(10 equiv) of activated zinc powder added in two portions
to a solution of substrate in 3:1 AcOH/H2O. Thus, the desired
â-amino ketone 5 was obtained, with only trace amounts of
the undesired R,â-unsaturated ketone being observed.
We next examined the substrate scope of the reaction with
a number of substituted 2,3-dihydroisoxazoles (Table 1). In
general, good to excellent yields were obtained. With C3-
aryl-substituted substrates (7 and 8), the competing elimina-
tion to the R,â-unsaturated ketone led to slightly diminished
yields.
When C5-aryl-substituted 2,3-dihydroisoxazoles (R2 ) Ph)
were subjected to zinc powder in acetic acid, instead of the
expected â-amino ketones, the corresponding anti-â-amino
alcohols were obtained in moderate to good diastereoselec-
tivities (Scheme 1). However, this observation did not prove
Table 2. Preparation of syn-â-Amino Alcohols
18
19
entry
R1
yield (%)a
drb
yield (%) (syn)
1
2
3e
4
Me
iPr
iPr
Cy
Ph
59c
89
80:20
91:9
96d
72
63
79
75
85
79
89:11
87:13
5
a Combined yield of syn- and anti-isoxazolidines 18. b Diastereomeric
1
ratios were determined by H NMR of the crude products. c Yield for the
syn-isoxazolidine 18. d Yield observed using syn-isoxazolidine 18 as starting
material for the N-O bond cleavage reaction. e One-pot procedure.
Scheme 1. Reduction to â-Amino Alcohols
2,3-dihydroisoxazole 17 (R1 ) Me), the resulting intermedi-
ate isoxazolidines obtained in 80:20 dr were readily separable
by column chromatography affording the pure syn-isomer
18 in 59% isolated yield (entry 1). Subsequent reductive NO-
bond cleavage with zinc powder in AcOH proceeded with
no stereochemical degradation, thus furnishing the dia-
stereomerically pure syn-â-amino alcohol 19 (R1 ) Me). For
the syn-selective reductions of the remaining substrates, the
inseparable diastereomeric mixtures of isoxazolidines 18
were subjected directly to NO-bond cleavage, affording the
readily separable â-amino alcohols 19 (entries 2, 4, and 5).
As exemplified by entry 3, it was possible to carry this out
as a one-pot process transformation.
In summary, we have shown that 2,3-dihydroisoxazoles
can serve as precursors for the preparation of either â-amino
ketones or â-amino alcohols depending on their substitution
pattern. The desired â-amino ketones can be obtained in
preparatively useful yields. Additionally, a borohydride
reduction followed by ring opening reaction provided a
general entry to syn-â-amino alcohols in high selectivities.
These versatile building blocks may find further synthetic
applications, in particular when derived from unusually
substituted 2,3-dihydroisoxazoles.
to be general with respect to substrate scope. In subsequent
investigations of various reducing conditions, we observed
that reduction with sodium borohydride in acetic acid
followed by NO-bond cleavage with zinc in acetic acid
provided the corresponding syn-â-amino alcohols as con-
firmed by NOE measurements. This observation proved to
be general.
To examine the scope of this process, various 2,3-
dihydroisoxazoles with R2 ) Ph were subjected to the
reaction conditions (NaBH4/AcOH then Zn/AcOH, Table 2).
In the NaBH4-promoted reduction of the 3-methyl-substituted
(5) For selected examples to prepare â-amino alcohols, see: (a) Pilli, R.
A.; Russowsky, D. J. Chem. Soc.,Chem. Commun. 1987, 1053. (b) Pilli, R.
A.; Russowsky, D.; Dias, L. C. J. Chem. Soc., Perkin Trans. 1 1990, 1213.
(c) Barluenga, J.; Aguilar, E.; Fustero, S.; Olano, B.; Viado, A. L. J. Org.
Chem. 1992, 57, 1219. (d) Keck, G. E.; Truong, A. P. Org. Lett. 2002, 4,
3131.
Acknowledgment. We thank the Swiss National Science
Foundation and F. Hoffmann-LaRoche for generous support.
L.K. thanks The Technical University of Denmark for a
doctoral fellowship. F.K. thanks the Fonds der Chemischen
Industrie for a fellowship.
(6) â-Amino alcohols are also commonly used as chiral ligands; see:
(a) ComprehensiVe Asymmetric Catalysis I-III; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Heidelberg, 1999. (b)
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New
York, 2000.
(7) (a) For a review, see: Freeman, J. P. Chem. ReV. 1983, 83, 241. (b)
Adachi, T.; Harada, K.; Miyazaki, R.; Kano, H. Chem. Pharm. Bull. 1974,
22, 61. (c) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826. (d) Curran,
D. P.; Scanga, S. A.; Fenk, C. J. J. Org. Chem. 1984, 49, 3474. (e) Muri,
D.; Lohse-Fraefel, N.; Carreira, E. M. Angew. Chem., Int. Ed. 2005, 44,
4036. (f) Bode, J. W.; Fraefel, N.; Muri, D.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2001, 40, 2082. (g) Bode, J. W.; Carreira, E. M. Org. Lett. 2001,
3, 1587. (h) Bode, J. W.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
3611.
Supporting Information Available: Experimental pro-
cedures and spectral data for all products. This material is
OL052540C
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Org. Lett., Vol. 7, No. 25, 2005