Veerman et al.
(m, 1H), 3.85 (d, J ) 14.9 Hz, 1H), 3.74 (q, J ) 7.0 Hz, 1H),
3.73 (s, 3H), 3.41 (dd, J ) 3.7, 14.5 Hz, 1H), 3.28 (dd, J ) 7.7,
14.5 Hz, 1H), 0.96 (d, J ) 7.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 168.9, 165.6, 137.0, 135.5, 128.8, 128.4, 128.2, 127.9,
127.6, 122.0, 119.5, 119.1, 109.3, 108.0, 56.5, 54.1, 32.6, 31.5,
18.1. IR: ν 3229, 1683, 1654. HRMS (FAB): calcd for
49.9, 48.9, 31.4. IR: ν 1781, 1729, 1667, 1268. HRMS (FAB):
calcd for C24H25N4O4 (MH+) 433.1876, found 433.1861.
4-Ben zyl-3,6-d ioxo-2-p r op -2-yn ylp ip er a zin e-1-ca r box-
ylic Acid Meth yl Ester (r a c-24e). According to general
procedure D, protection of rac-23e (0.64 g, 2.64 mmol) afforded
rac-24e (0.66 g, 84%) as a clear sticky oil after purification by
chromatography (Et2O). Rf ) 0.30. 1H NMR (400 MHz,
CDCl3): δ 7.37-7.29 (m, 5H), 4.89 (t, J ) 4.1 Hz, 1H), 4.86 (d,
J ) 14.5 Hz, 1H), 4.41 (d, J ) 14.5 Hz, 1H), 4.28 (d, J ) 18.4
Hz, 1H), 3.92 (s, 3H), 3.86 (d, J ) 18.4 Hz, 1H), 3.06-3.03 (m,
2H), 1.91 (t, J ) 2.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
164.9, 164.4, 152.7, 134.5, 128.9, 128.6, 128.3, 78.1, 73.3, 57.3,
54.6, 50.8, 49.4, 24.0. IR (film): 3285, 2250, 1718, 1655. HRMS
(FAB): calcd for C16H17N2O4 (MH+) 301.1188, found 301.1183.
2-Allyl-4-ben zyl-3,6-d ioxop ip er a zin e-1-ca r boxylic Acid
Meth yl Ester (r a c-24f). According to general procedure D,
protection of rac-23f (0.43 g, 1.77 mmol) afforded rac-24f (0.40
g, 75%) as a clear sticky oil after purification by chromatog-
raphy (PE/EtOAc, 1/1). Rf ) 0.28. 1H NMR (400 MHz, CDCl3):
δ 7.38-7.22 (m, 5H), 5.77-5.67 (m, 1H), 5.16-5.09 (m, 2H),
4.96 (t, J ) 3.9 Hz, 1H), 4.80 (d, J ) 14.4 Hz, 1H), 4.37 (d, J
) 14.4 Hz, 1H), 3.98 (d, J ) 18.5 Hz, 1H), 3.90 (s, 3H), 3.84
(d, J ) 18.5 Hz, 1H), 2.72-2.62 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 165.7, 164.6, 152.5, 134.8, 130.8, 129.0, 128.5, 128.3,
121.0, 58.7, 54.4, 50.5, 49.3, 37.7. IR: 1783, 1731, 1671, 1275.
HRMS (FAB): calcd for C16H19N2O4 (MH+) 303.1345, found
303.1344.
((E)/(Z))-4-Ben zyl-3,6-d ioxo-2-(4-tr im eth ylsila n ylbu t-2-
en yl)p ip er a zin e-1-ca r boxylic Acid Meth yl Ester (r a c-
24g). To solution of rac-24f (211 mg, 0.7 mmol) and allyltri-
methylsilane (0.33 mL, 2.1 mmol) in dry toluene (15 mL) under
argon, Ru-catalyst (59 mg, 70 µmol) was added and the
reaction mixture was stirred at 80 °C for 20 h. Concentration
of the reaction mixture and further purification by chroma-
tography (PE/EtOAc, 1.2/1 f 1/1) afforded rac-24g (141 mg,
52%) as an oil. Rf ) 0.40 (PE/EtOAc, 1.2/1). 1H NMR (500 MHz,
DMSO-d6, 130 °C, 3:1 mixture): δ 7.40-7.25 (m, 5H), 5.96-
5.90 (m, 0.25H), 5.83-5.78 (m, 0.25H), 5.55-5.48 (m, 0.75H),
5.24-5.11 (m, 0.75H), 4.80-4.63 (m, 2H), 4.43-4.37 (m, 1H),
4.18-4.10 (m, 1H), 4.02-3.94 (m, 1H), 3.81 (s, 3H), 2.75-2.55
(m, 2H), 1.45-1.25 (m, 2H), 0.02 (s, 2.25H), -0.04 (s, 6.75H).
