Synthesis of new chiral ketones from d-glucose derivatives and their use in the enantioselective epoxidation of arylalkenes

Article abstract of DOI:10.1002/ejoc.200900888

A new backbone model for a chiral carbohydrate-derived ketone for asymmetric epoxldatlon is presented. The oxo function is sited in a seven-membered ring fused to the sugar moety. The synthesized compound is an effective chirality-transfer agent in dioxirane-mediated epoxidation, giving ees of up to 74%.

Full text of DOI:10.1002/ejoc.200900888

FULL PAPER
DOI: 10.1002/ejoc.200900888
Synthesis of New Chiral Ketones from
D
-Glucose Derivatives and Their Use in
the Enantioselective Epoxidation of Arylalkenes
José Manuel Vega-Pérez,*[a] Margarita Vega Holm,[a] M. Luisa Martínez,[a]
Eugenia Blanco,[a] and Fernando Iglesias-Guerra*[a]
Keywords: Chiral ketones / Carbohydrates / Asymmetric catalysis / Chiral dioxiranes / Epoxidation / Asymmetric synthesis
A new backbone model for a chiral carbohydrate-derived
ketone for asymmetric epoxidation is presented. The oxo
function is sited in a seven-membered ring fused to the sugar
moety. The synthesized compound is an effective chirality-
transfer agent in dioxirane-mediated epoxidation, giving ees
of up to 74%.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
ployed in another epoxidation reaction. The reaction is ra-
pid and mild, and several efficient protocols have been de-
scribed by different research groups since the first one by
Curci et al.[4] High catalytic activity, high stereochemical
differentiation, usefulness on different structural types of
alkene, and easy and high-yielding synthesis are some cri-
teria required for ketones. The design of new chiral ketones
to provide successful stereochemical control in dioxirane-
mediated epoxidation reactions is an important issue in this
area. Because a dioxirane has two reacting sites, restriction
of possible competition between them is an important fac-
tor for stereochemical control and should be taken into
consideration during the ketone design process. Research
groups working in this area have reported very high enan-
tiomeric excess values for different types of alkene, with two
different approaches usually being applied. The first is to
design C2-symmetric ketones (different chiral backbones
have been employed) so that the two faces of the generated
dioxiranes have exactly the same chiral environment, and
there should be no problems of competition.[5–9] The second
option is the preparation of chiral ketones that yield dioxir-
anes with one face blocked, so that oxygen transfer occurs
almost selectively from the other face. In this area, many
research groups have achieved attractive and interesting re-
sults with different chiral ketone/Oxone® systems.[10–13]
Because of the important role of carbohydrate moieties
in stereochemical differentiation (they are cheap, available,
and offer various functional groups and stereogenic centres
in one molecule unit), the possibility of employing them as
precursors for chiral ketones – and subsequently as catalysts
in epoxidation reactions – is an interesting goal. In this con-
text, Shing and co-workers have developed new glucose-[14]
and arabinose-derived[1b,15] uloses and have achieved high
stereochemical communication between the ketone catalyst
and the alkene [(E)-, trisubstituted and (Z)-alkenes]. Shi
and co-workers have reported the synthesis of a variety of
Introduction
Chiral epoxides are widely employed in organic synthesis
because they are useful synthetic intermediates that can be
easily transformed into a variety of target molecules.[1] The
epoxide functional group itself is also an essential structural
moiety of many natural products and biologically active
compounds.[2]
The development of efficient methods to achieve access
to chiral epoxides with high enantiomeric excesses is an im-
portant objective of many research groups. Among such
methods, the asymmetric epoxidation of olefins is a power-
ful strategy, and is the most widely employed route. Epoxid-
ation of olefins is typically performed either with an organic
peracid (such as m-chloroperbenzoic acid) or with a combi-
nation of a transition metal catalyst and a co-oxidant. Sev-
eral chiral catalyst systems based on transition metal com-
plexes have been developed, and great success has been
achieved in metal-catalysed epoxidation reactions of un-
functionalised alkenes.
In the last few years, however, non-metal-based “organ-
ocatalysis” has become an emergent area.[3] One attractive
catalytic process in this field is dioxirane-mediated epoxid-
ation. Dioxiranes can be generated in situ from ketones and
potassium peroxomonosulfate (Oxone®), and when a chiral
ketone is employed its reaction with Oxone® yields a chiral
dioxirane, which may react selectively on one enantiotopic
face of the substrate alkene. After oxygen atom transfer
from dioxirane to alkene, the chiral ketone can be recovered
in high yield without loss of activity, and can thus be em-
[a] Departamento de Química Orgánica y Farmacéutica, Facultad
de Farmacia, Universidad de Sevilla
C/ Profesor García González no. 2, 41012 Sevilla, Spain
E-mail: vega@us.es
iglesias@us.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900888.
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J. M. Vega-Pérez, F. Iglesias-Guerra et al.
FULL PAPER
new fructose- and glucose-derived ketones that have been
shown to be effective and excellent catalysts for asymmetric
epoxidation of olefins with a broad substrate scope [high
enantioselectivities have been obtained with a wide variety
of (E)- and trisubstituted olefins, a number of (Z)-olefins
and certain terminal and tetrasubstituted olefins]. The same
authors have also extensively investigated the reaction tran-
sition states and factors for stereochemical control in order
to develop more efficient catalysts.[16]
Figure 1. Compounds 1 and 2.
Our research group has a long-term interest in the use of
carbohydrates in asymmetric processes. We have employed
carbohydrate derivatives as chiral templates for the stereo-
selective synthesis of different compounds: diamino sugars,
chiral oxazolidines and compounds with potential antican-
cer activity.[17]
Part of our work with carbohydrates involves their use
as auxiliaries in asymmetric transformations of olefins. Re-
cently, we have described the use of new carbohydrate deriv-
atives in the stereoselective synthesis of cyclopropanes.[18]
In the field of the development of epoxidation reactions
of olefins with the most successful stereocontrol (diastereo-
selectivity), our group has described the stereoselective
epoxidation of olefin moieties linked through various func-
tionalities (glycoside,[19,20] amide[21] and acetals[22]) to dif-
ferent positions of carbohydrate residues with m-chloroper-
benzoic acid as oxidant under mild conditions. The dif-
ferent types of chiral epoxide obtained (epoxyglycosides, ep-
oxyamides and epoxyacetals) can be transformed into a
variety of compounds.
Another reported approach for the design of chiral
ketones (and that we wish to mention here) is through the
incorporation of the ketone function on a cycle. In such
cases, the chiral environment necessary for the stereochemi-
cal differentiation is given by the axial chirality of a biaryl
moiety, linked to the ketone function through a spacer
group. Examples are Yang’s ketone 3,[5] Song’s ketone 4[6]
and Denmark’s ketone 5[8] (Figure 2).
Focusing on dioxirane-mediated epoxidations, we have
prepared new chiral carbohydrate-derived ketones and have
used them as catalysts. Here we present our initial effort in
this area in the shape of the synthesis of two new chiral
ketones: the first a chiral ketone with its carbonyl group on
a ring fused to the sugar moiety of methyl 4,6-O-benzyl-
idene-α--glucopyranoside as precursor, and the second a
C2-symmetric ketone derived from 1,2;5,6-di-O-isoprop-
ylidene-α--glucofuranose as starting material. We include
our stereochemical results for the epoxidation of (E)- and
trisubstituted alkenes with these ketones as chiral catalysts.
These preliminary results have encouraged us to continue
our studies in this area.
Figure 2. Compounds 3, 4 and 5.
