Asymmetric epoxidation via phase-transfer catalysis: Direct conversion of allylic alcohols into α,β-epoxyketones

Article abstract of DOI:10.1039/b206530d

Studies into the use of a chiral phase-transfer catalyst in conjunction with sodium hypochlorite to effect the enantio-selective formation of α,β-epoxyketones from allylic alcohols are described.

Full text of DOI:10.1039/b206530d

Asymmetric epoxidation via phase-transfer catalysis: direct conversion of
allylic alcohols into a,b-epoxyketones
Barry Lygo* and Daniel C. M. To
School of Chemistry, University of Nottingham, Nottingham, UK NG7 2RD.
E-mail: b.lygo@nottingham.ac.uk
Received (in Cambridge, UK) 8th July 2002, Accepted 29th August 2002
First published as an Advance Article on the web 17th September 2002
Studies into the use of a chiral phase-transfer catalyst in
conjunction with sodium hypochlorite to effect the enantio-
selective formation of a,b-epoxyketones from allylic alcohols
are described.
catalyst.8 Unfortunately the optimal conditions reported for this
transformation require the use of ethyl acetate as solvent and we
have previously established that the presence of this solvent
severely degrades selectivity in the asymmetric epoxidation.3
Hence for this approach to be successful it was necessary to
establish alternative conditions that would allow both trans-
formations to proceed smoothly.
Fortunately preliminary experiments indicated that it was
possible to convert allylic alcohols of type 4 directly to a,b-
epoxyketones 2 utilising our normal epoxidation conditions
(0.17 M substrate in PhMe, R4NBr, 15% aq. NaOCl, RT).3
Consequently we selected allylic alcohol 4a as a test substrate
and using chiral phase-transfer catalyst 3, examined the effect of
varying the catalyst loading (Fig. 1).
Chiral a,b-epoxyketones of type 2 are versatile synthetic
intermediates1 and consequently there is considerable interest in
the development of asymmetric processes that provide clean
and efficient access to these materials.2–4 We have examined the
utility of asymmetric phase-transfer catalysts in this context3
and have recently demonstrated that the Cinchona alkaloid
derived catalyst 3 is a highly effective additive in the NaOCl
epoxidation of enones 1 (Scheme 1). The resulting chemistry is
straightforward to perform, has minimal environmental impact
(the solvent and catalyst are readily recycled), and provides the
target a,b-epoxyketones 2 with high levels of enantiomeric
excess. In order to further enhance the utility of this chemistry,
we have been investigating whether it is possible to effect
additional transformations under the same reaction conditions.
Fig. 1 Effect of catalyst loading on reaction progress.
This study indicated that, under the conditions investigated,
at least 10 mol% catalyst was required in order to obtain
complete conversion of the substrate 4a to chalcone oxide 2a
within 24 h. With 2.5–5 mol% catalyst, the substrate 4a had
been completely consumed, but significant amounts of the
intermediate chalcone 1a remained. No reaction was observed
in the absence of catalyst.
The enantiomeric excess of the product 2a was also found to
vary (Fig. 2), with high enantiomeric excesses only being
obtained with !10 mol% catalyst. By monitoring the level of
enantioselectivity over time we were able to establish that the
reaction initially proceeded with poor enantioselectivity
( < 60% ee) and that this increased significantly once all the
initial allylic alcohol 4a had been consumed. We had previously
observed that polar additives reduced the enantioselectivity of
the asymmetric epoxidation,3c so it appeared likely that the high
concentration of the starting alcohol during the early stages of
the process may be responsible for this effect. In order to test
this we limited the concentration of alcohol via slow addition of
the substrate 4a to the reaction system (Fig. 2). This led to a
substantial improvement in enantioselectivity at lower catalyst
loadings. Intriguingly it also resulted in an increased rate of
reaction with 100% conversion was now possible within 24 h
using 5 mol% catalyst.
Scheme 1
During the course of our earlier studies the enone substrates
1 were prepared either via aldol condensation, Wittig reaction,
or by carbanion addition to an appropriate aldehyde. This latter
approach is often utilised as a means of accessing enones that
are not readily prepared via aldol condensation,5,6 but suffers
from the requirement for an additional oxidation step to convert
intermediate 4 into the target enone 1 (Scheme 2). Clearly this
approach would be substantially improved if the two sequential
oxidation processes could be effected under the same reaction
conditions.
With this in mind we have been investigating whether it is
possible to convert the allylic alcohol intermediate 4 directly to
