M. Lu¨bke et al. / Journal of Fluorine Chemistry 152 (2013) 144–156
153
[M+ꢁCH2CONHOBn], 226 (6) [246ꢁHF], 184 (8) [C9H14NO3+], 171
(38) [+], 150 (13) [C8H8NO2+], 140 (14) [C8H14NO+], 106 (38)
[C8H8O+], 91 (100) [C7H7+], 76 (54) [C6H4+]. Anal. calcd. for
C
arom), 164.2 (d, 1JCF = 258.9 Hz, C-4), 171.9 (s, C-10), 173.6 (s, C-1),
3
176.4 (s, C-80). 19F NMR (MeOH-d4):
d
ꢁ95.9 (ddt, JFH = 49.6 Hz,
3JFH = 21.0 Hz, JFH = 17.2 Hz). MS (direct insertion, EI, 70 eV): m/z
(%) 602 (0) [M+], 244 (28) [M+ꢁTrtONHCO(CH2)4], 243 (100) [Trt+],
242 (42), 215 (13) [C9H14FNO3+], 165 (99) [243ꢁC6H6], 88 (31)
[C4H7FN+], 59 (19) [C3H4F+], 57 (26) [C4H9+].
3
C21H31FN2O5 (410.5) C, 61.45; H, 7.61; N, 6.82. Found C, 61.30; H,
7.50; N, 6.53.
4.3.6. Methyl 4-fluoro-2-(7-tritylcarbamoyl-heptanoylamino)pent-
4-enoate (24f)
According to the general procedure 7-trityloxycarbamoylhep-
tanoic acid (23b) [9] (100 mg, 0.23 mmol) was coupled with
4.3.9. Methyl 5-fluoro-2-(7-tritylcarbamoyl-heptanoylamino)hex-5-
enoate (24i)
According to the general procedure 7-trityloxycarbamoylhep-
tanoic acid (23b) [9] (50 mg, 0.12 mmol) was coupled with methyl
2-amino-5-fluorohex-5-enoate (4a) (34 mg, 0.12 mmol). The
product was obtained as a white solid after chromatography
(silica gel, cyclohexane/ethyl acetate, 2:1). Yield: 34 mg (51%), mp
methyl
2-amino-4-fluoropent-4-enoate
(3a)
(34.8 mg,
0.23 mmol). The product was obtained as a white solid after
chromatography (silica gel, cyclohexane/ethyl acetate, 2:1). Yield:
81 mg (63%), mp 141 8C (cyclohexane/ethyl acetate, 2:1). 1H NMR
(CDCl3):
d
1.00–1.67 (m, 10H, H-30 to H-70), 2.16 (t, 2H,
98 8C (cyclohexane/ethyl acetate, 2:1). 1H NMR (MeOH-d4):
d 1.07–
3JHH = 7.4 Hz, H-20), 2.63–2.86 (m, 2H, H-3), 3.74 (s, 3H, H-6),
1.62 (m, 8H, H-30 to H-60), 1.81–2.12 (m, 4H, H-4/70), 2.22 (t, 2H,
3
2
4.30 (dd, 1H, JHF = 49.4 Hz, JHH = 2.9 Hz, H-5trans), 4.62 (dd, 1H,
3JHF = 17.2 Hz, 2JHH = 2.9 Hz, H-5cis), 4.71–4.78 (m, 1H, H-2), 7.21–
7.50 (m, 15H, Harom). 13C NMR (CDCl3):
3JHH = 7.1 Hz, H-20), 2.24–2.37 (m, 2H, H-3), 3.72 (s, 3H, H-7), 4.32
3
2
(dd, 1H, JHF = 50.1 Hz, JHH = 2.9 Hz, H-6trans), 4.46 (dd, 1H,
3
3
d
23.3 (t, C-60), 25.2 (t, C-30),
3JHH = 9.1 Hz, JHH = 5.0 Hz, H-2), 4.55 (dd, 1H, JHF = 17.4 Hz,
2JHH = 2.9 Hz, H-6cis), 7.29–7.49 (m, 15H, Harom). 13C NMR
2
28.6 (2 t, C-40/50), 34.5 (dt, JCF = 28.0 Hz, C-3), 36.1 (2 t, C–20/70),
49.7 (d, C-2), 52.5 (q, C-6), 93.2 (s, C-90), 93.5 (dt, 2JCF = 17.8 Hz, C-
5), 128.0, 129.0 (12 d, Carom), 141.1, 141.2 (3 s, Carom), 161.8 (d,
1JCF = 256.9 Hz, C-4), 171.5 (s, C-10), 172.6 (s, C-1), 176.8 (s, C-80).
