New mannose-derived ketones as organocatalysts for enantioselective dioxirane-mediated epoxidation of arylalkenes. Part 3: Chiral ketones from sugars

Article abstract of DOI:10.1016/j.tet.2011.07.014

New d-arabino-hexopyranosid-3-uloses were synthesized by a simple method from mannopyranoside derivatives. The common skeleton possesses a tunable alkoxy group as steric sensor on carbon 2 of the sugar. The new ketones were employed in the dioxirane-mediated epoxidation of a range of trans- and trisubstituted arylalkenes giving enantiomeric excesses from low to good (30-90%). The effect of the size of the steric sensor on the enantioselectivity was also studied. The least bulky group (methoxy group) enhanced the stereoselectivity (up to 90% ee toward triphenylethylene).

Full text of DOI:10.1016/j.tet.2011.07.014

Tetrahedron 67 (2011) 7057e7065
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New mannose-derived ketones as organocatalysts for enantioselective dioxirane-
mediated epoxidation of arylalkenes. Part 3: Chiral ketones from sugarsq
*
ꢀ
ꢀ
~ꢀ
Jose M. Vega-Perez , Ignacio Perinan, Margarita Vega-Holm, 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:
Received 6 April 2011
Received in revised form 27 June 2011
Accepted 6 July 2011
Available online 14 July 2011
New D-arabino-hexopyranosid-3-uloses were synthesized by a simple method from mannopyranoside
derivatives. The common skeleton possesses a tunable alkoxy group as steric sensor on carbon 2 of the
sugar. The new ketones were employed in the dioxirane-mediated epoxidation of a range of trans- and
trisubstituted arylalkenes giving enantiomeric excesses from low to good (30e90%). The effect of the size
of the steric sensor on the enantioselectivity was also studied. The least bulky group (methoxy group)
enhanced the stereoselectivity (up to 90% ee toward triphenylethylene).
Keywords:
Carbohydrate
Ó 2011 Elsevier Ltd. All rights reserved.
Chiral ketone
Dioxirane
Enantioselective epoxidation
Organocatalysis
1. Introduction
In this sense many research groups have described different
chiral ketones and high excess values have been reported for cat-
In the field of asymmetric transformations, the enantioselective
epoxidation of alkenes is an important objective of many research
groups for two reasons: optically active oxiranes are important
synthetic intermediates widely employed in organic synthesis1 and
the epoxide functional group itself is an essential structural moiety
of many natural products.2 Among the methods for enantiose-
lective epoxidation of olefins, the development of dioxirane-
mediated epoxidations employing chiral ketones constitutes an
attractive catalytic process since the first one was described by
Curci co-woekers3 A key issue to successfully obtain stereochemical
control is the design of new and efficient chiral ketones. High cat-
alytic activity, application on different structural types of alkenes,
easy and high-yielding synthesis and high stereochemical differ-
entiation are some criteria required for ketones. In order to obtain
good stereofacial discrimination, ketone process design should take
under consideration the two reacting sites of the dioxirane and
possible competition between them. A usual approach is the
preparation of chiral ketones that yield dioxiranes with one face
blocked, so oxygen transfer occurs almost exclusively from the
other face (efficient asymmetric environment is then maintained).4
alytic enantioselective alkene epoxidation, employing bile acids,5
(þ)-dihydrocarvone,6 N-carbethoxytropinone,7
D
-(ꢀ)-quinic acid,8
mannitol and (þ) tartaric acid,9 as chiral precursors for the syn-
thesis of ketones.
In 1996 Shi and co-workers described a new fructose-derived
ketone 1, as a highly reactive and enantioselective epoxidation
catalyst for trans- and trisubstituted olefins.10 Their contributions in
this area have extensively demonstrated that fructose- and
glucose-derived ketones are exceptionally stereoselective tools and
that they are applicable to a wide range of alkene substitution
patterns [high enantioselectivities have been obtained with a vari-
ety of (E)- and trisubstituted olefins, a number of (Z)-olefins and
certain terminal and tetrasubstituted olefins]. Their mechanistic
studies have contributed to the development of efficient catalysts,
(as example 2)11 (Fig. 1).
O
O
O
R
N
O
O
O
O
O
O
O
O
O
q
For Part 2 see: Ref. 17.
