Synthesis of new carbohydrate-derived ketones as organocatalysts in the enantioselective epoxidation of arylalkenes. Part 2: Chiral ketones from sugars

Article abstract of DOI:10.1016/j.tet.2010.11.033

A range of new, somewhat complex, stereochemically varied, and structurally related carbohydrate-derived ketones were synthesised by a simple method from the carbohydrate precursor (d-gluco and d-galacto derivatives). The common skeleton possesses the keto function sited on a seven-membered ring fused to positions 2 and 3 of the sugar moiety. Their chirality transfer capability in the dioxirane-mediated epoxidation of arylalkenes was evaluated. Copyright

Full text of DOI:10.1016/j.tet.2010.11.033

Tetrahedron 67 (2011) 364e372
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of new carbohydrate-derived ketones as organocatalysts in the
enantioselective epoxidation of arylalkenes. Part 2: Chiral ketones from sugarsq
*
ꢀ
ꢀ
~ꢀ
Jose M. Vega-Perez , Margarita Vega-Holm, Ignacio Perinan, Carlos Palo-Nieto,
*
Fernando Iglesias-Guerra
ꢀ
ꢀ
Departamento de Química Organica y Farmaceutica, Facultad de Farmacia, Universidad de Sevilla, E-41071 Sevilla, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A range of new, somewhat complex, stereochemically varied, and structurally related carbohydrate-
Received 1 September 2010
Received in revised form 28 October 2010
Accepted 8 November 2010
Available online 16 November 2010
derived ketones were synthesised by a simple method from the carbohydrate precursor (D-gluco and D-
galacto derivatives). The common skeleton possesses the keto function sited on a seven-membered
ring fused to positions 2 and 3 of the sugar moiety. Their chirality transfer capability in the dioxirane-
mediated epoxidation of arylalkenes was evaluated.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Carbohydrate
Chiral ketone
Dioxirane
Enantioselective epoxidation
Organocatalysis
1. Introduction
Enantioselective epoxidation of unfunctionalised alkenes is
another important issue in this area e in particular, dioxirane-
Due to the great importance of optically active epoxides as chiral
synthons in organic synthesis, the development of efficient
methods for asymmetric epoxidation of olefins provides a powerful
approach to the synthesis of such epoxides and is the goal of many
research groups. Our work in this field is focused on two in-
trinsically related aims: the access to chiral epoxides with high
stereocontrol, and the use of carbohydrates as crucial tools re-
sponsible for the process of stereofacial differentiation (carbohy-
drates are a naturally occurring, inexpensive, renewable, readily
available source of chirality which contain a high density of ster-
eogenic centers and may provide advantageously rigid
frameworks).1
We have previously described the diastereoselective epoxida-
tion of olefin moieties by using carbohydrate derivatives as chiral
auxiliaries. The olefinic chain was joined to different positions of
the sugar molecule, via various functionalities (glycoside,2 amide,3
and acetals4), employing m-chloroperoxybenzoic acid as oxidant
under mild conditions. This method has enabled us to synthesise
a variety of compounds with potential biological interest.4
mediated epoxidation, which constitutes an attractive catalytic
process. Indeed, many research groups are focused on designing
new chiral ketones to successfully obtain stereochemical con-
trol.5e7 Because of the important role of carbohydrate moieties in
stereochemical differentiations, the possibility of employing them
as precursors for chiral ketones e and subsequently as catalysts in
epoxidation reactions e is an interesting goal for various research
groups, and new chiral ketones from sugar derivatives have been
described and employed, giving high enantiomeric excess.8e10
Recently, we have described a new backbone model of chiral
carbohydrate-derived ketone and its use as an efficient chirality
transfer agent in dioxirane-mediated epoxidation, giving moder-
ate-to-good enantiomeric excesses in the epoxidation of a wide
range of arylalkenes, compound 111 (Fig. 1). Our model has features
of structure, synthesis, and catalytic properties that make it an
interesting catalyst motif. With regard to structure, its reactive
group is located on a seven-membered ring fused to positions 2 and
O
OMe
O
O
OR
O
O
O
*
*
Ph
O
Ph
O *
O
O
O
O
q
For Part 1 see: Ref. 11.
1
2
* Corresponding authors. Tel./fax: þ34 95 4556737; e-mail addresses: vega@us.es
ꢀ
(J.M. Vega-Perez), iglesias@us.es (F. Iglesias-Guerra).
Fig. 1.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.033

ꢀ
J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 364e372
365
3 of the sugar moiety in a rigid system, with the sugar chirality in its
structure and with electron-withdrawing groups on Ca.5,6,12 With
regard to its preparation, it is easily synthesised from the com-
mercial carbohydrate precursor in good yields; and finally, it is
recovered without loss of activity in high yields (70e75%).
Encouraged by these results, we decided to tackle the prepara-
tion of new chiral ketones derived from sugars with this general
skeleton 2 (Fig. 1) by this efficient and simple method using com-
mercial products, and study their chirality transfer capability. In
order to obtain the range of new ketones, we made the following
structural modifications in the proximity of the seven-membered
ring fused to positions 2 and 3 of the sugar moiety possessing the
reactive group: firstly, the modification of the substituent R at the
anomeric position, and secondly, the modification of the configu-
ration of the sugar stereocentres contiguous to carbons 2 and 3 of
the sugar residue. We used as starting materials different gluco- and
4,6-(R)-O-benzylidene-2,3-O-(2-oxo-1,3-propylene)-
b
-
D
-glucopyr-
anoside 9 and phenyl 4,6-(R)-O-benzylidene-2,3-O-(2-oxo-1,3-
propylene)- -glucopyranoside 10 were obtained in high yields as
white solids (Scheme 1).
b-D
Ph
O
HO
O
OR
O
O
O
O
i
OR
OH
Ph
O
3 R = Me
4 R = Ph
O
5 R = Me
6 R = Ph
ii
O
OR
O
O
O
OR
O
O
O
iii
galactopyranoside derivatives (
substituents on carbon 1).
a and b configuration, alkyl and aryl
Ph
O
O
Ph
O
Subsequently, we studied their usefulness as dioxirane pre-
cursors for the epoxidation reaction of unfunctionalised trans and
cis arylalkenes. Herein, we present our results in this area.
OH
OH
O
9 R = Me
7 R = Me
8 R = Ph
10 R = Ph
Scheme 1. (i) (ClCH2)2C]CH2, KOH, 18-crown-6, THF, 95%; (ii) OsO4 (t-BuOH), Me3NO,
CH2Cl2, 60e80%; (iii) NaIO4 (H2O), EtOHeH2O, 75e85%.
2. Results and discussion
The method followed, which we have previously described, in-
volves a simple sequence of three reactions starting from the cor-
responding benzylidene acetal derivatives. They take place with
good chemical yields, and enabled us to obtain, using different
carbohydrate precursors, a series of ketones of some complexity,
very functionalised, stereochemically varied, and all structurally
related.
Taking compound 1 as model, we first proceeded to change the
anomeric configuration. The carbohydrates chosen as precursors
for the synthesis of new ketones potentially useful as source of
chiral dioxiranes were the compounds methyl 4,6-O-(R)-benzyli-
Secondly, and with the aim of obtaining new structurally related
ketones derived from carbohydrates, we proceeded to the configu-
rationalvariationatother positions ofthesugar. Wechose D-galactose
as precursor. We had strong reasons for that choice. On one hand,
using this residue as carbohydrate precursor fulfills the aforemen-
tioned aims of structural modification on the general skeleton of
chiral ketone (Fig. 1, compound 2). On the other, our group has re-
cently reported thegreatefficiencyof the D-galactose residue aschiral
inducer in synthetically important reactions. Specifically, we have
carried out reactions of cyclopropanation and epoxidation of a wide
range of allyl alcohols joined to the chiral auxiliary via a glycosidic
dene-
-glucopyranoside 4, both
respectively, at the anomeric position.
b
-
D
-glucopyranoside 3 and phenyl 4,6-O-(R)-benzylidene-
b-
D
b
anomers and with alkyl and aryl group,
bond (alkenyl b-D-galactopyranoside derivatives were the precursors
The first step consisted of incorporating to the sugar residue the
cycle fused to positions 2 and 3 of the carbohydrate, which will later
possess the reactive group. This was incorporated to the mono-
saccharide residue from a simple substance, such as 3-chloro-2-
chloromethylpropene by a double etherification reaction.
Dialkylation of the starting compounds 3 and 4 in tetrahy-
drofurane with 3-chloro-2-chloromethylpropene, in presence of
solid potassium hydroxide and the 18-crown-6, leads e in 5e7 days
at room temperature e to the cyclic compound methyl 4,6-(R)-O-
for these reactions) and which take place with high diaster-
eoselectivity.2c In the present context, obtaining this skeleton of ke-
tone fused to a D-galactose residue was therefore an interesting goal.
