solvent was removed in vacuo. The product was extracted with
AcOEt (20 mL), and the organic layer was washed with H2O,
dried, and evaporated. The product was purified with siliga gel
column chromatography using hexane/AcOEt ) 6:1 to yield 0.14
g (79%) of 14 as an oil: [R]25D +17.39 (c ) 0.2, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 0.76 (d, J ) 6.35 Hz, 3H), 0.83 (d, J ) 6.45
Hz, 3H), 1.36-1.44 (m, 1H), 1.44(s, 9H), 1.67-1.71 (m, 2H), 4.3-
4.4 (br, 2 H), 4.63-4.64 (d, J ) 5.5 Hz, 2H), 5.23-5.36 (m, 2H),
5.90-5.97 (m, 2H), 6.85 (dd, J ) 15.64, 5.25 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 22.6, 23.1, 25.1, 28.8, 44.2, 50.2, 65.5, 118.7,
120.5, 132.6, 149.8, 155.5. 166.4; HRFAB MS m/z 298.2024 for
[M + H]+ (calcd 298.2030 for C16H28O4N).
5.11 Hz 2H), 5.02 (m, 1H), 5.23-5.31 (m, 2H), 5.83-5.86 (m,
2H), 6.01 (d, J ) 7.42 Hz, 1H), 6.70 (dd, J ) 15.28, 5.73 Hz,
1H), 7.21 (t, J ) 7.42 Hz 1H), 7.30 (t, J ) 7.33 Hz, 2H), 7.37 (s,
1H), 7.48 (d, J ) 7.75 Hz, 1H), 7.9-8.1 (br, 1H); 13C NMR (100
MHz, CDCl3) δ 22.7, 23.1, 25.1, 28.0, 28.6, 28.8, 44.5, 50.2, 53.2,
66.7, 84.2, 115.3, 115.7, 119.4, 119.7, 122.7, 123.0, 124.6, 125.0,
131.0, 131.7, 146.0, 149.9, 155.4, 165.4, 171.6; HRFAB MS m/z
606.3155for [M + Na]+ (calcd 606.3145 for C32H45O7N3Na).
2-[(2E,4R)-4-amino-6-methylhept-2-enoylamino]-(2S)-3-
indol-3-ylpropanoic Acid, 20. A solution of compound 18 (26
mg, 45 µmol) in THF (5 mL) was bubbled with argon for 5 min,
and [PPh3]4Pd(0) (15 mg, 13 µmol) was added to the solution.
After the solution was stirred for 10 min, formic acid (3.5 µL,
93 µmol), and n-butylamine (4.4 µL, 46 µmol) were added. The
reaction mixture was stirred for 3 h at 25 °C, and the solvent
was removed in vacuo. The residue was treated with 50% TFA/
CH2Cl2 (1 mL) for 30 min. After evaporation of the solvent, cold
ether (10 mL) was added. The resulting precipitate was washed
with ether (10 mL) and then dissolved in 0.1% aqueous TFA.
The solution was freeze-dried to yield 12 mg (80%) of 20 as a
white powder: HPLC tR 10.96 min [CH3CN (10-40%/40 min)];
1H NMR (400 MHz, D2O) δ 0.76 (d, J ) 6.33 Hz, 3H), 0.83 (d, J
) 6.44 Hz, 3H), 1.33-1.50 (m, 3H), 3.13-3.19 (m, 1H), 3.32-
3.37 (m, 1H), 3.85-3.88 (m, 1H), 6.10 (d, J ) 15.74 Hz, 1H),
6.36 (dd, J ) 15.57, 8.68 Hz, 1H), 7.04 (t, J ) 7.77 Hz 1H), 7.14
(t, J ) 6.05 Hz, 2H), 7.38 (d, J ) 8.06, 1H), 7.52 (d, J ) 8.09 Hz,
1H); 13C NMR (100 MHz, D2O) δ 21.1, 22.4, 24.2, 27.2, 41.2, 50.8,
54.9, 109.8, 112.2, 118.8, 119.7, 122.2, 124.7, 127.0, 136.4, 138.8,
166.9, 176.2; HRFAB MS m/z 344.1979 for [M + H]+ (calcd
344.1968 for C19H26O3N3).