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. Shi’s fructose-derived ketones.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.014

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J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 7057e7065
7058
Shing and co-workers have described the synthesis of new
rigidity, the sugar chirality and sugar substituents provided satis-
factory levels of stereofacial differentiation.
As a continuation of our work, we focused on the design of new
backbone models for carbohydrate-derived ketones with points of
glucose- 312 and arabinose-derived uloses 4,5,1b,13 and have
obtained high stereochemical communication between the ketone
catalyst and the alkene [(E)-, trisubstituted and (Z)-alkenes] (Fig. 2).
structural modifications. We present here a new D-arabino-hexo-
O
OBn
O
R1O
R2
O
OBn
O
pyranoside-3-ulose skeleton 10 with a tunable alkoxy group on
position 2 of the sugar moiety as the steric blocker (Fig. 5). The
features of this general structure comply with the requisites men-
tioned above as crucial in the design of the ketone. We would like to
point out two aspects: the reactive group is a sugar carbon is and no
mannose derivatives have been previously reported as precursors in
the field of the synthesis of new ketones from carbohydrates.
However, different glucose, arabinose, and fructose derivatives have
beenemployed, achieving largeenantiomeric excesses. According to
our catalyst’s design shown in Fig. 5, the effect of the structure of the
steric sensor on the enantioselectivity of the process is studied.
O
O
O
O
O
OR
O
RO
OR
O
O
RO
O
4
3
5
Fig. 2. Shing’s glucose and arabinose-derived uloses.
Recently a systematically varied series of conformationally re-
stricted ketones, readily prepared from N-acetyl-D-glucosamine,
were tested against representative olefins as asymmetric epoxi-
dation catalysts showing useful selectivities against terminal ole-
fins and, in particular, typically difficult 2,2-disubstituted terminal
olefins14 (6, Fig. 3).
O
OMe
OR
O
Ph
O
O
Ph
O
O
O
10
HN
O
OMe
O
Fig. 5. General structure of mannose-derived ketone.
R
6
This article reports the stereochemical results obtained when
we employed these new ketones as chiral precursors of dioxiranes
for the epoxidation reaction of a variety of unfunctionalised trans-
and trisubstituted arylalkenes.
Fig. 3. N-acetyl-D-glucosamine-derived ketone.
These new ketones belong to a new class designed on the basis
of the following considerations: (a) the reacting carbonyl placed
close to the chiral control elements, (b) conformational rigidity due
to the presence of fused ring (it has been noted that conformational
flexibility in such epoxidising organocatalysts might have dramat-
ically detrimental effects on stereoselectivity), (c) the approach of
an olefin to the reacting dioxirane is directed by sterically blocking
on one face, (d) the presence of electron-withdrawing substituents
2. Results and discussion
In order to prepare a systematically varied series of conforma-
tionally restricted ketones with general structure 10, we first
designed the synthetic sequence starting with the anhydro allo-
pyranoside derivative 11 through a nucleophilic opening reaction of
oxiranes with different sodium alkoxides (methoxide, ethoxide,
isopropoxide). The reaction with sodium methoxide yielded com-
on C-a
to activate the carbonyl group.4a,b,11a,b,15
One of our group’s lines of research pursues the development of
methods for the synthesis of enantiomerically pure epoxides,16 the
design of carbohydrate-derived ketones and their use to generate
new chiral ketoneeOxoneÒ systems.
We have recently described a new chiral carbohydrate-derived
ketone 7, with the reactive group located on a seven-membered
ring fused to positions 2 and 3 of the sugar moiety.17 Its general
structure is a tri-cyclic system: the trans -decalin- like benzylidene-
4,6-O-acetal, the dioxepane ring where the ketone function is lo-
cated, and the sugar moiety. Choosing the adequate commercially
pound 12, methyl 4,6-O-(R)-benzylidene-2-O-methyL-a-D-altro-
pyranoside,19 (90%). However for the rest of the other 2-O-alkyl-
derivatives designed, since the opening reaction did not take place,
we had to design a different synthetic strategy. To do this we
changed both the carbohydrate precursor, methyl 4,6-O-benzyli-
dene-a-D
-mannopyranoside20 13, and the reaction introducing
structural variation, in this case a selective 2-O-alkylation with
different alkyl halides. Compounds methyl 2-O-alkyl-4,6-O-(R)-
benzylidene-a-D-mannopyranoside (14e17) were obtained with
available precursor (alkyl and aryl,
a and b, D-gluco and D-galacto
yields between 50 and 60% after flash column chromatography. 3-
O-Alkyl mannopyranoside derivatives as well as starting diols were
also recovered in small amount21 (Scheme 1).
