Iminium salt-catalysed asymmetric epoxidation using hydrogen peroxide as stoichiometric oxidant

Article abstract of DOI:10.1002/adsc.200800303

Iminium salt organocatalysts can provide high selectivity and high efficiency in catalytic asymmetric epoxidation. They are normally used in conjunction with Oxone as the stoichiometric oxidant. Oxone, however, has limited stability and is insoluble in mo

Full text of DOI:10.1002/adsc.200800303

FULL PAPERS
DOI: 10.1002/adsc.200800303
Iminium Salt-Catalysed Asymmetric Epoxidation using Hydrogen
Peroxide as Stoichiometric Oxidant
Philip C. Bulman Page,a,* Phillip Parker,b Gerasimos A. Rassias,c
Benjamin R. Buckley,b and Donald Bethelld
a
School ofChemical Sciences & Pharmacy, University ofEast Anglia, Norwich, Norfolk NR4 7TJ, U.K.
Fax : (+44)-(0)1603-593008; e-mail: p.page@uea.ac.uk
Department ofChemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, U.K.
GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
Robert Robinson Laboratories, Department ofChemistry, University ofLiverpool, P O Box 147, Liverpool L69 3BX,
b
c
d
U.K.
Received: May 14, 2008; Revised: June 18, 2008; Published online: July 24, 2008
Abstract: Iminium salt organocatalysts can provide time the development ofa reaction system driven by
high selectivity and high efficiency in catalytic asym- hydrogen peroxide as the stoichiometric oxidant, in-
metric epoxidation. They are normally used in con- volving an unusual double catalytic cycle.
junction with Oxone as the stoichiometric oxidant.
Oxone, however, has limited stability and is insoluble Keywords: catalysis; epoxidation; iminium salts; or-
in most organic solvents; we report here for the first ganocatalysis; peroxides
Introduction
chiral substituent on the nitrogen atom,[6] and a diox-
ane-based substituent has proved to be optimum for
[7–9]
Epoxides are widely used in organic synthesis as they both yield and induction ofenantioselectivity.
are highly versatile building blocks,[1] and non-racemic Three ofthe most successufl catalysts are the dihy-
chiral epoxides with high ee are desirable synthetic in- droisoquinolinium salt 3a,[9,10] biphenylazepinium salt
termediates. Research over the past thirty years has 4,[8,9,11] and binaphthalene-azepinium salt 5, which can
[9,12]
seen the development ofa number ofmethodologies
provide enantiomeric excesses ofup to 97%.
capable of effecting asymmetric epoxidation.[2] Re-
The standard iminium salt epoxidation conditions
cently, asymmetric epoxidation utilising organocata- employ the triple salt Oxone (2KHSO5·KHSO4
lysts has received increased attention. Shiꢀs fructose- ·K2SO4) as a stoichiometric oxidant, sodium carbon-
derived dioxirane 1,[3] and oxaziridinium salts such as ate, and acetonitrile:water as the solvent mixture
2, first reported by Lusinchi,[4] have proven to be two
ofthe most reactive types ofasymmetric organocata-
lyst for oxygen transfer to weakly nucleophilic sub-
strates such as unfunctionalised alkenes. Several
groups have since published in the area ofiminium
salt-catalysed epoxidation.[5]
We were the first to report iminium salt catalysts
based on tetrahydroisoquinolines bearing an exocyclic
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Philip C. Bulman Page et al.
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(Scheme 1). The presence ofwater is essential ofr
Na2CO3·1.5H2O.[16] Richardson and Yao have since
Oxone solubility, and the base is essential for the ep- reported that, upon addition ofH O2 to sodium hy-
2
oxidation reaction to proceed. The major limitation to drogen carbonate, an equilibrium between hydrogen
carbonate and the corresponding percarbonate is es-
tablished [Eq. (1)].[17]
Scheme 1.
We reasoned that percarbonate could, in principle,
oxidise an iminium salt to the corresponding oxaziri-
dinium salt,[18] expelling carbonate as the leaving
group, the oxaziridinium salt could then directly oxi-
these systems is the restricted range oftemperatures
at which the epoxidation can be performed (08C to dise the alkene substrate to the corresponding epox-
room temperature). The upper limit is determined by ide. We were pleased to find that commercial sodium
the stability ofOxone, which decomposes relatively
percarbonate does indeed drive the reaction when
quickly in the basic medium at room temperature.[13] present in large excess. The essential features of this
The lower limit is determined by the use ofthe aque-
ous medium: the typical ratios ofacetonitrile to water
solvent used as solvent lie between 1:1 and 10:1, and
proposed double catalytic cycle are illustrated in
Scheme 2, Pathway A.