Lastly, because in the field of the synthesis of new chiral ketones (and
thus of new catalysts for epoxidation reactions) from carbohydrates,
the use has been described of different glucose, arabinose, and fruc-
tose derivatives as precursors, achieving large enantiomeric
excesses6e10 but the use of galactose-derived compounds has not
been reported.
benzylidene-2,3-O-(2-methylidene-1,3-propylene)-
anoside and phenyl 4,6-(R)-O-benzylidene-2,3-O-(2-methyl-
idene-1,3-propylene)-
-glucopyranoside 6. In 1H NMR spectra of
both compounds, the signals for the hydrogens of the alkene
function appear around 5.0 ppm, and the hydrogens of the OCH2
b
-
D
-glucopyr-
The synthetic procedure was carried out in the same way as for
compounds 9 and 10. In this case, we used as starting compounds the
corresponding benzylidene acetals readily synthesised from com-
5
b-D
merciallyavailablealkyloraryl
the compounds methyl 4,6-O-(S)-benzylidene-
side 11, phenyl 4,6-O-(S)-benzylidene- -galactopyranoside 12, and
methyl 4,6-O-(S)-benzylidene- -galactopyranoside 13 were sub-
D-galactopyranosidederivatives. Thus,
d
b-D-galactopyrano-
groups, which act as spacer groups between the ketone and the
stereocentres, in the range 4.5e4.2 ppm.
b-D
a-D
Next was the dihydroxylation of the double bond with osmium
tetroxide, in catalytic amounts, and trimethylamine N-oxide, using
dichloromethane as solvent. The reaction took place at room tem-
perature, and yielded the corresponding glycols methyl 4,6-(R)-O-
benzylidene-2,3-O-(2-hydroxy-2-hydroxymethyl-1,3-propylene)-
jected to double etherification reaction to generate the fused cycle
and introduce the double bond precursor of the keto function.
The compounds 14e16 were obtained with high chemical yields
(95%) (Scheme 2). Characteristic 1H NMR spectral data for these
compounds are the signals for alkene protons that appear at about
b
-
D
-glucopyranoside 7 and phenyl 4,6-(R)-O-benzylidene-2,3-O-
-glucopyranoside
d 4.9 ppm, and the signal for the protons of both OCH2 groups in the
range 4.5e4.3 ppm.
Hydroxylation of the double bond led to the corresponding
glycols 17e19. As the reaction generates a new stereocentre in the
molecule and the substrates are derived from another sugar
(2-hydroxy-2-hydroxymethyl-1,3-propylene)-
b
-
D
8 as a mixture of stereoisomers in the same proportion (1H NMR
spectral study). These compounds were employed directly in the
following step e the generation of the keto function. It was carried
out through an oxidative cleavage, using an aqueous solution of
sodium metaperiodate as oxidising agent. The compounds methyl
(D-galactose), we studied the stereochemical course of the reaction,
in the same way as we have done for the corresponding analogue

ꢀ
J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 364e372
366
atoms vicinal to the carbonyl group, which appear at around
4.4e4.3 ppm in all these ketones; those for the 13C NMR spectra
were the signal for the carbonyl carbon at 210 ppm and that for
C-1 at 99 ppm ( 72 ppm for compound 26).
Ph
O
OR
O
O
d
i
O
O
d
Ph
O
O
d
d
O
HO
OR
Having synthesised the ketones 9, 10, 20e22, and 26, our next
objective was to test their effectiveness as chiral catalysts in diox-
irane-mediated epoxidation reactions. First, we chose the sub-
strates for the epoxidation reaction e a variety of unfunctionalised
trans and trisubstituted alkenes. We chose the arylalkenes (27e30)
because they had shown the largest enantiomeric excesses
(57e74%) and highest chemical yields (66e73%) on being subjected
to epoxidation with the ketone 1.11 Our aim was to compare the
stereofacial differentiation capacity of these new ketones with that
reported, and thereby the effect of the structural modifications on
the stereochemical result of the process, with the idea of obtaining
a more efficient chiral catalyst.
Our preliminary essays employed sub-stoichiometric quantities
(0.5 equiv) of ketone, however, not only the reaction time was high
(1e2 days), but also the reaction was not completed (recovering
alkene without epoxidation). The use of different quantities of ke-
tone did not give different stereochemical results (enantiomeric
excess and major oxirane configuration). After screening various
reaction conditions with a view to improving the efficiency of the
epoxidation reaction (in terms of chemical and enantiomeric yields
as well as reaction times), an epoxidation reaction with these ke-
tones was carried out at 0 ꢀC with substrate (0.2 mmol), ketone
(0.2 mmol), OxoneÒ (0.4 mmol), and NaHCO3 (1.2 mmol) in DME/
4ꢁ10ꢂ4 M 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 com-
plete the reaction (3e7 h, TLC analysis) (Scheme 4). In all cases, the
absolute configuration of the major enantiomers obtained was
assigned by comparing the signal shifts in presence of (þ)-Eu(hfc)3
with those reported in the literature, and also by comparing the
sign of optical rotation with the reported ones.
OH
11 R = β-Me
12 R = β-Ph
13 R = α-Me
14 R = β-Me
15 R = β-Ph
16 R = α-Me
ii
O
O
OR
O
O
O
OR
O
O
O
iii
Ph
O
Ph
O
OH
OH
O
20 R = β-Me
21 R = β-Ph
22 R = α-Me
17 R = β-Me
18 R = β-Ph
19 R = α-Me
Scheme 2. (i) (ClCH2)2C]CH2, KOH, 18-crown-6, THF, 96%; (ii) OsO4 (t-BuOH), Me3NO,
CH2Cl2, 60e90%; (iii) NaIO4 (H2O), EtOHeH2O, 85e95%.
gluco derivatives (compound 1,11 compounds 9e10, although in
these cases the two stereoisomers were formed in equal amounts).
The 1H NMR spectral study shows the signal for hydrogen acetalic
PhCH as two singlets at
5.76 and 5.75 ppm (for compound 18), and at
(for compound 19); and that for H-1 of the sugar as two doublets at
4.40 and 4.33 ppm (J1,2 7.5 Hz) (for compound 17), at 4.97 and
4.96 ppm (J1,2 7.9 Hz) (for compound 18), and at 4.97 and 4.93 ppm
(J1,2 3.5 Hz) (for compound 19). The relative integral of the two
signals for the same hydrogen in each of the stereoisomers showed
that they were formed in equal amounts. Most of the 13C NMR
signals of these compounds were also split.
The diol oxidative rupture reaction (with sodium metaperiodate
as oxidising agent) of compounds 17e19 provided the new gal-
actopyranoside-derived ketones 20e22 in high yields.
d
5.59 and 5.58 ppm (for compound 17), at
d
d
5.54 and 5.53 ppm
d
d
d
R2
R3
O
R2
ketone
R1
O
R1
Oxone®
Thirdly, we used as precursor the compound 1,5-anhydro-4,6-O-
(R)-benzylidene- -glucitol 23, which we transformed into the ke-
R3
D
Ketones:
O
tone 26 following a sequence of reactions similar to that described
(Scheme 3). We were interested in obtaining this compound in
order to be able to study its chirality transfer capability. It is
a compound analogous to the ketones 1, 9, and 10 (gluco derivative),
but with the anomeric position defunctionalised, and thus lacking
stereocentre and substituent.
OMe
O
O
OPh
O
O
OMe
O
O
O
O
Ph
O
Ph
Ph
O
O
Ph
O
O
O
O
O
O
9
10
20
Ph
O
O
O
O
O
i
O
OPh
O
O
OMe
O
O
HO
O
O
OH
O
Ph
O
23
O
O
O
Ph
O
O
O
Ph
O
O
O
24
ii
O
O
21
22
26
Substrates:
Ph
O
O
O
Ph
CH3
Ph
Ph
Ph
O
O
iii
O
O
Ph
O
Ph
O
Ph
Ph
CH3 Ph
29 30
27
28
O
OH
OH
Scheme 4. Epoxidation conditions (see text).
O
26
25
Scheme 3. (i) (ClCH2)2C]CH2, KOH, 18-crown-6, THF, 97%; (ii) OsO4 (t-BuOH), Me3NO,
CH2Cl2, 80%; (iii) NaIO4 (H2O), EtOHeH2O, 60%.
