of the solution was adjusted to 3.0 with hydrochloric acid, and
extracted with ethyl acetate (30 ml ¥ 5). The organic phase was
dried over anhydrous MgSO4, and concentrated under reduced
pressure to give the crude products 3 (3a–3g and 3c, racemic)
(yield >95%) (predominantly as syrups unless otherwise stated),
which were used in the next step without further purification.
which showed two equal peaks with Rfs of 14.5 min and 15.5 min
for the (S)- and (R)-enantiomers respectively. IR (KBr) n 1698,
1674, 1622, 1578, 1506 cm-1; 1H NMR (500 MHz, CDCl3) 1.85–
2.02 (m, 1H), 2.11–2.21 (m, 2H), 2.45–2.49 (m, 1H), 3.39 (s, 3H),
3.67–3.72 (m, 2H), 4.29 (q, J 7.0 Hz, 1H), 7.21 (s, 1H), 7.31–7.33
(m, 3H), 7.45 (d, J 7.0 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3)
162.1, 159.4, 132.5, 130.7 (2), 128.6, 127.6 (2), 126.0, 120.3, 61.5,
58.1, 45.6, 28.2, 22.4; Anal. Calcd for C15H16N2O3: C, 66.16; H,
5.92; N, 10.29; Found: C,66.20; H, 5.97; N, 10.33.
General procedure the preparation of N-alkoxydiketopiperazines 4
To 100 ml reaction flask 0.1 mol compound 3a–h and 40 ml
anhydrous benzene were added and cooled to 0 ◦C. 0.15 ml SOCl2
was added dropwise with stirring. The reaction was continued
for 4 h at room temperature. The solution was concentrated in
vacuo to give a syrupy residue, then an equal volume of water was
added with stirring. The pH of the solution was adjusted to 8 with
hydrochloric acid, extracted with CH2Cl2 (30 ml ¥ 5). The organic
phase was dried over anhydrous MgSO4, filtered, concentrated
under reduced pressure to give a crude product, which was purified
by silica gel flash chromatography to give the title compounds 4,
predominantly as syrups unless otherwise stated.
Cyclo[N-butyloxy-2-(phenylmethylene)glycyl-prolyl] 4d
The product 4d was obtained according to the general procedure
in 80% yield after purification by silica gel flash chromatography
(EtOAc–hexane, 1 : 2). IR (KBr) n 1705, 1680, 1618, 1577, 1503
cm-1; 1H-NMR (500 MHz, CDCl3) 0.65 (t, J 7.0 Hz, 3H), 0.91–
0.95 (m, 2H), 1.03–1.13 (m, 2H), 1.96–1.99 (m, 1H), 2.10–2.18 (m,
2H), 2.46–2.48 (m, 1H), 3.49 (q, J 7.0 Hz, 1H), 3.66–3.74 (m, 3H),
4.29 (q, J 6.5 Hz, 1H), 7.18 (s, 1H), 7.28–7.33 (m, 3H), 7.44 (d,
J 7.0 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3) 162.2, 159.3,
132.8, 130.7(2), 128.5, 127.5(2), 126.6, 120.0, 74.1, 58.1, 45.6, 29.0,
28.3, 22.4, 18.5, 13.6; Anal. Calcd for C18H22N2O3: C, 68.77; H,
7.05; N, 8.91; Found: C,68.81; H, 7.09; N, 8.94.
Cyclo-[N-cyclohexyloxy-2-[(b-pyridyl)-methylene]glycyl-prolyl] 4a
The product 4a was obtained as a white solid according to the
general procedure in 88% yield after purification by silica gel
flash chromatography (EtOAc–hexane, 1 : 2). Crystals suitable for
single crystal X-ray analysis were grown by slow evaporation from
CHCl3. Mp 129.5~131 ◦C; IR (KBr) n 1712, 1666, 1631, 1586,
1480 cm-1; 1H NMR (500 MHz, CDCl3) 0.90–1.16 (m, 6H), 1.38–
1.41 (m, 1H), 1.47–1.49 (m, 1H), 1.59–1.62 (m, 1H), 1.67–1.69 (m,
1H), 1.97–2.02 (q, J 8.5 Hz, 1H), 2.09–2.17 (m, 2H), 2.50–2.54
(m, 1H), 3.66–3.76 (m, 4H), 4.30 (q, J 7.0 Hz, 1H), 7.05 (s, 1H),
7.76 (d, J 9.0 Hz, 1H), 8.50 (d, J 5.0 Hz, 1H), 8.65 (s, 1H) ppm;
13C NMR (125 MHz, CDCl3) 162.1, 157.8, 151.9, 150.1, 137.0,
128.6, 128.3, 121.4, 114.0, 81.9, 57.5, 44.5, 29.0, 28.9, 27.7, 24.1,
22.8, 22.6, 20.0; Anal. Calcd for C19H23N3O3: C, 66.84; H, 6.79; N,
12.31; Found: C, 66.88; H, 6.85; N, 12.33.