the a,b-epoxyketone 27 utilising asymmetric phase-transfer
catalysis. We considered that this ought to be possible, as it is
known that secondary alcohols can be oxidised to ketones using
sodium hypochlorite in conjunction with a phase-transfer
To test the generality of these observations we examined a
range of allylic alcohol substrates (Table 1). It was found that all
Scheme 2
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Scheme 3
oxidation of the resulting crude allylic alcohol gave the enone
2b in good overall yield.
The enantioselectivity observed was comparable with that
obtained in the previous synthesis,5 suggesting that, at least for
substrates of this type, asymmetric PTC oxidation is com-
petitive with Sharpless epoxidation chemistry.
In conclusion, we have demonstrated that it is possible to
obtain a,b-epoxyketones in high enantiomeric excess via direct
oxidation of allylic alcohols using asymmetric phase-transfer
catalysis. The operational simplicity of this chemistry should
make it a valuable alternative to existing methodology.
We thank EPSRC and GSK for studentship support (to D. C.
M. T.) and Dr. Jane Stewart (G. S. K.) for helpful discus-
sions.
Fig. 2 Effect of catalyst loading and rate of substrate addition on
enantioselectivity.
Table 1 Enantioselective oxidation of a range of allylic alcohols 4a
Ar
R
Timeb/h
20
Ee of 2c (%)
Notes and references
84
1 See, for example: W. P. Chen and S. M. Roberts, Chem. Commun., 1999,
103; N. W. Cappi, W-P. Chen, R. W. Flood, Y-W. Liao, S. M. Roberts,
J. Skidmore, J. A. Smith and N. M. Williamson, Chem. Commun., 1998,
1159; B. M. Adger, J. V. Barkley, S. Bergeron, M. W. Cappi, B. E.
Flowerdew, M. P. Jackson, R. McCague, T. C. Nugent and S. M. Roberts,
J. Chem. Soc., Perkin Trans. 1, 1997, 3501.
2 For a review on the asymmetric epoxidation of electron-deficient alkenes,
see: M. J. Porter and J. Skidmore, Chem. Commun., 2000, 1215.
3 For selected recent publications relating to the use of quaternary
ammonium PTC in the asymmetric epoxidation of enones, see: W. Adam,
P. B. Rao, H. G. Degen, A. Levai, T. Patonay and C. R. Saha-Moller, J.
Org. Chem., 2002, 67, 259; S. Arai, H. Tsuge, M. Oku, M. Miura and T.
Shioiri, Tetrahedron, 2002, 58, 1623; B. Lygo and D. C. M. To,
Tetrahedron Lett., 2001, 42, 1343; E. J. Corey and F-Y. Zhang, Org.
Lett., 1999, 1, 1287; B. Lygo and P. G. Wainwright, Tetrahedron, 1999,
55, 6289; S. Arai, H. Tsuge and T. Shioiri, Tetrahedron Lett., 1998, 39,
7563; G. Macdonald, L. Alcaraz, N. J. Lewis and R. K. Taylor,
Tetrahedron Lett., 1998, 39, 5433; B. Lygo and P. G. Wainwright,
Tetrahedron Lett., 1998, 39, 1599.
4 For examples of other recent publications relating to the asymmetric
epoxidation of enones, see: W. Adam, P. B. Rao, H. G. Degen and C. R.
Saha-Moller, Eur. J. Org. Chem., 2002, 630; O. Jacques, S. J. Richards
and R. W. F. Jackson, Chem. Commun., 2001, 2712; P. E. Coffey, K. H.
Drauz, S. M. Roberts, J. Skidmore and J. A. Smith, Chem. Commun.,
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Ohshima, K. Yamaguchi and M. Shibasaki, J. Am. Chem. Soc., 2001,
123, 2725; R. F. Chen, C. T. Qian and J. G. de Vries, Tetrahedron, 2001,
57, 9837; C. L. Dwyer, C. D. Gill, O. Ichihara and R. J. K. Taylor, Synlett,
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a Substrate 4 (0.25 mmol) in toluene (1 ml) was added dropwise over 4 h to
a rapidly stirred mixture of quaternary ammonium salt 3 (0.013 mmol),
toluene (0.5 ml), and 15% aqueous sodium hypochlorite (1.0 mmol) at room
temperature. The resulting mixture was then stirred for the time specified.
b Time to 100% conversion to epoxide 2, in all cases the yield of epoxide
was > 90% (by 1H NMR). c ee’s determined to ±3% by HPLC (Chiralpak
AD).
5 C. Hardouin, F. Chevallier, B. Rousseau and E. Doris, J. Org. Chem.,
2001, 66, 1046.
6 For reports that illustrate variations of this approach, see: C. D. Brown, J.
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7 For an alternative method for the direct oxidation of allylic alcohols to
racemic a,b-epoxyketones, see: K. Takai, K. Oshima and H. Nozaki,
Bull. Chem. Soc. Jpn., 1983, 56, 3791.
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reactions proceeded to completion within 24 h, and in all cases
high levels of enantioselectivity were obtained.
In order to demonstrate the utility of this chemistry we
examined its application in the synthesis of a,b-epoxyketone 2b
(Scheme 3). The enantioselective synthesis of this material
utilising Sharpless asymmetric epoxidation methodology has
recently been reported5 and so this provided an opportunity to
compare the effectiveness of these two approaches towards
targets of this type. We found that reaction of E-hept-2-enal
with phenylmagnesium bromide,9 followed by asymmetric PTC
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