The alternative pathway B involves the hydroper-
the medium freezes at around À108C.[7,12] A large oxide anion as the nucleophile that attacks the imini-
[2,13]
quantity ofinorganic by-product is also generated.
um salt, so generating the oxaziridinium species. In
Iminium salt catalysts 3b and 4 mediate the epoxi- contrast to Pathway A, the inorganic promoter acts
dation of1-phenylcyclohexene in 41% and 59% ee simply as a base.
when using Oxone as the oxidant. We have recently
We were pleased to find that initial experiments
prepared and utilised the tetraphenylphosphonium utilising hydrogen peroxide (50% aqueous, 6 equiv.)
salt (TPPP) ofmonoperoxysulafte as a stoichiometric
in the presence ofsodium hydrogen carbonate
oxidant that is soluble in organic solvents.[9,11] Enan- (0.2 equiv.) in an acetonitrile:water (9:1) solvent
tiocontrol increases in these cases when using TPPP system using catalyst 3b (10 mol%) induced asymmet-
in dichloromethane solution, to 43% and 67% ee re- ric epoxidation of1-phenylcyclohexene with up to
spectively.
22% ee at 208C.
We were keen to investigate other potential oxi-
dants in order to widen the range ofusable reaction
conditions, but most oxidants either do not drive the Results and Discussion
catalysed reaction or generate considerable achiral
product through background direct oxidation ofthe
alkene substrates. Hydrogen peroxide is perhaps the
Effects of the Base on the Reaction
second most environmentally friendly oxidant avail- Previous work in investigating the ability ofhydrogen
able after oxygen in terms of by-products, and its use peroxide to oxidise an iminium salt to the oxaziridini-
as stoichiometric oxidant would allow an inexpensive um salt in the presence ofan alkene showed no evi-
and ꢂgreenꢀ process to be developed.[14] Hydrogen per- dence ofepoxidation in the absence ofbase. In this
oxide can oxidise electron-deficient alkenes, such as context, we have tested several bases and other po-
enones and conjugated esters, to their corresponding tential promoters (Table 1). Our initial reactions were
epoxides, for example in the presence of base and completed at both 08C and 208C, using 0.2 equiva-
polyleucine catalyst.[15]
lents ofa range ofbases, as well as potassium hydro-
In order to develop a hydrogen peroxide-driven gen phosphate, potassium hydrogen sulfate, and
system using our iminium salts as catalyst, several sodium and potassium sulfates, in addition to those
problems had to be addressed. Hydrogen peroxide salts indicated in Table 1. Based on previous work
does not induce epoxidation in the presence ofimini-
um salts. A co-catalyst that could be oxidised to a spe- used a 9:1 ratio as the acetonitrile:water solvent
using Oxone as the stoichiometric oxidant,[5n,o,19] we
cies that is capable ofoxygen transefr to an iminium
salt, but would not itselfinduce epoxidation more
system, which gives good conversion and ee. Catalyst
4 has shown superior reactivity to catalyst 3b. We
rapidly than the resulting oxaziridinum salt, was therefore used this solvent ratio and catalyst 4 in our
therefore required. In the solid state, sodium percar- investigation.
bonate has been shown by X-ray crystallographic
analysis to consist ofa layered solid corresponding to
Background epoxidation utilising 0.2 equivalents of
base, at 08C over 24 h, in the absence ofany catalyst,
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Iminium Salt-Catalysed Asymmetric Epoxidation using Hydrogen Peroxide
FULL PAPERS
Scheme 2.
was not observed for sodium, potassium, or lithium enantiocontrol, but show the highest level ofback-
carbonates, but was observed at a low level when ground epoxidation at 08C, although this is still low at
using caesium or rubidium carbonates (<5%), and <5%. The sodium salts show decreased enantiocon-
when using ammonium bicarbonate (approx 2%). At trol compared with their analogous potassium salts.