(MeOH-d4):
d
26.5 (t, C-3), 26.9 (t, C-30), 29.4 (t, C-60), 29.6 (dt,
2JCF = 28.0 Hz, C-4), 30.0 (2 t, C-40/50), 33.8 (t, C-70), 36.9 (t, C-20),
53.1 (d, C-2), 53.2 (q, C-7), 91.1 (dt, 2JCF = 20.3 Hz, C-6), 94.7 (s, C-
90), 128.7 (3d, Carom), 129.0 (6d, Carom), 130.7 (6d, Carom), 144.0 (3 s,
19F NMR (CDCl3):
d
ꢁ95.6 (ddt, JFH = 49.6 Hz, JFH = 21.0 Hz,
3
3
3JFH = 17.2 Hz). MS (flow insertion, ESI+): m/z (%) 583 (23) [MNa+],
340 (100) [MNa+ꢁTrt], 243 (6) [Trt+]. Anal. calcd. for C33H37FN2O5
(560.7) C, 70.69; H, 6.65; N, 5.00. Found C, 70.18; H, 6.69; N, 4.89.
Carom), 167.1 (d, 1JCF = 256.6 Hz, C-5), 173.5 (s, C-10), 174.0 (s, C-1),
176.6 (s, C-80). 19F NMR (MeOH-d4):
3JFH = 17.2 Hz, 3JFH = 15.3 Hz). MS (flow insertion, ESI+): m/z (%) 598
(43) [MHNa+], 597 (100) [MNa+], 244 (7) [TrtH+], 243 (19) [Trt+], 87
(10) [C5H8F+], 73 (12) [C4H6F+].
3
d
ꢁ95.4 (ddt, JFH = 49.6 Hz,
4.3.7. Methyl (S)-2-(7-tritylcarbamoyl-heptanoylamino)pent-4-
enoate (24g)
According to the general procedure 7-trityloxycarbamoylhep-
tanoic acid (23b) [9] (100 mg, 0.232 mmol) was coupled with
methyl (S)-2-aminopent-4-enoate (3c) [53] (30 mg, 0.232 mmol).
The product was obtained as a white solid after chromatography
(silica gel, cyclohexane/ethyl acetate, 2:1). Yield: 50 mg (40%), mp
4.3.10. Methyl (S)-2-(7-tritylcarbamoyl-heptanoylamino)hex-5-
enoate (24j)
According to the general procedure 7-trityloxycarbamoylhep-
tanoic acid (23b) [9] (100 mg, 0.232 mmol) was coupled with
methyl (S)-2-aminohex-5-enoate (4c) [53] (33 mg, 0.232 mmol).
The product was obtained as a white solid after chromatography
(silica gel, cyclohexane/ethyl acetate, 2:1). Yield: 59 mg (46%), mp
136 8C (ethyl acetate). 1H NMR (CDCl3):
d
1.05–1.70 (m, 10H, H-20
to H-60), 2.12–2.18 (m, 2H, H-70), 2.45–2.61 (m, 2H, H-3), 3.74 (s,
3H, H-6), 4.69 (m, 1H, H-20), 5.09 (d, 1H, H-5A), 5.13 (d, 1H, H-5B),
5.67 (m, 1H, H-4), 6.03 (br d, 1H, NH), 7.27–7.46 (m, 15H, arom).
113 8C (ethyl acetate). 1H NMR (CDCl3):
d
1.15–1.25 (m, 4H, H-40,
H-50), 1.50–1.60 (m, 4H, H-30, H-60), 1.76 (m, 1H, H-3A), 1.93 (m,
1H, H-3B), 2.08 (m, 4H, H-4, H-20), 2.16 (m, 2H, H-70), 3.73 (s, 3H, H-
7), 4.63 (m, 1H, NH), 5.01 (d, 1H, H-6A), 5.02 (d, 1H, H-6B), 5.77 (m,
13C NMR (CDCl3): 25.15 (t, C-60), 25.18 (t, C-30), 28.4 (t, C-40), 28.6
d
(t, C-50), 36.1 (t, C-70), 36.3 (t, C-20), 36.5 (t, C-3), 51.4 (d, C-2), 52.3
(q, C-6), 93.3 (s, C-90), 119.0 (t, C-5), 128.0 (6d, arom), 129.0 (9d,
arom), 132.2 (d, C-4), 141.1 (3s, C-100), 172.3 (s, C-10), 172.6 (s, C-1),
176.7 (s, C-80). MS (direct insertion, EI, 70 eV): m/z (%) 542 (<0.1)
[M+], 300 (0.8) [M+ꢁC19H14], 285 (1), [M+ ꢁ C20H17], 268 (4)
[M+ ꢁ C20H18O], 243 (100) [C19H15+], 228 (6), 215 (5), 183 (3), 139
(4), 88 (8) [C4H8O2+], 70 (13) [C5H10+], 55 (6) [C4H7+]. Exact mass:
(flow injection, ESI+): C33H38N2O5Na, calcd. 565.2673, found
565.2669.
