1636
A. Minatti, K. H. Dötz
LETTER
Table 4 Asymmetric Epoxidation of Alkyl-Substituted Enones
(2) (a) Juliá, S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed.
Engl. 1980, 19, 929. (b) For a recent review, see: Porter, M.
J.; Roberts, S. M.; Skidmore, J. Bioorg. Med. Chem. 1999, 7,
2145. (c) Pu, L. Tetrahedron: Asymmetry 1998, 9, 1457.
(d) Ebrahim, S.; Wills, M. Tetrahedron: Asymmetry 1997, 8,
3163.
(3) (a) Enders, D.; Zhu, J.; Raabe, G. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1725. (b) Enders, D.; Zhu, J.; Kramps, L.
Liebigs Ann. Recl. 1997, 1101. (c) Enders, D.; Kramps, L.;
Zhu, J. Tetrahedron: Asymmetry 1998, 9, 3959.
1) (R)-BINOL (20 mol%), Et2O
2) ZnEt2 (36 mol%), 0 °C, 15 min
3) oxidant (1.2 equiv), 0 °C → r.t., 12 h
O
O
R1
Ph
R1
Ph
O
1
2
Entry Enone R1c Oxidant
Productd
Yield (%)a ee (%)b
1
Me
TBHP
CMHP
TBHP
CMHP
TBHP
CMHP
TBHP
CMHP
TBHP
CMHP
2f
24
40
54
48
50
60
40
54
40
80
80
(4) Yu, H.-B.; Zheng, X.-F.; Lin, Z.-M.; Hu, Q.-S.; Huang, W.-
S.; Pu, L. J. Org. Chem. 1999, 64, 8149.
1f
2
Me
1f
2f
60
(5) (a) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1997, 119, 2329.
(b) Kinoshita, T.; Okada, S.; Park, S.-R.; Matsunaga, S.;
Shibasaki, M. Angew. Chem. Int. Ed. 2003, 42, 4680.
(c) Ohshima T., Nemoto T., Tosaki S.-y., Kakei H.,
Gnanadesikan V., Shibasaki M.; Tetrahedron; 2003, 59:
10485. (d) Tosaki, S.-y.; Nemoto, T.; Ohshima, T.;
Shibasaki, M. Org. Lett. 2003, 5, 495. (e) Chen, R.; Qian,
C.; de Vries, J. G. Tetrahedron 2001, 57, 9837.
3
Et
1g
2g
2g
2h
2h
2i
28
4
Et
1g
79
5
Pr
1h
72
(6) Typical Procedure for the Asymmetric Epoxidation:
(R)-BINOL (57 mg, 0.2 mmol) was dissolved in Et2O (20
mL) in a 50 mL Schlenk flask equipped with a magnetic
stirring bar under an inert atmosphere. After cooling to 0 °C
with an ice-bath ZnEt2 (0.33 mL, 0.36 mmol, 1.1 M solution
in toluene) was added with stirring. After 15 min the a,b-
unsaturated ketone (1 mmol) and the oxidant (0.24 mL, 1.2
mmol, 5–6 M in decane in the case of TBHP; 0.22 mL, 1.2
mmol, 80% solution in cumene in the case of CMHP) were
added, and the resulting mixture was allowed to warm to r.t.
overnight. The reaction was quenched with aq sat. NaHSO3
and extracted with EtOAc. The organic layer was washed
with aq Na2CO3 and brine. The combined organic layers
were dried over MgSO4 and the solvent was evaporated in
vacuo. The residue was purified by column chromatography
(SiO2: Macherey–Nagel type 60, 0.063–-0.2 mm). CH2Cl2
was used as eluent in all cases and remaining starting
material and the a,b-epoxy-ketone were isolated in this
sequence. As the last fraction (R)-BINOL was recovered
almost quantitatively. The ee of the epoxides were
determined by HPLC analysis on a stationary phase:
Chiracel OD/OD-H column with n-hexane–2-propanol as
eluent and 254 nm UV detector. The absolute configuration
of the products has been assigned by comparison of optical
rotation with literature values and the elution order of the
two enantiomers on the HPLC column.
6
Pr
1h
78
7
i-Pr
1i
36
8
i-Pr
1i
2i
75
9
t-Bu
1k
2k
2k
<10
73
10
t-Bu
1k
a trans-Isomer (de >99%).
b Determined by HPLC analysis on a chiral stationary phase.8
c Ref.7
d Ref.8
In summary, we have shown that the combination of enan-
tiomerically pure BINOL and dialkylzinc provides an ef-
fective catalyst for the asymmetric epoxidation of a,b-
enones. This catalytic epoxidation proceeds with good
enantiomeric excesses and complete diastereoselectivity,
yielding exclusively the trans-isomer. A remarkable ef-
fect regarding the oxidant was observed and CMHP
proves to be the oxidant of choice. Overall, the ease of
conductance and the easy recovery of both commercially
available BINOL-enantiomers render the described pro-
cedure an attractive protocol.
(7) The syntheses of the a,b-unsaturated ketones have been
described previously: (a) 1a and 1e: Dimmock, J. R.; Zello,
G. A.; Oloo, E. O.; Quail, J. W.; Kraatz, H.-B.; Perjesi, P.;
Aradi, F.; Takacs-Novak, K.; Allen, T. M.; Santos, C. L.;
Balzarini, J.; De Clercq, E.; Stables, J. P. J. Med. Chem.
2002, 45, 3103. (b) 1b and 1d (1d was synthesised by an
analogous procedure as for the corresponding chloride):
Krauss, S. R.; Smith, S. G. J. Am. Chem. Soc. 1981, 103,
141. (c) 1f, 1g, 1h, and 1i: See ref.3b (d) 1k: Wiberg, K. B.;
Rowland, B. I. J. Am. Chem. Soc. 1955, 77, 1159.
Acknowledgment
(8) The characterisation of the a,b-epoxy ketones and the
conditions for the chiral HPLC analysis have been described
previously: (a) 2a, 2b, and 2e: Adam, W.; Rao, P. B.; Degen,
H.-G.; Saha-Möller, C. R. J. Am. Chem. Soc. 2000, 122,
5654. (b) 2d: Complete characterisation of 2d was
accomplished (c) 2f, 2g, 2h, and 2i: See ref.3b (d) 2k: See
ref.4
We thank the Fonds der Chemischen Industrie for a doctoral
fellowship (Ana Minatti) and financial support.
References
(1) For a recent review, see: (a) Porter, M. J.; Skidmore, J.
Chem. Commun. 2000, 1215. (b) Nemoto, T.; Ohshima, T.;
Shibasaki, M. J. Synth. Org. Chem. Jpn. 2002, 60, 94.
Synlett 2004, No. 9, 1634–1636 © Thieme Stuttgart · New York