room temperature, over 24 h, the extent ofthe back-
It appears that the enantioselectivity achieved
ground epoxidation varied with the cation used: shows a small but significant change with the type of
sodium (<5%), potassium (11%), rubidium (15%), anion (HCO3 , CO2 or OHÀ) used to promote the
caesium (15%) carbonates, ammonium bicarbonate reaction. As we have previously established, in the
(20%). These results suggest that large inorganic cat- absence ofbase no epoxidation occurs, and indeed ex-
ions, when present, enhance background epoxidation. periments containing very small amounts ofbase
This may result from solubility differemces and/or de- (0.01 equiv.) showed no epoxidation (entry 3). When
À
2À
creased ion association: the size ofthese ions may
the amount ofbase was increased to 0.1 equivalent,
make the interionic distance sufficiently large that the desired epoxidation reaction furnished 1-phenyl-
little electrostatic association occurs, allowing in- cyclohexene oxide with ees of35% for NaHCO 3, 33%
creased background reaction.
for Na2CO3 and 28% for NaOH. We also observed
Table 1 shows that, in conjunction with catalyst 4, that for any base added at greater than 0.1 equiva-
the potassium salts at 08C provide the highest enan- lents (up to 2 equivalents), the ee remained approxi-
tioselectivity for reasonable conversions, giving 34% mately constant.
ee (KOH), 35% ee (KHCO3), and 39% ee (K2CO3).
For the carbonate bases we next tested the effect of
Rubidium and caesium carbonate also gave good the accompanying counterion, but little variation in
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Philip C. Bulman Page et al.
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Table 1. Asymmetric epoxidation of1-phenylcyclohexene
mediated with H2O2 by catalyst 4.
Entry[a] Base
Equiv. Temp.
Conv.
[%][b]
ee
[8C]
[%][b]
1
2
3
4
5
6
7
8
Li2CO3
LiOH
NaHCO3 0.01
NaHCO3 0.1
NaHCO3 0.2
NaHCO3 0.2
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaOH
KHCO3
KHCO3
K2CO3
K2CO3
KOH
Rb2CO3
Rb2CO3
Cs2CO3
Cs2CO3
0.2
0.2
0
0
0
0
0
20
0
20
0
20
0
20
0
0
0
0
20
0
20
0
0
20
0
29
19
28
<5
35
33
29
35
31
35
32
36
27
34
36
28
35
32
39
34
34
35
31
36
30
40
100
<5
22
63
100
34
100
35
100
52
100
47
42
100
19
57
26
96
58
29
75
41
1
1
2
2
0.2
0.2
1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Scheme 3.
carbonate and percarbonate species will be present in
roughly equal concentrations and the hydroperoxide
ion concentration will be small, so that
[HOOÀ] is about 1000. Bearing in mind that
À
20
0
89
7
[HCO4 ]/
NH4HCO3 0.2
hydrogen percarbonate anion can exist in two Àproto-
À
[a]
À
À
À
À
tropic forms, HOO CO O and HO CO OO , only
the less stable ofwhich (the latter) is expected to be
Epoxidation conditions: Iminium salt catalyst (10 mol%),
H2O2 (50%, 6 equiv.), base, MeCN:H2O (9:1), 24 h.
[b]
Conversions and enantiomeric excesses were determined an effective oxidising agent for the iminium cation,
from the chiral GC spectra by comparison of the alkene/
epoxide and epoxide/epoxide peak areas respectively;
the major enantiomer generated was the (1S,2S) epoxide.
and that hydroperoxide anion may be intrinsically
more reactive, the balance ofreaction between Path-
ways A and B in Scheme 2 may be substantially less
than 1000. Percarbonate and hydroperoxide anions
can be expected to convert chiral iminium salts to the
oxaziridinium species with different facial selectivities,
giving different diastereoisomeric excesses. Since each
the product ee was observed (36% ee for Cs2CO3, diastereoisomeric oxaziridinium cation will have its
35% ee for Ru2CO3, 39% ee for K2CO3, 31% ee for own overall reactivity and enantioselectivity in trans-
Na2CO3). Interestingly, similar levels ofenantioselec-
ferring an oxygen atom to the alkene, the enantiose-
tivity were observed with rubidium and caesium car- lection observed in the epoxide produced in iminium
bonates despite increased background epoxidation in ion-catalysed oxidation will clearly be dependent on
the absence ofcatalyst. Presumably the presence of
an iminium salt catalyst offers a lower energy path- may thus be anticipated from iminium ion-mediated
way, leading to asymmetric epoxidation. oxygen transfer using as oxidant Oxone, hydrogen
the choice of oxidant. Different enantioselectivities
In interpreting these observations it must be borne peroxide in the presence ofa carbonate base, or per-
in mind that several equilibria determine the availa- oxide anion (hydrogen peroxide plus a strong base ca-
bility ofthe key species responsible for generating the
oxaziridinium cations. The interrelation ofthese is
pable only ofdeprotonating it).
