T. Liu et al.
JournalofFluorineChemistry207(2018)18–23
(m,1H), 1.47 and 1.42 (total 9H, s, each amide isomers); 13C NMR
1.42–1.41 (m, 7H), 1.38–1.36 (m, 11H), 1.30–1.20 (m, 5H), 1.21–1.14
(m, 3H), 1.12–1.09 (m, 3H); 13C NMR (100 MHz, (CD3)2SO): δ 206.8,
206.5, 206.2, 170.6, 170.0, 169.9, 169.6, 169.6, 131.6, 131.5, 131.5,
(100 MHz, CDCl3):
δ
173.1, 172.9, 154.1, 153.5, 91.8 (d,
1JCF = 178.6 Hz), 91.0 (d, JCF = 178.6 Hz), 80.5, 77.4, 77.1, 76.8,
1
2
2
1
1
57.6, 57.3, 53.2 (d, JCF = 23.0 Hz), 52.9 (d, JCF = 23.3 Hz), 52.3,
52.1, 37.5 (d, JCF = 22.8 Hz), 36.6 (d, JCF = 22.8 Hz), 28.3, 28.2.
{NMR data are consistent with those reported [30]}.
125.0, 124.9, 93.1 (d, JCF = 174.7 Hz), 91.8 (d, JCF = 174.7 Hz),
2
2
2
82.1, 82.0, 81.1, 80.9, 58.8, 58.1, 58.0, 54.2 (d, JCF = 23.4 Hz), 54.0
2
2
(d, JCF = 23.2 Hz), 51.3, 51.2, 36.1 (d, JCF = 21.3 Hz), 32.3, 32.3,
32.1, 28.9, 28.8, 28.8, 28.0, 28.0, 27.9, 23.2, 23.0, 22.9, 22.8, 18.2,
4.3. tert-butyl (2S,4S)-4-fluoropyrrolidine-2-carboxylate (10a)
13.8, 13.2, 13.0, 12.6; 19F NMR (376 MHz, (CD3)2SO):
δ
(−171.0)–(−171.4) (m, 1F); 19F {1H} NMR (376 MHz, (CD3)2SO): δ
−171.20 (s, 1F), −171.26 (s, 1F), −171.54 (s, 1F), −171.92 (s, 1F);
HRMS (ESI): m/z calcd for C20H32NFO4Na+ [M+Na]+ 392.2208,
found 392.2206.
Compound 15a (1.89 g, 7.64 mmol) was dissolved in 10 mL of 2N
HCl. The resulting solution was heated under reflux for 2–4 h. After the
reaction was complete (as monitored by TLC), the solution was deco-
lorized with charcoal while still hot, and filtered through a pad of celite.
Water was removed by rotary evaporation and further dried with
azeotropic distillation with dry toluene under reduced pressure.
Recrystallization (1:1 ethyl acetate/petroleum ether) afforded the hy-
drochloride salt of 11a (1.1 g, 85%) as a white solid. To a suspension of
4.6. (2R,4R)-tert-butyl 4-fluoro-1-((E)-2-methyl-3-oxodec-8-enoyl)
pyrrolidine-2-carboxylate (5)
To a solution of acid 24 [6] (438 mg, 2.2 mmol) in dry DMF (30 mL)
was added HATU (912 mg, 2.4 mmol). After stirring for 10 min, 10b
(416 mg, 2.2 mmol) was added and the mixture was stirred at room
temperature for 20 min. To this mixture was added DIPEA (0.99 mL,
6.6 mmol), and stirred for 24 h. The solution was washed with brine
and distilled water, extracted with ethyl acetate. The combined organic
extracts were dried over magnesium sulphate and evaporated in vacuo
t
compound 11a (0.945 g, 5.57 mmol) and BuOAc (0.5 mL) was added
HClO4 (70%, 0.17 mL, 0.35 equiv) and the solution was stirred for 24 h
at room temperature. It was poured into a saturated aqueous NaHCO3
solution (25 mL). The organic phase was separated and the aqueous
phase was extracted with CH2Cl2 (2 × 20 mL). The combined organic