Table 1 gathers the results of the epoxidation of the alkenes 27e30
with the ketones whose sugar residue is a derivative of gluco con-
The structure of the new ketone sugar derivatives 9, 10, 20e22,
and 26 was confirmed by analysis of their NMR spectra. Noteworthy
features for the 1H NMR spectra are the signals for the hydrogen
figuration, ketones 9 and 10 (methyl and phenyl
b-D-glucopyranoside
derivatives, respectively) and ketone 26 with position
1

ꢀ
J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 364e372
367
Table 1
Table 2
Catalytic asymmetric epoxidation of alkenes 27e30 in the presence of
D
-glucose
Catalytic asymmetric epoxidation of alkenes 27e30 in the presence of
D
-galactose
derived ketones 9, 10, and 26a
derived ketones 20e22a
Entry
Ketone
Alkene
Yieldb (%)
eec (%)
Configurationd
Entry
Ketone
Alkene
Yieldb (%)
eec (%)
Configurationd
1
2
3
4
5
6
7
8
9
9
9
9
27
28
29
30
27
29
30
27
28
29
30
27
28
29
30
68
70
74
80
71
72
76
55
57
78
52
73
68
72
66
49
46
49
50
47
38
59
48
47
60
39
68
57
67
74
(ꢂ)-(1S,2S)
(ꢂ)-(1S,2S)
(ꢂ)-(1S,2S)
(þ)-(2S)
1
2
3
4
5
6
7
8
20
20
20
20
21
21
21
22
22
22
1e
27
28
29
30
27
29
30
27
29
30
27
28
29
30
60
67
67
70
75
69
70
62
74
58
73
68
72
66
72
60
73
77
69
53
58
100
81
88
68
57
67
74
(ꢂ)-(1S,2S)
(ꢂ)-(1S,2S)
(ꢂ)-(1S,2S)
(þ)-(2S)
10
10
10
26
26
26
26
1e
1e
1e
1e
(ꢂ)-(1S,2S)
(ꢂ)-(1S,2S)
(þ)-(2S)
(ꢂ)-(1S,2S)
(ꢂ)-(1S,2S)
(þ)-(2S)
(ꢂ)-(1S,2S)
(ꢂ)-(1S,2S)
(ꢂ)-(1S,2S)
(þ)-(2S)
(ꢂ)-(1S,2S)
(ꢂ)-(1S,2S)
(þ)-(2S)
9
9
10
11
12
13
14
15
10
11
12
13
14
(ꢂ)-(1S,2S)
(ꢂ)-(1S,2S)
(ꢂ)-(1S,2S)
(þ)-(2S)
(ꢂ)-(1S,2S)
(ꢂ)-(1S,2S)
(ꢂ)-(1S,2S)
(þ)-(2S)
1e
1e
1e
a
Conditions: substrate (1 equiv), ketone (1 equiv), OxoneÒ (2 equiv), NaHCO3
a
Conditions: substrate (1 equiv), ketone (1 equiv), OxoneÒ (2 equiv), NaHCO3
(6 equiv), DME-aqueous EDTA (4ꢁ10ꢂ4 M) (1.2:1), 0 ꢀC.
(6 equiv), DME-aqueous EDTA (4ꢁ10ꢂ4 M) (1.2:1), 0 ꢀC.
Yields after column chromatography.
b
b
c
Yields after column chromatography.
Enantiomeric excesses were determined by 1H NMR spectroscopy of the
c
Enantiomeric excesses were determined by 1H NMR spectroscopy of the ep-
epoxide products directly with shift reagent (þ)-Eu(hfc)3.
d
oxide products directly with shift reagent (þ)-Eu(hfc)3.
The absolute configuration of the major enantiomer was assigned by comparing
d
The absolute configuration of the major enantiomer was assigned by comparing
the signal shifts with those reported in the literature and also by comparing the sign
of optical rotation with the reported one in each case.
the signal shifts with those reported in the literature and also by comparing the sign
of optical rotation with the reported one in each case.
e
Previously reported for us, see Ref. 11.
e
Previously reported for us, see Ref. 11.
It is of interest to understand the possible geometry of the
transition state in dioxirane epoxidations. Two mechanistic ex-
tremes (spiro and planar) are presented in Scheme 5 for the trans-
stilbene epoxidation catalyzed by ketone 22. A spiro transition state
was proposed by Baumstark,13 based on the observation that cis-
olefins were more reactive that the corresponding trans-olefins for
epoxidation using dimethyldioxirane. In our study, if the reaction
proceeds via a spiro mode, (S,S)-stilbene oxide is expected to be
favored (spiro-1 vs spiro-2). In contrast, (R,R)-enantiomer will be
favored if the reaction proceeds via a planar mode (planar-2 vs
planar-1). In the present study, it is found that (S,S)-stilbene oxide is
produced predominately, which supports the spiro transition state.
Beside, the attack on the other oxygen of the dioxirane yields also
the (S,S)-enantiomer. In addition, computational studies showed
that the spiro transition state is favored for the epoxidation of
defunctionalised (1,5-anhydroglucitol derivative). The epoxides were
isolated in satisfactory chemical yields (70e80%, entries 1e7) e
slightly lower when using the ketone 26 (52e78%, entries 8e11). The
epoxidationreactionwascompletedin a few hours. The enantiomeric
excesses obtained were low-to-moderate (38e60%, entries 1e11),
and somewhat lower than those obtained with the ketone 1, the
previously described methyl
a-D-glucopyranoside derivative
(57e74%, entries 12e15). The absolute configuration of the major
enantiomer obtained was in all cases the same for each alkene.
Comparison of the results obtained with the new
rived ketones showed that better enantiomeric excesses are
obtained with the derivative of methyl anomeric configuration 1,
than with the derivatives of anomeric configuration 9 and 10, or
with the -glucitol derivative 26. Moreover, the ees obtained with
both alkyl and aryl -glucopyranoside ketones are of the same or-
D-gluco-de-
a
b
D
b
der (Me entries 1e4 vs Ph entries 5e7), around 50%, and similar to
those obtained with 26, defunctionalised on 1 (entries 8e11).
The results of the epoxidation of the alkenes 27e30 with the
Ph
Ph
O
O
O
O
ketones of
all cases the chemical yields were good (60e75%, entries 1e10). The
ketone 20, methyl -galactopyranoside derivative, gave enantio-
meric excesses very similar to those obtained with the ketone 1,
methyl -glucopyranoside derivative (entries 1e4 vs 11e14).
However, the excesses obtained when using the ketone 21, phenyl
-galactopyranoside derivative, were somewhat smaller than
D
-galacto configuration 20e22 are gathered in Table 2. In
O
O
O
O
O
O
b-D
O
O
O
O
CH3
CH3
O
Ph
(S)
O
O
a-D
(S)
Ph
b-D
Spiro-1
Favored
Planar-1
Disfavored
with the ketone 1 (entries 6 and 7 vs 13e14). The ketone 22 gave
the largest enantiomeric excesses (81e100%, entries 8e10), ex-
ceeding those obtained with the ketone 1 (57e74%, entries 11e14).
The absolute configuration of the major enantiomer obtained is also
the same for each alkene in all cases.
Ph
Ph
O
O
O
O
We can also see that in contrast to the
-galacto configuration yield results stereochemically different
from one another, the enantiomeric excesses being larger with the
-methyl derivative 20 than with the -phenyl 21 (entries 1e4 vs
entries 5e7).
b-gluco, the ketones of
O
O
O
O
b
O
O
O
O
O
O
CH3
CH3
b
b
O
Ph
(R)
O
O
(R)
In all cases, ketones were recovered in high yields e 75e80% for
glucopyranoside derivatives (9, 10, and 26) and slightly lower for
galactopyranoside derivatives, 65e70% (20e22) e without loss of
activity. This shows their stability under the reaction conditions,
and thus the possibility of their being recycled and employed in
various catalytic cycles.
Ph
Spiro-2
Disfavored
Planar-2
Favored
Scheme 5. The spiro and planar transition states for trans-stilbene epoxidation cata-
lyzed by ketone 22.

ꢀ
J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 364e372
368
ethylene with dimethyldioxirane, presumably due to the stabilizing
The second part was focused on their use in the epoxidation
reaction of different arylalkenes, and the comparison of the
chemical and stereochemical yields both with those obtained with
the ketone 1 and among them.
interaction of an oxygen lone pair with the
*
p orbital of the alkene
in the spiro transition state.14
A complementary part of our work was to begin preliminary
trials to evaluate the efficiency of this type of ketone as chiral in-
ducer in the epoxidation of cis-olefins, because while dioxiranes
generated in situ from chiral ketones are efficient for asymmetric
epoxidation of trans-olefins and trisubstituted olefins,5a,b cis-al-
kenes remain challenging substrates for epoxidation with high
stereoselectivity. We chose the compounds 1, 10, and 22 as ketone
precursors of the reactive dioxiranes, and used the reaction con-
ditions described. The substrates employed for these preliminary
studies were the alkenes 31e33. We chose these cyclic olefins in
order to restrict reacting approach for the olefin substrate, hoping
thereby to obtain a greater enantiomeric excess (Scheme 6).
3. Conclusions
With regard to chemical yield, the results obtained were satis-
factory in all cases (70e80%), and similar to those obtained with the
ketone 1. The ketone 26 (D-glucitol-derived) gave smaller chemical
yields (52e78%). The percentages of recovery without loss of ac-
tivity of the new ketones were good, enabling their use in various
catalytic cycles.
With regard to stereochemical yield, firstly we observed that the
new ketones possess the same alkene stereofacial differentiation
pattern as the ketone 1 (they provide the same major enantiomer).
Secondly, to study the effect of the structural modifications (
a
or
R2
R3
O
R2
ketone
R1
R1
b
configuration, alkyl or aryl substituent at the anomeric position,
Oxone®
R3
and configuration at carbon 4 of the sugar residue,
D-gluco or
D-galacto derivative) on the stereochemical result of the process
(and thereby the possible obtaining of a more efficient chiral cat-
alyst), we compared the ees both with that of the ketone 1 and
among them.
Ketones:
O
O
O
OMe
O
O
OPh
O
O
O
OMe
O
O
O
Modifying the configuration at the anomeric position enables us
Ph
O
Ph
O
O
Ph
O
to deduce that the
meric excesses than their
The use of two types of sugar residue,
the deduction that when the ketones are
enantiomeric excesses are greater than for their
a
-configuration ketones give greater enantio-
configuration analogues.
