Communications
which is similar to that proposed for the a-aminoxylation of
Experimental Section
aldehydes,[6] explains the absolute stereochemistry of the a-
aminoxylated products.
Typical experimental procedure (Table 2, entry 6): To a solution of
4,4-dimethylcyclohexanone (151.4 mg, 1.2 mmol) and l-proline
(6.9 mg, 0.06 mmol) in DMF (2.7 mL) was added a solution of
nitrosobenzene (64.2 mg, 0.6 mmol) in DMF (0.9 mL) over 24 h at
08C by syringe pump, and the mixture was stirred for 30 min at that
temperature. The reaction was quenched with phosphate buffer
solution (pH 7.0), and the organic materials were extracted with ethyl
acetate three times. The combined organic extracts were washed with
brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
Purification by silica gel column chromatography (ethyl acetate/
hexane 1:10–1:5) gave a-aminoxy ketone (116.7 mg, 0.50 mmol) in
84% yield and > 99% ee, as determined by chiral HPLC analysis.[18]
Next this asymmetric a-aminoxylation was applied to the
asymmetric desymmetrization of a 4-substituted cyclohexa-
none (Table 3). When 4-tert-butylcyclohexanone was treated
Table 3: Asymmetric desymmetrization of 4-substituted cyclohexa-
nones.[a]
Received: October 14, 2003 [Z53085]
Published Online: February 11, 2004
Keywords: asymmetric catalysis · ketones · oxidation · proline
ee [%][b]
.
R
Yield[%]
3
4
3
4
tBu
OSi-tBuPh2
31
46
31
23
>99
>99
94
96
[1] a) Review: F. A. Davis, B. C. Chen, Chem. Rev. 1992, 92, 919, and
references therein; b) D. Enders, V. Bhushan, Tetrahedron Lett.
1988, 29, 2437; c) B. B. Lohray, D. Enders, Helv. Chim. Acta 1989,
72, 980; d) D. Enders, U. Reinhold, Synlett 1994, 792; e) D.
Enders, U. Reinhold, Liebigs Ann. 1996, 11; f) D. Enders, B.
Bockstiegel, Synthesis 1989, 493.
[a] Reactions were conducted with 10 mol% catalyst, 1.0 equiv nitro-
sobenzene, and2.0 equiv ketone in DMF at 0 8C with slow addition of
nitrosobenzene. [b] Determinedby chiral HPLC.
[2] a) K. Morikawa, J. Park, P. G. Andersson, T. Hashiyama, K. B.
Sharpless, J. Am. Chem. Soc. 1993, 115, 8463; b) T. Hashiyama,
K. Morikawa, K. B. Sharpless, J. Org. Chem. 1992, 57, 5067.
[3] a) Y. Zhu, Y. Yu, H. Yu, Y. Shi, Tetrahedron Lett. 1998, 39, 7819;
b) W. Adam, R. T. Fell, C. R. Saha-Moller, C.-G. Zhao, Tetrahe-
dron: Asymmetry 1998, 9, 397.
[4] a) T. Fukuda, T. Katsuki, Tetrahedron Lett. 1996, 37, 4389; b) W.
Adam, R. T. Fell, V. R. Stegmann, C. R. Saha-Moller, J. Am.
Chem. Soc. 1998, 120, 708.
[5] N. Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2003, 125, 6038.
[6] a) S. P. Brown, M. P. Brochu, C. J. Sinz, D. W. C. MacMillan, J.
Am. Chem. Soc. 2003, 125, 10808; b) G. Zhong, Angew. Chem.
2003, 115, 4379; Angew. Chem. Int. Ed. 2003, 42, 4247; c) Y.
Hayashi, J. Yamaguchi, K. Hibino, M. Shoji, Tetrahedron Lett.
2003, 44, 8293.
[7] Reviews, see a) B. List, Synlett 2001, 1675; b) B. List, Tetrahe-
dron 2002, 58, 5573.