derivatives) and applying this synthetic methodology a number of
ketones have been obtained with high chemical yields (8). We have
employed them in dioxirane-mediated epoxidation of arylalkenes
obtaining moderate-to-good excesses. Best ee’s were obtained with
compound 9, a-methyl-D
-galacto derivative18 (Fig. 4).
OMe
Ph
Ph
O
Ph
Ph
O
O
O
i
O
O
O
OMe
O
O
O
OMe
O
O
OMe
O
O
O
O
O
*
OMe
OH OMe
O
*
Ph
O
Ph O *
Ph
O
O
11
12
O
O
O
7
8
9
OH
O
OR
O
O
O
i
O
O
ꢀ
Fig. 4. General structure of Vega-Perez’s glucose and galactose-derived ketone.
HO
OMe
OH OMe
Our general structure 8 had properties that made it an effective
scaffold for organocatalyst in asymmetric epoxidation: easy and
high-yielding synthesis, conformational rigidity, the presence of
electron-withdrawing groups on C-a, appropriate control of the
approach to alkene by sterically blocking on one face and the re-
active group placed close to chiral elements. The conformational
13
14 R = Et
15 R = Bn
16 R = i-Pr
17 R = i-Bu
Scheme 1. (i) NaMeO, MeOH, reflux, 95%; (ii) NaOH, ReI, CH2Cl2, 45 ꢁC, 50e60%.

ꢀ
J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 7057e7065
7059
1H NMR spectral study shows characteristic signal of H-1 of the
sugar as a doublet around 4.70 ppm and a coupling constant J1,2
1.0e1.4 Hz, the signals for those hydrogen atoms vicinal to the
oxygen in the 2-O-alkyl groups at around 3.4e3.7 ppm in all cases,
except compound 15, whose benzylic hydrogens appear at 4.70
O
R2
R2
O
ketone
R1
R1
d
Oxone®
R3
R3
d
ketones:
O
d
O
O
OMe
OMe Ph
O
OMe
O
O
OMe
OBn
O
and 4.76 ppm. A doublet with almost the same coupling constant (J
8.9 Hz) is observed in 1H NMR spectrum of these compounds at
Ph
O
O
OEt Ph
O
O
d
2.3 ppm in all cases, corresponding to the hydroxyl group on
18
19
20
carbon 3 of the sugar, whose hydrogen is coupled with H-3 atom of
the sugar moiety.
O
OMe
O
O
OMe
O
O
O
The next step was the oxidation of the hydroxyl in position 3 of
the sugar without epimerisation occurring, in order to provide the
keto function on this carbon preserving the stereochemistry of
carbon 2.22 When the altropyranoside 12, and the mannopyrano-
sides 14e17 were treated with pyridinium chlorochromate in
dichloromethane, the corresponding methyl 2-O-alquil-4,6-O-(R)-
Ph
O
Ph
O
O
21
O
22
substrates:
Ph
Ph
Ph
Me
26
Ph
Ph
27
Me
Me
Ph
Ph
Ph
Ph
benzylidene-a-D-arabino-hexopiranoside-3-uloses (18e22) was
isolated in 70e84% yield. (Scheme 2).
25
28
Me
OR
OR
O
Ph
O
Ph
O
O
i
O
O
Ph
HO
O
OMe
OMe
29
Scheme 3. Epoxidation conditions: see text.
30
31
12 R = Me, altro
18 R = Me
19 R = Et
20 R = Bn
21 R = i-Pr
22 R = i-Bu
14 R = Et, manno
15 R = Bn, manno
16 R = i-Pr, manno
17 R = i-Bu, manno
The epoxides were isolated in satisfactory chemical yields
(60e80%) and were recovered in high percentages without loss of
activity (around 70%) showing their stability under the reaction
conditions and enabling their use in various catalytic cycles.