phases were dried over MgSO4, filtered and the solvent was evaporated
under reduced pressure to afford the title compound 10a (885 mg,
88%). colourless oil; [α]D25 8.9 (c = 0.45, CHCl3); IR (cm−1): 525, 660,
898, 1095, 1238, 1662, 1739, 2854, 3074, 3195; 1H NMR (400 MHz,
CD3OD): δ 5.22 (dm, JHF = 52.9 Hz, 1H), 4.26–4.23 (m, 1H), 3.53 (ddd,
J = 20.3 Hz, 13.6 Hz, 2.0 Hz, 1H), 3.29 (ddd, J = 36.1 Hz, 13.6 Hz,
3.6 Hz, 1H), 2.57–2.35 (m, 2H), 1.42 (s, 9H); 13C NMR (100 MHz,
25
to give a 1.7:1 diastereomers (270 mg, 37%) as a colourless oil. [α]D
−44.4 (c = 0.34, CHCl3); IR (cm−1): 771, 846, 964, 1081, 1189, 1209,
1367, 1457, 1653, 2340, 2853, 2923; 1H NMR (400 MHz, CD3OD): δ
5.45–5.41 (m, 2.9H), 5.38 (dm, JHF = 55.1 Hz, 1.5H), 4.46–4.39 (m,
1H), 4.15–4.01 (m, 2H), 3.93–3.88 (m, 1H), 3.86–3.82 (m, 1H),
3.81–3.76 (m, 1H), 2.70–2.60 (m, 2H), 2.58–2.48 (m, 2H), 2.24–2.16
(m, 1H), 2.14–2.05 (m, 1H), 2.14–2.05 (m, 1H), 2.04–1.94 (m, 3H),
1.65–1.63 (m, 4H), 1.61–1.54 (m, 3H), 1.53–1.52 (m, 2H), 1.50–1.48
(m, 11H), 1.39–1.34 (m, 3H), 1.31 (d, J = 6.9 Hz, 3H), 1.28 (d,
J = 6.9 Hz, 3H); 13C NMR (100 MHz, CD3OD): δ 206.5, 205.9, 170.8,
170.8, 170.7, 170.5, 130.9, 130.8, 130.7, 124.6, 124.5, 92.0 (d,
1
CD3OD): δ 169.8, 92.2 (d, JCF = 179.4 Hz), 84.5, 59.4, 53.5 (d,
2
2JCF = 23.4 Hz), 36.9 (d, JCF = 20.9 Hz), 28.0, 27.9, 27.8; 19F NMR
(376 MHz, CDCl3): δ (−173.7) − (−174.1) (m, 1F); 19F {1H} NMR
(376 MHz, CDCl3): δ −173.9 (s, 1F); HRMS (ESI): m/z calcd for
C9H17FNO2 +[M+H]+ 190.1238, found 190.1236.
1
1JCF = 178.1 Hz), 92.0 (d, JCF = 178.1 Hz), 81.7, 81.7, 58.6, 58.6,
2
2
4.4. tert-butyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate (10b)
54.0 (d, JCF = 22.5 Hz), 53.8 (d, JCF = 22.6 Hz), 51.8, 51.6, 40.0,
2
39.9, 35.4 (d, JCF = 22.4 Hz), 31.9, 31.9, 28.7, 28.6, 26.8, 26.8, 26.8,
Compound 10b was synthesized according to the procedure for 10a
(1.6 g, 78%). colourless oil; [α]D253.8 (c = 0.175, CHCl3); IR (cm−1):
668, 968, 1076, 1262, 1668, 1733, 728, 3195; 1H NMR (400 MHz,
CDCl3): δ 5.24 (dm, JHF = 54.1 Hz, 1H), 3.97 (t, J = 8.1 Hz, 1H),
3.33–3.16 (m, 2H), 2.50–2.38 (m, 1H), 2.05–2.01 (m, 2H), 1.47 (s, 9H);
22.7, 22.6, 16.7, 11.7, 11.4; 19F NMR (376 MHz, CD3OD):
δ
(−178.8)–(−179.5) (m, 1F) 19F {1H} NMR (376 MHz, CD3OD): δ
−179.1 (s, 1F), −179.1 (s, 1F), −179.3 (s, 1F), −179.4 (s, 1F); HRMS
(ESI): m/z calcd for C20H32NFO4Na+, [M+Na]+ 392.2208, found
392.2207.
1
13C NMR (100 MHz, CDCl3): δ 172.9, 94.1 (d, JCF = 179.4 Hz), 81.9,
58.7, 52.9 (d, 2JCF = 23.3 Hz), 37.7 (d, 2JCF = 22.5 Hz), 28.0; 19F NMR
(376 MHz, CDCl3): δ (−175.4) – (−175.7) (m, 1F); 19F {1H} NMR
(376 MHz, CDCl3): δ −175.4 (s, 1F); HRMS (ESI): m/z calcd for
C9H17FNO2+[M+H]+ 190.1238, found 190.1236.