13C NMR (125 MHz, DMSO-d6, 100 °C, 3:1 mixture): δ 164.9,
164.7, 163.7, 163.6, 151.8, 151.7, 139.2, 135.5, 131.2, 129.5,
128.1, 128.0, 127.5, 127.5, 127.1, 127.0, 120.9, 119.5, 58.6, 58.4,
57.9, 53.2, 50.0, 49.9, 48.0, 47.9, 35.4, 29.6, 21.9, 17.6, -2.1,
-2.5. IR: ν 2953, 1783, 1731, 1668, 1271. HRMS (FAB): calcd
for C20H29N2O4Si (MH+) 389.1897, found 389.1876.
C
22H22N3O2 (MH+) 362.1869, found 362.1871.
Gen er a l P r oced u r e D for Ca r b a m a t e P r ot ect ion of
Dik et op ip er a zin es. To a solution of the diketopiperazine,
DMAP (2 equiv), and triethylamine (2 equiv) in dry, ethanol-
free CH2Cl2 (0.5 M) at 0 °C was added dropwise methyl
chloroformate (4 equiv). The reaction mixture was allowed to
warm to room temperature and stirred for 20 h. The organic
layer was washed with 1 M HCl and brine, dried (MgSO4),
and evaporated to give the protected diketopiperazine.
(2S)-2,4-Diben zyl-3,6-dioxopiper azin e-1-car boxylic Acid
Meth yl Ester ((S)-24a ). According to general procedure D,
protection of (S)-23a (0.21 g, 0.71 mmol) afforded (S)-24a (0.19
g, 76%) as a white amorphous solid after purification by
chromatography (PE/EtOAc, 1/1). Rf ) 0.30. [R]21 ) +96 (c
D
1
1.0, CH2Cl2). Mp ) 115-117 °C. H NMR (200 MHz, CDCl3):
δ 7.31-6.89 (m, 10H), 5.19-5.09 (m, 1H), 4.40 (br s, 2H), 3.88
(s, 3H), 3.35 (d, J ) 18.3 Hz, 1H), 3.32 (dd, J ) 3.6, 13.9 Hz,
1H), 3.22 (dd, J ) 4.8, 13.9 Hz, 1H), 2.17 (d, J ) 18.3 Hz, 1H).
13C NMR (50 MHz, CDCl3): δ 165.3, 164.4, 152.5, 134.1, 134.0,
130.1, 128.9, 128.6, 128.5, 128.0, 127.5, 60.0, 54.3, 49.3, 49.1,
38.7. HRMS (FAB): calcd for C20H21N2O4 (MH+) 353.1501,
found 353.1506.
(2S)-4-Ben zyl-2-(4-ter t-b u t oxyb en zyl)-3,6-d ioxop ip er -
a zin e-1-ca r boxylic Acid Meth yl Ester ((S)-24b). According
to general procedure D, protection of (S)-23b (0.27 g, 0.74
mmol) afforded (S)-24b (0.26 g, 82%) as a clear oil after
purification by chromatography (PE/EtOAc, 2/3). Rf ) 0.47.
[R]21 ) +87 (c 1.0, CH2Cl2). 1H NMR (200 MHz, CDCl3): δ
D
7.29-7.14 (m, 5H), 6.82 (d, J ) 8.4 Hz, 2H), 6.62 (d, J ) 8.4
Hz, 2H), 5.10-4.99 (m, 1H), 4.35 (d, J ) 14.3 Hz, 1H), 4.31 (d,
J ) 14.3 Hz, 1H), 3.86 (s, 3H), 3.35 (d, J ) 18.2 Hz, 1H), 3.27
(dd, J ) 3.4, 16.0 Hz, 1H), 3.16 (dd, J ) 4.8, 16.0 Hz, 1H),
2.19 (d, J ) 18.2 Hz, 1H), 1.21 (s, 9H). 13C NMR (50 MHz,
CDCl3): δ 165.5, 164.3, 154.9, 152.5, 134.3, 130.7, 128.9, 128.8,
128.6, 128.1, 124.1, 78.3, 60.1, 54.7, 49.3, 49.1, 38.0, 28.6.
(2S)-4-Ben zyl-2-(1-m eth yl-1H-in d ol-3-ylm eth yl)-3,6-d i-
oxop ip er a zin e-1-ca r boxylic Acid Meth yl Ester ((S)-24c).
