1332
D.D. DesMarteau, C. Lu / Journal of Fluorine Chemistry 128 (2007) 1326–1334
(CF3SO2)2NH (3): white solid; 1H NMR (200.1 MHz,
CDCl3): d 7.84 (1H, s) (moisture dependent); 19F NMR
(188.3 MHz, CDCl3): d ꢀ75.6 (6F, s).
and dried under vacuum to yield white product Na-CF3CH2-
(L)tyrosine (6, n = 0) (3.939 g, 14.97 mmol, 94.9%).
Na-CF3CH2-(L)tyrosine (6, n = 0): white solid; mp 210–
1
Under a slow flow of nitrogen, trifluoroacetic anhydride
(35 mL) and CF2ClCFCl2 (100 mL) were added into the flask
containing CF3CH2I(OCOCF3)2 (2, n = 0) (196 mmol). The
solution of CF3CH2I(OCOCF3)2 was transferred to the flask
containing (CF3SO2)2NH (3) (222 mmol). The resulting
suspension was cooled in an ice bath, stirred under nitrogen,
and protected from light with Al-foil. After 15 min, benzene
(20.0 mL, 223 mmol) was added. The reaction mixture was
stirred with ice bath cooling for 3 h before it was allowed to
warm up to room temperature. After stirring 15 h at room
temperature, the second portion of benzene (7.0 mL, 78 mmol)
was added and the stirring was continued for another 5 h. The
reaction mixture was then transferred into a 500 mL round
bottom flask, and the volatiles were evaporated at 22 8C using
rotary evaporator. The obtained oily dark brown residue was
pumped under vacuum (5 ꢂ 10ꢀ3 torr) for 2 h. Crushed ice (ca.
150 g) was added into the flask with vigorous shaking to cause
the rapid formation of light gray solid which was separated
from water and crystallized from CH2Cl2. The white crystalline
product CF3CH2I(C6H5)N(SO2CF3)2 (4, n = 0) was obtained
(87.8 g, 155 mmol, 79.1%).
213 8C; H NMR (300.5 MHz, (CD3)2CO): d 2.91 (2H, qd,
J = 9.73 Hz, J = 5.83 Hz), 3.10–3.47 (2H, m), 3.59 (1H, dd,
J = 6.36 Hz, J = 6.36 Hz), 6.74 (2H, d, J = 8.60 Hz), 7.09 (2H,
d, J = 8.60 Hz); 13C NMR (75.6 MHz, (CD3)2CO): d 38.9, 49.3
(q, J = 31.1 Hz), 63.2, 115.8, 126.8 (q, J = 277.4 Hz), 129.0,
131.2, 156.9, 174.8; 19F NMR (282.8 MHz, (CD3)2CO): d
ꢀ71.9 (3F, t, J = 9.73 Hz); ESMS (M + H, C11H12NO3F3): m/z
264.0737.
Na-CF3CF2CH2-(L)tyrosine (6, n = 1): white solid; mp 218–
221 8C; 1H NMR (300.5 MHz, (CD3)2SO): d 2.74 (2H, m), 3.13
(1H, q, J = 15.7 Hz), 3.34 (1H, q, J = 15.7 Hz), 3.38 (1H, dd,
J = 6.55 Hz, J = 6.55 Hz), 6.63 (2H, d, J = 8.43 Hz), 6.96 (2H,
d, J = 8.43 Hz), 9.18 (1H, s, br); 13C NMR (75.6 MHz,
(CD3)2SO): d 38.2, 46.7 (t, J = 22.4 Hz), 62.9, 115.1 (m), 115.4,
119.3 (m), 128.1, 130.6, 156.4, 175.3; 19F NMR (282.8 MHz,
(CD3)2SO): d ꢀ82.5 (3F, s), ꢀ120.2 (2F, t, J = 15.8 Hz). ESMS
(M + H, C12H12NO3F5): m/z 314.0687.
Na-CF3CF2CF2CH2-(L)tyrosine (6, n = 2): white solid; mp
206–209 8C; 1H NMR (300.5 MHz, (CD3)2SO): d 2.73 (2H, m),
3.16 (1H, q, J = 16.0 Hz), 3.38 (1H, q, J = 16.0 Hz), 3.39 (1H,
dd, J = 6.55 Hz, J = 6.55 Hz), 6.63 (2H, d, J = 8.41 Hz), 6.95
(2H, d, J = 8.41 Hz), 9.23 (1H, s, br); 13C NMR (75.6 MHz,
(CD3)2SO): d 38.2, 46.8 (t, J = 22.4 Hz), 63.0, 115.1 (m), 115.4,
119.3 (m), 120.2 (m), 128.1, 130.6, 156.4, 175.2; 19F NMR
(282.8 MHz, (CD3)2SO): d ꢀ79.9 (3F, t, J = 9.47 Hz), ꢀ117.5
(2F, m), ꢀ126.6 (2F, s); ESMS (M + H, C13H12NO3F7): m/z
365.0538.