1H, H-5), 6.09–6.32 (br m, 1H, NH) 7.25–7.50 (br m, 15H, arom). 13
NMR (CDCl3):
25.1 (t, C-30), 25.2 (t, C-60), 28.3 (t, C-4), 29.4 (t, C-
C
d
40), 29.5 (t, C-50), 31.6 (t, C-3), 36.0 (t, C-20), 36.3 (t, C-70), 51.6 (d, C-
2), 52.2 (q, C-7), 94.7 (s, C-90), 115.6 (t, C-6), 127.9 (3d, Carom), 128.0
(6d, Carom), 129.0 (6d, Carom), 136.9 (d, C-5), 141.1 (s, C-100), 172.7
(C-10), 173.0 (C-1), 176.6 (C-80). Exact mass: (flow insertion, ESI+):
C34H40N2O5Na, calcd. 579.2829, found 579.2825.
4.3.11. Tert-butyl N-(7-benzylcarbamoyl)heptanoyl (S)-
asparaginate (24k)
4.3.8. Tert-butyl 4-fluoro-2-(7-tritylcarbamoyl-
heptanoylamino)pent-4-enoate (24h)
According to the general procedure 7-benzyloxycarbamoyl-
heptanoic acid (23a) [48] (50.5 mg, 0.18 mmol) was coupled with
tert-butyl (S)-asparaginate hydrochloride (5b) (41 mg, 0.18 mmol).
The product was obtained as a viscous oil after chromatography
According to the general procedure 7-trityloxycarbamoylhep-
tanoic acid (23b) [9] (50 mg, 0.12 mmol) was coupled with tert-
butyl 2-amino-4-fluoropent-4-enoate (3b) (26.1 mg, 0.12 mmol).
The product was obtained as a white solid after chromatography
(silica gel, cyclohexane/ethyl acetate, 2:1). Yield: 34 mg (48%), mp
(silica gel, methanol). Yield: 64 mg (79%). 1H NMR (MeOH-d4):
d
1.25–1.32 (m, 4H, H-40/50), 1.45 (s, 9H, H-6), 1.53–1.65 (m, 4H, H-
119 8C (cyclohexane/ethyl acetate, 2:1). 1H NMR (MeOH-d4):
d
30/60), 2.05 (t, 2H, 3JHH = 7.4 Hz, H-20), 2.21 (t, 2H, 3JHH = 7.2 Hz, H-
3
3
1.00–1.58 (m, 10H, H-30 to H-70), 1.46 (s, 9H, H-7), 2.17 (t, 2H,
70), 2.69 (dd, 2H, JHH = 6.7 Hz, JHH = 5.8 Hz, H-3), 4.63 (dd, 1H,
3JHH = 7.4 Hz, H-20), 2.51–2.79 (m, 2H, H-3), 4.38 (dd, 1H,
3JHH = 6.7 Hz, JHH = 5.8 Hz, H-2), 4.84 (s, 2H, H-90), 7.31–7.42 (m,
d
5H, H-110-150). 13C NMR (MeOH-d4): 26.7 (t, C-60), 26.9 (t, C-30),
3
2
3JHF = 49.4 Hz, JHH = 2.9 Hz, H-5trans), 4.45–4.51 (m, 1H, H-2),
3
2
4.59 (dd, 1H, JHF = 17.2 Hz, JHH = 2.9 Hz, H-5cis), 7.23–7.45 (m,
15H, Harom). 13C NMR (MeOH-d4): 26.6 (t, C-60), 27.0 (t, C-30), 28.6
28.5 (3 q, C-6), 30.0 (2 t, C-40/50), 34.0 (t, C-70), 37.0 (t, C-20), 38.1 (t,
C-3), 51.6 (d, C-2), 79.2 (s, C-5), 83.3 (t, C-90), 129.7 (2 d, C-110/150),
129.9 (d, C-130), 130.6 (2 d, C-120/140), 137.3 (s, C-100), 172.0 (s, C-
10), 173.1 (s, C-1), 175.1 (s, C-4), 176.1 (s, C-80). MS (direct insertion,
EI, 70 eV): m/z (%) 449 (0.5) [M+], 393 (2) [M+ꢁC4H10], 376 (1)
d
(2 t, C-40/50), 30.0 (3 q, C-7), 34.5 (dt, 2JCF = 28.0 Hz, C-3), 36.1 (2 t,
C–20/70), 52.0 (d, C-2), 83.5 (q, C-6), 93.3–94.7 (s und dt, C-90/5),
128.7 (3d, Carom), 129.0 (6 d, Carom), 130.7 (6 d, Carom), 144.0 (3 s,