Enantiopure Piperazines and Ketopiperazines
freshly distilled chloroacetyl chloride was added. The mixture was
stirred and allowed to warm to room temperature until disappearance
of the starting material (TLC). The layers were separated, and the
aqueous phase was extracted twice with CH2Cl2 (5 mL/mmol). The
combined organic extracts were washed with a saturated solution
of NaCl, dried over Na2SO4, and filtered to give, after evaporation
of the solvents, a crude product that was purified by chromatography
on silica gel to afford chloroacetamide 7 or 11.
mixture was cooled to room temperature and water (5 mL/mmol
of NaH), and CH2Cl2 (5 mL/mmol) was added. The layers were
separated, and the aqueous phase was extracted with CH2Cl2 (3 ×
5 mL/mmol). The combined organic extracts were washed with a
saturated solution of NaCl (10 mL/mmol), dried over Na2SO4,
filtered, and concentrated under reduced pressure to give a crude
product that was purified by column chromatography on silica gel.
(+)-(5R,6S)-1-Benzyl-6-(t-butyldimethylsilyloxymethyl)-5-(2-
phenylethyl)-5,6-dihydro-1H-pyrazin-2-one, 9b. 9b (27 mg, 0.062
mmol, 87%) was obtained as a yellow oil from 8b (41 mg, 0.071
mmol) according to the general procedure (2 h 30 min) and after
purification by column chromatography (20-40% Et2O-hexane).
(+)-N-Benzyl-N-[(1S,2R,SS)-1-(t-butyldimethylsilyloxymethyl)-
4-phenyl-2-(p-tolylsulfinylamino)but-1-yl] 2-chloroacetamide,
7b. 7b (76 mg, 0.831 mmol, 83%) was obtained as a white solid
from 6b (80 mg, 0.149 mmol) following the general procedure (24
h) and after purification by column chromatography (20-40%
Et2O-hexane) and crystallization (CH2Cl2-hexane). Data for 7b:
Rf ) 0.18 (60% Et2O-hexane). mp: 110-112 °C. [R]D20 +356.3
(c ) 1.00). 1H NMR (400 MHz) δ -0.44 (s, 3 H), -0.20 (s, 3 H),
0.71 (s, 9 H), 1.55 (m, 2 H), 2.35-2.41 (m, 1 H), 2.38 (s, 3 H),
2.46-2.59 (m, 1 H), 3.71-3.87 (m, 4 H), 4.02 (d, 1 H, J ) 13.7
Hz), 4.27 (d, 1 H, J ) 13.9 Hz), 4.60 (br s, 1 H), 4.85 (d, 1 H, J
) 17.0 Hz), 4.96 (d, 1 H, J ) 18.1 Hz), 7.02-7.08 (m, 4 H), 7.14-
7.34 (m, 8 H), 7.60 (d, 2 H, J ) 8.1 Hz). 13C NMR (75 MHz) δ
-6.4 (2 C), 18.0, 21.4, 25.6 (3 C), 30.8, 35.0, 42.9, 49.4, 52.2,
58.7, 61.3, 125.6 (2 C), 125.8 (2 C), 127.4, 128.3 (3 C), 128.4 (2
C), 128.9 (2 C), 129.5 (2 C), 137.5, 141.5, 141.6, 141.9, 169.9. IR
(KBr): ν ) 3435, 3028, 2954, 2928, 2856, 1634, 1495, 1452, 1257,
1092, 1070, 986, 836, 813, 778, 727, 699 cm-1. MS (ES): 1249
[2M + Na]+, 615 [M + 3]+, 613 [M + 1]+ (100%), 481 [M
-(OTBDMS)]+. Anal. Calcd for C33H45ClN2O3SSi (613.3): C,
64.62; H, 7.40; N, 4.57; found: C, 64.97; H, 7.77; N, 4.36.
General Procedure for Synthesis of Ketopiperazines. A
solution of chloroacetamide 7 or 11 in DMF (10 mL/mmol) and
1.8 equiv of solid Cs2CO3 were stirred at 65 °C until the starting
material disappearance was monitored by TLC. The mixture was
cooled to room temperature and was diluted with CH2Cl2 (10 mL/
mmol) and H2O (10 mL/mmol). The layers were separated, and
the organic phase was washed with cold water (3 × 10 mL/mmol)
and a saturated solution of NaHCO3 (10 mL/mmol), dried over Na2-
SO4, filtered, and concentrated under reduced pressure to give a
crude product that was purified by gradient column chromatography.
