3636 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10
Liu et al.
Hz, 3 H), 1.40-1.50 (m, 2 H), 1.55-1.62 (m, 2 H), 1.72, (t, J )
6.5 Hz, 1 H), 1.89-1.95 (m, 2 H), 2.05-2.08 (m, 2 H), 3.00 (s,
3 H), 3.19 (dd, J ) 14 Hz, 5 Hz, 1 H), 3.34 (dd, J ) 14.0 Hz,
9 Hz, 1 H), 3.44 (t, J ) 7.5 Hz, 1 H), 3.97 (d, J ) 6.0 Hz, 1 H),
4.09 (t, J ) 8.0 Hz, 1 H), 4.25-4.31 (m, 1 H), 4.60 (brs, 1 H),
4.84 (t, J ) 12.0 Hz, 1 H), 6.54 (brs, 1 H), 7.08 (d, J ) 8.0 Hz,
2 H), 7.42 (d, J ) 8.0 Hz, 2 H), 7.68 (d, J ) 8.0 Hz, 1 H), 7.85
(brs, 1 H); 13C NMR (125 MHz, CDCl3) δ 18.6, 19.6, 22.3 (2 C),
22.5, 22.8, 23.1 (2 C), 24.9, 25.1, 29.9, 30.0, 36.3, 38.4, 38.5,
40.0, 41.2, 49.2, 54.1, 57.6, 59.8, 69.3, 121.4, 131.0 (2 C), 132.1
(2 C), 135.8, 171.0, 171.9, 172.1, 172.9, 173.3; HRMS (EI, M+)
calcd for C33H52BrN5O5 677.3152 and 679.3131, found 677.3172
and 679.3155.
Cyclic Peptide (8) (7.8 mg, 70% yield from 200 mg of resin
19): 1H NMR (500 MHz, CDCl3) δ 0.78 (d, J ) 6.5 Hz, 3 H),
0.88 (t, J ) 5.0 Hz, 12 H), 0.92 (d, J ) 6.0 Hz, 3 H), 0.97 (t, J
) 7.0 Hz, 6 H), 1.47-1.51 (m, 1 H), 1.53-1.58 (m, 2 H), 1.65-
1.71 (m, 4 H), 1.88 (t, J ) 6.5 Hz, 1 H), 2.92-2.98 (m, 1 H),
3.16-3.21 (dd, J ) 14.0 Hz, 8 Hz, 1 H), 3.29 (dd, J ) 14.0 Hz,
9 Hz, 1 H), 4.02-4.07 (m, 1 H), 4.20 (dd, J ) 14.5 Hz, 9 Hz, 1
H), 4.41 (dd, J ) 15.0 Hz, 6 Hz, 1 H), 4.87 (dd, J ) 15.5 Hz, 8
Hz, 1 H), 6.35 (d, J ) 6.5 Hz, 1 H), 7.20 (d, J ) 7.5 Hz, 2 H),
7.25-7.32 (m, 3 H), 7.33 (d, J ) 6.0 Hz, 1 H), 7.59 (d, J ) 6.0
Hz, 1 H), 7.69 (d, J ) 9.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ 19.5, 20.3, 21.3, 22.2, 22.8, 22.9 (2 C), 23.4, 25.0 (2 C), 25.1,
26.6, 27.6, 30.0, 35.4, 40.2, 40.5, 41.3, 46.6 (2 C), 48.8 (2 C),
52.2, 55.2, 57.4, 127.3, 129.0 (2 C), 129.1 (2 C), 136.8, 170.9,
171.3, 171.8, 172.9, 174.1; HRMS (EI, M+) calcd for C33H53N5O5
599.4047, found 599.4042.