-gluco or -galacto, enables
-galacto derivatives, the
-gluco analogues.
b
O
O
O
D
D
1
10
22
D
D
Substrates:
The alkyl (Me) or aryl (Ph) nature of the substituent at the
anomeric position does not affect the chiral induction capacity of
Me
the
structural modification does affect the stereoselectivity obtained on
using -galacto derivatives, with the Ph group causing a decrease
b-gluco ketones, similar ees being obtained. However, this
31
32
33
b-D
Scheme 6. Epoxidation conditions (see text).
in the enantiomeric excess obtained.
The use of the ketone with structure derived from 1,5-anhydro-
D-glucitol 26, enables the conclusion that the defunctionalisation of
The reaction took place with good chemical yields in all cases
(55e73% for the gluco ketone derivatives, 70e80% for those of
galacto configuration), and the chiral catalysts had satisfactory
percentages of recovery (though somewhat higher for the gluco
(65e70%) than for the galacto (40%)). However, in no case did we
achieve enantioselectivity. These results are in agreement with the
transition state proposed (Scheme 5), because in the epoxidation of
cis-alkenes spiro-1 and spiro-2 are favored.
In summary, our group has recently described a new backbone
model for a chiral carbohydrate-derived ketone 1, and tested its
efficiency as catalyst in the asymmetric epoxidation of alkenes.11 As
a continuation of that work, and as part of our line of research on
the synthesis of new sugar-derived ketones, this work had two
general aims.
On one hand, the synthesis of different ketones structurally
related to that previously described, having the same type of gen-
eral skeleton e the tri-cyclic system comprising the trans- or cis-
decalin-like benzylidene-4,6-O-acetal, the dioxepane ring where
the ketone function is sited, and the sugar moiety e but varying
stereochemically. For this, in the structural and stereochemical
modification, we began with the anomeric position and position 4
of the sugar residue when choosing the carbohydrate precursor.
In the first part of the work we have applied our synthetic
method to obtain the new ketones 9, 10, and 20e22 from the ap-
propriate commercially available carbohydrate precursor: alkyl and
the anomeric position generates a reduction in the efficacy as cat-
alyst in comparison with the ketone 1, generating ees similar to
those of the
In summary, for the epoxidation of trans-olefins and tri-
substituted olefins, the presence of a sugar residue of -galacto
b-D-derivatives.
a-D
configuration and an alkyl (methyl) group are structural charac-
teristics that potentiate the eficacia as chiral catalyst of this type of
general structure of ketones, and will be taken into account for the
design of new ketones, and in tackling modifications to the 4,6-O-
acetal system.
Lastly, we began the study of the epoxidation of cis-olefins, us-
ing the ketones 1, 10, and 22 as source of chiral dioxiranes. We
chose these three ketones because one of them 1 had been our
starting compound when proposing this type of general skeleton of
chiral ketones; another 22 has given in this work the best degree of
enantioselectivity in the epoxidation of trans-olefins; and 10 has
given the lowest ees. The aim was to evaluate their capacity of chiral
induction with these substrates, and to be able to reach structural
conclusions. Unfortunately, in no case was stereoselectivity
achieved.
4. Experimental
4.1. General
aryl,
a
and
b
,
D
-gluco and
D
-galacto derivatives. A new ketone 26, D-
All solvents were reagent or analysis grade. Evaporations were
conducted under reduced pressure. Reactions were monitored us-
ing thin-layer chromatography (TLC) on aluminium-backed plates
coated with Merck Kieselgel 60 F254 silica gel. Compounds were
glucitol-derived, was also synthesised using this method. All these
new ketones were synthesised with good chemical yields and were
duly characterised.

ꢀ
J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 364e372
369
visualised by UVA radiation at a wavelength of 254 nm or stained
by exposure to an ethanolic solution of phosphomolybdic acid and
subsequent heating. Silica gel 60 (230e400 ASTM) was used for all
flash column chromatography. Melting points were obtained on
a Stuart Melting Point Apparatus SMP 10 and are uncorrected.
Optical rotations were obtained on a PerkineElmer Polarimeter
Model 341 at 25 ꢀC. Mass spectra were recorded on a Micromass
AUTOSPECQ mass spectrometer: EI at 70 eV and CI at 150 eV, HR
mass measurements with resolutions of 10,000. FAB mass spectra
were recorded using a thioglycerol matrix. NMR spectra were
recorded at 25 ꢀC on a Bruker AMX500 spectrometer and on
a Bruker AV500 spectrometer at 500 MHz for 1H and 125 MHz for
13C. The chemical shifts are reported in parts per million on the
H-1), 4.52 [1H, d, Jgem 14.1 Hz, (OCHAHB)C(CHDHEO)], 4.46 [1H, d,
Jgem 13.6 Hz, (OCHAHB)C(CHDHEO)], 4.38e4.33 [2H, m, H-6e,
(OCHAHB)C(CHDHEO)], 4.28 [1H, d, Jgem 13.6 Hz, (OCHAHB)C
(CHDHEO)], 3.78 (1H, t, J5,6a¼J6e,6a 10.4 Hz, H-6a), 3.69e3.66 (2H, m,
H-3, H-4), 3.56e3.51 (2H, m, H-2, H-5); 13C NMR (125 MHz, CDCl3):
d
146.8 (C]CH2), 137.6e126.0 (Ph), 114.5 (C]CH2), 101.9 (PhCH),
100.1 (C-1), 83.5 (C-2), 82.7 (C-3), 78.8 (C-4), 73.4, 73.0 [(OCH2)C
(CH2O)], 68.7 (C-6), 66.6 (C-5); MS (CI): m/z 397 (90%, [MþH]þ);
HRMS (CI): [MþH]þ, found 397.1648. C23H25O6 requires 397.1651.
4.2.3. Methyl 4,6-O-(S)-benzylidene-2,3-O-(2-methylidene-1,3-pro-
pylene)-b-D-galactopyranoside (14). The solid obtained was purified
by flash chromatography on silica gel (1:1 hexaneeethyl acetate) to
give compound 14 (11.4 g, 97%) as a white solid; [Found: C, 64.76; H,
d
scale relative to TMS. COSY, DEPT, HSQC, and NOESY experiments
were performed to assign the signals in the NMR spectra. Enan-
tiomeric excesses were determined by proton nuclear magnetic
resonance spectroscopy in the presence of europium (III) tris[3-
(heptafluoropropylhydroxymethylene)-(þ)-camphorate] as the
chiral shift reagent. Absolute configuration was assigned by com-
parison with the signal shifts reported in the literature for epoxides
of alkenes 27e33.12a,c,15e18 The absolute configuration was also
determined by comparing the sign of optical rotations with the
reported ones.12a,c,15e18
6.60. C18H22O6 requires C, 64.66; H, 6.63%]; mp 161e162 ꢀC; [
a]
D
þ67.0 (c 1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d 7.5e7.3 (5H, m,
Ph), 5.54 (1H, s, PhCH), 4.97e4.94 (2H, m, C]CH2), 4.56 [1H, d, Jgem
14.6 Hz, (OCHAHB)C(CHDHEO)], 4.51 [1H, d, Jgem 14.6 Hz, (OCHAHB)C
(CHDHEO)], 4.37e4.27 [5H, m, H-1, H-4, H-6e, (OCHAHB)C(CHDHEO)],
4.07 (1H, dd, J5,6a 1.3 Hz, J6e,6a 12.5 Hz, H-6a), 3.74 (1H, dd, J1,2 7.8 Hz,
J2,3 9.3 Hz, H-2), 3.58 (3H, s, OCH3), 3.43 (1H, dd, J2,3 9.8 Hz, J3,4
3.4 Hz, H-3), 3.41 (1H, m, H-5); 13C NMR (125 MHz, CDCl3):
d 147.3
(C]CH2), 137.6e126.7 (Ph), 111.9 (C]CH2), 102.4 (C-1), 101.6
(PhCH), 83.2 (C-2), 80.2 (C-3), 75.8 (C-4), 73.8, 73.3 [(OCH2)C
(CH2O)], 69.1 (C-6), 66.6 (C-5), 56.9 (OCH3); MS (EI): m/z 334 (40%,
4.2. Synthesis of 2,3-O-(2-methylidene-1,3-propylene)-
hexopyranoside derivatives (5, 6, 14e16, 24)
D-
ꢃ
[M]þ ); HRMS (EI): [M]þ$, found 334.1417. C18H22O6 requires
334.1416.