Cyclo[N-benzyloxy-2-(phenylmethylene)glycyl-prolyl] 4e
The product 4e was obtained according to the general procedure
in 88% yield after purification by silica gel flash chromatography
(EtOAc–hexane, 1 : 2). IR (KBr) n 1706, 1681, 1618, 1589, 1577,
1511, 1503 cm-1; 1H NMR (500 MHz, CDCl3) 1.92–2.08 (m, 3H),
2.39–2.44 (m, 1H), 3.63–3.66 (m, 2H), 4.26 (q, J 6.5 Hz, 1H), 4.56
(s, 2H), 6.83–6.85 (m, 2H), 7.14–7.17 (m, 2H), 7.23–7.25 (m, 2H),
7.30–7.32 (m, 3H), 7.48–7.49 (m, 2H) ppm; 13C NMR (125 MHz,
CDCl3) 162.4, 159.2, 132.7, 132.5, 131.0(2), 130.1(2), 128.9, 128.7,
128.1(2), 127.7(2), 126.5, 120.4, 75.8, 58.0, 45.6, 29.5, 22.4; Anal.
Calcd for C21H20N2O3: C, 72.40; H, 5.79; N, 8.04; Found: C,72.44;
H, 5.82; N, 8.08.
Cyclo[N-cyclohexyloxy-2-(phenylmethylene)glycyl-prolyl] 4b
Cyclo[N-cyclohexyloxy-2-[(3,4,5-trimethyloxy) phenylmethylene]
glycyl-prolyl] 4f
The product 4b was obtained according to the general procedure
in 85% yield after purification by silica gel flash chromatography
(EtOAc–hexane, 1 : 2). IR (KBr) n 1701, 1670, 1624, 1585, 1503
cm-1; 1H NMR (500 MHz, CDCl3) 0.88–1.08 (m, 5H), 1.18–1.20
(m, 1H), 1.36–1.39 (m, 1H), 1.46–1.47 (m, 1H), 1.63–1.66 (m, 2H),
1.97–2.00 (m, 1H), 2.10–2.15 (m, 2H), 2.59–2.51 (m, 1H), 3.63–
3.74 (m, 3H), 4.29 (q, J 6.5 Hz, 1H), 7.12 (s, 1H), 7.28–7.33 (m,
3H), 7.43 (d, J 7.0 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3):
163.2, 159.6, 132.7, 130.9(2), 128.4, 127.4(2), 119.8, 82.2, 58.4,
45.4, 30.0, 29.5, 28.7, 25.2, 23.8, 23.6, 22.6, 22.4; Anal. Calcd for
C20H24N2O3: C, 70.56; H, 7.11; N, 8.23; Found: C, 70.59; H, 7.15;
N, 8.26.
The product 4f was obtained according to the general procedure
in 83% yield after purification by silica gel flash chromatography
(EtOAc–hexane, 1 : 2). IR (KBr) n 1693, 1678, 1621, 1583,
1503,1099 cm-1; 1H-NMR (500 MHz, CDCl3): 1.01–1.14 (m, 4H),
1.19 (br, 1H), 1.28–1.29 (m, 2H), 1.42 (br, 1H), 1.65–1.72 (m, 2H),
1.99–2.01 (m, 1H), 2.13–2.19 (m, 2H), 2.49–2.51 (m, 1H), 3.69–
3.77 (m, 3H), 3.86–3.90 (m, 9H), 4.29 (q, J 7.0 Hz, 1H), 6.77 (s,
2H), 7.04 (s, 1H) ppm; 13C NMR (125 MHz, CDCl3) 163.2, 159.9,
152.2, 138.8, 127.9, 126.9, 119.9, 108.5(2), 82.28, 65.9, 61.0, 58.4,
56.3(2), 45.5, 30.8, 30.1, 28.6, 25.2, 23.8, 23.6, 22.5; Anal. Calcd
for C23H30N2O6: C, 64.17; H, 7.02; N, 6.51; Found: C, 64.21; H,
7.07; N, 6.48.
Cyclo[N-methyloxy-2-(phenylmethylene)glycyl-prolyl] 4c
Cyclo[N-benzyloxy-2-[(3,4,5-trimethyloxy)phenylmethylene]
glycyl-prolyl] 4g
The product 4c was obtained according to the general procedure
in 87% yield after purification by silica gel flash chromatography
(EtOAc–hexane, 1 : 2). Chiral HPLC analyses of the product
showed a major peak for the (S)-enantiomer at Rf 14.5 min (99.3%
e.e.) compared to racemic 4c (synthesized by using racemic 3c)
The product 4g was obtained according to the general procedure
in 87% yield after purification by silica gel flash chromatography
(EtOAc/hexane, 1 : 2). IR (KBr) n 1698, 1677, 1621, 1608, 1583,
7480 | Org. Biomol. Chem., 2011, 9, 7476–7481
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The Royal Society of Chemistry 2011
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