Our aim was to design new chiral ketones derived from
sugars, based on the two methods described below. For the
first method we employed the carbohydrate moiety as chiral
backbone in order to obtain an efficient asymmetric envi-
ronment, and for the second approach we used the presence
of the ketone function on a cycle fused to the sugar moiety
(in this case through positions 2 and 3 as can be seen in
compound 9; Scheme 2, bottom). Our compound also fea-
tures spacer groups between the ketone and the ste-
reocentres (Scheme 1).
Results and Discussion
Syntheses of new carbohydrate-derived ketones are de-
scribed in the literature. The reactive centre in such a com-
pound is close to the stereogenic centres, and the sugar moi-
ety is suitably functionalised in order to optimise the role as
chiral catalyst. Compounds of this type function as efficient
catalysts in dioxirane-mediated epoxidations and yield high
enantiomeric excesses. Examples are Shi’s fructose-derived
Scheme 1.
Given that to synthesise compound 9 we had to fuse a
ketone 1[23] and Shing’s arabinose-derived ketone 2[15] (Fig- cycle containing a ketone function to the sugar ring, we
ure 1).
decided to conduct its synthesis by using a double bond as
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New Chiral Ketones from -Glucose for Enantioselective Epoxidation
precursor. This could be incorporated through the use of a white solid, the compound methyl 4,6-(R)-O-benzylidene-
simple substance such as 3-chloro-2-(chloromethyl)propene 2,3-O-(2-oxo-1,3-propanediyl)-α--glucopyranoside (9), the
by means of a double etherification reaction with a mono- spectroscopic data for which are consistent with the pro-
saccharide residue – in our case, the commercial product posed structure (Scheme 2).
methyl 4,6-O-(R)-benzylidene-α--glucopyranoside (6). The
On the other hand, the C2-symmetric ketones reported
aim, beyond the preparation of the designed compound 9, in the literature to act as efficient chiral catalysts in epoxid-
was to establish a simple sequence of reactions that could ation reactions are rigid systems.[5–9] In this context, our
be used to obtain a series of precursor substances of some second aim was to design a ketone possessing the structure
complexity, highly functionalised and stereochemically rel- of acetone substituted on C-1 and C-3 by two identical,
evant, and endowed with diverse but constitutionally sim- appropriately functionalised molecules of -glucose, thus
ilar chemical features.
representing a ketone with C2 symmetry but with confor-
Dialkylation of the starting compound 6 (Scheme 2) in mational flexibility. Our goal was to assess whether this new
tetrahydrofuran with 3-chloro-2-(chloromethyl)propene in molecule would afford good stereofacial discrimination in
the presence of solid potassium hydroxide and 18-crown-6 the epoxidation reaction (Scheme 3).
leads (at room temperature in 5 d) to the cyclic compound
methyl
4,6-(R)-O-benzylidene-2,3-O-(2-methylidene-1,3-
propanediyl)-α--glucopyranoside (7), one of the key inter-
mediates.
Scheme 3.
For this we used 1,2;5,6-di-O-isopropylidene-α--gluco-
furanose (10, Scheme 4) as starting material. Treatment of
1,2;5,6-di-O-isopropylidene-α--glucofuranose with 3-chloro-
2-(chloromethyl)propene (2 equiv.) in tetrahydrofuran, in
the presence of potassium hydroxide and 18-crown-6, led to
the compound 3-[(1,2:5,6-di-O-isopropylidene-α--gluco-
furanos-3-yl)oxy]-2-{[(1,2:5,6-di-O-isopropylidene-α--glu-
cofuranos-3-yl)oxy]methyl}propene (11) as a syrup, in ex-
cellent yield.
Scheme 2. Reagents and conditions: (i) (ClCH2)2CH2/KOH/18-
crown-6/THF, 63%; (ii) OsO4 (tBuOH)/Me3NO/CH2Cl2, 81%; (iii)
NaIO4 (H2O)/EtOH/H2O, 85 %.
The C2 symmetry presented by the molecule of com-
1
pound 11 is confirmed by the simplicity of its H and 13C
NMR spectra – there are single sets of signals for the two -
glucose fragments. The 1H NMR spectrum presents a single
Next was the dihydroxylation of the double bond with signal at δ = 5.12 ppm (singlet) for the two equivalent pro-
osmium tetroxide (in catalytic amounts) and trimeth- tons of the double bond, whereas two doublets with the
ylamine N-oxide, in dichloromethane as solvent. The reac- same coupling constant (3.7 Hz) are observed at δ = 5.76
tion took place at room temperature, yielding the glycol and 4.46 ppm, corresponding to the 1-H and 2-H atoms of
methyl 4,6-(R)-O-benzylidene-2,3-O-[2-hydroxy-2-(hydroxy- the two sugar molecules. The 2-H doublet indicates that it
methyl)-1,3-propanediyl]-α--glucopyranoside (8) as
a
is coupled only with 1-H and not with 3-H, which is typical
white solid. The dihydroxylation reaction generates a new of α--furanose rings blocked at the 1-OH and 2-OH
1
stereocentre in the molecule. In our case, H NMR spectral groups and in which there is a relative trans arrangement
study shows the signal for the acetal PhCH hydrogen atom between hydrogen atoms 2-H and 3-H, which have a cou-
as two singlets at δ = 5.51 and 5.49 ppm, that for 1-H of pling constant between them that is practically zero. The
the sugar as two doublets at δ = 4.82 and 4.78 ppm (J1,2
=
13C NMR spectrum shows the typical signals for the double
3.6 Hz), and that for the methyl group as two singlets at δ bond at δ = 141.6 and 115.6 ppm and for C-1 at δ =
= 3.43 and 3.42 ppm. The relative integrals for the two sig- 105.0 ppm. The rest of the signals in the two spectra were
nals for the same hydrogen atom in each of the stereoiso- assigned with the help of two-dimensional experiments.
mers show that they were formed in equal amounts.
The transformation of 11 into the corresponding ketone
The second step was an oxidative cleavage carried out followed a sequence of reactions similar to that described
with an aqueous solution of sodium metaperiodate as oxi- for the synthesis of compound 9. Dihydroxylation with os-
dising agent. An ethanol/water mixture was used as solvent mium tetroxide and trimethylamine oxide gave the glycol 3-
to dissolve compound 8 (insoluble in water) and the ionic [(1,2:5,6-di-O-isopropylidene-α--glucopyranos-3-yl)oxy]-2-
reagent (not very soluble in ethanol). The reaction was {[(1,2:5,6-di-O-isopropylidene-α--glucofuranos-3-yl)oxy]-
complete at room temperature overnight and yielded, as a methyl}-1,2-propanediol (12) as a syrup in high yield.
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J. M. Vega-Pérez, F. Iglesias-Guerra et al.
FULL PAPER
a broad singlet for the four hydrogen atoms vicinal to the
carbonyl group, whereas those of the 13C NMR spectrum
are the signal for the carbonyl carbon atom at δ =
204.9 ppm and that for C-1 at δ = 105.2 ppm.
Catalytic Asymmetric Epoxidation
Having synthesised the ketones 9 and 13, we were able
to test their efficiencies as chiral catalysts in dioxirane-medi-
ated epoxidation reactions. As test substrates we first chose
(E)-stilbene and phenylcyclohexene, representing (E)- and
trisubstituted alkenes, respectively, and screened various
sets of reaction conditions with a view to improving the
efficiency of the epoxidation (in terms of chemical and en-
antiomeric yields). Our preliminary essays employed sub-
stoichiometric quantities (0.5 equiv.) of ketone; not only
were the reaction times long (1–2 d), however, but in ad-
dition the reactions did not go to completion (recovery of
alkene without epoxidation). The use of different quantities
of ketone did not give different stereochemical results (en-
antiomeric excesses or major oxirane configuration). That
is why, finally, all epoxidations were carried out at 0 °C with
substrate (0.2 mmol), ketone (0.3 mmol), Oxone®
(0.4 mmol) and NaHCO3 (1.2 mmol) in DME/4ϫ10–4

aqueous EDTA (1.2:1, v/v). The pH of the mixture was
maintained at about 8.0 for the period of time necessary to
complete the reaction (3–7 h, TLC analysis).