CF3CH2I(C6H5)N(SO2CF3)2 (4, n = 0): crystal; mp 74–
1
77 8C; H NMR (200.1 MHz, CD3CN): d 4.69–4.83 (2H, q,
J = 9.72 Hz), 7.56–7.64 (2H, m), 7.77–7.85 (1H, m), 8.10–8.14
(2H, m); 19F NMR (188.3 MHz, CD3CN): d ꢀ78.9 (6F, s),
ꢀ61.8 (3F, t, J = 9.72 Hz).
1
CF3CF2CH2I(C6H5)N(SO2CF3)2 (4, n = 1): semisolid; H
NMR (300.5 MHz, (CD3)2CO): d 5.29 (2H, t, J = 17.2 Hz),
7.62–7.68 (2H, m), 7.82–7.87 (1H, m), 8.37–8.41 (2H, d,
J = 7.90 Hz); 19F NMR (282.8 MHz, (CD3)2CO): d ꢀ78.8 (6F,
s), ꢀ83.2 (3F, s), ꢀ107.8 (2F, t, J = 16.9 Hz).
3.3. Solid phase synthesis of N-terminus-2,2,2-
trifluoroethylated leucine enkephalin (7)
CF3CF2CF2CH2I(C6H5)N(SO2CF3)2 (4, n = 2): thick liquid;
1H NMR (300.5 MHz, CD3CN): d 4.86 (2H, t, J = 17.6 Hz),
7.60–7.66 (2H, m), 7.82–7.87 (1H, m), 8.17–8.20 (2H, d,
J = 8.10 Hz); 19F NMR (282.8 MHz, CD3CN): d ꢀ78.2
(6F, s), ꢀ79.9 (3F, t, J = 9.61 Hz), ꢀ104.2 (2F, m), ꢀ125.0
(2F, s).
Wang resin (1.000 g, 0.980 meq) was pre-swelled in CH2Cl2
and used in solid phase syntheses. Coupling reactions were
carried out in the presence of Na-Fmoc protected amino acids
(6.000 mmol), O-benzotriazol-1-yl-N,N,N0,N0-tetramethyluro-
nium tetrafluoroborate (1.927 g, 6.000 mmol), and diisopro-
pylethylamine (1.8 mL, 10 mmol) in N,N-dimethylformamide
(25 mL) at room temperature (60 8C for the coupling reaction
of Na-CF3CH2-(L)tyrosine) for 20 h with nitrogen gas sparging.
Fmoc-removal was carried out in the presence of 25 mL of 20%
piperidine in DMF for 15 min twice. Trifluoroacetic acid (95%,
25 mL) was used to cleave the peptide from resin at room
temperature for 1 h twice. N-terminus-2,2,2-trifluoroethylated
leucine enkephalin analogue (7) (0.336 g, 0.527 mmol, 53.8%
in yield based on resin substitution level 0.980 meq/g resin) was
obtained after recrystallization of the product from CH3CN
twice and lyophilization.
3.2. Preparation of Na-CF3(CF2)nCH2-(L)tyrosine
(6, n = 0) and NMR data (6, n = 0–2)
(L)Tyrosine ethyl ester (3.299 g, 15.77 mmol) was dissolved
in 50 mL of CH2Cl2. Water (50 mL) and NaHCO3 (1.596 g,
19.00 mmol) were added and the mixture was stirred.
CF3CH2I(C6H5)N(SO2CF3)2 (4, n = 0) (9.836 g, 17.35 mmol)
was added with stirring at room temperature. After 4 h, the
CH2Cl2 layer was separated and washed with 3 ꢂ 50 mL of
water. After evaporation of organic solvent, the obtained
residue was subjected to column chromatography using 10–
40% acetone in n-hexane. The obtained ester intermediate
(5, n = 0) was stirred in 50 mL of 1 M NaOH aqueous solution
at room temperature for 10 h. The aqueous solution was then
acidified with conc. HCl to pH around 4.5 in an ice bath cooling
to form white precipitate, which was filtered, washed with H2O,
N-CF3CH2-Leu-enkephalin analogue (7): white solid; mp
1
85–88 8C; H NMR (500.1 MHz, (CD3)2SO): d 0.85 (3H, d,
J = 6.42 Hz), 0.90 (3H, d, J = 6.42 Hz), 1.53 (2H, m), 1.63 (1H,
m), 2.61 (1H, m), 2.76 (2H, m), 3.06 (2H, m), 3.20 (1H, m),
3.62 (2H, m), 3.73 (2H, m), 4.22 (1H, m), 4.56 (1H, m), 6.63
(2H, d, J = 8.71 Hz), 6.99 (2H, d, J = 8.71 Hz), 7.18 (1H, m),
7.25 (4H, m), 7.98 (1H, m), 8.08 (1H, d, J = 8.25 Hz), 8.16 (1H,