To a cooled solution (5 ꢀC) of the corresponding 4,6-O-(R)-
benzylidene- -hexopyranoside derivative (obtained using the
D
4.2.4. Phenyl 4,6-O-(S)-benzylidene-2,3-O-(2-methylidene-1,3-pro-
procedure describe by our group2c) (35.4 mmol) in dry THF (70 mL)
were added, successively, freshly powdered potassium hydroxide
(7.0 g, 125 mmol), 18-crown-6 (0.38 g, 1.4 mmol), and 3-chloro-2-
chloromethylpropene (4.1 mL, 35.4 mmol). The reaction mixture
was stirred at this temperature for 3 h, and left at room tempera-
ture until all the starting material had been consumed, as moni-
tored by TLC (5e7 days, approximately), then diluted with
dichloromethane (60 mL) and washed successively with water and
aqueous saturated solution of sodium bicarbonate, dried (MgSO4),
filtered, and the filtrate was evaporated to dryness.
pylene)-b-D-galactopyranoside (15). The solid obtained was purified
by flash chromatography on silica gel (4:1 hexaneeethyl acetate) to
give compound 15 (13.5 g, 95%) as a white solid; [Found C, 69.57; H,
6.34. C23H24O6 requires C, 69.68; H, 6.10%]; mp 85e87 ꢀC; [
a]
D ꢂ3.0
(c 0.5, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d 7.5e7.1 (10H, m, 2Ph),
5.52 (1H, s, PhCH), 5.00 (1H, d, J1,2 7.8 Hz, H-1), 4.97 (2H, m, C]CH2),
4.53 [1H, d, Jgem 14.1 Hz, (OCHAHB)C(CHDHEO)], 4.51 [1H, d, Jgem
14.1 Hz, (OCHAHB)C(CHDHEO)], 4.37e4.29 [5H, m, H-1, H-4, H-6e,
(OCHAHB)C(CHDHEO)], 4.07 (1H, dd, J5,6a 1.8 Hz, J6e,6a 12.4 Hz, H-6a),
3.95 (1H, dd, J1,2 7.7 Hz, J2,3 9.3 Hz, H-2), 3.52 (1H, m, H-5), 3.51 (1H,
dd, J2,3 9.2 Hz, J3,4 3.4 Hz, H-3); 13C NMR (125 MHz, CDCl3):
d 147.3
4.2.1. Methyl 4,6-O-(R)-benzylidene-2,3-O-(2-methylidene-1,3-pro-
pylene)-b-D-glucopyranoside (5). The solid obtained was purified by
flash chromatography on silica gel (7:1 hexaneeethyl acetate) to
(C]CH2), 137.6e117.9 (Ph), 112.1 (C]CH2), 101.6 (C-1), 100.2
(PhCH), 83.3 (C-2), 79.8 (C-3), 75.5 (C-4), 73.9, 73.3 [(OCH2)C
(CH2O)], 69.1 (C-6), 66.8 (C-5); MS (EI): m/z 396 (20%, [M]þ$); HRMS
(EI): [M]þ$, found 396.1543. C23H24O6 requires 335.1573.
give compound 5 (11.3 g, 95%) as a white solid; [Found: C, 64.74; H,
25
6.94. C18H22O6 requires C, 64.66; H, 6.63%]; mp 130e132 ꢀC; [
a]
D
ꢂ19.9 (c 1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d
7.6e7.3 (5H, m,
4.2.5. Methyl 4,6-O-(S)-benzylidene-2,3-O-(2-methylidene-1,3-pro-
pylene)-a-D-galactopyranoside (16). The solid obtained was purified
by flash chromatography on silica gel (1:1 hexaneeethyl acetate) to
give compound 16 (11.6 g, 98%) as a white solid; [Found: C, 64.56; H,
Ph), 5.51 (1H, s, PhCH), 5.04, 5.02 (2H, 2s, C]CH2), 4.48 [1H, d, Jgem
14.1 Hz, (OCHAHB)C(CHDHEO)], 4.44 [1H, d, Jgem 14.1 Hz, (OCHAHB)C
(CHDHEO)], 4.36 (1H, d, J1,2 7.7 Hz, H-1), 4.33 (1H, dd, J5,6e 4.9 Hz,
J6e,6a 10.5 Hz, H-6e), 4.28 [1H, d, Jgem 14.1 Hz, (OCHAHB)C(CHDHEO)],
4.26 [1H, d, Jgem 14.1 Hz, (OCHAHB)C(CHDHEO)], 3.75 (1H, t,
J5,6e¼J6e,6a 10.2 Hz, H-6a), 3.58e3.51 (5H, m, H-3, H-4, OCH3),
3.44e3.36 (1H, m, H-5), 3.29e3.25 (1H, m, H-2); 13C NMR
6.61. C18H22O6 requires C, 64.66; H, 6.63%]; mp 54e55 ꢀC; [
a]
D
þ280.0 (c 0.5, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d 7.5e7.3 (5H, m,
Ph), 5.53 (1H, s, PhCH), 4.97 (1H, d, J1,2 3.6 Hz, H-1), 4.89e4.87 (2H,
m, C]CH2), 4.52 [1H, d, Jgem 14.7 Hz, (OCHAHB)C(CHDHEO)], 4.50
[1H, d, Jgem 14.4 Hz, (OCHAHB)C(CHDHEO)], 4.34e4.29 [3H, m, H-4,
(OCHAHB)C(CHDHEO)], 4.25 (1H, dd, J5,6e 1.6 Hz, J6e,6a 12.5 Hz, H-6e),
4.07 (1H, dd, J5,6a 1.7 Hz, J6e,6a 12.5 Hz, H-6a), 3.96 (1H, dd, J1,2 3.6 Hz,
J2,3 9.8 Hz, H-2), 3.84 (1H, dd, J2,3 9.8 Hz, J3,4 3.4 Hz, H-3), 3.66 (1H,
(125 MHz, CDCl3):
d 146.6 (C]CH2), 137.0e126.4 (Ph), 114.3 (C]
CH2), 102.8 (PhCH), 101.8 (C-1), 86.7 (C-2), 82.6 (C-3), 78.9 (C-4),
73.2, 72.9 [(OCH2)C(CH2O)], 68.7 (C-6), 66.4 (C-5), 57.4 (OCH3); MS
(CI): m/z 335 (80%, [MþH]þ); HRMS (CI): [MþH]þ, found 335.1495.
C18H23O6 requires 335.1495.
m, H-5), 3.44 (s, 3H, OCH3); 13C NMR (125 MHz, CDCl3):
d 147.7 (C]
CH2), 137.8e126.6 (Ph), 110.6 (C]CH2), 101.3 (C-1), 99.8 (PhCH),
79.3 (C-2, C-3), 76.2 (C-4), 73.9 [(OCH2)C(CH2O)], 69.3 (C-6), 62.8
(C-5), 55.6 (OCH3); MS (CI): m/z 335 (70%, [MþH]þ); HRMS (CI):
[MþH]þ, found 335.1479. C18H23O6 requires 335.1495.
4.2.2. Phenyl 4,6-O-(R)-benzylidene-2,3-O-(2-methylidene-1,3-pro-
pylene)-b-D-glucopyranoside (6). The solid obtained was purified by
flash chromatography on silica gel (3:1 hexaneeethyl acetate) to
give compound 6 (13.5 g, 96%) as a white solid; [Found: C, 69.62; H,
6.29. C23H24O6 requires C, 69.68; H, 6.10%]; mp 96e97 ꢀC; [
a
]
D ꢂ3.8
7.5e7.0 (10H, m, 2Ph),
5.54 (1H, s, PhCH), 5.07, 5.01 (2H, 2s, C]CH2), 5.04 (1H, d, J1,2 7.7 Hz,
4.2.6. 1,5-Anhydro-4,6-O-(R)-benzylidene-2,3-O-(2-methylidene-1,3-
(c 1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d
propylene)-D-glucitol (24). The solid obtained was purified by flash
chromatography on silica gel (2:1 hexaneeethyl acetate) to give

ꢀ
J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 364e372
370
compound 24 (10.4 g, 97%) as a white solid; [Found: C, 67.11; H,
6.40. C17H20O5 requires C, 67.09; H, 6.62%]; mp 79e81 ꢀC; [
D þ9.5
(c 1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3):
7.5e7.2 (5H, m, Ph),
5.51 (1H, s, PhCH), 5.04 (2H, m, C]CH2), 4.50e4.24 [6H, m, H-1e, H-
6e, (OCH2)C(CH2O)], 4.03e3.97 (1H, m, H-1a), 3.68e3.45 (3H, m, H-
3, H-4, H-6a), 3.40e3.31 (1H, m, H-5), 3.28e3.21 (1H, m, H-2); 13C
hexaneeethyl acetate) to give compound 19 (1.4 g, 95%) as a pale
a
]
yellow solid; [Found: C, 58.55; 6.53.C18H24O8 requires C, 58.69; H,
d
6.57%]; mp 80e82 ꢀC; [
(500 MHz, CDCl3) d 7.5e7.3 (m, 5H, Ph), 5.54, 5.53 (2s, 1H, PhCH),
a
]
D
þ140.1 (c 1.0, CH2Cl2); 1H NMR
4.97, 4.93 (2d, 1H, J1,2 3.5 Hz, H-1), 4.34, 4.32 [2d, 1H, Jgem 11.4 Hz,
(OCHAHB)C(CHDHEO)], 4.25, 4.24 [2d, 1H, Jgem 12.5 Hz, (OCHAHB)C
(CHDHEO)], 4.17e3.86 [m, 5H, H-4, H-6e, H-6a, (OCHAHB)C
(CHDHEO)], 3.80e3.56 [m, 4H, H-2, H-3, CH2(OH)], 3.43, 3.42 (2s,
3H, OCH3), 3.40e3.37 (m, 2H, H-5, OH); 13C NMR (125 MHz, CDCl3):
NMR (125 MHz, CDCl3):
d 147.0 (C]CH2), 137.2e126.4 (Ph), 112.1
(C]CH2), 101.9 (PhCH), 83.9 (C-2), 79.9 (C-3), 79.3 (C-4), 73.1, 72.9
[(OCH2)C(CH2O)], 71.4 (C-1), 68.8 (C-6), 62.7 (C-5); MS (EI): m/z 304
(80%, [M]þ$); HRMS (EI): [M]þ$, found 304.1316. C17H20O5 requires
304.1311.
d
137.7e126.2 (Ph), 101.1, 100.9 (PhCH), 100.1, 100.0 (C-1), 84.5, 83.5
(C-2), 79.9, 79.7 (C-3), 77.2, 76.7 [C(OH)], 76.2, 76.1 (C-4), 73.3, 73.1,
72.5, 72.84 [(OCH2)C (CH2O)], 69.4, 69.2 (C-6), 64.4, 64.3 (CH2OH),
63.1, 62.9 (C-5), 55.7, 55.6 (OCH3); MS (CI): m/z 369 (20%, [MþH]þ);
HRMS (CI): [MþH]þ, found 369.1538. C18H25O8 requires 369.1549.