Whereas the epoxidation reactions of (E)-stilbene and
phenylcyclohexene with ketone 9 and Oxone® gave 68%
and 74% enantiomeric excesses, respectively (Table 1), no
Scheme 4. Reagents and conditions: (i) (ClCH2)2CH2/KOH/18-
crown-6/THF, 96%; (ii) OsO4 (tBuOH)/Me3NO/CH2Cl2, 88%; (iii)
NaIO4 (H2O)/EtOH/H2O, 72 %.
It should be noted that compound 12 has lost the C2 enantioselectivity was achieved with the use of ketone 13 as
symmetry of its precursor. The quaternary carbon atom chiral dioxirane source. We think that despite its being a
bearing the hydroxy group is a prochiral carbon atom, so molecule with C2 symmetry, its conformational flexibility (a
that the two equal substituents on this carbon atom are two structural feature conspicuously absent in the C2-symmetric
diastereotopic groups. This is demonstrated by the NMR ketones described in the literature, which are characterised
spectra of compound 12, which present different signals for by their rigidities) is responsible for the absence of stereo-
all of the hydrogen and carbon atoms of the two -glucose discrimination in the dioxirane formed in its interaction
fragments that form part of the two diastereotopic groups with the alkene. We believe that as a result of this confor-
1
of the molecule. The H NMR spectrum shows two dou- mational flexibility in ketone 13 the two reactive centres of
blets (with coupling constants of 3.7 Hz) at δ = 5.88 and the generated dioxirane never attain the same chiral envi-
5.84 ppm for the two 1-H atoms, together with two doublets ronment.
(with the same coupling constant) at δ = 4.55 and 4.52 ppm
Encouraged by the preliminary results with ketone 9, we
for the two 2-H atoms, as well as two double doublets at δ went on to investigate its chiral induction capability in the
= 3.61 and 3.48 ppm, assigned to the diastereotopic methyl- asymmetric epoxidation of a variety of unfunctionalised
ene hydrogen atoms of the CH2OH group. The 13C NMR (E)- and trisubstituted olefins (a–g) in order to explore the
spectrum shows signals at δ = 105.7 and 105.6 ppm for the substrate scope of this catalyst (Scheme 5).
two C-1 atoms, and signals at δ = 74.7 and 64.0 ppm for
Moderate to good enantiomeric excesses were obtained
the two carbon atoms bearing the hydroxy groups.
(57–74%, Entries 1–4, 6). Triphenyloxirane and phenyl-
Oxidative cleavage of the glycol 12 with sodium meta- cyclohexene oxide were obtained with highest excess (74%,
periodate under the conditions described above led to 1,3- Entries 4 and 6). However, both 2,2-dimethyl-3-phenyloxir-
bis[(1,2:5,6-di-O-isopropylidene-α--glucofuranos-3-yl)- ane (Entry 5) and 2-phenylindene oxide (Entry 7) were ob-
oxy]acetone (13) as a syrup that was purified by column tained with poor stereoselectivity (6% and 25%).
chromatography. Its structure was confirmed by analysis of
The absolute configurations of the major enantiomers
its NMR spectra, which featured single sets of signals for obtained were assigned by comparison of the signal shifts
the two groups joined to the carbonyl group. Noteworthy in the presence of (+)-Eu(hfc)3 with those reported in the
1
features of the H NMR spectrum are the doublets for the literature, and also by comparison of the signs of optical
1-H and 2-H atoms at δ = 5.92 and 4.66 ppm, together with rotation with the reported ones. In one case (Entry 7) a ten-
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New Chiral Ketones from -Glucose for Enantioselective Epoxidation
1
Table 1. Catalytic asymmetric epoxidation of alkenes in the pres-
Table 2. Comparative H NMR chemical shifts of epoxide proton
ence of ketone 9.[a]
signals.[a]
Entry
Alkene
Yield[b]
(%)
ee[c]
(%)
Configuration[d]
Entry
Epoxide
Signal profiles[b]
Configuration[c]
1
2
3
aЈ
fЈ
gЈ
4.15 (M)/4.13 (m)
3.70 (M)/3.58 (m)
4.62 (M)/4.60 (m)
(–)-(1S,2S)
(–)-(1S,2S)
(–)-(1S,2S)[d]
1
2
3
4
5
6
7
a
b
c
d
e
f
73
68
72
66
54
68
57
67
74
6
74
25
(–)-(1S,2S)
(–)-(1S,2S)
(–)-(1S,2S)
(+)-(2S)
[a] 1H NMR spectroscopic data for epoxide in the presence of the
shift reagent (+)-Eu(hfc)3. [b] (M) for the major enantiomer, (m)
for the minor enantiomer. [c] Absolute configuration assigned ac-
cording to literature data. [d] Tentatively assigned.
(–)-(2S)
61
(–)-(1S,2S)
g
35[e]
(–)-(1S,2S)[f]
[a] Epoxidation conditions: substrate (1 equiv.), ketone (1.5 equiv.),
Oxone® (2 equiv.), NaHCO3 (6 equiv.), DME/aqueous EDTA
[4ϫ10–4  (1.2:1)], 0 °C. [b] Yields after column chromatography.
1
[c] Enantiomeric excesses were determined by direct H NMR ex-
amination of the epoxide products with shift reagent (+)-Eu(hfc)3.
[d] The absolute configuration of the major enantiomer was as-
signed by comparison of the signal shifts with those reported in
the literature and also by comparison of the sign of optical rotation
with the reported one in each case. [e] Unreacted alkene was reco-
vered after column chromatography. [f] Tentatively assigned (see
text).
Scheme 6. Epoxidation conditions (see Table 3).
Table 3. Catalytic asymmetric epoxidation of allylic alcohols in the
presence of ketone 9.[a]
Entry Substrate
Yield (%)[b]
ee (%)[c]
Configuration[d]
1
2
h
i
43[e]
56
9
(–)-(2S,3S)
(–)-(2S,3S)
41[e]
[a] Epoxidation conditions: substrate (1 equiv.), ketone (1.5 equiv.),
Oxone® (2 equiv.), NaHCO3 (6 equiv.), DME/aqueous EDTA
[4ϫ10–4  (1.2:1)], 0 °C. [b] Yields after column chromatography.
1
[c] Enantiomeric excesses were determined by direct H NMR ex-
amination of the epoxide products in the presence of the shift rea-
gent (+)-Eu(hfc)3. [d] The absolute configuration of the major en-
antiomer was assigned in each case by comparison of the signal
chemical shifts with those reported in the literature and also by
comparison of the sign of optical rotation with that reported.
[e] Attributed to isolation problems.
Scheme 5. Epoxidation conditions (see Table 1).
tative assignment was made. For this it was important to
analyse the chemical shifts of the oxirane protons for the
epoxides, shown in Figure 3 (Table 2). For epoxides of (E)-
stilbene and phenylcyclohexene, the signal for the major en-
antiomer appears in each case at a higher chemical shift
than that for the minor enantiomer (Entries 1 and 2), and
the profile is the same as for phenylindene oxide, so we ten-
tatively assigned the same configuration for its major epox-
ide (Entry 3).