(+)-(5R,6S,SS)-1-Benzyl-6-[(t-butyldimethylsilyloxy)methyl]-
5-(i-propyl)-4-(p-tolylsulfinyl)piperazin-2-one, 8c. 8c (38 mg,
0.074 mmol, 77%) was obtained from 7c (53 mg, 0.096 mmol) as
a white foam following the general procedure (2 h 30 min) and
after chromatography on silica gel (30-40% Et2O-hexane). Data
for 8c: Rf ) 0.21 (80% Et2O-hexane). [R]D20 +6.2 (c ) 1.40). 1H
NMR (300 MHz) δ 0.06 (s, 3 H), 0.10 (s, 3 H), 0.36 (d, 3 H, J )
6.6 Hz), 0.91 (s, 9 H), 1.09 (d, 3 H, J ) 6.6 Hz), 1.55-1.68 (m,
1 H), 2.39 (s, 3 H), 3.31 (d, 1 H, J ) 18.1 Hz), 3.36 (ddd, 1 H, J
) 8.6, 5.3, 1.3 Hz), 3.43 (dd, 1 H, J ) 10.8, 1.3 Hz), 3.49 (ap t,
1 H, J ) 8.6 Hz), 3.63 (dd, 1 H, J ) 10.0, 5.3 Hz), 3.71 (d, 1 H,
J ) 18.3 Hz), 3.83 (d, 1 H, J ) 14.4 Hz), 5.25 (d, 1 H, J ) 14.4
Hz), 7.22-7.31 (m, 7 H), 7.54 (d, 2 H, J ) 8.3 Hz). DNOE between
CH3 (1.09)/CH3 (0.36): 5.8%; CH3 (1.09)/CH (iPr): 11.0%; CH3
(1.09)/H-5: 4.6%; CH3 (1.09)/H-3 (3.71): 3.0%; CH (iPr)/H-3
(3.71): 3%; CH (iPr)/ H-5: 1.2%; CH (iPr)/H-6: 1.2. 13C NMR
(75 MHz) δ -5.3 (2 C), 18.1, 19.7, 21.0, 21.3, 25.8 (3 C), 26.8,
40.6, 48.7, 57.5, 62.3, 63.6, 125.4 (2 C), 128.1, 128.8 (2 C), 129.1
(2 C), 129.6 (2 C), 136.6, 139.9, 141.8, 165.3. IR (film): ν ) 3028,
2954, 2927, 2855, 1658, 1470, 1457, 1374, 1254, 1152, 1089, 955,
837, 777, 701 cm-1. MS (ES): 537 [M + Na]+, 515 [M + 1]+
(100%), 375 [M - (pTolSO)]+. Anal. Calcd for C28H42N2O3SSi
(514.8): C, 65.33; H, 8.22; N, 5.44; S, 6.23; Si, 5.46; found: C,
65.45; H, 8.07; N, 5.28.
20
Data for 9b: Rf ) 0.28 (70% Et2O-hexane). [R]D +243.5 (c )
2.20). 1H NMR (300 MHz) δ 0.00 (s, 3 H), 0.01 (s, 3 H), 0.85 (s,
9 H), 1.18-1.32 (m, 1 H), 1.64-1.76 (m, 1 H), 2.28 (t, 2 H, J )
7.8 Hz), 3.32 (ap t, 1 H, J ) 6.3 Hz), 3.52 (dd, 1 H, J ) 10.2, 7.0
Hz), 3.61 (dd, 1 H, J ) 10.3, 5.9 Hz), 3.91 (ap t, 1 H, J ) 7.1 Hz),
3.94 (d, 1 H, J ) 14.2 Hz), 5.34 (d, 1 H, J ) 14.2 Hz), 6.90 (d, 2
H, J ) 8.1 Hz), 7.11-7.23 (m, 3 H), 7.29-7.36 (m, 5 H), 7.74 (d,
1 H, J ) 1.2 Hz). 13C NMR (75 MHz) δ -5.6 (2 C), 18.1, 25.8 (3
C), 31.8, 34.3, 48.4, 55.8, 56.9, 62.9, 126.0, 128.1, 128.3 (4 C),
128.9 (2 C), 129.1 (2 C), 136.2, 140.7, 154.9, 155.3. IR (film): ν
) 3086, 3063, 3028, 2951, 2929, 2857, 1951, 1674, 1627, 1604,
1585, 1496, 1470, 1454, 1390, 1361, 1313, 1257, 1155, 1119, 1030,
1006, 938, 924, 838, 814, 778, 748, 699, 667 cm-1. MS (ES): 438
[M + 2]+, 437 [M + 1]+ (100%). Anal. Calcd for C26H36N2O2Si
(436.7): C, 71.51; H, 8.31; N, 6.42; O, 7.33; Si, 6.43; found: C,
71.57; H, 8.62; N, 6.53.