The relationship between the size of the alkoxy group and the
enantioselectivity of the epoxidation is summarized in Table 1.
ꢁ
Scheme 2. (i) PCC, CH2Cl2, molecular sieves 3 A, rt, 70e85%.
A noteworthy feature for the 1H NMR spectra of these com-
pounds is the signal for H-1 atom of the sugar moiety as a doublet
(coupling constant J1,2 1.0e1.2 Hz in all these ketones) at
Table 1
d
4.99 ppm,
21; and for the 13C NMR spectra was the signal for the carbonyl
carbon at 198 ppm in all cases. The rest of the signals in the two
d 5.57 ppm for compound 19, d 4.91 ppm for compound
Catalytic asymmetric epoxidation of alkenes (25e31) in the presence of ketones
18e22a
Yieldb (%)
eec (%)
Configurationd
d
Entry
Ketone
Alkene
spectra were assigned with the help of two-dimensional experi-
ments and confirmed the structure of these sugar derived ketones.
After obtaining these ketone organocatalysts, we investigated
suitable conditions for the epoxidation reaction. Our preliminary
essays chose trans-stilbene as a testing model olefin, and ketone 18
as catalyst, indicating similar reactivity to our previously described
ketones.17,18 When we employed sub-stoichiometric quantities
(0.5 equiv) of ketone, the reaction time was high (1e2 days) and
conversion was low under these conditions (recovering alkene
without epoxidation). Increasing the amount of ketone allowed us
to improve the efficiency of the epoxidaton reaction (yields and
reaction times) but without changing stereochemical results (ee
and major oxirane configuration). After screening various reaction
conditions the epoxidation 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/4.10ꢀ4 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 complete the reaction (3 h, TLC analysis) (Scheme 3).
We chose as substrates for the epoxidation reaction a variety of
unfunctionalised trans- and trisubstituted olefins (25e31) in order
to explore the substrate scope of these catalysts. Our aim was to
study the stereofacial differentiation capacity of these new ketones
and the effect of the structural differences on the stereochemical
result of the process, in order to obtain a more efficient chiral
catalyst. In all cases, the absolute configuration of the major en-
antiomers obtained was assigned by comparing both the signal
shifts in presence of (þ)-Eu(hfc)3 and the sign of optical rotation
with those reported in the literature.
1
2
3
4
5
6
7
8
18
18
18
18
18
18
18
19
19
19
19
20
20
20
20
20
21
21
21
21
21
22
22
22
22
25
26
27
28
29
30
31
25
26
27
30
25
26
27
29
30
25
26
27
29
30
25
26
27
30
68
70
74
76
80
71
55
78
71
67
62
78
52
73
68
72
76
79
65
77
61
67
59
75
64
80
70
90
28
60
52
31
70
58
78
39
65
59
71
63
33
68
58
73
62
38
47
44
64
28
(þ)-(1R,2R)
(þ)-(1R,2R)
(e)-(R)
(þ)-(R)
(þ)-(1R,2R)
(þ)-(1R,2R)e
(e)-(1R,2S)
(þ)-(1R,2R)
(þ)-(1R,2R)
(e)-(R)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
(þ)-(1R,2R)e
(þ)-(1R,2R)
(þ)-(1R,2R)
(e)-(R)
(þ)-(1R,2R)
(þ)-(1R,2R)e
(þ)-(1R,2R)
(þ)-(1R,2R)
(e)-(R)
(þ)-(1R,2R)
(þ)-(1R,2R)e
(þ)-(1R,2R)
(þ)-(1R,2R)
(e)-(R)
(þ)-(1R,2R)e
Conditions: substrate (1 equiv), ketone (1 equiv), OxoneÒ (2 equiv), NaHCO3
a
(6 equiv), DMEeaqueous EDTA (4ꢂ10ꢀ4 M) (1.2:1), 0 ꢁC.
b
Yields after column chromatography.
c
Enantiomeric excesses were determined by 1H NMR spectroscopy of the ep-
oxide products directly with shift reagent (þ)-Eu(hfc)3.
d
The absolute configuration of the major enantiomer was assigned by comparing
the signal shifts and the sign of optical rotation with those reported in the literature.
e
Previously reported by us, see Ref. 16.

