Ö. Davidsson et al.
FULL PAPER
4
0 mL) and then sonicated to finely
divide the crystals. TiCl
4
(1.5 mL,
1
3.7 mmol) was added to a mixture
H
of NaBH
4
(1.09 g, 29.0 mmol) in dry
C
[12]
DME (20 mL) at 08C. The diketo-
piperazine slurry was added to the
flask at 08C. DME (10 mL) was then
added, and the reaction mixture was
stirred at room temperature overnight
and then quenched with water. The
precipitate which had formed was
filtered off, and the filtrate was made
Li
N
H
C
O
Li
O
Zn
N
Li
N
Zn
Li
N
3
alkaline with 25% NH . The alkaline
solution was extracted with dichloro-
Figure 6. The six-center reactive complex that is suggested to be involved in the addition reaction.
methane (3 Â 75 mL). The combined
tion reactions were dried at 508C in a vacuum oven before transfer into a
glove box (Mecaplex GB80 equipped with a gas-purification system to
remove oxygen and moisture) containing a nitrogen atmosphere. Typical
moisture content was <0.5 ppm. Ethereal solvents, distilled from sodium
and benzophenone under nitrogen, were kept over 4 molecular sieves in
a septum-sealed flask inside the glove box. The concentration of the
commercially available nBuLi solution (nBuLi, 2.5m solution in hexanes,
4
organic layers were dried over anhydrous MgSO and evaporated. The
residue was dissolved in methanol (50 mL) and HCl (6m, 30 mL) and
stirred over night to hydrolyze the titanium complexes formed. Methanol
was evaporated, and the remaining solution was made alkaline with NaOH
(1m). The solution was extracted with CH
combined organic layers were dried over anhydrous MgSO
2
Cl
2
(3 Â 75 mL) and the
4
and evapo-
1
rated. Yield 0.84 g (70%); H NMR (CDCl
1.23 (m, 1H), 1.47 (m, 1H), 1.63 (m, 1H), 1.67 (m, 2H), 1.88 (m, 1H), 2.25
(m, 1H), 2.64 (m, 1H), 2.81 (m, 4H).
3
, 500 MHz): d 0.90 (m, 12H),
[11]
Aldrich) was determined by titration with biphenylmethanol. Routine
1
13
1
D H and C NMR spectra were recorded on a Varian Unity 400 MHz
instrument. Chromatographic analyses were carried out on a Varian Star
400CX gas chromatograph. All GC analyses were run on a chiral
Enantioselective alkylation of benzaldehyde: Compound
0.04 mmol) was dissolved in toluene (3 mL) and cooled to 08C. nBuLi
38 mL, 0.09 mmol, 2.4m in hexane) was added and stirred for 10 min at
8C. Pure Et Zn (160 mL, 1.56 mmol, 9.76m) was added to the ice-cooled
1 (8 mL,
3
ꢁ
stationary phase column (CP-Chirasil-DEXCB, 25 m, 0.32 mm) from
(
Chrompack. All analyses were performed at 1158C (injector: 2258C;
0
2
�
1
detector: 2508C) with He (2 mLmin ) as the carrier gas.
mixture, and the resulting solution was stirred for 30 min. Benzaldehyde
(78 mL, 0.76 mmol) was added and the reaction mixture was stirred at 208C
for 20 h. The reaction was monitored by withdrawing 20 mL samples, which
were quenched in diethylether (1 mL) and HCl (0.5 mL, 1m). The layers
were separated, and the organic phase was washed with saturated NaCl and
NMR spectroscopy: All NMR spectra were recorded on a Varian Unity 500
1
13
6
15
spectrometer equipped with three channels and a 5 mm H, C, Li,
N
quad-resonance probe head, custom built by Nalorac. Measuring frequen-
1
6
1
13
cies were 500 MHz ( H) and 74 MHz ( Li). The H and C spectra were
referenced to the solvent signals: [D
8
]THF d 3.58. Lithium spectra were
2
dried over anhydrous Na S. The same procedure was followed for the
mono- and nonlithiated piperazine reactions; however, the amount of
nBuLi was altered.
6
referenced to external [ Li]Cl in [D
4
]MeOH (0.3m; d 0.0). A typical 908
6
Li pulse was 12 ms.
Preparation of (2S,5S)-2-isobutyl-5-isopropylpiperazine (1)
Boc-Val-Leu-OMe: Boc-(l)-Val-OH (12.67 g, 58.3 mmol) and H-(l)-Leu-
OMe (9.83 g, 58.6 mmol) was dissolved in dichloromethane (180 mL).
Triethylamine (8.5 mL, 61.0 mmol) was added, and the reaction mixture
cooled to 08C. N,N'-dicyclohexylcarbodiimide (DCC; 12.53 g, 60.7 mmol)
was added. The reaction mixture was stirred at 08C. After 4 h the mixture
was heated to room temperature and stirred overnight. The solid was
filtered off by suction, and the filtrate was evaporated. The residue was
dissolved in ethyl acetate and washed with 2% HCl (3 Â 100 mL), 4%
Acknowledgments
We thank the Swedish Natural Science Research Council and the Carl
Trygger Foundation for financial support.
