Improved procedure for the room temperature asymmetric phase-transfer mediated epoxidation of α,β-unsaturated ketones

Article abstract of DOI:10.1016/S0040-4039(00)02208-5

Studies into the factors affecting the rate of reaction in the enantioselective epoxidation of α,β-unsaturated ketones utilising Cinchona alkaloid-derived quaternary ammonium phase-transfer catalysts are reported. This has led to the identification of imp

Full text of DOI:10.1016/S0040-4039(00)02208-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1343–1346
Improved procedure for the room temperature asymmetric
phase-transfer mediated epoxidation of a,b-unsaturated ketones
Barry Lygo* and Daniel C. M. To
School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
Received 16 October 2000; revised 20 November 2000; accepted 29 November 2000
Abstract—Studies into the factors affecting the rate of reaction in the enantioselective epoxidation of a,b-unsaturated ketones
utilising Cinchona alkaloid-derived quaternary ammonium phase-transfer catalysts are reported. This has led to the identification
of improved conditions for the room temperature epoxidation process, which require only 1 mol% catalyst and lead to isolation
of the epoxide products in high enantiomeric excess. © 2001 Elsevier Science Ltd. All rights reserved.
The enantioselective epoxidation of a,b-unsaturated
ketones has been the subject of considerable investiga-
tion in recent years, and a variety of methods involving
asymmetric catalysis have been developed.1 In this con-
text, we recently reported that N-anthracenylmethyl
derivatives of cinchona alkaloids (e.g. 2)2 could be used
for this transformation, leading to the formation of
a,b-epoxy ketones in excellent yields and high enan-
tioselectivity (Scheme 1).3 It has also been demon-
strated by others that related cinchona alkaloid
derivatives can give high enantioselectivity in reaction
processes of this type,4 and more recently it has been
shown that using 65% KOCl as oxidant allows the
reaction to be conducted at lower temperatures, leading
to improved enantioselectivities.5
results could be obtained. We chose to employ the
epoxidation of chalcone 1a in this study because the
1
reaction could be monitored by both H NMR spec-
troscopy and HPLC.8
Initial investigations indicated that the rate of epoxida-
tion of chalcone 1a was dependant on the concentration
of both sodium hypochlorite and catalyst.9 Although
the reaction appeared to be approximately first order
with respect to hypochlorite concentration in the
aqueous phase, the relationship between catalyst con-
centration and rate of reaction was more complex (Fig.
1).
It was found that for [cat.]org >8×10−3 M, the reaction
system appears to become saturated in catalyst (Fig.
1b). This may be a solubility effect, since at higher
concentrations undissolved catalyst 2 is visible in the
reaction system. By varying the concentration of sub-
strate it was possible to obtain 100% conversion of
enone 1a within 24 h at 25°C with catalyst loading
In this paper, we wish to report the initial results of a
study designed to identify the factors that affect the rate
and selectivity in the above epoxidation processes, a
study that has led to the development of a significantly
improved procedure for the room temperature epoxida-
tion of enones via phase-transfer catalysis.
N
At the outset of this study we were aware that the
efficiency of agitation influenced the rate of reaction;6
therefore, in order to minimise this effect we performed
all reactions in a standard reaction vessel (round-bot-
tom flask) with near identical agitation (magnetic stir-
ring at ca. 1000 rpm).7 This particular set-up was
chosen because it utilises apparatus that is available in
most synthetic chemistry laboratories, and because pre-
liminary experiments had confirmed that reproducible
N
H
OBn
Br
2
O
O
(10 mol%)
O
aq. NaOCl
PhMe, rt, 24-48 h
R
R'
R
R'
3
1
69-90% e.e.
* Corresponding author.
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02208-5

1344
B. Lygo, D. C. M. To / Tetrahedron Letters 42 (2001) 1343–1346
Figure 1.
Figure 2.
down to 0.5 mol%; however, with lower catalyst load-
ings the concentration of substrate required for rapid
reaction led to a significant reduction in enantioselectiv-
ity. For example using 10–1 mol% 2, and an initial
chalcone concentration of 0.09–0.34 M in toluene,
resulted in the formation of enone 3a in 86 1% e.e.,
whereas 0.1 mol% 2, and an initial chalcone concentra-
tion of 3.4 M in toluene, gave enone 3a in 60% e.e. The
drop in enantioselectivity observed at higher substrate
concentrations could not be accounted for by back-
ground epoxidation, and so we speculated that this
might be a result of medium effects. In order to test
this, a series of experiments were performed using
toluene–ethyl acetate mixtures of differing composition
(Fig. 2).
and suggests that high concentrations of polar sub-
strates or products may well be detrimental to
enantioselectivity.
Although we have been able to demonstrate that it is
possible to use catalyst loadings down to 0.1 mol% with
higher substrate concentrations, based on the above
results, we would suggest that an optimal general pro-
cedure for the room temperature epoxidation of enones
1 with sodium hypochlorite requires 1 mol% of catalyst
and a substrate concentration of 0.34 M.7 These condi-
tions have been chosen because they should be directly
applicable to a wide range of substrates 1, and the
enantioselectivity obtained should be the same as that
produced with higher catalyst loading. For a given
substrate it may well be possible to further optimise the
reaction parameters as outlined above.
It was found that the enantioselectivity was linearly
dependant upon the concentration of ethyl acetate in
toluene, the highest enantioselectivity being obtained
with 100% toluene. This would seem to confirm our
earlier observation that polarity of the organic phase
significantly influences the level of enantioselectivity,3
In order to illustrate the generality of these conditions,
we have investigated epoxidation of a series of enones
1a–e (Table 1). In all cases the epoxidations were
complete within 24 h, and high levels of enantioselectiv-

