C O M M U N I C A T I O N S
Table 2. Scope of the Organocatalytic â-Hydroxylation of
Scheme 3. Gram-Scale Reaction and Deprotection to the 1,3-Diol
R,â-Unsaturated Aldehydes 1a-h Using (E)-Benzaldehyde Oxime,
2aa
entry
R
time (h)
yield (%)b
ee (%)c
In conclusion, we have presented the first catalytic, highly
stereoselective â-hydroxylation of R,â-unsaturated aldehydes using
aromatic oximes as the hydroxylating agent. After reduction, the
optically active products were isolated in good to excellent yield
and enantiomeric excess.
1
2
3
4
5
6
7
8
Et
Me
Pr
Bu
Hep
i-Pr
1
1
1
1
1
1.5
1
5a - 72
5b - 72
5c - 75
5d - 75
5e - 64
5f - 62
5g - 68
5h - 60
95
95
95
93
95
97
95
88
Acknowledgment. This work was made possible by a grant
from The Danish National Research Foundation. P.D. thanks the
Wenner-Gren Foundation for financial support.
Hex-3-enyl
CO2Et
8
a Performed with 1 (0.25 mmol), 2a (0.75 mmol), 3a (0.025 mmol), and
PhCO2H (0.025 mmol) in toluene at 4 °C. b Purified by flash chromatog-
raphy. c Determined by chiral HPLC.
Supporting Information Available: Complete experimental pro-
cedures and characterization. This material is available free of charge
potassium trimethylsilanol salt, but no â-addition product was
observed (entry 11).
References
L-Proline 3b, proline amide 3c, the C2-symmetric catalyst 3d,
and the imidazoline tetrazoline 3e (Table 1, entries 7-10) also
catalyzed the â-hydroxlation reaction and gave full conversion, but
only with a modest enantioselectivity.
(1) For recent reviews on organocatalysis see e.g.: (a) Dalko, P. L.; Moisan,
L. Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Berkessel, A.; Gro¨ger, H.
Asymmetric Organocatalysis; VCH: Weinheim, Germany, 2004. (c)
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With the optimized condition, several R,â-unsaturated aldehydes
1a-h were reacted with (E)-benzaldehyde oxime 2a using catalyst
3a, yielding products 5a-h after reduction with NaBH4 (Table 2,
entries 1-8). The results show that several different linear R,â-
unsaturated aldehydes (entries 1-5) reacted smoothly and gave the
optically active oxime addition products in high yields (up to 75%)
and high enantioselectivities (up to 95% ee). The incorporation of
a branched alkyl substituent, such as an isopropyl group, increases
the ee to 97% (entry 6), and nearly similar results were also obtained
(95% ee, entry 7) for R,â-unsaturated aldehydes having an extra
double bond. Also the R,â-unsaturated aldehyde having an ester
functionality in the â-position (1h) (entry 8) was converted to the
optically active O-protected R-hydroxy carboxylic acid 5h, with
high stereocontrol and good yields. This latter product might be of
importance for a number of further transformations. It should be
noted that R,â-unsaturated aldehydes having aromatic substitutents
did not react under these reaction conditions.
In order to broaden the scope for the reaction, we also wanted
to show that the reaction could be performed at larger scales,
demonstrating that the catalyst 3a could be suitable for scale-up
chemistry. Therefore, we were pleased to find that catalyst 3a in
10 mol % catalyzed the reaction between 2-trans-pentenal, 1a (7
mmol), and (E)-benzaldehyde oxime, 2a (21 mmol), in high yield
and enantioselectivity (83%, 96% ee) at 0 °C, yielding the optically
active 5a in a gram scale (Scheme 3). From the â-addition product
5a, the deprotected 1,3-diol 6a was easily accessed by hydrogena-
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products was determined by comparison of the optical rotation of
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92% ee in 16 h with full recovery of excess of oxime 2a.
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