(+)-(5R,6S)-1-Benzyl-6-(t-butyldimethylsilyloxymethyl)-5-(i-
propyl)-5,6-dihydro-1H-pyrazin-2-one, 9c. 9c (20 mg, 0.053
mmol, 84%) was obtained as a colorless oil from 8c (33 mg, 0.064
mmol) according to the general procedure (3 h 45 min) and after
purification by column chromatography (20-30% Et2O-hexane).
20
Data for 9c: Rf ) 0.22 (60% Et2O-hexane). [R]D +189.5 (c )
0.60). 1H NMR (300 MHz) δ 0.00-0.09 (m, 6 H), 0.41 (d, 3 H, J
) 6.8 Hz), 0.85 (d, 3 H, J ) 6.8 Hz), 0.86 (s, 9 H), 1.38-1.48 (m,
1 H), 3.38 (ap t, 1 H, J ) 6.1 Hz), 3.50 (dd, 1 H, J ) 10.1, 6.7
Hz), 3.56 (dd, 1 H, J ) 10.3, 5.6 Hz), 3.62 (ap d, 1 H, J ) 7.8
Hz), 4.01 (d, 1 H, J ) 14.4 Hz), 5.21 (d, 1 H, J ) 14.2 Hz), 7.30
(m, 5 H), 7.79 (d, 1 H, J ) 1.5 Hz). 13C NMR (75 MHz) δ -5.6,
-5.5, 18.1, 19.0, 19.2, 25.8 (3 C), 32.0, 48.5, 54.4, 63.2, 63.7,
128.1 (2 C), 128.8, 129.3 (2 C), 136.1, 155.0, 155.1. IR (film): ν
) 3028, 2949, 2929, 2855, 1676, 1632, 1470, 1257, 1103, 837,
778 cm-1. MS (ES): 397 [M + Na]+, 375 [M + 1]+ (100%). Anal.
Calcd for C21H34N2O2Si (374.6): C, 67.33; H, 9.15; N, 7.48; O,
8.54; Si, 7.50; found: C, 67.55; H, 9.02; N, 7.23.
Procedure for Addition of Allyltributylstannane and TiCl4.
A solution of 9c (28 mg, 0.075 mmol) in CH2Cl2 (5 mL/mmol)
and 1 equiv of TiCl4 (14 mg, 8 µL, 0.075 mmol) was stirred at
-78 °C for 3 h, and then 2 equiv of allyltributylstannane (50 mg,
46 µL, 0.150 mmol) was added. After 1 h, the mixture was warmed
to room temperature and monitored by TLC (48 h). Then, the
mixture was hydrolyzed with 2 N aqueous NaOH (10 mL/mmol).
The solvent was evaporated in vacuo, and the residue was extracted
with CH2Cl2 (4 × 10 mL/mmol). The organic extracts were washed
with a saturated solution of NaHCO3, dried over Na2SO4, filtered,
and concentrated in vacuo to afford 13d and 14d as a 43:57 mixture.
The combined yield of the mixture after purification by column
chromatography (5-10% EtOAc-hexane) was 77% (24 mg, 0.058
mmol). Small amounts of 13d and 14d were separated after careful
chromatography on silica gel.
Procedure for Zinc-Mediated Barbier Allylation.23d To a
suspension of Zn powder (2 equiv), (12 mg, 0.176 mmol) in THF
(1.5 mL/mmol) at 0 °C, was added CeCl3‚7H2O (0.1 equiv, 3 mg,
0.009 mmol) and a solution of 9c (1 equiv) and 1.5 equiv of allyl
bromide in THF (3.0 mL/mmol 9c). The mixture was stirred from
0 °C to room temperature monitored by TLC (23-24 h) and then
was quenched with NH4Cl (6 mL/mmol). The layers were separated,
and the aqueous phase was extracted with CH2Cl2 (3 × 10 mL/
General Procedure for Synthesis of Imino Ketopiperazines
9. A solution of 8 in THF (5 mL/mmol) was added dropwise to a
cold (0 °C) suspension of 4 equiv of NaH (60% in mineral oil) in
anhydrous THF (5 mL/mmol of NaH), and the reaction mixture
was stirred at room temperature (1 h) and at reflux (1 h) until the
disappearance of the starting material was observed by TLC. The
J. Org. Chem, Vol. 71, No. 4, 2006 1447