL/min, 254 nm) tR
12H12FNO2 [MþNa]þ 244.0744; found 244.0745; HPLC (DAICEL
(minor)¼20.0 min, tR (major)¼23.8 min.
CHIRALPAK AD-H, n-hexane/IPA¼95:5, 1.0 mL/min, 254 nm) tR
(major)¼12.6 min, tR (minor)¼16.9 min.
4.7. Determination of absolute configurations of Michael ad-
duct 7c and fluorinated b-ketoamide (8c)
4.6.3. 1-Fluoro-2-oxo-N-methyl-N-phenylcyclopentanecarboxamide
(8e). Colorless oil; 81%, 59% ee; [
a
]
25 þ43.4 (c 0.43, CHCl3) 59% ee;
4.7.1. (R)-N-(tert-Butyl)-2-oxo-1-(3-oxyobuthyl)cyclo-
pentanecarboxamide ((R)-7c) from (R)-7b. (R)-7b (11.2 mg,
0.0440 mmol, 90% ee) was dissolved in TFA (0.2 mL), and the so-
lution was stirred at ambient temperature for 20 min. The solvent
was evaporated under reduced pressure to give the carboxylic acid,
which was used directly in the synthesis of the tert-butyl amide. To
the solution of carboxylic acid in DMF (0.1 mL) were added HATU
D
1H NMR (400 MHz, CDCl3):
d
7.39 (dd, J¼7.6, 7.2 Hz, 2H), 7.33 (t,
J¼7.2 Hz, 1H), 7.25 (d, J¼7.6 Hz, 2H), 3.30 (br s, 3H), 2.76e2.55 (m,
1H), 2.54e2.30 (m, 2H), 2.23e2.04 (m, 2H), 2.03e1.88 (m, 1H); 13
NMR (75 MHz, DMSO-d6):
C
d
209.4 (d, JCeF¼17.3 Hz), 167.3 (d,
JCeF¼21.6 Hz), 142.6, 129.1 (2C), 127.6, 126.7 (2C), 96.9 (d,
JCeF¼206.6 Hz), 38.8, 35.6, 34.7, 17.6; 19F NMR (376 MHz, CDCl3):
d
ꢁ153.9 (br s); HRMS (ESI) calcd for C13H14FNO2 [MþNa]þ
(33.2 mg, 0.0873 mmol), DIPEA (38
mL, 0.221 mmol), and tert-butyl
258.0901 found 258.0901; HPLC (DAICEL CHIRALPAK AD-H, n-
hexane/IPA¼95:5, 1.0 mL/min, 254 nm) tR (major)¼13.1 min, tR
(minor)¼14.4 min.
amine (9.5 L, 0.088 mmol). The solution was stirred under a N2
m
atmosphere at ambient temperature for 1.5 h, and then the reaction
mixture was purified by flash column chromatography on silica gel
(n-hexane/AcOEt¼1:1) to give the desired product (R)-7c (8.8 mg,
25
4.6.4. N-(tert-Butyl)-3-fluoro-2-oxotetrahydro-3-furancarboxamide
0.0347 mmol, 78%, two steps). [
a
]
þ20.9 (c 0.44, CHCl3); HPLC
D
24
(8f). White solid; 96%, 79% ee; [
1H NMR (400 MHz, CDCl3):
3.03e2.94 (m, 1H), 2.64e2.51 (m, 1H), 1.42 (s, 9H); 13C NMR
(100 MHz, CDCl3):
170.2 (d, JCeF¼23.8 Hz), 165.0 (d, JCeF¼21.0 Hz),
a
]
ꢁ8.02 (c 0.38, CHCl3) 79% ee;
(DAICEL CHIRALPAK AD-H, n-hexane/EtOH¼97:3, 0.5 mL/min,
254 nm) tR¼23.7 min. The spectra of 1H NMR, 13C NMR, and HRMS
were consistent with compound 7c.