B. Lygo, D. C. M. To / Tetrahedron Letters 42 (2001) 1343–1346
1345
Table 1.
Alkene
Product
% d.e.a
% e.e.10,11
86
Yield (%)
98
1a
]95
1b
1c
]95
]95
]98 (92)b
76
75
]98 (87)b
1d
1e
]95
]95
88
84
93
97
a Estimated to 5% by 1H NMR (400 MHz).
b After purification by recrystallisation, crude e.e.s are in parentheses.
ity were obtained. We also established that in a number
of cases the crude reaction products were most conve-
niently purified by recrystallisation, giving the epoxides
in good overall yield and excellent enantiomeric purity.
References
1. For a recent review on the asymmetric epoxidation of
electron-deficient alkenes, see: Porter, M. J.; Skidmore, J.
Chem. Commun. 2000, 1215.
In conclusion, the results of this study suggest that ion
exchange is the rate-limiting step in the room tempera-
ture epoxidation of a,b-unsaturated ketones using
sodium hypochlorite and catalyst 2. Using this informa-
tion it has been possible to develop optimised reaction
conditions that only require 1 mol% of catalyst and
allow straightforward access to a,b-epoxyketones with
high enantiomeric purity.
2. For other applications of N-anthracenylmethyl substi-
tuted Cinchona alkaloids in enantioselective phase-trans-
fer catalysed processes, see: (a) Lygo, B.; Wainwright, P.
G. Tetrahedron Lett. 1997, 38, 8595; (b) Corey, E. J.; Xu,
F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414; (c)
Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998,
39, 5347; (d) O’Donnell, M. J.; Delgado, F.; Hostettler,
C.; Schwesinger, R. Tetrahedron Lett. 1998, 39, 8775; (e)
Corey, E. J.; Bo, Y.; Busch-Petersen, J. J. Am. Chem.
Soc. 1998, 120, 13000; (f) Lygo, B.; Crosby, J.; Peterson,
J. A. Tetrahedron Lett. 1999, 40, 1385; (g) Lygo, B.
Tetrahedron Lett. 1999, 40, 1389; (h) Horikawa, M.;
Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999,
40, 3843; (i) Lygo, B.; Crosby, J.; Peterson, J. A. Tetra-
hedron Lett. 1999, 40, 8671; (j) Dehmlow, E. V.; Wagner,
S.; Mu¨ller, A. Tetrahedron 1999, 55, 6335; (k) O’Donnell,
M. J.; Delgado, F.; Pottorf, R. S. Tetrahedron 1999, 55,
Acknowledgements
We thank the EPSRC and GlaxoWellcome for a stu-
dentship (to D.C.M.T.). We would also like to thank
Dr. Jane Stewart (GlaxoWellcome) for helpful discus-
sions.

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B. Lygo, D. C. M. To / Tetrahedron Letters 42 (2001) 1343–1346
tert-butylmethylether/petroleum ether gave the purified
6347; (l) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2,
epoxides.
1097; (m) Perrard, T.; Plaquevent, J.-C.; Desmurs, J.-R.;
8. HPLC retention times (Chiralpak AD, 10% ethanol, 90%
hexane): Chalcone 1a (13.2 min), trans-chalcone oxide 3a
(16.1 min, 23. 9 min), cis-chalcone oxide (12.9 min, 13.8
min).
He´brault, D. Org. Lett. 2000, 2, 2959.
3. (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1998,
39, 1599; (b) Lygo, B.; Wainwright, P. G. Tetrahedron
1999, 55, 6289.
9. These data appear to be most consistent with the rate-
limiting step being ion exchange between the quaternary
ammonium halide and sodium hypochlorite. Catalysts of
type 2 have very low solubility in water, so it seems likely
that ion exchange takes place in the interfacial region.
For related discussion, see: Do, J. S.; Chou, T. C. J.
Appl. Electrochem. 1989, 19, 922 and references cited
therein.
10. Enantiomeric excesses (e.e.s) were determined to 2% by
HPLC analysis (Chiralcel OD-H, i-propanol/hexane,
epoxides 3b,d,e, Chiralpak AD ethanol/hexane, epoxides
3a,c). In all cases the stereochemically enriched samples
were compared with racemic samples generated using
tetra-n-butylammonium bromide as the catalyst for epox-
idation.
4. (a) Arai, S.; Tsuge, H.; Shioiri, T. Tetrahedron Lett. 1998,
39, 7563; (b) Macdonald, G.; Alcaraz, L.; Lewis, N. J.;
Taylor, R. K. Tetrahedron Lett. 1998, 39, 5433.
5. Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287.
6. For a general discussion on the effects of agitation in
phase-transfer catalysed reactions, see: Starks, C. M.;
Liotta, C. L.; Halpern, M. Phase-Transfer Catalysis;
Chapman and Hall: London, 1994; p. 319.
7. Typical procedure: A solution of enone (3.4 mmol) and
catalyst 2 (0.03 mmol) in toluene (10 ml) in a 25 ml
round-bottom flask was treated with 15% aqueous
sodium hypochlorite solution (6.8 mmol) and the result-
ing mixture was stirred vigorously (magnetic stirrer at ca.
1000 rpm) at 25°C for 12–24 hours. After this time water
(20 ml) was added and the layers separated. The aqueous
layer was further extracted with ethyl acetate (30 ml), and
the combined organic extracts dried (Na2SO4). Concen-
tration under reduced pressure gave the crude epoxide.
Chromatography on silica gel or recrystallisation from
11. The absolute stereochemistry depicted for the epoxide
products 3 is based on the established stereochemistry of
compound 3a (Marsman, B.; Wynberg, H. J. J. Org.
Chem. 1979, 44, 2312). In this paper it is assumed that the
same sense of selectivity applies to the other substrates.
.
.