[8] a) A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
124, 6798; b) C. Pidathala, L. Hoang, N. Vignola, B. List, Angew.
Chem. 2003, 115, 2797; Angew. Chem. Int. Ed. 2003, 42, 2785, and
references therein.
[9] a) B. List, P. Pojarliev, W. T. Biller, H. J. Martin, J. Am. Chem.
Soc. 2002, 124, 827; b) A. Córdova, S. Watanabe, F. Tanaka, W.
Notz, C. F. Barbas III, J. Am. Chem. Soc. 2002, 124, 1866; c) Y.
Hayashi, W. Tsuboi, I. Ashimine, T. Urushima, M. Shoji, K.
Sakai, Angew. Chem. 2003, 115, 3805; Angew. Chem. Int. Ed.
2003, 42, 3677; d) A. Córdova, Synlett 2003, 1651, and referenes
therein.
[10] a) B. List, J. Am. Chem. Soc. 2002, 124, 5656; b) N. Kumaragur-
ubaran, K. Juhl, W. Zhuang, A. Bøgevig, K. A. Jørgensen, J. Am.
Chem. Soc. 2002, 124, 6254; c) A. Bøgevig, K. Juhl, N.
Kumaragurubaran, W. Zhuang, K. A. Jørgensen, Angew.
Chem. 2002, 114, 1868; Angew. Chem. Int. Ed. 2002, 41, 1790;
d) Review, see R. O. Duthaler, Angew. Chem. 2003, 115, 1005;
Angew. Chem. Int. Ed. 2003, 42, 975.
with nitrosobenzene in the presence of l-proline, (2R,4R)-2-
anilinoxy-4-tert-butylcyclohexanone and the (2R,4S) isomer
were obtained in 31% yield and > 99% ee and 31% yield
and 94% ee, respectively. The absolute stereochemistry of the
(2R,4R) isomer was deduced based on that of the corre-
sponding hydroxycyclohexanone,[17] while that of the (2R,4S)
isomer was determined by the CD-chirality method after
conversion into (1S,2R,4S)-4-tert-butyl-1,2-dibenzoyloxycy-
clohexane. 4-tert-Butyldiphenylsilyloxycyclohexanone gave
almost the same results, affording (2R,4R)-2-anilinooxy-4-
tert-butyldiphenylsilyloxycyclohexanone and the (2R,4S)
isomer in 46% yield and > 99% ee, and 23% yield and
96% ee, respectively. These reactions are composed of two
successive steps, an asymmetric desymmetrization for the
enamine formation, and diastereoselective a-aminoxylation
of the generated enamine. These results indicate that the
asymmetric induction in the initial enamine formation is not
high, while the diastereoselectivity of the second a-amin-
oxylation is excellent.
In summary, we have developed the direct catalytic
enantioselective a-aminoxylation of ketones by using nitro-
sobenzene as the oxygen source and l-proline as the catalyst.
This reaction has several noteworthy features: The reaction
proceeds with high yield and excellent enantioselectivity. This
a-aminoxylation can be successfully applied not only to
cyclohexanone derivatives but also to 4-monosubstituted
cyclohexanones with asymmetric desymmetrization, afford-
ing both a-aminoxylated products with very high enantiose-
lectivities. Because of the easy conversion of a-aminoxylated
ketones into a-hydroxy ketones, operational simplicity, and
the availability and low cost of the catalyst, the present
method is one practical approach to the preparation of
optically active a-hydroxy ketones.
[11] Y. Hayashi, W. Tsuboi, M. Shoji, N. Suzuki, J. Am. Chem. Soc.
2003, 125, 11208.
[12] a) N. Momiyama, H. Yamamoto, Angew. Chem. 2002, 114, 3112;
Angew. Chem. Int. Ed. 2002, 41, 2986; b) N. Momiyama, H.
Yamamoto, Org. Lett. 2002, 4, 3579.
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Angew. Chem. Int. Ed. 2004, 43, 1112 –1112