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J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 7057e7065
7060
For trans- and trisubstituted 1,2-diarylalkenes (25e27 and 30) we
Finally, the next objective was to prepare the 2-deoxy derivative
methyl 4,6-O-(R)-benzylidene-2-deoxy- -erythro-3-ulose 24 by
reaction of compound 11 with LiAlH4 and following oxidation to
generate the keto function on carbon 3 of the sugar residue
(Scheme 5).
have found a relationship between the enantioselectivity and the size
of thealkoxygrouponcarbon2.Ketonecatalyst18 withtheleastbulky
alkoxygroup (OMe) displayed the best enantioselectivity (entries 1e3
and 6, highest ee 90% for alkene 27). Lower enantioselectivities and
similar values of ee’s were obtained with ketones 19 (OEt group, en-
tries 8e11, highestee 78% foralkene 27), 20 (OBn group, entries 12e14
and 16, highest ee 71% for alkene 27), and 21 (Oi-Pr, entries 17e19 and
21, highest ee 73% for alkene 27). Ketone 22 with an O-isobutyl group
a-D
Ph
O
Ph
O
O
O
i, ii
O
O
O
O
OMe
OMe
(branching
b to oxygen) induced low degree of enantioselectivity
(entries 22e24, highest ee 64% for alkene 27). The absolute configu-
ration of the major enantiomer is the same for each alkene in all cases.
Shing and co-workers13c,d have reported the epoxidation re-
action of trans- and -trisubstituted alkenes with new arabinose-
derived 4-uloses containing tunable cyclohexane-1,2-diacetal and
butane-1,2-diacetal as steric blockers. Their results showed that the
enantioselectivity was sensitive and increased with the size of the
11
24
ꢁ
Scheme 5. (i) LiAlH4, THF, reflux, 66%; (ii) PCC, CH2Cl2, molecular sieves 3 A, rt, 71%.
1H NMR spectrum of compound 24 shows the signal for H-1 at
5.18 ppm (J1,2a 4.7 Hz). In the 13C NMR spectrum the carbonyl group
signal appears at 198 ppm.
acetal alkoxy group. Steric blockers branched
b to the acetal oxygen
We carried out the epoxidation of alkenes 25e27 with this ke-
tone under the same reaction conditions. The stereochemical yields
compared with those obtained with ketone 18, are presented in
Table 3. The same major enantiomer configuration was found, but
with lower ee’s.
also exhibited good stereochemical communication toward this
type of alkenes.
In all cases we have obtained the opposite major enantiomer
than Shing’s epoxides, and based on our results we concluded that
the enantioselectivity was also sensitive decreasing with the size of
the alkoxy group (best ee’s were obtained when an OMe group is
present, ketone 18) as well as steric blockers with branching
b to
oxygen exhibited poor stereofacial discrimination (ketone 22 with
an O-isobutyl group).
However, the epoxidation reaction of the phenylcyclohexene (1-
arylalkene) afforded similar ee’s with ketones 18 (O-methyl group),
20 (O-benzyl group), and 21 (O-isopropyl group) as catalysts
(60e62%, entries 5, 15, and 20).
In order to determine the influence of the C-2 configuration in
the enantiofacial discrimination, we have synthesized the C-2
epimeric ribo-hexopyranoside-3-ulose, 2323 (Scheme 4).
Table 3
Catalytic asymmetric epoxidation of alkenes (25e27) in the presence of ketones 18
and 24a
Entry
Ketone
Alkene
Yieldb (%)
eec (%)
Configurationd
1
2
3
4
5
6
24
18
24
18
24
18
25
25
26
26
27
27
67
68
65
70
58
74
33
80
6
70
39
90
(þ)-(1R,2R)
(þ)-(1R,2R)
(þ)-(1R,2R)
(þ)-(1R,2R)
(e)-(R)
(e)-(R)
a
Conditions: substrate (1 equiv), ketone (1 equiv), Oxone (2 equiv), NaHCO3
(6 equiv), DMEeaqueous EDTA (4ꢂ10ꢀ4 M) (1.2:1), 0 ꢁC.
OMe
Ph
O
Ph
O
b
i
Yields after column chromatography.