4.3. Dihydroxylation reaction
To a solution of compounds 5, 6, 14e16, 24 (4.0 mmol) in
dichloromethane (300 mL) were added trimethylamine N-oxide
(0.58 g, 5.2 mmol) and a solution of osmium tetroxide in 2-prop-
anol (2.5% w/v) in catalytic amount (0.5 mL, 0.04 mmol). The
mixture was stirred for 24 h at room temperature. The solution was
washed successively with dilute aqueous solution of sodium
bisulphite and water, dried (MgSO4), and evaporated to dryness.
The solid obtained was purified by flash chromatography on silica
gel, yielding a pale yellow solid, as a diastereoisomeric mixture
(1:1).
4.4. Diol oxidative rupture reaction
To a solution of compounds 7, 8, 17e19, 25 (1.8 mmol) in etha-
nolewater (1:2) (120 mL), a solution of sodium periodate (0.77 g) in
water (9 mL) was added, and the reaction mixture was stirred
overnight at room temperature. The solvent was evaporated to
a small volume (40e50 mL), and the solution was extracted with
dichloromethane (5ꢁ40 mL), dried (MgSO4), and evaporated to
dryness. The solid obtained was purified by flash chromatography
on silica gel.
4.3.1. Methyl 4,6-O-(S)-benzylidene-2,3-O-(2-hydroxy-2-hydroxy-
methyl-1,3-propylene)-
b
-D-galactopyranoside (17). Two stereoiso-
4.4.1. Methyl 4,6-O-(R)-benzylidene-2,3-O-(2-oxo-1,3-propylene)-
b-
mers were obtained in 1:1 ratio. The pure diastereomeric mixture
was obtained by flash chromatography on silica gel (1:1 hex-
aneeethyl acetate) to give compound 17 (0.9 g, 60%) as a pale
yellow solid; [Found: C, 58.42; 6.70.C18H24O8 requires C, 58.69; H,
D
-glucopyranoside (9). The solid obtained was purified by flash
chromatography on silica gel (4:1 hexaneeethyl acetate) to give
compound 9 (0.4 g, 73%) as a white solid; [Found: C, 60.82; H, 6.01.
C17H20O7 requires C, 60.71; H, 5.99%]; mp 163e164 ꢀC; [
a
]
D þ34.8 (c
6.57%]; mp 161e162 ꢀC; [
(500 MHz, CDCl3)
a
]
D
þ8.4 (c 0.3, CH2Cl2); 1H NMR
0.5, CH2Cl2); 1H NMR (500 MHz, CDCl3)
d 7.6e7.3 (5H, m, Ph), 5.53
d
7.5e7.3 (5H, m, Ph), 5.59, 5.58 (1H, 2s, PhCH),
(1H, s, PhCH), 4.43 (1H, d, J1,2 7.8 Hz, H-1), 4.41e4.22 [5H, m, H-6e,
(OCH2)C(CH2O)], 3.79 (1H, t, J5,6a¼J6e,6a 10.1 Hz, H-6a), 3.73e3.66
(2H, m, H-3, H-4), 3.55 (3H, s, OCH3), 3.46 (1H, dt, J5,6e 5.0 Hz,
J4,5¼J5,6a 9.9 Hz, H-5), 3.71 (1H, t, J1,2¼J2,3 8.0 Hz, H-2); 13C NMR
4.40, 4.33 (1H, 2d, J1,2 7.5 Hz, H-1), 4.37, 4.36 [1H, 2d, Jgem 12.5 Hz,
(OCHAHB)C(CHDHEO)], 4.32, 4.31 (1H, 2dd, J5,6e 1.0 Hz, J6e,6a 12.8 Hz,
H-6e), 4.12, 4.10 (1H, 2dd, J5,6a 1.9 Hz, J6e,6a 12.6 Hz, H-6a), 4.08e4.02
[3H, m, (OCHAHB)C(CHDHEO)], 3.96e3.68 [5H, m, H-2, H-3, H-4,
CH2(OH)], 3.62, 3.61 (3H, 2s, OCH3), 3.55e3.42 (3H, m, H-5, 2OH);
(125 MHz, CDCl3):
d 203.0 (C]O), 129.8e119.3 (Ph), 95.4 (PhCH),
94.8 (C-1), 87.0 (C-2), 86.0 (C-3), 78.4 (C-4), 78.0, 77.7 [(OCH2)C
(CH2O)], 68.6 (C-6), 66.7 (C-5), 57.5 (OCH3); MS (CI): m/z 337 (40%,
[MþH]þ); HRMS (CI): [MþH]þ, found 337.1292. C17H21O7 requires
337.1287.
13C NMR (125 MHz, CDCl3):
d 137.6e126.4 (Ph), 102.3, 102.1 (PhCH),
101.2, 101.1 (C-1), 82.3, 81.6 (C-2), 79.7, 79.2 (C-3), 76.9, 76.5 [C
(OH)], 76.4, 76.3 (C-4), 73.7, 73.6 [(OCH2)C(CH2O)], 69.1 (C-6), 66.5,
66.4 (CH2OH), 64.6, 64.2 (C-5), 56.8, 56.7 (OCH3); MS (CI): m/z 369
(25%, [MþH]þ); HRMS (CI): [MþH]þ, found 369.1556. C18H25O8
requires 369.1549.
4.4.2. Phenyl 4,6-O-(R)-benzylidene-2,3-O-(2-oxo-1,3-propylene)-
b-
D-glucopyranoside (10). The solid obtained was purified by flash
chromatography on silica gel (4:1 hexaneeethyl acetate) to give
compound 10 (0.6 g, 88%) as a white solid; [Found: C, 66.14; H, 5.62.
4.3.2. Phenyl 4,6-O-(S)-benzylidene-2,3-O-(2-hydroxy-2-hydroxy-
methyl-1,3-propylene)-
b
-D-galactopyranoside (18). Two stereoiso-
C22H22O7 requires C, 66.32; H, 5.57%]; mp 148e150 ꢀC; [
a
]
D þ13.4 (c
mers were obtained in 1:1 ratio. The pure diastereomeric mixture
was obtained by flash chromatography on silica gel (1:1 hex-
aneeethyl acetate) to give compound 18 (1.5 g, 88%) as a pale yel-
low solid; [Found: C, 64.03; 6.12. C23H26O8 requires C, 64.18; H,
0.9, CH2Cl2); 1H NMR (500 MHz, CDCl3)
d 7.5e7.1 (10H, m, 2Ph), 5.55
(1H, s, PhCH), 5.12 (1H, d, J1,2 7.7 Hz, H-1), 4.44e4.26 [5H, m, H-6e,
(OCH2)C(CH2O)], 3.84e3.73 (3H, m, H-3, H-4, H-6a), 3.64 (1H, t,
J1,2¼J2,3 8.0Hz, H-2)3.59(1H,dt, J5,6e 5.0Hz, J4,5¼J5,6a 10.0 Hz, H-5); 13
C
6.09%]; mp 175e176 ꢀC; [
(500 MHz, CDCl3)
a
]
þ52.9 (c 0.9, CH2Cl2); 1H NMR
NMR (125 MHz, CDCl3): d 209.8 (C]O), 136.7e117.4 (Ph), 101.9
D
d
7.8e7.1 (10H, m, 2Ph), 5.76, 5.75 (1H, 2s, PhCH),
(PhCH), 99.6 (C-1), 86.6 (C-2), 86.0 (C-3), 78.2 (C-4), 78.0, 77.8 [(OCH2)
C(CH2O)], 68.6 (C-6), 66.9 (C-5); MS (CI): m/z 399 (35%, [MþH]þ);
HRMS (EI): [M]þ$, found 398.1359. C22H22O7 requires 398.1366.