Cyclic Peptide (9) (8.5 mg, 70% yield from 200 mg of resin
19): 1H NMR (500 MHz, CDCl3) δ 0.82 (d, J ) 6.0 Hz, 3 H),
0.88-0.95 (m, 15 H), 0.97 (dd, J ) 10.5 Hz, 6.5 Hz, 6 H), 1.49-
1.52 (m, 1 H), 1.55-1.58 (m. 2 H), 1.61-1.75 (m, 4 H), 1.87-
1.89 (m, 1 H), 2.90 (dd, J ) 12.5 Hz, 6.5 Hz, 1 H), 3.08 (dd, J
) 13 Hz, 7 Hz, 1 H), 3.22-3.26 (m, 1 H), 3.99 (dd, J ) 15 Hz,
6.5 Hz, 1 H), 4.18 (dd, J ) 14.5 Hz, 6.0 Hz, 1 H), 4.44 (brs, 1
H), 4.88 (dd, J ) 13.5 Hz, 8.0 Hz, 1 H), 6.3 (brs, 1 H), 7.09 (d,
J ) 8.0 Hz, 2 H), 7.39 (brs, 1 H), 7.42 (d, J ) 8.0 Hz, 2 H),
7.56 (d, J ) 9.0 Hz, 1 H), 7.64 (brs, 1 H); 13C NMR (125 MHz,
CDCl3) δ 19.5, 20.3, 21.4, 22.0, 22.7, 23.0 (2 C), 23.3, 24.0, 25.2
(2 C), 27.5, 29.9, 35.2, 40.5, 40.7, 41.4, 48.2, 51.3, 52.4, 55.8,
61.8, 121.1, 131.1 (2 C), 132.0 (2 C), 135.9, 170.8, 171.1, 171.8,
173.1, 173.8; HRMS (EI, M+) calcd for C33H52BrN5O5 677.3152
and 679.3131, found 677.3132 and 679.3109.
Cyclic Peptide (10) (7.4 mg, 69% yield from 200 mg of
resin 19): 1H NMR (500 MHz, CDCl3) δ 0.81 (d, J ) 6.5 Hz, 3
H), 0.84 (dd, J ) 6.5 Hz, 2 Hz, 12 H), 0.89 (t, J ) 7.0 Hz, 6 H),
0.92 (d, J ) 7.0 Hz, 3 H), 1.34-1.40 (m, 2 H), 1.44-1.49 (m, 2
H), 1.51-1.55 (m, 2 H), 1.71-1.76 (m, 1 H), 2.02-2.07 (m, 1
H), 3.07 (dd, J ) 14.0 Hz, 5 Hz, 1 H), 3.37 (dd, J ) 14.0 Hz, 6
Hz, 1 H), 3.24 (s, 3 H), 3.44 (t, J ) 5.5 Hz, 1 H), 4.40 (dd, J )
15.5 Hz, 7.5 Hz, 1 H), 4.5 (T, J ) 10 Hz, 1 H), 4.80-4.84 (m,
1 H), 4.91 (dd, J ) 15.5 Hz, 9 Hz, 1 H), 5.90 (d, J ) 8.9 Hz, 1
H), 6.25 (d, J ) 7.5 Hz, 1 H), 7.17 (d, J ) 6.3 Hz, 2 H), 7.25-
7.29 (m, 3 H), 7.81 (d, J ) 8.0 Hz, 1 H), 8.68 (d, J ) 9.5 Hz, 1
H); 13C NMR (125 MHz, CDCl3) δ 18.1, 19.5, 22.2, 22.6, 22.7
(3 C), 23.2, 23.5, 24.5, 25.1, 25.4, 29.9, 30.6, 37.4, 41.5, 42.2,
51.7, 51.9, 53.5, 55.1, 65.7, 127.3, 128.9 (2 C), 129.6 (2 C), 136.7,
169.6, 170.6, 171.6, 172.3, 172.5; HRMS (ESI, M + 1) calcd
for C33H54N5O5 600.4125, found 600.4115.