The active oxidant in Oxone is KHSO5, and so
shown in Scheme 3, in which are indicated pK values KHSO4 was tested to determine ifthe hydrogen per-
for some of the individual processes in water that can oxide oxidant could oxidise the potassium salt to the
be deduced from literature values for the pKa values active persulfate in situ, in the hope that this system
ofwater, hydrogen peroxide and carbonic acid, to-
might give similar enantioselectivity to the Oxone ep-
gether with that for the equilibrium in Eq. (1). It is oxidation system. Na2SO4, K2SO4 and KHSO4 were
clear that, at a fixed pH in the range 10–11, and a used in test reactions, but only poor levels ofconver-
ofrmal concentration ofhydrogen peroxide of1M,
sion to the epoxide (<15%) were observed.
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Iminium Salt-Catalysed Asymmetric Epoxidation using Hydrogen Peroxide
FULL PAPERS
Table 2. Effect of temperature on the asymmetric epoxida-
tion of1-phenylcyclohexene mediated by catalysts 3 and 4.[a]
Reactions were carried out using six molar equiva-
lents ofH O2 from a 50% aqueous solution; the re-
2
sults are shown in Table 3. In each case the volumes
ofwater and hydrogen peroxide in the reagent were
taken into account when determining the proportion
ofwater present in the total solvent volume. A 0%
water solvent system was achieved by the use ofethe-
real hydrogen peroxide.
Table 3 clearly shows that increasing the proportion
ofwater present decreases the observed ee under
these conditions. This is in sharp contrast to our aque-
ous Oxone system, in which ee is unaffected by the
proportion ofwater, but in which the rate ofreaction
increases sharply as the proportion ofwater is increa-
sed.[6b] Although many hours or even days may be re-
quired for these reactions to reach completion, the
enantioselectivity ofthe epoxide product remains
constant throughout this time. Maximum enantiose-
lectivity was obtained under the anhydrous reaction
conditions (56% ee); this is comparable to the
Entry Catalyst Temp.
Time
[h]
Conv.
[%][b]
ee
[8C]
[%][b]
1
2
3
4
5
3b
3b
3b
4
4
4
0
0
20
À10
À5
0
24
7 days
23
24
24
24
7 days
24
22
2.5
62
15
13
18
35
38
36
34
32
29
32
100
100
19
21
48
100
66
100
100
6
7
4
0
8
9
10
4
4
4
10
20
30
[a]
Epoxidation conditions: Iminium salt (10 mol%), H2O2
(50%, 6 equiv.), NaHCO3 (0.2 equiv), MeCN:H2O (9:1),
24 h.
Conversions and enantiomeric excesses were determined
from the chiral GC spectra by comparison of the alkene/
epoxide and epoxide/epoxide peak areas respectively;
[b]
the major enantiomer generated was the (1S,2S)-epoxide. Oxone-mediated system (60% ee), when using 1-phe-
nylcyclohexene as the substrate and iminium salt 4 as
catalyst.[7] This effect of water content with respect to
enantioselectivity may perhaps be interpreted in
Effect of Temperature on the Reaction
Table 3. Asymmetric epoxidation of1-phenylcyclohexene
mediated by catalyst 4 with varying concentrations ofaceto-
nitrile and water solvent system.
We next investigated the effect of temperature on the
enantioselectivity in epoxidation reactions carried out
between À10 and 308C (Table 2). A small increase in
enantioselectivity occurred as the temperature was re-
duced. As the temperature decreased the rate also de-
creased, requiring one week for the reaction to reach
completion at 08C, whereas full conversion to the ep-
oxide at 208C was observed in less than 24 h. At
308C, the reaction is complete after 2.5 h. Catalyst 4
showed increased levels ofenantioselectivity over cat-
alyst 3b, but 3b generally gave better conversion to
the epoxide at lower temperatures.