O
O
O
O
c
Enantiomeric excesses were determined by 1H NMR spectroscopy of the
MeO
O
O
epoxide products directly with shift reagent (þ)-Eu(hfc)3.
OMe
OMe
d
The absolute configuration of the major enantiomer was assigned by comparing
18
23
the signal shifts and the sign of optical rotation with those reported in the literature.
Scheme 4. (i) EtOH 96%, Et3N, reflux, 61%.
A complementary part of our work involved preliminary trials to
evaluate the efficiency of this type of ketone as chiral inductor in
the epoxidation of cis-olefins. It has been extremely challenging for
chiral dioxiranes to epoxidize cis-olefins and terminal olefins with
high enantioselectivity.24
We chose ketone 18 (that gave best ee’s) and used the reaction
conditions described above. The substrates employed for these
preliminary studies were styrene (terminal olefin) and dihy-
dronaphthalene (cis-alkene).
The signal for H-1 atom, appears at
J1,2 4.3 Hz), and the signal for H-2 atom, at
d
5.2 ppm (coupling constant
4.0 ppm as a double
d
4
doublet (coupling constants J1,2 4.3 Hz, J2,4 1.5 Hz).
We performed the epoxidation reaction of alkenes 25e27 with
ketone 23 as catalyst in similar reaction conditions. We obtained
the major enantiomer in all cases but with lower stereochemical
yields. (Table 2).
Table 2
Catalytic asymmetric epoxidation of alkenes (25e27) in the presence of ketones 18
Although the reaction took place with good chemical yields (72
and 57%, respectively) the ee was low for terminal alkene (20%) and
no ee was found for cis one.
and 23a
Entry
Ketone
Alkene
Yieldb (%)
eec (%)
Configurationd
1
2
3
4
5
6
23
18
23
18
23
18
25
25
26
26
27
27
55
68
57
70
72
74
d
d
Finally, we wanted to study the oxidation reaction of alky-
lalkenes using this model of ketone as catalyst. We chose appro-
priate alkenes in order to obtain optically active oxyranes that could
act as precursors for interesting compounds, particularly new
enantiomerically pure glycerol analogues. To prepare these alkenes
we synthesized ketone 3425 following a simple sequence, and it
reacted with different alkyl triphenylphosphonium bromides to
give alkenes 35 and 36 (Scheme 6).
80
14
70
23
90
(þ)-(1R,2R)
(þ)-(1R,2R)
(þ)-(1R,2R)
(e)-(R)
(e)-(R)
a
Conditions: substrate (1 equiv), ketone (1 equiv), Oxone (2 equiv), NaHCO3
(6 equiv), DMEeaqueous EDTA (4ꢂ10ꢀ4 M) (1.2:1), 0 ꢁC.
b
Yields after column chromatography.
Enantiomeric excesses were determined by 1H NMR spectroscopy of the
c
Their epoxidation reaction with ketone 18 gave 37 and 38
(Fig. 6). Chemical yields and enantioselectivities obtained are
summarized in Table 4.
epoxide products directly with shift reagent (þ)-Eu(hfc)3.
d
The absolute configuration of the major enantiomer was assigned by comparing
the signal shifts and the sign of optical rotation with those reported in the literature.

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J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 7057e7065
7061
planar transition state for the epoxidation of ethylene with dime-
thyldioxirane, presumably due to the stabilizing interaction of an
BnO
BnO
Cl
Cl
BnO
BnO
ii
i
O
oxygen lone pair with the
p
* orbital of the alkene in the spiro
transition state.27 In our study, the proposed mechanism is pre-
sented in Scheme 7 for the trans-stilbene epoxidation catalyzed by
ketone 18. The corresponding dioxirane of ketone 18 has two di-
astereomeric oxygens, and the equatorial oxygen is likely to be
sterically more accessible for olefin approach.4c If the reaction
proceeds via a spiro mode, (R,R)-stilbene oxide is expected to be
favored (spiro-1 vs spiro-2). In the present study, it is found that
(R,R)-stilbene oxide is produced predominantly, which supports
the spiro transition state proposed.
