1,3,4,6-Tetrasubstituted 2,5-Diketopiperazines
6.90 (d, J ) 8.4 Hz, 2H), 5.62 (dddd, J ) 17.4, 9.9, 4.7, 0.8 Hz,
1H), 5.18 (dd, J ) 10.1, 0.9 Hz, 1H), 5.01 (dd, J ) 17.0, 1.7 Hz,
1H), 4.63-4.59 (m, 1H), 4.63 (dd, J ) 17.6, 2.6 Hz, 1H), 4.47 (d,
J ) 12.1 Hz, 1H), 4.38 (d, J ) 12.1 Hz, 1H), 4.38-4.36 (m, 1H),
4.20 (t, J ) 5.9 Hz, 1H), 3.88 (dd, J ) 17.6, 2.6 Hz, 1H), 3.69 (dd,
J ) 9.9, 2.6 Hz, 1H), 3.12 (dd, J ) 9.9, 2.6 Hz, 1H), 3.13-3.10
(m, 2H), 3.01 (dd, J ) 15.2, 7.9 Hz, 1H), 2.26 (t, J ) 2.6 Hz, 1H).
13C NMR (CDCl3): δ 165.5, 164.2, 137.1, 135.9, 132.0, 131.9,
131.5, 131.2, 128.7, 128.2, 128.1, 121.3, 119.6, 77.5, 73.5, 73.3,
69.9, 60.3, 60.2, 47.3, 39.3, 34.2. Anal. Calcd for C25H25BrN2O3:
C, 62.38; H, 5.23; N, 5.82. Found C, 62.2; H, 5.4; N, 5.9.
(3S,6S)-1-Allyl-3-(benzyloxymethyl)-6-(4-bromobenzyl)-4-[((1-
(1S)-1-hydroxy-3-phenyl-prop-2-yl)-1H-1,2,3-triazol-4-yl)meth-
yl]piperazine-2,5-dione (29). Compound 28 (0.35 g, 0.73 mmol)
and (S)-2-azido-3-phenyl-propan-1-ol18 (0.13 g, 0.73 mmol) were
dissolved in CH2Cl2 (1 mL) and a premixed solution of sodium
ascorbate (73 µL, 73 µmol) (1.0 M in H2O), copper(II) sulfate
pentahydrate (0.73 mL, 7.3 µmol) (10 mM in H2O) was added,
and the mixture was stirred vigorously for 20 h at rt. The reaction
mixture was concentrated in vacuo and purified by flash chroma-
tography using CH2Cl2/CH3OH (8:1) as eluent to give pure 29 as
a white fluffy powder (0.46 g, 95%). [R]D: -109° (c 1, CH2Cl2).
1H NMR (CDCl3): δ 7.42 (s, 1H), 7.32 (d, J ) 8.4 Hz, 2H), 7.26
(d, J ) 7.0 Hz, 2H), 7.25-7.17 (m, 2H), 7.16 (d, J ) 7.0 Hz, 2H),
7.13 (d, J ) 7.0 Hz, 2H), 6.98 (d, J ) 7.0 Hz, 2H), 6.82 (d, J )
8.4 Hz, 2H), 5.54 (dddd, J ) 17.4, 9.9, 4.7, 0.8 Hz, 1H), 5.10 (d,
J ) 10.3 Hz, 1H), 4.92 (d, J ) 17.2 Hz, 1H), 4.84 (d, J ) 15.0
Hz, 1H), 4.69-4.59 (m, 1H), 4.46 (dd, J ) 15.2, 4.6 Hz, 1H),
4.32 (q, J ) 21.6, 11.3 Hz, 2H), 4.26 (d, J ) 15.0 Hz, 1H), 4.11-
4.07 (m, 2H), 4.00 (t, J ) 5.5 Hz, 1H), 3.95-3.87 (m, 1H), 3.76
(dd, J ) 9.9, 2.6 Hz, 1H), 3.34 (dd, J ) 9.9, 2.6 Hz, 1H), 3.21-
3.03 (m, 4H), 3.00 (dd, J ) 15.9, 7.0 Hz, 1H). 13C NMR (CDCl3):
δ 166.0, 164.5, 141.7, 137.1, 136.6, 136.2, 131.7, 131.4, 131.3,
129.0, 128.8, 128.6, 128.3, 128.2, 124.3, 121.1, 119.3, 73.5, 69.6,
65.2, 63.5, 61.0, 60.6, 47.4, 39.8, 39.7, 37.8. Anal. Calcd for C34H36-
BrN5O4: C, 62.01; H, 5.51; N, 10.63. Found C, 62.1; H, 5.6; N,
10.7.