D
d
6.32 (br s, 1H), 4.59e4.48 (m, 2H),
d
92.7 (d, JCeF¼206.2 Hz), 66.4 (d, JCeF¼4.8 Hz), 52.4, 32.8 (d,
4.7.2. (R)-N-(tert-Butyl)-1-fluoro-2-oxocyclopentanecarboxylate
(8b). To a solution of 5b (101 mg, 0.547 mmol) in IPA (0.55 mL)
were added (R)-DTBM-SEGPHOS Pd m-hydroxo complex 2c
(39.6 mg, 0.0137 mol) and NFSI (260 mg, 0.821 mmol). The solution
was stirred under a N2 atmosphere at ambient temperature for
27 h, and then the reaction mixture was purified by flash column
JCeF¼20.0 Hz), 28.6 (3C); 19F NMR (376 MHz, CDCl3):
ꢁ159.6 (ddd,
d
J¼26.3, 10.4, 4.7 Hz); HRMS (ESI) calcd for C9H14FNO3 [MþNa]þ
226.0850; found 226.0853. HPLC (DAICEL CHIRALPAK AD-H, n-
hexane/IPA¼95:5, 1.0 mL/min, 254 nm) tR (major)¼9.22 min, tR
(minor)¼11.4 min.
chromatography on silica gel (CH2Cl2) to give the desired product
25
4.6.5. N-(tert-Butyl)-3-fluoro-1-methyl-2-oxo-3-pyrrolidine carbox-
(R)-8b (103 mg, 0.509 mmol, 93%). [
a
]
þ81.4 (c 1.04, CHCl3) 90%
D
25
amide (8g). White solid; 66%, 83% ee; [
83% ee; 1H NMR (400 MHz, CDCl3):
1H), 3.44e3.39 (m, 1H), 2.94 (s, 3H), 2.86e2.77 (m, 1H), 2.33e2.19
(m, 1H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3):
167.5 (d,
a
]
D
þ17.2 (c 0.26, CHCl3)
ee; HPLC (DAICEL CHIRALPAK AD-H, n-hexane/IPA¼99:1, 0.4 mL/
min, 280 nm) tR (minor)¼21.8 min, tR (major)¼27.6 min. The
spectra of 1H NMR were consistent with the literature.3b
d
6.39 (br s, 1H), 3.57e3.50 (m,
d
JCeF¼23.8 Hz), 166.9 (d, JCeF¼22.0 Hz), 95.7 (d, JCeF¼199.5 Hz), 52.0,
4.7.3. (R)-N-(tert-Butyl)-1-fluoro-2-oxocyclopentanecarboxamide
((R)-8c) from (R)-8b. (R)-8b (28.2 mg, 0.139 mmol, 90% ee) was
dissolved in TFA (0.3 mL), and the solution was stirred at ambient
temperature for 40 min. The solvent was evaporated under reduced
pressure to give the carboxylic acid, which was used directly in the
synthesis of the tert-butyl amide. To the solution of carboxylic acid
in DMF (0.1 mL) were added HATU (82.0 mg, 0.216 mmol), DIPEA
46.3 (d, JCeF¼3.8 Hz), 30.6, 29.4 (d, JCeF¼21.0 Hz), 28.7 (3C); 19F
NMR (376 MHz, CDCl3):
d
ꢁ155.7 to ꢁ155.8 (m); HRMS (ESI) calcd
for C10H17FN2O2 [MþNa]þ 239.1166; found 239.1194. HPLC (DAICEL
CHIRALPAK AD-H, n-hexane/IPA¼95:5, 1.0 mL/min, 254 nm) tR
(major)¼9.45 min, tR (minor)¼14.4 min.
4 . 6 . 6 . N - ( t e r t - B u t y l ) - 2 - fl u o r o - 2 - m e t h y l - 3 - o x o - 3 -
(95.6 mL, 0.558 mmol), and tert-butyl amine (30.2 mL, 0.279 mmol).
24
phenylpropanamide (10c). White solid; 95%, 65% ee; [
0.80, CHCl3) 65% ee; 1H NMR (400 MHz, CDCl3):
2H), 7.56 (t, J¼7.6 Hz,1H), 7.44 (dd, J¼8.4, 7.6 Hz, 2H), 6.28 (br s, 1H),
a
]
þ77.5 (c
The solution was stirred under a N2 atmosphere at ambient tem-
perature for 21 h, and then the reaction mixture was purified by
flash column chromatography on silica gel (CH2Cl2) to give the
D
d
7.99 (d, J¼8.4 Hz,