Enantioselective oxidation of vic-diols to optically active α-hydroxy ketones by a fructose-derived dioxirane

Article abstract of DOI:10.1016/S0957-4166(98)00444-3

Optically active α-hydroxy ketones 3 have been prepared in moderate to good enantioselectivities through asymmetrization of meso-, and kinetic resolution of, racemic vic-diols 2 by enantioselective oxidation with the in situ generated dioxirane from the fructose-derived ketone 1; the opposite sense in-the-enantioselectivity of the two processes is explained in terms of the hydrogen-bonded transition-state structures for the concerted C-H oxygen insertion.

Full text of DOI:10.1016/S0957-4166(98)00444-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4117–4122
Enantioselective oxidation of vic-diols to optically active
α-hydroxy ketones by a fructose-derived dioxirane
Waldemar Adam,∗ Chantu R. Saha-Möller and Cong-Gui Zhao
Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany
Received 23 October 1998; accepted 29 October 1998
Abstract
Optically active α-hydroxy ketones 3 have been prepared in moderate to good enantioselectivities through
asymmetrization of meso-, and kinetic resolution of, racemic vic-diols 2 by enantioselective oxidation with the in
situ generated dioxirane from the fructose-derived ketone 1; the opposite sense in the enantioselectivity of the two
processes is explained in terms of the hydrogen-bonded transition-state structures for the concerted C–H oxygen
insertion. © 1998 Elsevier Science Ltd. All rights reserved.
Dioxiranes,1 either in isolated form2 or in situ generated,3 have been established as very reac-
tive yet highly selective oxidants. One of the highlights of dioxirane chemistry is the efficient oxy-
functionalization of unactivated as well as activated C–H bonds.4 Although the possibility of a radical-
chain reaction has been recently raised,5 convincing experimental evidence6 as well as theoretical
work7 have confirmed the concerted mechanism for this insertion reaction. The latter fact provides the
opportunity to conduct enantioselective C–H oxidations, which still present a formidable challenge in
organic chemistry.8
Several methods are available for the preparation of optically active α-hydroxy ketones, which
are valuable building blocks in synthetic chemistry.9 Recently we have reported a metal-free method
in which silyl enol ethers have been oxidized to optically active α-hydroxy ketones by the in situ
generated dioxirane from the fructose-derived ketone 1.10 Furthermore, it is known that vic-diols may
be readily oxidized by dioxiranes to yield the corresponding α-hydroxy ketones.11 When optically
active vic-diols were used, the resulting α-hydroxy ketones were obtained with complete retention of
configuration.11b While optically active dioxiranes have been established as efficient oxidants for the
asymmetric epoxidation of unfunctionalized olefins,12 there is as yet no report on the enantioselective
oxidation of C–H bonds.13 Thus, we envisaged that optically active α-hydroxy ketones should be
accessible through asymmetrization of meso-vic-diols or kinetic resolution of racemic vic-diols by
enantioselective oxidation with an optically active dioxirane. We report herein the first example of such an
∗
Corresponding author. Tel: +49-931-8885340; fax: +49-931-8884756; e-mail: adam@chemie.uni-wuerzburg.de
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00444-3

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oxidation of vic-diols to enantiomerically enriched α-hydroxy ketones by the optically active dioxirane,
generated in situ from the fructose-derived ketone 112a (Scheme 1).
Of the several recently reported optically active ketones which were employed as precursors of di-
oxiranes for asymmetric epoxidation, in particular the ones prepared from binaphthol,12c–e TADDOL,12d
and the fructose-derived ketone 1,12a the latter was the best choice for the enantioselective oxidation of
vic-diols to optically active α-hydroxy ketones (Scheme 1). The results are summarized in Table 1. Under
nearly neutral conditions (NaHCO3 buffer, pH ca. 8), there was no conversion of meso-hydrobenzoin 2a,
even with a stoichiometric amount of ketone 1 (Table 1, entry 1). However, at the higher pH of 10.512a
a conversion of 67% and an ee value of 46% for the α-hydroxy ketone 3a was achieved (Table 1, entry
2). The use of a catalytic amount (0.3 equiv.) of ketone 1 resulted in a lower conversion, but the ee value
remained unchanged (Table 1, entry 3); thus, the direct oxidation by Caroate is negligible under such
conditions. A control experiment also showed that the resulting α-hydroxy ketone 3a racemizes slowly
(ca. 10% ee in 3 h) under the reaction conditions. To guarantee complete conversion of 2a within a short
reaction time, 3 equiv. of the ketone 1 were used (Table 1, entry 4). While 89% conversion of the diol 3a
was obtained, the ee value remained the same; about 50% of ketone 1 could be recovered after reaction.16
Under these conditions, similiar conversions and enantioselectivities were obtained with the meso-diols
2b (entry 6) and 2c (entry 8). It can also be seen from Table 1 that the electronic nature of the para
substituents in the meso-hydrobenzoins 2a–c (Table 1, entries 4, 6, 8) influences the enantioselectivity
of the C–H oxidation in the order H (45%)>CH3 (30%)>OCH3 (24%); in all these cases, the (R)-
(−) enantiomers of the α-hydroxy ketones 3a–c were formed preferentially. The diminution of the
enantioselectivity can hardly be of steric origin because the para substituent is too far away from the
reaction center; besides, these groups are not sufficiently sterically demanding.
Scheme 1. Enantioselective oxidation of vic-diols by the dioxirane generated in situ from the fructose-derived ketone 1
For the kinetic resolution of the racemic diols by enantioselective oxidation, the conversion of the
substrate was controlled below 50% by employing an insufficient amount of Caroate. With 3 equiv. of
ketone 1, the diol rac-2a gave a good ee value of 65% for the α-hydroxy ketone (S)-(+)-3a at 51%
conversion (Table 1, entry 5). In addition, a good enantioselectivity (ee 61%) was observed for the diol
rac-2b at 12% conversion (Table 1, entry 7). Noteworthy is the finding that the sense of enantioselectivity
in the oxidation of the racemic diols (S configuration) is reversed from that of the meso-diols (R
configuration). These results may be explained in terms of the transition-state structures for the concerted
oxygen transfer6,7 in Scheme 2, in which assistance through hydrogen bonding by the remote hydroxy
group plays a central role.7,11 Thus, the S-configured site is more readily oxidized than the R-configured
one since the sterically demanding phenyl group minimally interacts with the exocyclic dioxolane ring
of the dioxirane. In the case of the kinetic resolution of rac-2a (Scheme 2, left), the S,S-configured diol
is oxidized preferentially to give the S-3a, while in the asymmetric oxidation of meso-2a (Scheme 2,
right) the S-configured site is favored to give the R-3a. The better enantioselectivity observed in the
kinetic resolution of rac-2a (65% ee) than in the asymmetric oxidation of meso-2a (45% ee) appears to
be a consequence of the hydrogen bonding between the diol and dioxirane, which is known to accelarate
the oxidation, since a considerably polarized transition state applies in the oxygen transfer.7,11 In the
oxidation of the meso-2a diastereomer, steric hindrance operates between the two phenyl groups, even in