dried (Na2SO4), and concentrated in vacuo. The crude product was
purified by flash chromatography using CH2Cl2/CH3OH (8:1) as
the eluent to give pure 30 as a colorless oil (82 mg, 81%). [R]D:
-54.8° (c 2, CH2Cl2). 1H NMR (CDCl3): δ 7.37-6.90 (m, 15H),
4.79 (d, J ) 14.6 Hz, 1H), 4.65 (s, 1H), 4.55 (t, J ) 11.0 Hz, 1H),
4.23 (q, J ) 20.5, 12.1 Hz, 2H), 4.13 (d, J ) 14.6 Hz, 1H), 4.02-
3.92 (m, 4H), 3.63 (t, J ) 5.9 Hz, 1H), 3.58-3.50 (m, 1H), 3.22-
3.06 (m, 4H), 3.00-2.88 (m, 2H), 2.33-2.27 (m, 1H), 2.19 (dd, J
) 12.1, 3.6 Hz, 1H), 1.75-1.55 (m, 2H), 1.13 (dd, J ) 23.1, 6.2
Hz, 1H). 13C NMR (CDCl3): δ 169.3, 169.0, 147.2, 146.1, 142.8,
136.7, 132.2, 131.1, 129.1, 128.8, 128.7, 128.5, 127.8, 127.2, 124.5,
120.3, 73.3, 70.0, 67.2, 63.7, 61.6, 55.0, 52.3, 47.7, 41.55, 37.8,
35.4, 28.8. Anal. Calcd for C34H38BrN5O5: C, 60.36; H, 5.66; N,
10.35. Found C, 60.3; H, 5.6; N, 10.3.
(3S,6S)-3-(Benzyloxymethyl)-4-[((1-(1S)-1-hydroxy-3-phenyl-
prop-2-yl)-1H-1,2,3-triazol-4-yl)methyl]-1-(3-hydroxypropyl)-6-
(4-(2-methoxycarbonyletenyl)benzyl)piperazine-2,5-dione (31).
Compound 30 (48 mg, 71 µmol), palladium(II) acetate (1.6 mg,
7.1 µmol), tri(o-tolyl)phosphine (4.0 mg, 14 µmol), triethylamine
(20 µL, 1.4 mmol), and methyl acrylate (13 µL, 1.4 mmol) were
dissolved in DMF (3 mL) and heated in a microwave at 150 °C
for 30 min. The reaction mixture was filtered through Celite with
EtOAc and concentrated in vacuo. The crude product was purified
by flash chromatography using CH2Cl2/CH3OH (8:1) as the eluent
to give pure 31 as a colorless oil (40 mg, 83%). [R]D: -65.6° (c
1, CH2Cl2). 1H NMR (CDCl3): δ 7.62 (d, J ) 16.1 Hz, 1H), 7.40-
6.90 (m, 15H), 6.35 (d, J ) 16.1 Hz, 1H), 4.81 (d, J ) 15.0 Hz,
1H), 4.68-4.62 (m, 1H), 4.54 (t, J ) 11.0 Hz, 1H), 4.23 (d, J )
6.6 Hz, 2H), 4.13 (d, J ) 15.0 Hz, 1H), 4.02-3.93 (m, 4H), 3.78
(s, 3H), 3.63 (t, J ) 5.9 Hz, 1H), 3.58-3.50 (m, 1H), 3.22-3.06
(m, 4H), 3.00-2.88 (m, 2H), 2.33-2.27 (m, 1H), 2.22-2.15 (m,
1H), 1.74-1.56 (m, 2H), 1.12 (dd, J ) 23.1, 6.2 Hz, 1H). 13C NMR
(CDCl3): δ 169.5, 169.4, 167.6, 144.7, 141.1, 138.3, 138.0, 136.7,
136.6, 132.1, 131.1, 129.0, 128.9, 128.8, 128.5, 127.8, 127.6, 127.1,
123.8, 117.3, 73.5, 73.3, 69.9, 63.7, 61.6, 54.9, 51.8, 48.3, 41.5,
37.8, 35.4, 31.5. Anal. Calcd for C38H43N5O7: C, 66.94; H, 6.36;
N, 10.27. Found C, 66.8; H, 6.35; N, 10.4.
(3S,6S)-3-(Benzyloxymethyl)-6-(4-bromobenzyl)-4-[((1-(1S)-
1-hydroxy-3-phenyl-prop-2-yl)-1H-1,2,3-triazol-4-yl)methyl]-1-
(3-hydroxypropyl)piperazine-2,5-dione (30). Compound 29 (0.10
g, 0.15 mmol) was dissolved in THF (2 mL) and cooled to -40
°C followed by addition of BH3·THF complex (0.38 mL, 0.38
mmol) (1 M in THF). After 2 h the reaction was allowed to reach
rt over a period of 3 h. After 12 h the reaction mixture was cooled
to 0 °C whereupon NaOH (2 mL, 6 mmol) (3 M aq) and H2O2 (2
mL, 18 mmol) (30% w/w in H2O) were added. The reaction was
stirred for 2 h whereupon the mixture was extracted with EtOAc,
Acknowledgment. Financial support was obtained from the
Knut and Alice Wallenberg Foundation and the Swedish
Research Council.
Supporting Information Available: Compound characterization
data for compounds 1, 3-10, 12-19, 21-23, and 25-27; NMR
spectra of compounds 28-31. This material is available free of
JO0619635
J. Org. Chem, Vol. 72, No. 1, 2007 199