Synthesis of optically active α-hydroxy ketones by enantioselective oxidation of silyl enol ethers with a fructose-derived dioxirane

Article abstract of DOI:10.1016/S0957-4166(98)00005-6

Optically active α-hydroxy ketones 3 have been prepared in moderate to high enantioselectivities by the asymmetric oxidation of the silyl enol ethers 2 with in situ generated dioxirane from the fructose-derived ketone 1. Best results (ee values up to 82%) for this novel non-transition metal mediated asymmetric α-hydroxylation may be obtained, when an excess of the fructose-derived ketone 1 is employed at pH ca. 8 and short reaction times. Valuable mechanistic information on the spiro versus planar transition states for the oxygen-transfer process has been aquired through the absolute configuration of the resulting α-hydroxy ketone 3 products.

Full text of DOI:10.1016/S0957-4166(98)00005-6

Pergamon
Tetrahedron: Asymmetry 9 (1998) 397–401
Synthesis of optically active α-hydroxy ketones by
enantioselective oxidation of silyl enol ethers with a fructose-
derived dioxirane
Waldemar Adam,∗ Rainer T. Fell, Chantu R. Saha-Möller and Cong-Gui Zhao
Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany
Received 12 December 1997; accepted 2 January 1998
Abstract
Optically active α-hydroxy ketones 3 have been prepared in moderate to high enantioselectivities by the
asymmetric oxidation of the silyl enol ethers 2 with in situ generated dioxirane from the fructose-derived ketone 1.
Best results (ee values up to 82%) for this novel non-transition metal mediated asymmetric α-hydroxylation may
be obtained, when an excess of the fructose-derived ketone 1 is employed at pH ca. 8 and short reaction times.
Valuable mechanistic information on the spiro versus planar transition states for the oxygen-transfer process has
been aquired through the absolute configuration of the resulting α-hydroxy ketone 3 products. © 1998 Elsevier
Science Ltd. All rights reserved.
The optically active α-hydroxy-keto functional unit is widespread in natural products and has been
frequently used for convenient building blocks in organic synthesis during recent years.1 Consequently,
efficient methods for the construction of enantiomerically pure or at least enriched α-hydroxy carbonyl
compounds are in demand.2 Their preparation has mainly employed electrophilic hydroxylation of
enolates, in which the optically active organic or organometallic auxiliary is covalently bound to the enol
functionality.3,4 Alternatively, prochiral enolates have been directly oxidized by optically active oxidants,
e.g. chiral oxaziridines.2,5 Highly enantioselective catalytic oxidations of enol ethers by the osmium-
catalyzed asymmetric dihydroxylation6 and by the (salen)Mn(III)-catalyzed asymmetric oxidation7,8
have been described.
Recently Shi9 developed an attractive metal-free, asymmetric epoxidation of trans olefins, in which
the optically active oxidant was the in situ generated dioxirane from the fructose-derived ketone 1, that
operates even under catalytic conditions. In principle, this enantioselective oxidation should be applicable
to prochiral silyl enol ethers 2. Indeed, we report herein that this method constitutes a convenient
asymmetric preparation of optically active α-hydroxy ketones 3 (Scheme 1).
∗
Corresponding author. Fax: +49(0)931/8884756; e-mail: Adam@chemie.uni-wuerzburg.de
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00005-6

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W. Adam et al. / Tetrahedron: Asymmetry 9 (1998) 397–401
Scheme 1. Asymmetric oxidation of the silyl enol ethers 2 by in situ generated dioxirane from the fructose-derived ketone 1
Table 1
Enantioselective oxidation of the silyl enol ethers 2a–ea by in situ generated dioxirane from the
fructose-derived ketone 1
The results of the asymmetric α-hydroxylation of trimethylsilyl- (2a–e) and tert-butyldimethylsilyl-
substituted (2b0) enol ethers6,10,7b are summarized in Table 1. These oxidations were carried out in an
acetonitrile/buffer medium with 3 equiv. of the fructose-derived ketone 1 for the non-catalytic (pH 8)9a
and 0.3 equiv. for the catalytic method (pH 10.5).9b After 1.5 to 18 h of stirring at 0°C, the mixture
was diluted with water, extracted with ethyl ether and treated with HCl/MeOH to desilylate the primary
α-silyloxy carbonyl product to the corresponding literature-known7b,10,11 optically active α-hydroxy
ketone 3.
In the case of the diphenyl-substituted silyl enol ether 2a, for the non-catalytic method (3 equiv. of