The development of efficient methods for the asymmetric
epoxidation of α,β-enones is another important goal in or-
ganic synthesis. Although a variety of valuable systems have
been proposed for this reaction, the development of mild
and convenient methods of epoxidation with use of recycla-
ble catalysts remains an emergent area. In this context, we
carried out the epoxidation reaction of (E)-chalcone in the
presence of ketone 9 (Scheme 7, Table 4) and Oxone®.
Scheme 7. Epoxidation conditions (see Table 4).
Figure 3. Oxirane protons used for stereochemical assignments.
In almost all cases the epoxides were isolated in satisfac-
Focusing on testing the oxidant capacity of ketone 9 and tory chemical yields (60–73%), and the epoxidation reac-
studying its potential for employment for the epoxidation tions were complete after a few hours, indicating that
of a variety of alkenyl substrates (unfunctionalised and dif- ketone 9 is an efficient catalyst (in terms of reactivity) for
ferently functionalised olefins) – in other words, the gener- generation of the active dioxirane. In the cases of phenyl-
ality of this system – we carried out epoxidations of two indene (Table 1, Entry 7) and (E)-chalcone (Table 4), how-
allylic alcohols as another kind of test substrate (Scheme 6, ever, the reactions were not complete even after 24 h, and
Table 3).
significant amounts of the starting materials were reco-
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J. M. Vega-Pérez, F. Iglesias-Guerra et al.
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Table 4. Catalytic asymmetric epoxidation of (E)-chalcone in the cess and in good chemical yield (72%; Scheme 8, Table 5).
presence of ketone 9.[a]
However, in order to be able to determine to what extent
Yield (%)[b]
ee (%)[c]
Configuration[d]
that excess could be attributed to the chirality of ketone 9
and what was the effect of the chirality of the substrate
(the pre-existing stereocentres are the carbon atoms derived
from hydrobenzoin – C-4 and C-5 of the dioxolane ring,
rather distant from the double bond) we also carried out
the epoxidation of compound 14 in the presence of two dif-
ferent oxidative systems: m-chloroperoxybenzoic acid and
CF3COCH3/Oxone®. Neither reaction resulted in dia-
stereoselection, so all of the chirality obtained is attributed
to good stereochemical communication between the alkenyl
acetal 15 and the dioxirane derived from ketone 9.
52
38
(–)-(2R,3S)
[a] Epoxidation conditions: substrate (1 equiv.), ketone (1.5 equiv.),
Oxone® (2 equiv.), NaHCO3 (6 equiv.), DME/aqueous EDTA
[4ϫ10–4  (1.2:1)], 0 °C. [b] Unreacted substrate was recovered af-
ter column chromatography. [c] Enantiomeric excess was deter-
mined by chiral HPLC analysis on a Chiralcel OD column. [d] The
absolute configuration of the major enantiomer was assigned by
comparison of the sign of optical rotation with the reported one
and of the HPLC retention times with the literature.
vered. We observed that for most reactions the ees were
about 57–74%, except in two cases in which they were dra-
matically decreased (Table 1, Entry 5; Table 3, Entry 2) to
6% and 9%, respectively, indicating that ketone 9 could not
induce enough stereofacial discrimination to afford high
ees. In each of these cases, one of the carbon atoms in the
double bond of the precursor is a quaternary centre without
aromatic substituents (two methyl groups in one case, and
a methyl and a hydroxymethyl group in the other), in con-
trast with the cases of the other trisubstituted alkenes used,
each of which possesses a quaternary centre but with aro-
matic substituents (Table 1, Entries 3 and 4); in these cases
the enantioselectivities are considerably higher and similar
to those obtained with the (E)-olefins employed (Table 1,
Entries 1, 2 and 6; Table 3 Entry 1). It should be mentioned
that at least one of the carbon atoms in the double bond
possesses a phenyl group as substituent in all the substrates
employed. We suggest that not only steric interactions but
also electronic ones are factors controlling the approach be-
tween groups with π-systems both in the alkene substrate
Scheme 8. Reagents and conditions: (i) PhCH=CHCH(OCH3)2/
camphorsulfonic acid/ACN, 81%; (ii) ketone 9 (1.5 equiv.), Oxone®
(2 equiv.), NaHCO3 (6 equiv.), DME/aqueous EDTA [4ϫ10–4
(1.2:1)], 0 °C, 72 %.

Table 5. Catalytic asymmetric epoxidation of compound 15 in the
presence of ketone 9.[a]
Yield (%)[b]
de (%)[c]
Configuration[d]
72
79
(–)-(2R,3S)
and in the ketone. Further studies in this area are in pro- [a] Epoxidation conditions: substrate (1 equiv.), ketone (1.5 equiv.),
Oxone® (2 equiv.), NaHCO3 (6 equiv.), DME/aqueous EDTA
gress to determine what influence the aromatic or aliphatic
[4ϫ10–4  (1.2:1)], 0 °C. [b] Yield after column chromatography.
natures of the blocking groups at the two positions in the
ketone – acetal and anomeric carbon atoms – and the use
[c] Diastereoisomeric excess was determined by 1H NMR spec-
troscopy of the epoxide by signal integration. [d] For oxirane
of substrates lacking aromatic substituents on the carbon
atoms of the double bond have on the enantioselectivities
of the reactions.
stereocentres, tentatively assigned.
We chose this alkenylidene acetal because it is a simple
In all cases, ketone 9 was recovered in high yields (70– substrate in which the alkenyl portion is similar to those in
75%) without loss of activity. This shows its stability under other acetals that we have described previously[22] and with
the reaction conditions, and thus the possibility of its being which we have carried out epoxidation reactions diastereo-
recycled.
selectively with metachloroperbenzoic acid. In these cases
In the synthesis of natural products, an important goal the stereochemical courses of the reactions depend on the
is to obtain epoxides highly diastereoselectively. Our group sugars chosen as chiral auxiliaries to which the alkenyl resi-
has described stereoselective epoxidations of olefin moieties dues are attached through acetal functions, and afford the
linked through various functionalities to different positions major oxirane of (2R,3S) configuration when the sugar
of carbohydrate residues[19–22] in the presence of m-chloro- used is of gluco configuration {compound 17, dodecyl
peroxybenzoic acid as oxidant under mild conditions. A 2-acetamido-2-deoxy-4,6-O-[(R,E)-3-phenyl-2-propenylid-
logical consequence was that in this work we would study ene]-β--glucopyranoside; Scheme 9}, or that of (2S,3R)
the capacity of ketone 9 to induce diastereoselectivity – in configuration when the sugar residue has the allo configura-
other words, double asymmetric induction. For this, we tion {compound 18, cyclohexyl 2-acetamido-2-deoxy-4,6-
chose as substrate the simple alkenylidene acetal 15 O-[(R,E)-3-phenyl-2-propenylidene]-β--allopyranoside}.
(Scheme 8), derived from (S,S)-hydrobenzoin (14), that we In this way we had previously synthesized both diastereo-
had synthesised previously in good yield (81%). Its epoxid- isomeric oxiranes and so could compare them (NMR spec-
ation with ketone 9 under the conditions described gave the troscopic data) with compound 16 to determine the config-
corresponding oxirane 16 with a 79% diastereoisomeric ex- uration of its major oxirane.
6014
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6009–6018

New Chiral Ketones from -Glucose for Enantioselective Epoxidation
(allo configuration). This showed a different profile in the
3Ј-H and C-3Ј signals, so a different configuration was as-
signed to its major isomer. Compound 16 showed the same
profile as compound 19 for 3Ј-H and C-3Ј, and a different
profile in these signals, as well as in the C-2Ј signal, from
that of compound 20. From these profiles we assigned a
(2R,3S) configuration for the major isomer of compound
16.