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Table 1
Enantioselective oxidation of vic-diols by the in situ generated dioxirane from the fructose-derived
ketone 1

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the favored S,R configuration, which is absent in the case of the favored S,S configuration of the rac-2a
diastereomer.
Scheme 2. Transition-state structures for the kinetic resolution of rac-2a and the asymmetrization of meso-2a by oxidation with
the fructose-derived dioxirane
The oxidation of the unsymmetrical threo-1-phenyl-1,2-propanediol (threo-2d) led to the two S-
configured products 2-hydroxy-1-phenyl-1-propanone and 1-hydroxy-1-phenyl-2-propanone in a ratio
of 84:1617 with ee values of 69% and 44% (Table 1, entry 9). The oxidation of the erythro-2d also
yielded these two products in a ratio of 89:11 (Table 1, entry 10)17 with ee values of 23% (S) and
8% (R). Two facts are remarkable about these data: the drastically lower (less than one-third) extent of
enantioselectivity for the erythro diastereomer and the opposite configuration of the product 1-hydroxy-
1-phenyl-2-propanone derived from this diastereomer. These results may also be rationalized in terms
of the concerted mechanism depicted in Scheme 2, with the exception of the (S)-2-hydroxy-1-phenyl-
1-propanone from the erythro-2d. The oxidation of cis- and trans-1,2-indanediol 2e both gave low ee
values for the α-hydroxy ketone 3e and again opposite configurations (entries 11 and 12). However, in
these cyclic cases it is not possible to form the intermolecular hydrogen bonds because of constraints
imposed by the ring structures and, therefore, the mechanism depicted in Scheme 3 applies. As shown in
Scheme 3, the R-configured site is favored for oxidation because steric interactions between the exocyclic
dioxolane ring and the peri-hydrogen of the phenyl ring are avoided in the transition state. Thus, in the
kinetic resolution of cis-2e (Scheme 3, left), the α-hydroxy ketone (S)-3e is formed preferentially, while
in the case of trans-2e the α-hydroxy ketone (R)-3e is favored (Scheme 3, right). Although the trans-2e
diastereomer is oxidized in a substantially higher enantioselectivity than the corresponding cis-2e one,
the extent of stereocontrol is low and hardly of synthetic value.
In summary, we have shown that optically active α-hydroxy ketones 3 may be prepared in moderate
to good ee values by the asymmetrization of meso- and kinetic resolution of racemic diols 2, through
enantioselective oxidation with the fructose-derived dioxirane generated in situ from 1. The different
sense in the enantioselectivity is explained in terms of steric interaction in the transition states for these
concerted C–H oxygen insertions.

W. Adam et al. / Tetrahedron: Asymmetry 9 (1998) 4117–4122
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Scheme 3. Transition-state structures for the kinetic resolution of cis- and trans-2e by the fructose-derived dioxirane
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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16. General procedure: To a solution of meso-diol 2a (21.43 mg, 0.10 mmol), ketone 1 (77.48 mg, 0.30 mmol) and Bu4NHSO4
(1.5 mg, 4.0 µmol) in 1.5 ml CH3CN at 0°C, was added 1.0 ml of 0.05 M Na2B4O7 in 4×10−4 M aqueous Na2EDTA
while stirring. Both solutions of Caroate (92.0 mg, 0.15 mmol) and K2CO3 (87.0 mg, 0.63 mmol) in 0.65 ml of 4×10−4
M
aqueous Na2EDTA were added simultaneously by means of separate syringes over ca. 2 h. The mixture was further stirred
for 1 h and then diluted with H2O (20 ml), extracted with ether (3×20 ml), washed with H2O (2×10 ml), and dried over
MgSO4. After removal of the solvent (20°C/20 mbar), the residue was purified by silica-gel chromatography to give the
recovered ketone 1 (38.0 mg, 49%) and benzoin 3a (17.5 mg, 82%).
17. The oxidation of 1-phenyl-1,2-propanediol by dimethyldioxirane (DMD) gave a mixture of 2-hydroxy-1-phenyl-1-
propanone, 1-hydroxy-1-phenyl-2-propanone and 1-phenyl-1,2-propanedione in a ratio of 52:32:16 (see ref. 11d).