Entry H2O
[%]
Temp.
[8C]
Time
[h]
Conv.
[%][b]
ee
[%][b]
1[d]
2
0[c]
0[c]
0[c]
13
13
13
20
20
24
24
35
35
50
50
61
61
À5
0
20
À5
0
20
0
20
0
20
0
20
0
20
0
20
7 days
24
24
7 days
24
24
24
24
24
24
24
24
24
24
24
24
100
39
100
100
59
100
78
100
77
100
71
100
46
100
27
100
56
42
45
46
42
39
35
32
35
28
34
26
30
23
30
23
3
5[d]
6
4
7
8
9
10
11
12
13
14
15
16
Effects of Solvents on the Reaction
Effects of the Ratio of Co-solvents Used
Our first reactions were carried out using an acetoni-
trile:water (9:1) solvent system. We have investigated
the effect of the proportion of water on the enantiose-
lectivity ofthe epoxidation process (Scheme 4).
[a]
Epoxidation conditions: Iminium salt catalyst (10 mol%),
H2O2 (50%, 6 equiv.), NaHCO3 (0.2 equiv), MeCN:H2O,
08C, 24 h.
Conversions and enantiomeric excesses were determined
from the chiral GC spectra by comparison of the alkene/
epoxide and epoxide/epoxide peak areas respectively;
the major enantiomer was the (1S,2S)-epoxide in each
case.
[b]
[c]
[d]
Ethereal hydrogen peroxide used; reaction volume con-
tained 13% Et2O.
K2CO3 used as base.
Scheme 4.
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Philip C. Bulman Page et al.
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Table 4. Asymmetric epoxidation of1-phenylcyclohexene
mediated by catalyst 4 in various solvent systems.[a]
terms ofwater inlfuencing the stereochemical course
of the reaction by affecting the diastereofacial selec-
tivity ofaddition ofthe peroxy anion to the iminium
carbon atom (Pathway B, Scheme 2), for example, by
diastereofacially selective co-ordination of water mol-
ecules to the electron-deficient iminium units. Chang-
ing the solvent will alter the equilibria shown in
Scheme 3, perhaps slowing down the percarbonate
generation relative to the fast proton transfers; thus
hydroperoxide may become relatively more important
than percarbonate, and this also might reduce enan-
tioselectivity. Further, anions generally are less active
in aqueous solvents than in dipolar aprotic ones, and
this might retard the addition ofpercarbonate or hy-
droperoxide to the iminium ion.
Entry
Co-solvent
Conv. [%][b]
ee [%][c]
1
2
Cyclohexane
Hexane
26
0
32
0
3
Toluene
0
0
4
5
6
7
8
9
10
11
12
13
Ether
27
0
0
53
0
69
5
12
13
19
27
0
0
30
0
26
53
0
Chloroform
Ethyl acetate
THF
Dichloromethane
Methyl isobutyl ketone
Acetone
Ethanol
Methanol
Acetonitrile
42
35.2
Dissociation ofthe organic cÀatalyst salt may also be
a factor. In the iminium–BPh4 ion pair, in low dielec-
tric solvents where ion association is appreciable, the
large anion would be expected to be positioned on
the more accessible face of the iminium bond, so forc-
ing reaction with the oxidant to occur at the other
face. An increasing proportion of water would help to
dissociate the salt into the individually solvated spe-
cies, which would be expected to expose more ofthe
face of the iminium salt previously blocked by the
[a]
Epoxidation conditions: Iminium salt catalyst 4 (10
mol%), H2O2 (50%, 6 equiv.), K2CO3 (0.2 equiv.), solvent
(1 mL), À58C, 24 h.
[b]
[c]
Conversions were evaluated from the chiral GC spectra
by comparison ofthe alkene and epoxide peak areas.
Enantiomeric excesses were determined by chiral GC
spectra by comparison ofthe two epoxide peak areas;
the major enantiomer generated was the (1S,2S) epoxide
in each case.