According to general procedure D, protection of (S)-23c (100
mg, 0.29 mmol) afforded (S)-24c (59 mg, 50%) as a white solid
after purification by chromatography (PE/EtOAc, 1/1). Rf )
1
0.23. [R]21 ) +107.5 (c 1.0, CH2Cl2). Mp ) 147 °C. H NMR
D
(2S,5S)-2,4-Dib en zyl-5-m et h yl-3,6-d ioxop ip er a zin e-1-
ca r boxylic Acid Meth yl Ester ((S,S)-27a ). According to
general procedure D, protection of (S,S)-26a (192 mg, 0.62
mmol) afforded (S,S)-27a (140 mg, 62%) as a colorless oil after
(400 MHz, CDCl3): δ 7.53 (d, J ) 7.9 Hz, 1H), 7.29-7.13 (m,
6H), 7.00-6.96 (m, 2H), 6.72 (s, 1H), 5.15-5.13 (m, 1H), 4.80
(d, J ) 14.6 Hz, 1H), 3.92 (s, 3H), 3.66 (s, 3H), 3.65 (dd, J )
2.9, 15.1 Hz, 1H), 3.41 (dd, J ) 4.9, 15.1 Hz, 1H), 3.36 (d, J )
14.6 Hz, 1H), 3.22 (d, J ) 18.3 Hz, 1H), 2.06 (d, J ) 18.3 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 166.3, 165.0, 152.7, 136.9,
134.4, 129.6, 128.7, 128.5, 128.0, 127.5, 122.2, 119.7, 119.1,
109.3, 106.3, 54.4, 49.3, 48.8, 32.7, 28.8. IR: ν 1781, 1730, 1667.
HRMS (FAB): calcd for C23H24N3O2 (MH+) 406.1767, found
406.1771.
purification by chromatography (PE/EtOAc, 1/1). Rf ) 0.42.
1
[R]21 ) +17.6 (c 1.0, CH2Cl2). H NMR (400 MHz, CDCl3): δ
D
7.34-7.15 (m, 10H), 5.30 (d, J ) 14.8 Hz, 1H), 5.16 (t, J ) 5.3
Hz, 1H), 3.86 (q, J ) 7.1 Hz, 1H), 3.83, (d, J ) 14.8 Hz, 1H),
3.82 (s, 3H), 3.35 (dd, J ) 5.3, 14.0 Hz, 1H), 3.29 (dd, J ) 5.1,
14.0 Hz, 1H), 0.74 (d, J ) 7.1 Hz, 3H). 13C NMR (50 MHz,
CDCl3): δ 167.4, 164.6, 135.1, 135.0, 130.4, 128.9, 128.8, 128.4,
128.1, 127.6, 60.2, 55.5, 54.4, 46.5, 39.6, 17.4. IR (film): ν 1781,
1730, 1660, 1256. HRMS (FAB): calcd for C21H23N2O4 (MH+)
367.1658, found 367.1639.
(2S)-4-Ben zyl-2-(1-ben zyl-1H-im id a zol-4-ylm eth yl)-3,6-
d ioxop ip er a zin e-1-ca r boxylic Acid Meth yl Ester ((S)-
24d ). According to general procedure D, protection of (S)-23d
(253 mg, 0.63 mmol) afforded (S)-24d (159 mg, 72%) as a white
solid after purification by chromatography (MeOH/EtOAc,
(2R,5S)-2,4-Dib en zyl-5-m et h yl-3,6-d ioxop ip er a zin e-1-
ca r boxylic Acid Meth yl Ester ((R,S)-27a ). According to
general procedure D, protection of (R,S)-26a (240 mg, 0.78
mmol) afforded (R,S)-27a (108 mg, 38%) as a colorless oil after
purification by chromatography (PE/EtOAc, 1/1). Rf ) 0.41.
1/20). Rf ) 0.21. [R]21 ) +16.6 (c 1.0, CH2Cl2). Mp ) 58 °C.
D
1H NMR (400 MHz, CDCl3): δ 7.38-7.20 (m, 9H), 7.11-7.08
(m, 2H), 6.59 (d, J ) 1.1 Hz, 1H), 5.08 (dd, J ) 3.7, 5.2 Hz,
1H), 4.91 (d, J ) 15.1 Hz, 1H), 4.87 (d, J ) 15.1 Hz, 1H), 4.51
(d, J ) 14.5 Hz, 1H), 4.24 (d, J ) 14.5 Hz, 1H), 3.87 (s, 3H),
3.50 (d, J ) 18.2 Hz, 1H), 3.31 (dd, J ) 3.7, 14.8 Hz, 1H), 3.21
(dd, J ) 5.2, 14.8 Hz, 1H), 2.84 (d, J ) 18.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 165.8, 165.2, 152.7, 136.1, 135.9, 134.8,
129.0, 128.8, 128.7, 128.4, 128.0, 127.3, 118.4, 59.4, 54.3, 50.8,
[R]21 ) -94.6 (c 0.97, CH2Cl2). 1H NMR (400 MHz, CDCl3):
D
δ 7.33-7.03 (m, 10H), 5.16 (t, J ) 4.5 Hz, 1H), 4.82 (d, J )
15.2 Hz, 1H), 4.30 (d, J ) 15.2 Hz, 1H), 3.90 (s, 3H), 3.38 (dd,
J ) 4.2, 14.0 Hz, 1H), 3.32 (dd, J ) 4.8, 14.0 Hz, 1H), 2.88 (q,
J ) 7.0 Hz, 1H), 1.37 (d, J ) 7.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 168.1, 166.3, 152.9, 135.7, 134.4, 130.4, 128.7, 128.6,
4492 J . Org. Chem., Vol. 68, No. 11, 2003