W. Adam et al. / Tetrahedron: Asymmetry 9 (1998) 397–401
399
ketone 1 at pH 8) a longer reaction time leads to a slightly higher conversion but a lower enantioselectivity
(entries 1 and 2). With 3 equiv. of ketone 1 at pH 10.5, a similar conversion as at pH 8 was observed, but
the ee value dropped drastically to 22% (entries 1 and 3). Application of the catalytic method (0.3 equiv.
of catalyst 1 at pH of 10.5) gives only 20% of a racemic mixture of the α-hydroxy ketone 3a (entry 4).
Control experiments without the fructose-derived ketone 1 showed that only 2% conversion was achieved
at pH 8 and 10.5 to afꢀford the racemic product 3a. This confirms that the enantioselectivity is not lowered
by the direct Caroate™ oxidation of the enol ether 2a.
The silyl enol ethers 2b,b0 of propiophenone have the bulky group in the geminal position. For the
TMS-substituted derivative 2b, the enantiomeric excess of the non-catalytic oxidation was 54% (entry
5), but the change to the TBDMS-substituted derivative 2b0 increased the ee value by up to 82% at a
conversion of up to 92% (entry 6). This high conversion in only 3 h reaction time encouraged us to test the
catalytic method for this substrate. Not only low conversion (<10%), but also a lower enantioselectivity
(ee 42%) was obtained (entry 7).
For the substrate 2c, which bears an ethyl group in the β position to the siloxy group, the non-
catalytic method resulted in an ee value of 67% for the (R)-configured α-hydroxy ketone 3c (entry 8).
The silyl enol ether 2d (entry 9), with a methyl group in the α position to the siloxy group instead of
a phenyl group, possesses through the two bulky Z groups more cis-like character than the substrates
2a–c. Presumably, this feature decreases the enantioselectivity to 18% (R), as would be expected for cis
olefins.12
When the steric bulk of the α-substituent is increased by means of a tert-butyl group, the enol ether
2e has again more trans character and as expected the ee value was significantly augmented: 52% for
the non-catalytic (entry 10) and 43% for the catalytic (entry 11) methods. More significantly, while all
the other substrates 2a–d led to (R)-configured products, the (S) configuration was obtained for the α-
hydroxy ketone 3e. This change in the sense of the dioxirane-mediated, asymmetric α-hydroxylation
required further mechanistic scrutiny of this oxygen-transfer process.
The established mechanism of dioxirane epoxidation is a spiro-structured transition state, in which
steric repulsions of the dioxirane and olefin substituents are minimized.13 This geometry is also favored
by Shi9a,c in the epoxidation of trans alkenes by the in situ generated, fructose-derived dioxirane.
Calculations performed by Bach et al. show that a spiro-like transition state benefits from the stabilizing
interaction of an oxygen lone pair with the π* orbital of the alkene.14 For the planar arrangement of the
oxygen transfer, usually more severe steric interactions between the substituents of the trans olefin and
the chiral dioxirane would afford the minor epoxide enantiomer.9c
Application of this spiro model to the enol–ether substrates 2 is illustrated in Fig. 1, with the 2a
derivative as a prototype for those derivatives which afford mainly the (R)-enantiomer. The approach
of the chiral dioxirane is defined by Plane 1, with the dioxirane moiety in this plane; the favored
orientation of the 2a substrate is defined by Plane 2, with the π bond horizontally aligned and all its
substituents within that plane. Oxygen-atom transfer, rearrangement of the silyloxy-substituted epoxide,
and desilylation leads to the observed (R)-configured α-hydroxy ketone 3a as final product.
How can the opposite product configuration be rationalized for substrate 2e? For the 2e substrate,
the spiro transition state would also predict the (R)-configured α-hydroxy ketone 3e. However, in this
case R2 is the bulky tert-butyl group and the steric interaction of this R2 group with the fructose moiety
of the dioxirane is larger than in the substrates 2a–d. This steric repulsion in the spiro transition state
of substrate 2e outweighs the stabilizing interaction of the oxygen lone pair with the π* orbital of the
alkene and the (S) enantiomer is observed as the major enantiomer.9c Inspection of molecular models
reveals that in the planar transition state, with the π bond vertical and all its substituents also in Plane 2
(Fig. 1, right-hand structure), the non-bonded interactions between the dioxirane and olefin are minimal,

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W. Adam et al. / Tetrahedron: Asymmetry 9 (1998) 397–401
Fig. 1. Orientation of the enol ether 2a (also for 2b–d) in the spiro and the planar transition states for the substrate 1e
so that the (S)-configured α-hydroxy ketone 3e should result, as observed (Table l). This constitutes the
first case for which the planar dioxirane–olefin arrangement is preferred. Thus, a judicious choice of
the substitution pattern in the olefinic substrate permitted us to probe the preferred substrate–oxidant
arrangement through the resulting configuration of the oxidation product from the oxygen transfer with
the chiral dioxirane of the fructose-derived ketone 1.
In summary, the optically active, in situ generated dioxirane from the fructose-derived ketone 1
oxidizes silyl enol ethers 2 enantioselectively to the corresponding α-hydroxy ketones 3 with ee values
up to 82% for the non-catalytic method. The (R) configuration of the resulting α-hydroxy ketones 3a–d
is in accordance with a spiro transition state, but the (S)-configured α-hydroxy ketone 3e implicates a
preferred planar geometry. This unprecedented asymmetric oxidation constitutes a synthetically valuable
α-hydroxylation of ketones without the use of transition-metal oxidants.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (Schwerpunktprogramm ‘Peroxid-
chemie: mechanistische und präparative Aspekte des Sauerstofftransfers’) and the Fonds der Chemischen
Industrie. C.-G. Zhao thanks the DAAD (Deutscher Akademischer Austauschdienst) for a doctoral
fellowship.
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