Cyclic Peptide (12) (7.8 mg, 72% yield from 200 mg of
resin 19): 1H NMR (500 MHz, CDCl3) δ 0.81 (d, J ) 6.5 Hz, 3
H), 0.85 (d, J ) 6.5 Hz, 6 H), 0.89 (t, J ) 3.0 Hz, 6 H), 0.90 (t,
J ) 6.5 Hz, 6 H), 0.94 (dd, J ) 6.5 Hz, 4.5 Hz, 3 H), 1.42-1.45
(m, 1 H), 1.49-1.56 (m, 2 H), 1.59-1.64 (m, 2 H), 1.68-1.72
(m, 2 H), 2.08 (brs, 1 H), 2.76 (s, 3 H), 3.17 (dd, J ) 13.0 Hz,
5.5 Hz, 1 H), 3.32 (t, J ) 7.5 Hz, 1 H), 3.50 (m, 1 H), 3.66 (dd,
J ) 10.5 Hz, 6 Hz, 1 H), 4.28 (m, 2 H), 4.75 (m, 1 H), 6.64 (brs,
1 H), 6.97 (brs, 1 H), 7.15 (d, J ) 6.5 Hz, 2 H), 7.23-7.30 (m,
3 H), 7.62 (brs, 1 H), 7.83 (d, J ) 9.0 Hz, 1 H); 13C NMR (125
MHz, CDCl3) δ 19.5, 191.9, 21.7, 22.0, 22.5, 22.9, 23.2, 23.3,
25.1, 25.2, 25.3, 27.9, 34.2, 39.7, 40.0, 40.8, 41.0, 48.4, 53.4,
53.5, 60.5, 69.5, 127.4, 129.0 (2 C), 129.1 (2 C), 136.9, 170.4,
172.6 (2 C), 172.7, 174.1; HRMS (EI, M+) calcd for C33H53N5O5
599.4047, found 599.4046.
Cyclic Peptide (13) (8.7 mg, 71% yield from 200 mg of
resin 19): 1H NMR (500 MHz, CDCl3) δ 0.85 (d, J ) 6.5 Hz, 3
H), 0.89 (d, J ) 6.5 Hz, 3 H), 0.92 (d, J ) 7.0 Hz, 3 H), 0.94 (d,
J ) 6.0 Hz, 12 H), 0.97 (d, J ) 6.5 Hz, 3 H), 1.38-1.42 (m, 1
H), 1.48-1.53 (m, 2 H), 1.58-1.61 (m, 2 H), 1.71 (d, J ) 5.0
Hz, 1 H), 2.38 (brs, 1 H), 2.83 (s, 3 H), 3.18 (dd, J ) 13.5 Hz,
5.5 Hz, 1 H), 3.46 (t, J ) 6.5 Hz, 1 H), 3.51-3.56 (m, 1 H),
3.66 (dd, J ) 9.5 Hz, 5.0 Hz, 1 H), 4.24 (d, J ) 7.0 Hz, 1 H),
4.32 (dd, J ) 14.0 Hz, 5.5 Hz, 1 H), 4.79 (m, 1 H), 6.88 (brs, 1
H), 7.06 (d, J ) 8.5 Hz, 2 H), 7.44 (d, J ) 8.5 Hz, 2 H), 7.67
(brs, 1 H), 7.77 (d, J ) 9.0 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ 19.2, 19.9, 21.8, 22.2, 22.6, 22.7, 23.1, 23.2, 25.1, 25.3 (2 C),
28.3, 33.9, 39.3, 40.2, 40.8, 41.1, 48.5, 53.4, 53.7, 66.1, 69.9,
121.3, 130.8 (2 C), 132.1 (2 C), 136.0, 170.3, 172.2, 172.5, 172.9,
174.0; HRMS (EI, M+) calcd for C33H52BrN5O5 677.3152 and
679.3131, found 677.3150 and 679.3138.
N-Trifluoroacetyl-4-iodophenylalanine (15). To a solu-
tion of 4-iodophenylalanine (14, 2 mmol, 0.58 g) and triethy-
lamine (16 mmol, 4.6 mL) in acetone (20 mL) was added slowly
trifluoroacetic anhydride (16 mmol, 2.3 mL) with stirring at
room temperature. The mixture was stirred overnight and then
concentrated. The residue was dissolved in 1 N HCl (20 mL)
and then extracted with ethyl acetate (3 × 20 mL), and the
organic layer was washed with brine. The solution was dried
over anhydrous Na2SO4 and concentrated to give the crude
product (0.73 g), which was taken on without further purifica-
tion.