À
BPh4 moiety, increasing the accessibility ofthat afce
to the oxidant. Diastereofacial selectivity in the for-
mation ofthe oxaziridinium species would then be re-
generally lower than when using Oxone as oxidant,
duced. Electrostatic interaction between component but is largely independent ofthe amount ofbase and
ions in these ion pairs will, however, be small because catalyst, and the nature ofcation associated with the
ofthe large ionic radii, even in 90% acetonitrile, lim-
iting the effect of this phenomenon.
base. In contrast, water content and temperature
appear to have the greatest impact on the enantiose-
lectivity and rate. We believe that this process oper-
ates through a double catalytic cycle, the promoter
acting either as a base (hydroxide) or a peroxido-
phore (carbonate) (Scheme 2).
Effects of Change of Organic Co-solvent
A range ofreactions with deiffrent co-solvents was
Optimisation ofthe oxidative system enabled asym-
carried out using catalyst 4, hydrogen peroxide, and metric epoxidation of1-phenylcyclohexene with 56%
potassium carbonate, at À58C to prevent background ee utilising catalyst 4 and ethereal hydrogen peroxide
epoxidation (Table 4).
in the absence ofwater at À58C. Further work on al-
It is worth noting that many ofthe experiments in
ternative oxidants and catalysts with a view to devel-
Table 4 are multiphase. It appears that some solvents oping more enantioselective systems is in progress.
that provide a more homogeneous reaction reaction
mixture may increase the enantioselectivity ofthe ep-
oxidation, for example acetone (53% ee) methanol
(44% ee) and acetonitrile (37% ee).
Experimental Section
General Experimental Details
All infrared spectra were obtained using a Perkin–Elmer
Conclusions
Paragon 1000 FT-IR spectrophotometer; thin film spectra
were acquired using sodium chloride plates. All 1H and
We have successfully demonstrated the use of hydro-
13C NMR spectra were measured at 400.13 and 100.62 MHz,
gen peroxide as the stoichiometric oxidant in iminium
respectively, using a Bruker DPX 400 MHz spectrometer, in
salt-catalysed asymmetric epoxidation, providing a
deuteriochloroform solution unless otherwise stated, using
cheaper and greener alternative to Oxone. The reac-
TMS (tetramethylsilane) as the internal reference. Mass
tion is promoted by a catalytic amount ofan inorganic
promoter such as carbonate, hydrogen carbonate and
hydroxide. The enantioselectivity ofthe reaction is
spectra were recorded using a Jeol-SX102 instrument utilis-
ing electron-impact (EI), fast atom bombardment (FAB), or
by the EPSRC national mass spectrometry service at the
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Iminium Salt-Catalysed Asymmetric Epoxidation using Hydrogen Peroxide
FULL PAPERS
University ofWales, Swansea. Optical rotation values were
measured with an Optical Activity-polAAar 2001 instru-
ment, operating at l=589 nm, corresponding to the sodium
D line, at the temperatures indicated. All chromatographic
manipulations used silica gel as the adsorbent. Reactions
were monitored using thin layer chromatography (TLC) on
aluminium-backed plates coated with Merck Kieselgel 60
F254 silica gel. TLC plates were visualised by UV radiation
at a wavelength of254 nm, or stained by exposure to an
ethanolic solution ofphosphomolybdic acid (acidiifed with
concentrated sulfuric acid), followed by charring where ap-
propriate. Reactions requiring anhydrous conditions were
carried out using glassware dried overnight at 1508C, under
a nitrogen atmosphere unless otherwise stated. Reaction sol-
vents were used as obtained commercially unless otherwise
stated. Light petroleum (b.p. 40–608C) was distilled from
calcium chloride prior to use. Ethyl acetate was distilled
over calcium chloride. Dichloromethane was distilled over
calcium hydride. Tetrahydrofuran and diethyl ether were
distilled under a nitrogen atmosphere from the sodium/ben-
zophenone ketyl radical. Acetone was dried over 4 A Linde
molecular sieve, and distilled under a nitrogen atmosphere.
Enantiomeric excesses were determined either by proton
nuclear magnetic resonance spectroscopy in the presence of
completely consumed (TLC analysis). The reaction mixture
was diluted with ice-cooled diethyl ether (20 mL per 100 mg
substrate) followed by the same volume of water. The aque-
ous phase was washed four times with diethyl ether, and the
organic solutions combined, washed with brine, and dried
(MgSO4). Filtration and evaporation ofthe solvents gave a
yellow/brown residue. The pure epoxide was obtained after
column chromatography, eluting with ethyl acetate/light pe-
troleum (1:99).