(2E,4R)-4-[(tert-Butoxy)carbonylamino]-6-methylhept-
2-enoic Acid, 16. A solution of compound 14 (0.13 g, 0.44 mmol)
in THF (5 mL) was bubbled with argon for 5 min, and [PPh3]4-
Pd(0) (0.17 g, 0.15 mmol) was added to the solution. After the
mixture was stirred for 10 min, formic acid (40 µL, 1.0 mmol),
and n-butylamine (50 µL, 0.50 mmol) were added, and the
reaction mixture was stirred for 3 h at 25 °C. After removal of
the solvent in vacuo, the residue was dissolved in CHCl3 (15
mL) and washed with 1 N HCl (2 × 4 mL) and saturated NaCl
(2 × 4 mL). The organic layer was dried over Na2SO4 and
concentrated in vacuo. The product was purified with siliga gel
column chromatography using CHCl3/MeOH ) 7:1 to afford 75
mg (67%) of 16 as an oil: [R]25 +28.57 (c ) 0.3, CHCl3); 1H
D
NMR (400 MHz, CDCl3) δ 0.76 (d, J ) 6.32 Hz, 3H), 0.84 (d, J
) 6.45 Hz, 3H), 1.34-1.37 (m, 1 H), 1.44 (s, 9H), 1.67-1.72 (m,
2H), 4.37-4.45 (br, 2H), 5.92 (d J ) 15.67 Hz, 1H), 6.84 (dd, J
) 15.78, 5.73 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.5, 23.1,
25.2, 28.7, 44.1, 50.3, 112.0, 151.9, 155.5, 170.9; HRFAB MS m/z
280.1517 for [M + Na]+ (calcd 280.1508 for C13H23O4NNa).
Prop-2-enyl 2-{(2E,4R)-4-[(tert-butoxy)carbonylamino]-
6-methylhept-2-enoylamino}-(2S)-3-{1-[(tert-butyl)oxycar-
bonyl]indol-3-yl}propanoate, 18. To a solution of 16 (85 mg,
0.33 mmol) in DMF (5 mL) were added Nin-Boc-D-tryptophan
allyl ester (0.14 g, 0.41 mmol), HATU (0.16 g, 0.42 mmol), HOAt
(57 mg, 0.42 mmol), and NEM (53 µL, 0.42 mmol). The mixture
was stirred at 25 °C for 24 h. The solvent was removed in vacuo,
and the residue was dissolved in AcOEt (15 mL). The organic
phase was washed with H2O (2 × 10 mL) and saturated aq NaCl
(2 × 10 mL). The organic layer was dried over Na2SO4 and
concentrated in vacuo. The product was purified with silica gel
column chromatography using hexane/AcOEt ) 2:1 to afford 0.14
g (73%) of 18 as an oil: [R]25D -36.17 (c )1.2, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 0.76 (d, J ) 6.35 Hz, 3H), 0.83 (d, J ) 6.43
Hz, 3H), 1.34-1.37 (m, 1H), 1.43 (s, 9H), 1.60-1.65 (m, 2H),
1.67 (s, 9H), 3.28-3.30 (m, 2H), 4.31-4.54 (br, 2H), 4.58 (d, J )
Acknowledgment. We are grateful to Ms. Kayoko
Oda (Kyoto Pharmaceutical University) for measure-
ment of the HRFAB MS spectra. We acknowledge a
Grant-in-Aid for Scientific Research from the Fujisawa
Foundation and the Mistubishi Pharma Research Foun-
dation.
Supporting Information Available: General experimen-
tal procedures, preparation of olefin-peptide libraries, the
degree of epimerization, syntheses and HPLC chromatograms
of olefin peptides listed in Table 1, synthesis of compound 21,
1H NMR spectra of compounds 14-21, and a typical sigmoidal
dose-response curve. This material is available free of charge
JO051872S
J. Org. Chem, Vol. 70, No. 25, 2005 10599