Conclusions
We present a new chiral carbohydrate-derived ketone –
compound 9 – easily prepared in four steps from the com-
mercially available methyl 4,6-O-(R)-benzylidene-α--gluco-
pyranoside. We have carried out epoxidation reactions of
different (E)- and trisubstituted alkenes with this ketone,
which afforded satisfactory chemical yields (60–73%). The
excellent catalytic properties were demonstrated by the re-
covery of the ketone without loss of activity, in high yields
(70–75%).
Ketone 9 has features of structure, synthesis and as chi-
rality transfer agent that make it an interesting catalyst mo-
tif. Firstly, its reactive group is located on a seven-mem-
bered ring fused to positions 2 and 3 of the sugar moiety
and not close to stereocentres (there are no problems of
epimerisation). Secondly, although not a C2-symmetric sys-
tem, it is rigid, with the sugar chirality in its structure and
with electron-withdrawing groups on C-α (it is known that
this increases the reactivity of the carbonyl group to gener-
ate the active dioxirane).[5,8,16] Thirdly, the substituents on
the acetal and anomeric positions are points of structural
modification, and fourthly, it is easily synthesized from the
commercially available carbohydrate precursor in a simple
process that can also be applied with other precursors. Fi-
nally, the moderate-to-good excesses obtained (57–74%)
indicate the efficient chirality transfer capability of this
ketone, and thus its usefulness as a dioxirane precursor for
the epoxidation reaction.
Scheme 9. Reagents and conditions: (i) m-CPBA/CHCl3/–15 °C.
In order to assign the configuration on the stereogenic
centres in the oxirane ring in compound 16 formed in the
epoxidation reaction, it is important to analyse the NMR
chemical shifts of the proton and carbon signals corre-
sponding to the oxidised acetal system and to compare
them with the spectroscopic data for the cinnamaldehyde
acetals previously described by us (Figure 4, Table 6). For
oxiranes derived from (E)-cinnamaldehyde, the signal corre-
sponding to 3Ј-H is easily identifiable in the 1H NMR spec-
tra at δ ≈ 4 ppm as a doublet, with the signal for C-3Ј in
the 13C NMR spectra at δ ≈ 55 ppm. In a previous paper[22a]
we assigned the (2R,3S) configuration to the major isomer
of compound 19 (gluco configuration), and it can be seen
that the doublet corresponding to 3Ј-H of the major isomer
appeared at a lower chemical shift than that of the minor
isomer, and that the signal for C-3Ј of the major isomer
appeared at a higher chemical shift than that of the minor
isomer. In another previous paper[22b] we assigned the
(2S,3R) configuration to the major isomer of compound 20
On the basis of the results presented here, we are encour-
aged to continue our research in this area, focusing on two
general aims. The first is to carry out epoxidations of other
kinds of olefins [(Z)- and terminal alkenes and electron-
deficient olefins] in the presence of ketone 9, and to study
the presence of both steric and electronic effects in the chi-
rality transfer process. The second is the preparation of new
chiral ketones by this efficient and easy synthetic methodol-
ogy and their use in epoxidation reactions of different al-
kenes.
Figure 4. Oxirane protons used for stereochemical assignments.
Table 6. NMR spectroscopic data (δ [ppm]) for the acetal group in oxiranes derived from (E)-cinnamaldehyde.[a]
Entry
Compound
2Ј-H
3Ј-H
C-2Ј
C-3Ј
Configuration[b]
1
2
3
16
19
20
3.44(M)/3.40(m)
4.10(m)/4.08(M)
3.99(m)/3.98(M)
3.93(M)/3.91(m)
62.1(m)/61.9(M)
60.1
60.7(M)/60.5(m)
55.8(M)/55.1(m)
54.7(M)/54.5(m)
56.3(m)/55.4(M)
(2R,3S)[c]
(2R,3S)
(2S,3R)
–
3.18
[a] (M) for the major, (m) for the minor enantiomer. [b] Absolute configuration of the stereogenic centres in the oxirane ring. [c] Tentatively
assigned.
Eur. J. Org. Chem. 2009, 6009–6018
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6015

J. M. Vega-Pérez, F. Iglesias-Guerra et al.
FULL PAPER
(0.58 g, 5.2 mmol) and a solution of osmium tetroxide in propan-
2-ol (2.5% w/v) in catalytic amount (0.5 mL, 0.04 mmol) were
added to a solution of 7 (1.3 g, 4.0 mmol) in dichloromethane
(300 mL). The mixture was stirred at room temperature for 24 h.
The solution was washed successively with dilute aqueous sodium
bisulfite and water and dried (MgSO4), and the solvents were evap-
orated to dryness. The solid obtained was purified by flash
chromatography on silica gel, with dichloromethane/hexane (80:1)
as eluent, yielding a pale yellow solid (1.2 g, 81%) as a diastereoiso-
meric mixture (1:1). M.p. 48–50 °C. [α]2D5 = +74.2 (c = 1.0, CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 7.6–7.2 (m, 5 H, Ph), 5.51, 5.49
(2 s, 1 H, PhCH), 4.82, 4.78 (2 d, J1,2 = 3.6 Hz, 1 H, 1-H), 4.26
(m, 1 H, 6e-H), 3.43, 3.42 (2 s, OCH3), 3.05, 2.10 (2 s, 2 H, 2 OH)
ppm. 13C NMR (125 MHz, CDCl3): δ = 137.1, 137.0, 129.2, 129.1,
128.3, 128.2, 126.4 (Ph), 102.0, 101.9 (PhCH), 99.8, 99.5 (C-1),
83.1, 82.2 (C-2), 80.4, 79.7 (C-3), 79.6, 79.5 (C-4), 77.1 [C(OH)],
75.8, 75.5, 75.3, 74.8 [(OCH2)C (CH2O)], 69.0, 68.9 (C-6), 64.9,
64.5 (CH2OH), 62.9, 62.8 (C-5), 55.5, 55.4 (OCH3) ppm. MS (EI):
m/z (%) = 368 (45) [M]+·. HRMS (EI): calcd. for C18H24O8 (368.15)
[M]+· 368.147118; found 368.146992. C18H24O8 (368.15): calcd. C
58.69, H 6.57; found C 58.57, H 6.67.
Experimental Section
General: Melting points were obtained with a Stuart SMP 10 melt-
ing point apparatus and are uncorrected. Optical rotations were
obtained with a Perkin–Elmer Model 341 polarimeter at 25 °C.
Mass spectra were recorded with a Micromass AUTOSPECQ mass
spectrometer: EI at 70 eV and CI at 150 eV, HR mass measure-
ments with resolutions of 10000. FAB mass spectra were recorded
by use of a thioglycerol matrix. NMR spectra were recorded at
25 °C with a Bruker AMX 500 spectrometer and a Bruker AV 500
spectrometer at 500 MHz for 1H and 125 MHz for 13C. The chemi-
cal shifts are reported in ppm on the δ scale relative to TMS. COSY,
DEPT, HSQC and NOESY experiments were performed to assign
the signals in the NMR spectra. Silica gel 60 (230–400 ASTM) was
used for flash column chromatography. All solvents were reagent
or analysis grade. Evaporations were conducted under reduced
pressure. Reactions were monitored by thin-layer chromatography
(TLC) on aluminium-backed plates coated with Merck Kieselgel
60 F254 silica gel. Compounds were visualised with the aid of UVA
irradiation at a wavelength of 254 nm or stained by exposure to an
ethanolic solution of phosphomolybdic acid and subsequent heat-
ing. Enantiomeric excesses were determined by proton nuclear
magnetic resonance spectroscopy in the presence of europium(III)
Methyl 4,6-O-(R)-Benzylidene-2,3-O-(2-oxo-1,3-propanediyl)-α-D-
glucopyranoside (9): A solution of sodium periodate (0.77 g) in
water (9 mL) was added to a solution of 8 (0.67 g, 1.8 mmol) in
ethanol/water (1:2, 120 mL), and the reaction mixture was stirred
at room temperature overnight. The mixture was concentrated to a
small volume (40–50 mL), the solution was extracted with dichloro-
methane (5ϫ40 mL) and dried (MgSO4), and the solvents were
evaporated to dryness. The solid obtained was purified by flash
chromatography on silica gel with dichloromethane/hexane (10:1)
as eluent, yielding a white solid (0.5 g, 85%). M.p. 124–125 °C.
tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate]
as
the chiral shift reagent, or by chiral HPLC with a Chiralcel OD
column. Absolute configurations were assigned by comparison
with the signal shifts reported in the literature in the cases of epox-
ides a–i[5a,23–25] and by chiral HPLC retention times and compari-
son with the literature in that of epoxide j.[27] Absolute configura-
tions were also determined by comparison of the signs of optical
rotation with the reported ones.[5a,23–27]
1
[α]2D5 = +208.8 (c = 1.0, CH2Cl2). H NMR (500 MHz, CDCl3): δ
Methyl 4,6-O-(R)-Benzylidene-2,3-O-(2-methylidene-1,3-propane-
diyl)-α-D-glucopyranoside (7): Freshly powdered potassium hydrox-
= 7.6–7.3 (m, 5 H, Ph), 5.53 (s, 1 H, PhCH), 4.88 (d, J1,2 = 3.7 Hz,
1 H, 1-H), 4.4–4.2 [m, 5 H, 6e-H, (OCH2)C(CH2O)], 4.04 (t, J2,3
ide (7.0 g, 125 mmol), 18-crown-6 (0.38 g, 1.4 mmol) and 3-chloro-
2-(chloromethyl)propene (4.1 mL, 35.4 mmol) were added success-
ively to a cooled solution (5 °C) of methyl 4,6-O-(R)-benzylidene-
α--glucopyranoside (1; 10.0 g, 35.4 mmol) in dry THF (70 mL).
The reaction mixture was stirred at this temperature for 3 h and
left at room temperature until all the starting material had been
consumed, as monitored by TLC (5 d, approximately). It was then
diluted with dichloromethane (60 mL), washed successively with
water and aqueous sodium hydrogen carbonate, dried (MgSO4) and
filtered, and the filtrate was concentrated to dryness. The solid ob-
tained was purified by flash chromatography on silica gel with
dichloromethane/hexane (10:1) as eluent, yielding a white solid
(7.5 g, 63%). M.p. 114–115 °C. [α]2D5 = +118.2 (c = 1.0, CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 7.5–7.3 (m, 5 H, Ph), 5.51 (s, 1
H, PhCH), 4.98, 4.96 (2 s, 2 H, C=CH2), 4.80 (d, J1,2 = 4.8 Hz, 1
= J3,4 = 9.2 Hz, 1 H, 3-H), 3.88 (dt, J5,6e = 4.7, J4,5 = J5,6a
10.0 Hz, 1 H, 5-H), 3.75 (t, J5,6e = J6e,6a = 10.3 Hz, 1 H, 6a-H),
3.63 (t, J3,4 = J4,5 = 9.4 Hz, 1 H, 4-H), 3.59 (dd, J1,2 = 3.7, J2,3
=
=
9.0 Hz, 1 H, 2-H), 3.47 (s, 3 H, OCH3) ppm. 13C NMR (125 MHz,
CDCl3): δ = 209.7 (C=O), 137.1, 129.3, 128.3, 126.4 (Ph), 102.0
(PhCH), 99.1 (C-1), 85.2 (C-2), 82.8 (C-3), 79.2 (C-4), 77.9, 77.3
[(OCH2)C(CH2O)], 68.9 (C-6), 62.7 (C-5), 55.5 (OCH3) ppm. MS
(EI): m/z (%) = 336 (100) [M]+·. HRMS (EI): calcd. for C17H20O7
(336.12) [M]+ 336.120903; found 336.120591. C17H20O7 (336.12):
calcd. C 60.71, H 5.99; found C 60.55, H 6.12.
3-[(1,2:5,6-Di-O-isopropylidene-α-D-glucofuranos-3-yl)oxy]-2-{[(1,2:5,6-
di-O-isopropylidene-α- -glucofuranos-3-yl)oxy]methyl}propene (11):
D
Freshly powdered potassium hydroxide (6.0 g, 107 mmol), 18-
crown-6 (0.33 g, 1.2 mmol) and 3-chloro-2-(chloromethyl)propene
(1.8 mL, 15.1 mmol) were added successively to a cooled solution
(5 °C) of 1,2;5,6-di-O-isopropylidene-α--glucofuranose (10; 7.8 g,
30.0 mmol) in dry THF (40 mL). The reaction mixture was stirred
at this temperature for 3 h and left at room temperature until all
the starting material had been consumed, as monitored by TLC
(7 d, approximately). It was then diluted with dichloromethane
(100 mL), washed successively with water and aqueous sodium hy-
drogen carbonate, dried (MgSO4) and filtered, and the filtrate was
concentrated to dryness. The syrup obtained was purified by flash
chromatography on silica gel, with hexane/ethyl acetate (6:1) as elu-
ent, to yield a colourless oil (8.2 g, 96%). [α]2D5 = –24.0 (c = 1.0,
2
H, 1-H), 4.54 [d, JA,B = 14.4 Hz, 1 H, (OCHAHB)C(CHDHEO)],
2
4.44 [d, JD,E = 14.3 Hz, 1 H, (OCHAHB)C(CHDHEO)], 4.31–4.25
[m, 3 H, 6e-H, (OCHAHB)C(CHDHEO)], 3.87 (t, J2,3 = J3,4
9.2 Hz, 1 H, 3-H), 3.83 (dt, J5,6e = 4.8, J4,5 = J5,6a = 10.0 Hz, 1 H,
5-H), 3.71 (t, J5,6e = J6e,6a = 10.2 Hz, 1 H, 6a-H), 3.55 (t, J3,4
=
=
J4,5 = 9.4 Hz, 1 H, 4-H), 3.45–3.41 (m, 4 H, 2-H, OCH3) ppm. 13C
NMR (125 MHz, CDCl3): δ = 147.2 (C=CH2), 137.2, 129.1, 128.2,
126.4 (Ph), 112.2 (C=CH2), 102.0 (PhCH), 99.5 (C-1), 83.1 (C-2),
80.3 (C-3), 79.7 (C-4), 73.8, 73.1 [(OCH2)C(CH2O)], 69.0 (C-6),
62.3 (C-5), 55.3 (OCH3) ppm. MS (FA): m/z (%) = 357 (50) [M +
Na]+. HRMS (FAB): calcd. for C18H22O6Na (357.13) [M + Na]+
357.131408; found 357.132039. C18H22O6 (334.14): calcd. C 64.66,
H 6.63; found C 64.51, H 6.58.