NaHCO
3
(3 Â 100 mL), and finally brine (3 Â 100 mL). The organic layer
, filtrated, and evaporated. The residue
[
[
1] K. Soai, S. Niwa, Chem. Rev. 1992,92, 833 ± 856.
2] T. Mukaiyama, K. Soai, T. Sato, H. Shimizu; K. Suzuki, J. Am. Chem.
Soc. 1979, 101, 1455; J. P. Mazaleyrat, D. J. Cram, J. Am. Chem. Soc.
was dried over anhydrous MgSO
4
was recrystallized from ethyl acetate/diethyl ether. Yield 12.72 g (67%);
1
H NMR (CDCl
3
, 500 MHz): d 0.99 (dd, 12H), 1.48 (d, 9H), 1.60 (q, 1H),
1
2
981, 103, 4585; M. B. Eleveld, H. Hogeveen, Tetrahedron Lett. 1984,
5, 5187; S. Kanoh, H. Muramoto, K. Maeda, N. Kawaguchi, M.
1
.69 (m, 3H), 2.15 (m, 1H), 3.76 (s, 3H), 3.93 (dd, 1H), 4.66 (dt, 1H), 5.09
(
d, 1H), 6.26 (s, 1H).
Motoi, H. Suda, Bull. Chem. Soc. Jpn. 1988, 61, 2244; M. Ye, S.
Logaraj, L. M. Jackman, K. Hillegrass, K. A. Hirsh, A. M. Bollinger,
A. L. Grosz, Tetrahedron 1994, 50, 6109; A. Basu, P. Beak, J. Am.
Chem. Soc. 1996, 118, 1575; A. Corruble, J.-Y. Valnot, J. Maddaluno,
Y. Prigent, D. Davoust, P. Duhamel, J. Am. Chem. Soc. 1997, 119,
0042; K. Tomioka, M. Nakajima, K. Koga, Chem. Lett. 1987, 65; T. D.
Inch, G. J. Lewis, G. L. Sainsbury, D. J. Sellers, Tetrahedron Lett. 1969,
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985, 118, 3673; M. T. Reetz, T. Kükenhöhner, P. Weinig, Tetrahedron
(
2S,5S)-2-isobutyl-5-isopropyldiketopiperazine: The tBoc-protected di-
amino acid (38.7 mmol) prepared above was deprotected in formic acid
100 mL). After the solution was stirred at room temperature for 2 h, the
(
reaction mixture was evaporated under reduced pressure at a temperature
below 308C. The residue was dissolved in methanol and was evaporated
under reduced pressure at a temperature below 308C. One-third of the
residue was then dissolved in s-butanol (130 mL) and toluene (80 mL). The
solvent was distilled off and fresh s-butanol was added continuously. The
distillation was interrupted after 2 h and the reaction mixture was allowed
to cool to room temperature. The crystals formed were filtered off, and the
filtrate was evaporated. A second crop of crystals was obtained by
evaporating the filtrate, redissolving the precipitate in methanol, and
precipitating by addition of DEE. The precipitate was filtered off and
1
3
1
Lett. 1986, 27, 5711.
[
3] R. Noyori, M. Kitamura, Angew. Chem. 1991, 103, 34; Angew. Chem.
Int. Ed. Engl. 1991, 30, 49; H. Urabe, T. Yamakawa, F. Sato,
Tetrahedron: Asymmetry 1992, 3, 5; K. Stingl, J. Martens, Liebigs.
Ann. 1994, 491; M. Asami, S. Inoue, Bull. Chem. Soc. Jpn. 1997, 70,
pooled together with the first crop of crystals. Yield (based on the tboc-
1
687, and references therein; A. Vidal-Ferran, A. Moyano, M. A.
1
diamino acid): 3.53 g (46%); H NMR (CDCl
3
3
, 500 MHz): d 0.96 (d,
Pericas, A. Riera, Tetrahedron Lett. 1997, 38, 8773; A. Vidal-Ferran, A.
Moyano, M. A. Pericas, A. Riera, J. Org. Chem. 1997, 62, 4970; W.-S.
Huang, Q.-S. Hu, L. Pu, J. Org. Chem. 1998, 63, 1364; K. R. K. Prasad,
N. N. Joshi, J. Org. Chem. 1997, 62, 3770; H. Kotsuki, M. Wakao, H.
Hayakawa, T. Shimanouchi, M. Shiro, J. Org. Chem. 1996, 61, 8915; E.
Rijnberg, N. J. Hovestad, A. W. Kleij, J. T. B. H. Jastrzebski, J.
H), 1.01 (d, 3H), 1.06 (d, 3H), 1.56 (m, 2H), 1.63 (ddd, 1H), 1.78 (m, 1H),
1.92 (ddd, 1H), 2.45 (m, 1H), 3.92 (s, 1H), 4.03 (d, 1H), 5.89 (s, 1H), 6.04
(
s, 1H).
(
2S,5S)-2-isobutyl-5-isopropylpiperazine (1): The diketopiperazine crys-
tals (0.91 g, 0.46 mmol) were suspended in dry dimethoxyethane (DME,
2
360
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