4.97, 4.96 (1H, 2d, J1,2 7.9 Hz, H-1), 4.38e4.05 [6H, m, H-6e, H-6a,
(OCH2)C(CH2O)], 3.93e3.67 [5H, m, H-2, H-3, H-4, CH2(OH)],
3.56e3.38 (3H, m, H-5, 2OH); 13C NMR (125 MHz, CDCl3):
d
134.4e116.4 (Ph), 101.9, 101.8 (PhCH), 98.9, 98.7 (C-1), 82.9, 82.7
4.4.3. Methyl 4,6-O-(S)-benzylidene-2,3-O-(2-oxo-1,3-propylene)-
b-
(C-2), 79.7, 79.2 (C-3), 76.9, 76.5 [C(OH)], 75.7, 75.6 (C-4), 73.7, 73.6
[(OCH2)C (CH2O)], 69.1 (C-6), 66.5, 66.4 (CH2OH), 64.6, 64.2 (C-5);
MS (CI): m/z 431 (30%, [MþH]þ); HRMS (CI): [MþH]þ, found
431.1721. C23H27O8 requires 431.1706.
D
-galactopyranoside (20). The solid obtained was purified by flash
chromatography on silica gel (4:1 hexaneeethyl acetate) to give
compound 20 (0.5 g, 90%) as a white solid; [Found: C, 60.41; H, 6.01.
C17H20O7 requires C, 60.71; H, 5.99%]; mp 90e91 ꢀC; [
a
]
D
þ38.8 (c
0.7, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d 7.5e7.3 (5H, m, Ph), 5.54
4.3.3. Methyl 4,6-O-(S)-benzylidene-2,3-O-(2-hydroxy-2-hydroxy-
methyl-1,3-propylene)-a-D-galactopyranoside (19). Two stereoiso-
mers were obtained in 1:1 ratio. The pure diastereomeric mixture
was obtained by flash chromatography on silica gel (4:1
(1H, s, PhCH), 4.40 (1H, d, J1,2 7.6 Hz, H-1), 4.38e4.33 [4H, m, H-4,
(OCH2)C(CHAHBO)], 4.31 (1H, dd, J5,6e 1.5 Hz, J6e,6a 11.9 Hz, H-6e),
4.25 [1H, d, Jgem¼16.2 Hz, (OCH2)C(CHAHBO)], 4.09 (1H, dd, J5,6a
1.8 Hz, J6a,6e 12.2 Hz, H-6a), 3.90 (1H, dd, J1,2 7.5 Hz, J2,3 9.5 Hz, H-2),

ꢀ
J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 364e372
371
3.60e3.57 (4H, m, H-3, OCH3), 3.47 (1H, m, H-5); 13C NMR
(125 MHz, CDCl3): 209.9 (C]O), 137.4e126.6 (Ph), 101.9 (PhCH),
101.6 (C-1), 85.4 (C-2), 82.6 (C-3), 77.8, 77.4 [(OCH2)C(CH2O)], 75.6
(C-4), 69.1 (C-6), 66.6 (C-5), 57.0 (OCH3); MS (CI): m/z 337 (20%,
[M þ H]þ); HRMS (CI): [M þ H]þ, found 337.1279. C17H21O7 requires
337.1287.
then diluted with water (10 mL). The solution was extracted with
dichloromethane (3ꢁ10 mL), dried (MgSO4), and evaporated to
dryness. The crude reaction mixture obtained was purified by flash
chromatography, using a mixture of hexaneeethyl acetate (80:1) as
eluent (50:1) for indene and methylindene, to afford the alkene
epoxide. The eluent was changed to a mixture of hexaneeethyl
acetate (2:1), and the chiral ketone was recovered in a 75e80% (for
glucopyranoside derivatives) and 60e65% (for galactopyranoside
derivatives).
d
4.4.4. Phenyl 4,6-O-(S)-benzylidene-2,3-O-(2-oxo-1,3-propylene)-
b-
D-galactopyranoside (21). The solid obtained was purified by flash
chromatography on silica gel (4:1 hexaneeethyl acetate) to give
compound 21 (0.6 g, 84%) as a white solid; [Found: C, 66.26; H, 5.82.
4.5.1. (e)-(1S,2S)-trans-Stilbene oxide12a,15
.
1H NMR (500 MHz,
C22H22O7 requires C, 66.32; H, 5.57%]; mp 104e106 ꢀC; [
a
]
D þ15.6 (c
CDCl3): 7.4e7.3 (10H, m, 2Ph), 3.88 [2H, s, 2CH(O)].
d
1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d 7.8e7.2 (10H, m, 2Ph),
5.55 (1H, s, PhCH), 5.12 (1H, d, J1,2 7.7 Hz, H-1), 4.44e4.26 [4H, m, H-
4, H-6e, (OCH2)C(CH2O)], 3.84e3.73 [3H, m, H-6a, (OCH2)C(CH2O)],
3.64 (1H, t, J1,2¼J2,3 7.7 Hz, H-2), 3.61e3.53 (2H, m, H-3, H-5); 13C
4.5.2. (ꢂ)-(1S,2S)-
b
-Methylstyrene oxide15 1H NMR (500 MHz,
.
CDCl3): 7.4e7.3 (5H, m, Ph), 3.59 [1H, d, Jtrans 2.0 Hz, PhCH(O)
d
CHCH3], 3.02 [1H, dq, J 5.1 Hz, Jtrans 2.0 Hz, PhCH(O)CHCH3], 1.44
(3H, d, J¼5.1 Hz, CH3).
NMR (125 MHz, CDCl3):
d 209.9 (C]O), 136.8e116.7 (Ph), 102.0
(PhCH), 99.6 (C-1), 89.7 (C-2), 86.0 (C-3), 78.3, 78.0 [(OCH2)C
(CH2O)], 75.6 (C-4), 68.6 (C-6), 66.9 (C-5), 57.0 (OCH3); MS (CI): m/z
399 (20%, [MþH]þ); HRMS (CI): [MþH]þ, found 399.1440. C22H23O7
requires 399.1444.
4.5.3. (ꢂ)-(1S,2S)-trans-
a
-Methylstilbene
oxide15,16
.
1H
NMR
(500 MHz, CDCl3):
(3H, s, CH3).
d 7.4e7.3 (10H, m, 2Ph), 3.96 [1H, s, CH(O)], 1.46
4.4.5. Methyl 4,6-O-(S)-benzylidene-2,3-O-(2-oxo-1,3-propylene)-
a
-
4.5.4. (þ)-(2S)-Triphenylethylene oxide12a,15,16
.
1H NMR (500 MHz,
CDCl3): d 7.4e7.1 (15H, m, 3Ph), 4.32 [1H, s, CH(O)].
D-galactopyranoside (22). The solid obtained was purified by flash
chromatography on silica gel (4:1 hexaneeethyl acetate) to give
compound 22 (0.6 g, 94%) as a white solid; [Found: C, 60.44; H, 5.98.
4.5.5. Dihydronaphtalene oxide16,17
d 7.4e7.2 (4H, m, Ar), 3.85 [1H, d, J 4.5 Hz, CH(O)CHCH2], 3.73 [1H,
dd, J 4.3 Hz, J 3.0 Hz, CH(O)CHCH2], 2.80 (1H, m), 2.55 (1H, dd, J
6.0 Hz, J 15.5 Hz), 2.43 (1H, m), 1.78 (1H, m).
.
1H NMR (500 MHz, CDCl3):
C17H20O7 requires C, 60.71; H, 5.99%]; mp 99e101 ꢀC; [
a
]
D þ19.0 (c
0.5, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d
7.5e7.3 (5H, m, Ph), 5.55
(1H, s, PhCH), 5.03 (1H, d, J1,2 3.6 Hz, H-1), 4.40 (1H, m, H-4),
4.32e4.29 [4H, m, (OCH2)C(CH2O)], 4.27 (1H, dd, J5,6e 1.4 Hz, J6e,6a
12.5 Hz, H-6e), 4.13 (1H, dd, J1,2 3.6 Hz, J2,3 9.8 Hz, H-2), 4.09 (1H, dd,
J5,6a 1.5 Hz, J6e,6a 12.5 Hz, H-6a), 4.02 (1H, dd, J2,3 9.7 Hz, J3,4 3.4 Hz,
H-3), 3.70 (1H, m, H-5), 3.47 (3H, s, OCH3); 13C NMR (125 MHz,
4.5.6. Indene oxide12c,18 1H NMR (500 MHz, CDCl3):
. d 7.4e7.2 (4H,
m, Ar), 3.48 [1H, dd, J 3.0 Hz, J 0.5 Hz, CH(O)CHCH2], 4.15 [1H, t, J
3.0 Hz, CH(O)CHCH2], 3.23 (1H, dd, J 0.5 Hz, J 18.0 Hz), 3.00 (1H, dd, J
3.0 Hz, J 18.0 Hz).
CDCl3):
d 209.9 (C]O), 137.4e126.5 (Ph), 101.4 (PhCH), 99.3 (C-1),
80.8 (C-2), 80.7 (C-3), 77.5, 77.4 [(OCH2)C(CH2O)], 75.8 (C-4), 69.2
(C-6), 62.8 (C-5), 55.7 (OCH3); MS (CI): m/z 337 (30%, [MþH]þ);
HRMS (CI): [MþH]þ, found 337.1278. C17H21O7 requires 337.1287.