32
33
34
iii
R
BnO
OBn
35 R = CH2CH3
3. Conclusions
36 R = (CH2)10CH3
Scheme 6. (i) KOH (8.3 mmol), 18-crown-6 (20 mg), BnBr (4.1 mol), THF, 3 h, 90%; (ii)
OsO4 (t-BuOH)/Me3NO/CH2Cl2, 90%; (iii) NaIO4 (H2O)/EtOH/H2O, 95%; (iv) RCH2PPh3Br
(2 mmol), BuLi (2 mmol), THF, ꢀ78 ꢁC, 55%.
In this article we have reported a new backbone model for chiral
ketones from sugar easily prepared from commercially available
methyl
a-D-mannopyranoside in four steps with high chemical
yields. These are the first mannose-derived ketones to be described.
The general structure of our ketones, methyl 2-O-alkyl-4,6-O-(R)-
benzylidene-a-D-arabino-hexopyranoside-3-ulose, contains as
a point of structural modification the tunable alkoxy group on po-
sition 2 of the sugar moiety, being the steric blocker.
( )10
O
O
BnO
OBn
BnO
OBn
The epoxidation reaction of trans- and trisubstituted olefins
with these ketones were performed with satisfactory chemical
yields (60e80%) and the percentages of recovery without loss of
activity of ketones were good (70%), enabling their use in various
catalytic cycles.
With regard to stereochemical yield, firstly we observed that
these new ketones possess the same alkene sterofacial differenti-
ation, which is opposite to the other sugar ketones previously de-
scribed by us,17,18 displaying enantioselectivity from low to good
(30e90% ee). Secondly, we studied the effect of the size of the steric
blocker on the stereochemical results of the process and we found
that enantioselectivity was sensitive and decreased with the size of
the steric blocker. Ketone 18 with the least bulky alkoxy group
(OMe) displayed the best enantioselectivity (up to 90% ee).
The C-2 epimeric ketone, methyl 4,6-O-(R)-benzylidene-2-O-
37
38
Fig. 6. New chiral dialkyl epoxide.
Table 4
Catalytic asymmetric epoxidation of alkenes (33, 34) in the presence of ketone 18a
Entry
Ketone
Alkene
Yieldb (%)
eec (%)
Configuration
1
2
18
18
35
36
61
53
53
17
(ꢀ)d
(ꢀ)d
a
Conditions: substrate (1 equiv), ketone (1 equiv), Oxone (2 equiv), NaHCO3
(6 equiv), DMEeaqueous EDTA (4ꢂ10ꢀ4 M) (1.2:1), 0 ꢁC.
b
Yields after column chromatography.
Enantiomeric excesses were determined by 1H NMR spectroscopy of the
c
epoxide products directly with shift reagent (þ)-Eu(hfc)3.
d
The absolute configuration was not determined.
methyl-a-D-ribo-hexopyranoside-3-ulose, 23, as well as the 2-
deoxy-derivative 24, as catalysts did not improve the ee’s.
In summary the choice of the ketone with an alkoxy steric
sensor of suitable size (OMe) and with the appropriate sugar con-
figuration (arabino) would provide high values of stereoselectivity
in the epoxidation of trans- and trisubstituted 1,2-diarylalkenes.
Preliminary assays of epoxidation reaction of dialkyl olefins with
this ketone gave moderate values of ee’s.
It is of interest to understand the possible geometry of the
transition state in dioxirane epoxidations. A spiro transition state
was proposed by Baumstark,26 based on the observation that cis-
olefins were more reactive than the corresponding trans-olefins for
epoxidation using dimethyldioxirane. In addition, computational
studies showed that the spiro transition state is favored versus the
H3C
O
4. Experimental
4.1. General
O
O
O
O
Ph
O
Ph
(R)
O
O
(R)
H3C
Ph
Melting points were obtained on a Stuart Melting Point Appa-
ratus 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
Spiro-1
Favored
H3C
O
O
O
O
O
Ph
O
Ph
O
(S)
O
H3C
(S)
Ph
per million on the
d scale relative to TMS. COSY, DEPT, HSQC, and
NOESY experiments were performed to assign the signals in the
NMR spectra. Silica gel 60 (230e400 ASTM) was used for all flash
column chromatography. All solvents were reagent or analysis
grade. Evaporations were conducted under reduced pressure. Re-
actions were monitored using thin-layer chromatography (TLC) on
Spiro-2
Disfavored
Scheme 7. The spiro transition states for trans-stilbene epoxidation catalyzed by
ketone 18.