4.7. tert-butyl (1R,2S,6S,7aR)-6-fluoro-1-((E)-hept-5-en-1-yl)-1-hydroxy-
2-methyl-3-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (7)
To a solution of 4 (257 mg, 0.69 mmol) in EtOH (3 mL) was added
NaOEt (234 mg, 3.5 mmol), and the mixture was stirred for 9 h at room
temperature. The reaction was quenched by the addition of a saturated
NH4Cl aqueous solution and extracted twice with EtOAc. The combined
organic layers were dried over MgSO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (hexane/
EtOAc, 2:1) to afford 7 (163 mg, 65%) as a white crystalline solid; m.p.:
142–143 °C; [α]D25 −48.9 (c = 0.5, CH3OH); IR (cm−1): 668, 759, 843,
964, 1016, 1153, 1284, 1368, 1430, 1669, 2361, 2854, 2931; 1H NMR
(400 MHz, CD3OD): δ 5.47–5.45 (m, 2H), 5.42 (dm, JHF = 52,8 Hz, 1H),
3.68 (ddd, J = 34.7 Hz, 13.6 Hz, 4.4 Hz, 1H), 3.33 (qd, J = 3.4 Hz,
2.2 Hz, 1.6 Hz, 1H), 3.31–3.24 (m, 1H), 2.91 (q, J = 7.1 Hz, 1H), 2.62
(dd, J = 18.3 Hz, 14.4 Hz, 1H), 2.46 (ddd, J = 42.5 Hz, 14.4 Hz, 4.1 Hz,
1H), 2.06 (td, J = 7.5 Hz, 4.7 Hz, 2H), 1.75–1.69 (m, 1H), 1.67–1.65
(m, 3H), 1.51 (s, 9H), 1.38–1.36 (m, 2H), 1.34–1.31 (m, 2H), 1.03 (d,
J = 7.3 Hz, 3H); 13C NMR (100 MHz, CD3OD): δ 176.6, 170.8, 131.0,
4.5. tert-butyl (2S,4S)-4-fluoro-1-((E)-2-methyl-3-oxodec-8-enoyl)
pyrrolidine-2-carboxylate (4)
To a solution of acid 24 [6] (120 mg, 0.60 mmol) in dry DMF
(20 mL) was added HATU (250 mg, 0.66 mmol). After stirring for
10 min, 10a (113 mg, 0.6 mmol) was added and the mixture was stirred
at room temperature for 20 min. To this mixture was added DIPEA
(0.28 mL, 1.74 mmol) and stirring was continued for 24 h. The solution
was washed with brine and distilled water, extracted with ethyl acetate.
The combined organic extracts were dried over magnesium sulphate
and evaporated in vacuo to give a 1.2:1 diasteromers (101 mg, 46%) as
a white solid. m.p.: 73–75 °C; [α]D25-95.8 (c = 0.19, CH3OH); IR
(cm−1): 962, 1014, 1057, 1153, 1222, 1632; 1H NMR (400 MHz,
(CD3)2SO): δ 5.39–5.36 (m, 3.3H), 5.37 (dm, JHF = 51.7 Hz, 1.7H), 4.47
(d, J = 9.9 Hz, 1H), 3.97–3.84 (m, 2H), 3.82–3.65 (m, 2H), 3.62–3.48
(m, 1H), 2.64–2.53 (m, 1H), 2.53–2.50 (m, 4H), 2.48–2.43 (m, 3H),
2.39 (dd, J = 9.3 Hz, 5.2 Hz, 1H), 2.23 (ddd, J = 19.8 Hz, 14.6 Hz,
5.4 Hz, 1H), 1.94–1.89 (m, 3H), 1.60–1.59 (m, 5H), 1.47–1.43 (m, 1H),
1
124.5, 95.6 (d, JCF = 174.7 Hz), 82.5, 81.3, 79.9, 49.6, 48.5 (d,
2
2JCF = 25.6 Hz), 35.2 (d, JCF = 20.8 Hz), 32.3, 30.1, 26.7, 22.7, 16.7,
6.2; 19F NMR (376 MHz, CD3OD): δ −169.93 (ddddd, J = 52.8 Hz,
42.3 Hz, 34.7 Hz, 27.6 Hz, 18.3 Hz, 1F); 19F {1H} NMR (376 MHz,
21