1
CH2Cl2). H NMR (500 MHz, CDCl3): δ = 5.76 (d, J1,2 = 3.7 Hz,
2 H, 2 1-H), 5.12 (s, 2 H, C=CH2), 4.46 (d, J1,2 = 3.7 Hz, 2 H, 2 2-
Methyl 4,6-O-(R)-Benzylidene-2,3-O-[2-hydroxy-2-(hydroxymethyl)- H), 4.20 (m, 2 H, 2 5-H), 4.12 [d, 2JA,B = 12.3 Hz, 2 H, (OCHAHB)-
1,3-propanediyl]-α-
D-glucopyranoside (8): Trimethylamine N-oxide
C(CHAHBO)], 4.00–3.95, 3.90–3.85 [2 m, 10 H, 2 3-H, 2 4-H, 2 6A-
6016
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6009–6018

New Chiral Ketones from -Glucose for Enantioselective Epoxidation
H, 2 6B-H, (OCHAHB)C(CHAHBO)], 1.38, 1.32, 1.26, 1.21 [4 s, 24
neutralise the medium. The solvent was evaporated to dryness. The
H, 4 C(CH3)2] ppm. 13C NMR (125 MHz, CDCl3): δ = 141.6 syrup obtained was purified by flash chromatography on silica gel,
(C=CH2), 115.6 (C=CH2), 111.5, 108.8 [4 C(CH3)2], 105.0 (2 C-1),
with hexane/ethyl acetate (50:1) as eluent, yielding a colourless oil
82.1 (2 C-2), 81.3, 81.0 (2 C-3, 2 C-4), 72.1 (2 C-5), 70.3 [(OCH2)- (0.53 g, 81%). [α]2D5 = –71.8 (c = 0.6, CH2Cl2). 1H NMR (500 MHz,
C(CH2O)], 67.2 (2 C-6), 26.6, 26.1, 25.2 [4 C(CH3)2] ppm. MS (EI):
m/z (%) = 572 (2) [M]+·. HRMS (EI): calcd. for C28H44O12 (572.28)
[M]+· 572.283277; found 572.282660.
CDCl3): δ = 7.5–7.3 (m, 15 H, 5 Ph), 6.90 (d, J(E) = 16.0 Hz, 1 H,
PHCH=CH), 6.43 (dd, J = 6.0, J(E) = 16.0 Hz, 1 H, PHCH=CH),
5.99 (dd, J = 6.0, J = 0.8 Hz, 1 H, CH), 4.84 (m, 2 H, 2 OCHPh)
ppm. 13C NMR (125 MHz, CDCl3): δ = 137.9–126.4 (Ph), 128.1,
125.5 (PhCH=CH), 104.7 (CH), 86.6, 84.8 (2OCHPh) ppm. MS
(CI): m/z (%) = 328 (70) [M + H]+.
3-[(1,2:5,6-Di-O-isopropylidene-α-D-glucofuranos-3-yl)oxy]-2-{[(1,2:5,6-
di-O-isopropylidene-α- -glucofuranos-3-yl)oxy]methyl}propane-1,2-
D
diol (12): Trimethylamine N-oxide (1.16 g, 10.4 mmol) and a solu-
tion of osmium tetroxide in propan-2-ol (2.5 % w/v) in catalytic
amount (1.0 mL, 0.08 mmol) were added to a solution of 11 (4.3 g,
8.0 mmol) in dichloromethane (300 mL). The mixture was stirred at
room temperature for 24 h. The solution was washed successively
with dilute aqueous sodium bisulfite and water and dried (MgSO4),
and the solvents were evaporated to dryness. The syrup obtained
was purified by flash chromatography on silica gel with dichloro-
methane/methanol (100:1) as eluent, yielding a pale yellow oil (4.3 g,
Typical Epoxidation Procedure: Chiral ketone 9 or 13 (0.3 mmol)
and nBu4NHSO4 (5 mg) were added to a solution of an alkene (a–
j; 0.2 mmol) in 1,2-dimethoxyethane (5 mL). The reaction mixture
was cooled to 0 °C in an ice/water bath. Oxone® (0.4 mmol) was
dissolved in a solution of Na2EDTA (4ϫ10–4 , 2 mL), and sepa-
rately, NaHCO3 (1.2 mmol) was dissolved in a solution of
Na2EDTA (4ϫ10–4 , 2 mL). The two solutions were added sepa-
rately to the reaction mixture (first the Oxone® solution, and then
the NaHCO3 solution) dropwise over a period of 1 h. The pH of
the mixture was maintained at about 8.0. The reaction mixture was
stirred until TLC showed that the epoxidation reaction was finished
(3–7 h), and was then diluted with water (10 mL). The solution was
extracted with dichloromethane (3ϫ10 mL) and dried (MgSO4),
and the solvents were evaporated to dryness. The obtained crude
reaction mixture was purified by flash chromatography, with hex-
ane/ethyl acetate mixture as eluent, to afford the alkene epoxide.
The eluent was changed to a mixture of dichloromethane/methanol
(50:1), and the chiral ketone was recovered in a 70–75% yield.
88%) as a diastereoisomeric mixture (1:1). [α]D = –41.5 (c = 1.0,
1
CH2Cl2). H NMR (500 MHz, CDCl3): δ = 5.88, 5.84 (2 d, J1,2
=
3.7 Hz, 2 H, 2 1-H), 4.55, 4.52 (2 d, J1,2 = 3.7 Hz, 2 H, 2 2-H), 4.28,
4.23 (2 m, 2 H, 2 5-H), 4.15–4.05 (m, 4 H, 2 4-H, 2 6A-H), 4.00–
2
3.95 (m, 4 H, 2 4-H, 2 6B-H), 3.79, 3.75 [2 dd, J = 10.2, 9.7 Hz, 2
H, (OCHAHB)C(CHAHBO)], 3.72 (s, 1 H, COH), 3.61 (dd, JHA,OH
2
= 5.8, JA,B = 11.6 Hz, 1 H, CHAHBOH), 3.48 (dd, JHB,OH = 8.3,
2
2JA,B = 11.6 Hz, 1 H, CHAHBOH), 3.37, 3.35 [2 dd, JA,B = 9.6,
10.2 Hz, 2 H, (OCHAHB)C(CHAHBO)], 2.76 (dd, JHA,OH = 5.8,
JHB,OH = 8.3 Hz, 1 H, CHAHBOH), 1.47, 1.46, 1.41, 1.40, 1.35,
1.33, 1.30, 1.29 [8 s, 24 H, 4 C(CH3)2] ppm. 13C NMR (125 MHz,
CDCl3): δ = 112.0, 109.5, 109.4 [4 C(CH3)2], 105.7, 105.6 (2 C-1),
84.5, 84.0 (2 C-3), 82.3 (2 C-2), 81.4, 81.3 (2 C-4), 74.7 (COH), 73.0,
72.8 (2 C-5), 71.7, 71.1 [(OCH2)C(CH2O)], 67.9, 67.8 (2 C-6), 64.0
(CH2OH), 26.9, 26.8, 26.7, 26.3, 26.2, 25.1 [4 C(CH3)2] ppm. MS
(CI): m/z (%) = 607 (10) [M + H]+. HRMS (CI): calcd. for
C28H47O14 (607.30) [M + H]+ 607.296582; found 607.294492.
Experimental Data for the (E)-Stilbene Epoxidation Reaction with
Ketone 9: Column chromatography with elution with hexane/ethyl
acetate (100:1) afforded (E)-stilbene oxide as white crystals
1
(0.028 g, 73%), 68% ee, (–)-(2S,3S). H NMR (500 MHz, CDCl3):
δ = 7.4–7.3 (m, 10 H, 2 Ph), 3.88 [s, 2 H, 2 CH(O)] ppm. 13C
NMR (125 MHz, CDCl3): δ = 137.8, 128.5, 128.1, 125.6, 62.7 ppm.
Ketone, methyl 4,6-O-(R)-benzylidene-2,3-O-(2-oxo-1,3-propane-
diyl)-α--glucopyranoside, recovered (0.072, 71%).
1,3-Bis[(1,2:5,6-di-O-isopropylidene-α-D-glucofuranos-3-yl)oxy]ace-
1H NMR Spectroscopic Data for Epoxides
(–)-(1S,2S)-(E)-Stilbene Oxide:[5a,23] 1H NMR (500 MHz, CDCl3):
δ = 7.4–7.3 (m, 10 H, 2 Ph), 3.88 [s, 2 H, 2 CH(O)] ppm.