General Procedure for Catalytic Asymmetric Epox-
idation of Simple Alkenes Mediated by Iminium Salts
using Hydrogen Peroxide and Bicarbonate Salts
The bicarbonate salt (0.2 equiv.) and the iminium salt cata-
lyst (10 mol%) were added to acetonitrile (1 mL), and the
mixture cooled to À58C. The substrate alkene (1 equiv.) was
added, and the mixture allowed to reach equilibrium. Hy-
drogen peroxide (6 equiv.) was added. The reaction mixture
was stirred vigorously and monitored by TLC. After a maxi-
mum of24 h except where indicated, ice-cold brine was
added, followed by ice-cooled diethyl ether (20 mL per
100 mg substrate). The aqueous phase was washed four
times with diethyl ether, and the organic solutions combined
and dried (MgSO4). Filtration and evaporation ofthe sol-
vents gave a yellow/brown residue. The pure epoxide was
obtained after column chromatography, eluting with ethyl
acetate/light petroleum (1:99).
europium(III) tris[3-(heptafluropropylhydroxymethylene)-
A
(+)-camphorate] as the chiral shift reagent, by chiral HPLC
using a Chiracel OD column on a TSP Thermo-Separating-
Products Spectra Series P200 instrument, with a TSP Spec-
tra Series UV100 ultra-violet absorption detector set at
254 nm and a Chromojet integrator, or by chiral GC using a
Chiraldex B-DM column on a Fisons GC8000 series instru-
ment with a flame ionisation detector and a CE Instruments
ChromeCard data station.
General Procedure for the Background Epoxidation
Reaction with Hydrogen Peroxide and Bicarbonate
Salts in the Absence of Iminium Salt Catalyst
The bicarbonate salt (0.2 equiv.) was dissolved in acetoni-
trile (1 mL), and the solution cooled to À58C. The substrate
alkene (1 equiv.) was added, and the mixture allowed to
reach equilibrium. Hydrogen peroxide (6 equiv.) was added.
The reaction mixture was stirred vigorously and monitored
by TLC. After 24 h, brine was added, the mixture extracted
with diethyl ether, and the ethereal layer dried (MgSO4).
Filtration and evaporation ofthe solvents gave the crude
product mixture. Analysis by chiral GC-FID showed less
than 5% conversion to the epoxide (conversion was evaluat-
ed by comparison ofthe epoxide versus the alkene peak
areas).
General Procedure for the Formation of Racemic
Epoxides for ee Determinations
The alkene (1 equiv.) was dissolved in dichloromethane
(10 mLgÀ1) and cooled to 08C. m-CPBA (2 equiv.) was
added as a solution also in dichloromethane (10 mLgÀ1).
The reaction mixture was allowed to attain ambient temper-
ature and stirred until complete consumption ofthe sub-
strate was observed by TLC. The reaction was quenched
with the addition ofsaturated aqueous NaHCO (10 mLgÀ1)
3
and the layers separated. The organic layer was washed with
saturated NaOH (1.0M) (10 mLgÀ1) and dried (MgSO4).
Solvents were removed under reduced pressure. The pure
epoxide was obtained after column chromatography eluting
with ethyl acetate/light petroleum (1:99).
Acknowledgements
This investigation has enjoyed the support ofLoughborough
University, the EPSRC, and GlaxoSmithKline. We are indebt-
ed to the Royal Society for an Industry Fellowship (to
PCBP) and to the Mass Spectrometry Unit, Swansea.
General Procedure for Catalytic Asymmetric Epox-
idation of Simple Alkenes Mediated by Iminium Salts
using Oxone
Oxone (2 equiv.) was added to an ice-cooled solution of
sodium carbonate (4 equiv.) in water (12 mL per 1.50 g of
sodium carbonate), and the resulting foaming solution References
stirred for 5–10 min. The iminium salt (10 mol%) was added
as a solution in acetonitrile (6 mL per 3.6 mmol ofalkene),
followed by the alkene substrate (1 equiv.), also as a solution
in acetonitrile ofthe same volume as the solution ofthe cat-
alyst. The mixture was stirred at 08C until the substrate was
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