4.5.7. Methylindene oxide. 1H NMR (500 MHz, CDCl3):
(4H, m, Ar), 4.04 [1H, s, CH(O)C(CH3)CH2], 3.17 (1H, d, J 17.5 Hz),
2.92 (1H, d, J 17.5 Hz), 1.71 (3H, s, CH3).
d 7.4e7.2
4.4.6. 1,5-Anhydro-4,6-O-(R)-benzylidene-2,3-O-(2-oxo-1,3-pro-
pylene)- -glucitol (26). The solid obtained was purified by flash
D
Acknowledgements
chromatography on silica gel (4:1 hexaneeethyl acetate) to give
compound 26 (0.3 g, 60%) as a white solid; [Found: C, 62.57; H, 6.15.
We are grateful to the Junta de Andalucía, Ministerio de Edu-
C16H18O6 requires C, 62.74; H, 5.92%]; mp 138e139 ꢀC; [
a
]
D þ14.7 (c
ꢀ
cacion y Ciencia (Spain), and to the FEDER programme for financial
1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d 7.8e7.2 (10H, m, 2Ph),
support (P06-FQM-01885 and CTQ2007-61185). I.P. thanks Junta de
Andalucía for a predoctoral grant. The help of Dr. M. Angulo in 1H
NMR spectra recording is gratefully acknowledged.
5.51 (1H, s, PhCH), 4.39e4.21 [6H, m, H-1e, H-6e, (OCH2)C(CH2O)],
4.09e4.03 (1H, m, H-1a), 3.69 (1H, t, J5,6a¼J6e,6a 10.3 Hz, H-6a),
3.64e3.58 (2H, m, H-3, H-4), 3.44e3.35 (1H, m, H-5), 3.32e3.29
(1H, m, H-2); 13C NMR (125 MHz, CDCl3):
d 210.0 (C]O),
Supplementary data
137.0e126.4 (Ph), 101.9 (PhCH), 87.4 (C-2), 83.3 (C-3), 78.9 (C-4),
77.8, 77.6 [(OCH2)C(CH2O)], 71.8 (C-1), 68.8 (C-6), 62.6 (C-5); MS
(EI): m/z 306 (100%, [M]þ$); HRMS (EI): [M]þ$, found 306.11073.
C16H18O6 requires 306.1103.
These data include 1H and 13C NMR spectra of chiral ketones
described in this article, and 1H NMR used in the determination of
enantiomeric excesses in the epoxidation reactions of arylalkenes.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.11.033. These data include
MOL files and InChIKeys of the most important compounds de-
scribed in this article.
4.5. General procedure for the enantioselective epoxidation
To a solution of the alkene (27e33) (0.2 mmol) in 1,2-dime-
thoxyethane (5 mL) were added chiral ketones 9, 10, 20e22, and 26
(0.2 mmol) and n-Bu4NHSO4 (5 mg). The reaction mixture was
cooled to 0 ꢀC into an ice-water bath. OxoneÒ (0.4 mmol) was
dissolved in a solution of Na2EDTA 4ꢁ10ꢂ4 M (2 mL), and NaHCO3
References and notes
(1.2 mmol) was dissolved in a solution of Na2EDTA 4ꢁ10ꢂ4
M
1. (a) Pleus, N.; Zech, G.; Furman, B.; Kunz, H. Sugars as Chiral Auxiliaries. In The
Organic Chemistry of Sugars; Levy, D. E., Fugedi, P., Eds.; Taylor & Francis Group:
Boca Raton, 2006; pp 427e488; (b) Adam, W.; Zhang, A. Synlett 2005,
1047e1072; (c) Emmerson, D. P. G.; Hems, W. P.; Davis, B. G. Org. Lett. 2006, 8,
207e210; (d) Ferreira, V. F.; Leao, R. A. C.; Silva, F. C.; Pinheiro, S.; Lhoste, P.;
€
(2 mL). The two solutions were added separately to the reaction
mixture (first the OxoneÒ solution, and then the NaHCO3 solution)
dropwise over a period of 1 h. The pH of the mixture was main-
tained at about 8.0. The reaction mixture was stirred until TLC
showed that the epoxidation reaction was finished (3e7 h), and
ꢀ
Sinou, D. Tetrahedron: Asymmetry 2007, 18, 1217e1223; (e) Vega-Perez, J. M.;
~ꢀ
Perinan, I.; Vega, M.; Iglesias-Guerra, F. Tetrahedron: Asymmetry 2008, 19,
ꢀ
~ꢀ
1720e1729; (f) Vega-Perez, J. M.; Perinan, I.; Iglesias-Guerra, F. Tetrahedron:

ꢀ
J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 364e372
372
Asymmetry 2009, 20, 1065e1072; (g) Pu, X.-W.; Peng, F.-Z.; Zhang, H.-B.; Shao,
59, 2159e2168; (c) Shing, T. K. M.; Leung, G. Y. C.; Luk, T. J. Org. Chem. 2005, 70,
7279e7289; (d) Shing, T. K. M.; Luk, T.; Lee, C. M. Tetrahedron 2006, 62,
6621e6629; (e) Shing, T. K. M.; Luk, T. Tetrahedron: Asymmetry 2009, 20,
883e886.
Z.-H. Tetrahedron 2010, 66, 3655e3661.
ꢀ
2. (a) Vega-Perez, J. M.; Candela, J. I.; Romero, I.; Blanco, E.; Iglesias-Guerra, F. Eur.
ꢀ
J. Org. Chem. 2000, 3949e3956; (b) Vega-Perez, J. M.; Candela, J. I.; Blanco, E.;
Iglesias-Guerra, F. Tetrahedron: Asymmetry 2002, 13, 2471e2483; (c) Vega-
Perez, J. M.; Perinan, I.; Palo-Nieto, C.; Vega-Holm, M.; Iglesias-Guerra, F. Tet-
10. Boutureira, O.; McGouran, J. F.; Stafford, R. L.; Emmerson, D. P. G.; Davis, B. G.
Org. Biomol. Chem. 2009, 7, 4285e4288.
11. Vega-Perez, J. M.; Vega Holm, M.; Martínez, M. L.; Blanco, E.; Iglesias-Guerra, F.
ꢀ
~ꢀ
ꢀ
rahedron: Asymmetry 2010, 21, 81e95.
ꢀ
3. Vega-Perez, J. M.; Vega, M.; Blanco, E.; Iglesias-Guerra, F. Tetrahedron: Asym-
Eur. J. Org. Chem. 2009, 6009e6018.
metry 2001, 12, 3189e3203.
4. (a) Iglesias-Guera, F.; Candela, J. I.; Blanco, E.; Alcudia, F.; Vega-Perez, J. M.
Chirality 2002, 14, 199e203; (b) Vega-Perez, J. M.; Vega, M.; Blanco, E.; Iglesias-
Guerra, F. Tetrahedron: Asymmetry 2004, 15, 3617e3633; (c) Vega-Perez, J. M.;
12. (a) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J.-H.; Cheung, K.-K. J.
Am. Chem. Soc. 1996, 118, 491e492; (b) Yang, D.; Wang, X.-C.; Wong, M.-K.; Yip,
Y.-C.; Tang, M.-W. J. Am. Chem. Soc. 1996, 118, 11311e11312; (c) Denmark, S. E.;
Matsuhashi, H. J. Org. Chem. 2002, 67, 3479e3486.
ꢀ
ꢀ
ꢀ
Vega, M.; Blanco, E.; Iglesias-Guerra, F. Tetrahedron: Asymmetry 2007, 18,
1850e1867.
5. (a) Shi, Y. Acc. Chem. Res. 2004, 37, 488e496 and referenced cited herein; (b)
Wong, O. A.; Shi, Y. Chem. Rev. 2008, 108, 3958e3987 and references cited
herein; (c) Wang, B.; Wong, O. A.; Zhao, M.-X.; Shi, Y. J. Org. Chem. 2008, 73,
9539e9543.
13. Baumstark, A. L.; McCloskey, C. J. Tetrahedron Lett. 1987, 28, 3311e3314.
14. (a) Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B.; McDouall, J. J. W. J.
Am. Chem. Soc. 1992, 114, 7207e7217; (b) Houk, K. N.; Liu, J.; DeMello, N. C.;
Condroski, K. R. J. Am. Chem. Soc. 1997, 119, 10147e10152; (c) Jenson, C.; Liu, J.;
Houk, K. N.; Jorgensen, W. L. J. Am. Chem. Soc. 1997, 119, 12982e12983.
15. Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806e9807.
16. Page, P. C. B.; Buckley, B. R.; Backler, A. J. Org. Lett. 2004, 6, 1543e1546.
17. Wang, Z.-X.; Tu, Y.; Frohn, M.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224e11235.
18. (a) Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc. 2000, 122,
11551e11552; (b) Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3, 1929e1931;
(c) Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67, 2435e2446.
6. Yang, D. Acc. Chem. Res. 2004, 37, 497e505.
7. Armstrong, A.; Bettati, M.; White, A. J. P. Tetrahedron 2010, 66, 6309e6320.
8. Shing, T. K. M.; Leung, G. Y. C. Tetrahedron 2002, 58, 7545e7552.
9. (a) Shing, T. K. M.; Leung, G. Y. C.; Yeung, K. W. Tetrahedron Lett. 2003, 44,
9225e9228; (b) Shing, T. K. M.; Leung, G. Y. C.; Yeung, K. W. Tetrahedron 2003,