N-Methyl-N-trifluoroacetyl-4-iodophenylalanine Meth-
yl Ester (16). To a solution of 15 (0.73 g) in 50 mL of
anhydrous acetone was added anhydrous K2CO3 (18 mmol,
2.48 g) and iodomethane (36 mmol, 2.25 mL), and the reaction
mixture stirred at room temperature for 16 h. The reaction
was monitored by TLC. The suspension was filtered off, the
solvent was evaporated, and the residue was taken up in 100
mL of ethyl acetate. The solution was washed with water, 0.5
N HCl, and brine, respectively, dried over anhydrous Na2SO4,
filtered, and concentrated to give an oily residue. The crude
product was purified by flash chromatography on silica gel to
afford a light yellow oil product (0.7 g, 87%); 1H NMR (400
MHz, CDCl3) δ 2.90 (s, 3 H), 3.03 (dd, J ) 14.8 Hz, 5.6 Hz, 1
H), 3.32 (d, J ) 14.8 Hz, 11.2 Hz, 1 H), 3.70 (s, 3 H), 4.91 (m,
1 H), 6.91 (d, J ) 7.6 Hz, 2 H); 13C NMR (10 MHz, CDCl3) δ
33.8, 52.9, 60.8, 61.1, 92.8, 114.8, 130.9, 136.0 (2 C), 137.9 (2
C), 157.3, 169.2; HRMS (ESI, M + 1) calcd for C13H14F3INO3
415.9971, found 415.9980.
N-Methyl-4-iodophenylalanine (17). To a solution of 16
(0.7 g, 1.69 mmol) in 50 mL of acetone and water (1:1) was
added 0.37 g (2.7 mmol) of anhydrous K2CO3. The mixture was
heated to 45 °C and was stirred overnight. After the starting
material had disappeared (TLC monitoring), the reaction
solution was concentrated to about half volume and diluted
with brine, and the pH of the solution was adjusted to 3. The
precipitate was collected by filtration and washed with water
and THF to give 0.48 g (93%) of a white solid, which was used
for the next reaction without further purification.
N-Boc-N-methyl-4-iodophenylalanine Methyl Ester (18).
To a solution of NaOH (63 mg, 1.58 mmol) in 25 mL of water
was added 17 (0.48 g) and then the mixture stirred until the
solid dissolved. A solution of Boc2O (6.32 mmol, 1.38 g) in 20
Cyclic Peptide (11) (8.6 mg, 71% yield from 200 mg of
resin 19): 1H NMR (500 MHz, CDCl3) δ 0.89 (d, J ) 9.5 Hz, 6
H), 0.92 (d, J ) 7.0 Hz, 12 H), 0.96 (t, J ) 7.5 Hz, 6 H), 1.40-
1.46 (m, 1 H), 1.58-1.66 (m. 2 H), 1.86-1.93 (m, 4 H), 2.01-
2.05 (m, 1 H), 3.08 (brs, 1 H), 3.22 (s, 3 H), 3.43 (brs, 1 H),
3.68-3.70 (m, 1 H), 3.87 (brs, 1 H), 4.21 (brs, 1 H), 4.50 (t, J
) 8.5 Hz, 1 H), 4.63 (d, J ) 8 Hz, 1 H), 6.64 (brs, 1 H), 6.84
(brs, 1 H), 7.09 (d, J ) 7.0 Hz, 2 H), 7.43 (d, J ) 7.0 Hz, 2 H),
7.48 (brs, 1 H), 7.53 (brs, 1 H); 13C NMR (125 MHz, CDCl3) δ
18.5, 19.8, 21.9, 22.3 (2 C), 23.0 (2 C), 23.1 (2 C), 24.9, 25.5,
25.6, 29.9, 30.7, 37.8, 39.6, 40.6, 53.5 (2 C), 54.8, 55.6, 67.2,
121.5, 131.1 (2 C), 132.1 (2 C), 135.4, 171.2, 172.5, 173.4, 173.8;
HRMS (ESI, M + Na) calcd for C33H52BrN5O5Na 700.3052 and
702.3032, found 700.3038 and 702.3022.