(–)-(1S,2S)-β-Methylstyrene Oxide:[23] 1H NMR (500 MHz,
CDCl3): δ = 7.4–7.3 (m, 10 H, 2 Ph), 3.59 [d, J(E) = 2.0 Hz, 1 H,
CH(O)], 3.02 [dq, J = 5.1, J(E) = 2.0 Hz, 1 H, CH(O)], 1.44 (d, J
= 5.1 Hz, 3 H, CH3) ppm.
(–)-(1S,2S)-(E)-β-Methylstilbene Oxide:[23,24] 1H NMR (500 MHz,
CDCl3): δ = 7.4–7.3 (m, 10 H, 2 Ph), 3.96 [s, 1 H, CH(O)], 1.46 (s,
3 H, CH3) ppm.
(+)-(2S)-Triphenylethylene Oxide:[5a,23,24] 1H NMR (500 MHz,
CDCl3): δ = 7.4–7.1 (m, 15 H, 3 Ph), 4.32 [s, 1 H, CH(O)] ppm.
(–)-(2S)-1,1-Dimethyl-2-phenylethylene Oxide:[25] 1H NMR
(500 MHz, CDCl3): δ = 7.4–7.3 (m, 5 H, Ph), 3.85 [s, 1 H, CH(O)],
1.47 (s, 3 H, CH3), 1.06 (s, 3 H, CH3) ppm.
(–)-(1S,2S)-1-Phenylcyclohexene Oxide:[5a,23,24] 1H NMR
(500 MHz, CDCl3): δ = 7.4–7.3 (m, 5 H, Ph), 3.5 [m, 1 H, CH(O)],
2.3–2.2 (m, 1 H, CHAHB), 2.2–2.0 (m, 1 H, CHAHB), 2.0–1.9 (m,
2 H, CH2), 1.6–1.5 (m, 2 H, CH2), 1.5–1.4 (m, 1 H, CHAHB), 1.3–
1.2 (m, 1 H, CHAHB) ppm.
tone (13): A solution of sodium periodate (0.86 g, 4.0 mmol) in
water (5 mL) was added to a solution of 12 (1.20 g, 2.0 mmol) in
ethanol/water (1:2, 120 mL), and the reaction mixture was stirred
at room temperature overnight. The mixture was concentrated to a
small volume (40–50 mL), the solution was extracted with dichloro-
methane (5ϫ40 mL) and dried (MgSO4), and the solvents were
evaporated to dryness. The syrup obtained was purified by flash
chromatography on silica gel, with hexane/ethyl acetate (2:1) as elu-
ent, yielding a colourless oil (0.85 g, 72%). [α]2D5 = –9.3 (c = 1.0,
1
CH2Cl2). H NMR (500 MHz, CDCl3): δ = 5.92 (d, J1,2 = 3.7 Hz,
2 H, 2 1-H), 4.66 (d, J1,2 = 3.7 Hz, 2 H, 2 2-H), 4.45 [br. s, 4 H,
(OCH2)C(CH2O)], 4.33 (m, 2 H, 2 5-H), 4.14 (dd, J5,6A = 6.2,
J6A,6B = 8.7 Hz, 2 H, 2 6A-H), 4.11 (dd, J3,4 = 3.0, J4,5 = 8.3 Hz, 2
H, 2 4-H), 4.03 (dd, J5,6B = 5.3, J6A,6B = 8.7 Hz, 2 H, 2 6B-H), 3.92
(d, J3,4 = 3.0 Hz, 2 H, 2 3-H), 1.52, 1.45, 1.38, 1.34 [4 s, 24 H, 4
C(CH3)2] ppm. 13C NMR (125 MHz, CDCl3): δ = 204.9 (C=O),
112.0, 109.2 [4 C(CH3)2], 105.2 (2 C-1), 83.8 (2 C-3), 82.8 (2 C-2),
81.1 (2 C-4), 74.6, 72.4 [(OCH2)C(CH2O)], 67.5 (2 C-6), 62.7 (2 C-
5), 26.9, 26.8, 26.2, 25.4 [4 C(CH3)2] ppm. MS (CI): m/z (%) = 575
(100) [M + H]+. HRMS (CI): calcd. for C27H43O13 (575.27) [M +
H]+ 575.270367; found 575.267985.
(4S,5S)-4,5-Diphenyl-2-styryl-1,3-dioxolane (15): Cinnamaldehyde
dimethyl acetal (2 equiv., 0.8 g), and camphorsulfonic acid (cata-
lytic) were added to a solution of (–)-(S,S)-hydrobenzoin (14;
0.43 g, 2.0 mmol) in acetonitrile (15 mL). The reaction mixture was
stirred at room temperature for 6 d. Triethylamine was added to
1
(–)-(1S,2S)-2-Phenylindane Oxide: H NMR (500 MHz, CDCl3): δ
= 7.5–7.2 (m, 9 H, 2 Ph), 4.33 [dd, J = 0.45, J = 1.3 Hz, 1 H,
CH(O)], 3.57 (d, Jgem = 17.7 Hz, 1 H, 1 H, CHAHB), 3.41 (d, Jgem
= 17.7 Hz, 1 H, 1 H, CHAHB) ppm. 13C NMR (125 MHz, CDCl3):
Eur. J. Org. Chem. 2009, 6009–6018
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6017

J. M. Vega-Pérez, F. Iglesias-Guerra et al.
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(–)-(2S,3S)-2-(Hydroxymethyl)-3-phenyloxirane:[23,24] 1H NMR
(500 MHz, CDCl3): δ = 7.4–7.3 (m, 5 H, Ph), 3.91 [d, J(E) = 2.1 Hz,
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[6]
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CH3) ppm.
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4.07 [d, J(E) = 1.9 Hz, 1 H, PhCH(O)] ppm.
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[13]
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[15]
J
= 8.3 Hz, OCHBPhmajor), 4.10 [d, J(E) = 2.0 Hz, CH(O)
CHPhminor], 4.08 [d, J(E) = 2.0 Hz, CH(O)CHPhmajor], 3.44 [dd, J(E)
= 2.0, J = 3.1 Hz, CH(O)CHPhmajor], 3.40 [dd, J(E) = 2.0, J =
3.1 Hz, CH(O)CHPhminor] ppm. 13C NMR (125 MHz, CDCl3): δ
= 136.7–125.5 (Ph), 102.9 (CHmajor), 102.8 (CHminor), 86.7 (OCHA-
Phminor), 86.5 (OCHAPhmajor), 85.7 (OCHBPhmajor), 85.3
(OCHBPhminor), 62.1 [CH(O)CHPhminor], 61.9 [CH(O)CHPhmajor],
55.8 [CH(O)CHPhmajor], 55.1 [CH(O)CHPhminor] ppm. MS (CI):
m/z (%) = 344 (65) [M + H]+.
[16]
[17]
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis and characterization of the chiral ketones (9 and
13), their precursors (7, 8, 11 and 12), hydrobenzoin acetal 15 and
its epoxide 16, experimental procedure and characterization of all
epoxides from the employed alkenes (a–j), and data for the determi-
nation of the enantiomeric excesses obtained with ketone 9.
Acknowledgments
[18]
We are grateful to the Junta de Andalucía and the Ministerio de
Educación y Ciencia (Spain) and to the FEDER programme for
financial support (P06-FQM-01885 and CTQ2007-61 185). The
1
help of Dr. M. Angulo in recording H NMR spectra is gratefully
[19]
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Received: August 4, 2009
Published Online: October 7, 2009
6018
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6009–6018