ꢀ
J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 7057e7065
7062
aluminum-backed plates coated with Merck Kieselgel 60 F254 silica
gel. Compounds were visualized by UVA radiation at a wavelength
of 254 nm or stained by exposure to an ethanolic solution of
phosphomolybdic acid and subsequent heating. Enantiomeric ex-
cesses were determined by proton nuclear magnetic resonance
spectroscopy in the presence of europium (III) tris[3-(hepta-
fluoropropylhydroxymethylene)-(þ)-camphorate] as the chiral
shift reagent. Absolute configuration was assigned by comparison
with the signal shifts reported in the literature for epoxides
(25e31).4b,9,23e28 The absolute configuration was also determined
by comparing the sign of optical rotations with the reported
ones.4b,10,28e30
silica gel with (4:1 hexaneeethyl acetate) to give compound 16
(0.17 g, 50%) as a white solid; [Found: C, 62.62; H, 7.45. C17H24O6
requires C, 62.95; H, 7.46%]; mp 87e88 ꢁC; ½a D25
þ47.1 (c 1.0,
ꢃ
CH2Cl2); 1H NMR (500 MHz, CDCl3):
d 7.51e7.32 (5H, m, Ph), 5.57
(1H, s, PhCH), 4.69 (1H, d, J1,2 1.1 Hz, H-1), 4.24 (1H, dd, J5,6e 4.7 Hz,
J6e,6a 10.2 Hz, H-6e), 4.00 (3H, m, H-3, H-4, H-6a), 3.63 (1H, dd, J1,2
1.2 Hz, J2,3 4 Hz, H-2), 4.00 (1H, dt, J3,4¼J3,OH 9.5 Hz, J2,3 4.0 Hz, H-3),
3.79 [4H, m, H-4, H-5, H-6a, OCH(CH3)2], 3.73 (1H, dd, J1,2 1.2 Hz, J2,3
4.0 Hz, H-2), 3.38 (3H, s, OCH3), 2.28 (1H, d, J3,OH 8.9 Hz, OH), 1.22
[6H, m, OCH(CH3)2]; 13C NMR (125 MHz, CDCl3):
d 137.4e126.3 (Ph),
102.1 (PhCH), 100.5 (C-1), 79.6 (C-2), 77.2 [OCH(CH3)2], 73.0 (C-3),
68.8 (C-3), 68.2 (C-6), 63.2 (C-5), 54.8 (OCH3), 22.9e22.1
[OCH(CH3)2]; MS (CI): m/z 325 (80%, [MþH]þ); HRMS (CI): [MþH]þ,
found 325.1657. C17H25O6 requires 325.11651.
4.2. Methyl 4,6-O-(R)-benzylidene-2-O-methyl-a-D-
altropyranoside 1219
4.3.4. Methyl
4,6-O-(R)-benzylidene-2-O-isobuyl-a-D-mannopyr-
To a sodium methoxide (9.0 mmol) in methanol (15 mL) solution
methyl 2,3-anhydro-4,5-O-(R)-benzylidene- -allopyranoside 11
anoside (17). The syrup was purified by flash chromatography on
silica gel with (5:1 hexaneeethyl acetate) to give compound 17
a-D
was added (3.0 mmol). The mixture was heated at reflux overnight.
The reaction mixture was cooled at room temperature, poured into
water (50 mL), and extracted with dichloromethane (3ꢂ20 mL). The
organic extracts were dried (MgSO4), filtered, and evaporated to dry-
ness. Yield: 0.8 g (90%). The organic compound isolated was employed
without purification in the oxidation reaction (see Section 4.4).
(0.2 g, 60%) as a pale yellow syrup; ½a D25
ꢃ
ꢀ3.6 (c 0.5, CH2Cl2); 1H
NMR (500 MHz, CDCl3): d 7.36e7.26 (5H, m, Ph), 5.58 (1H, s, PhCH),
4.77 (1H, d, J1,2 1.2 Hz, H-1), 4.25 (1H, dd, J5,6e 5.3 Hz, J6e,6a 9.9 Hz, H-
6e), 4.06 (1H, dt, J2,3 3.9 Hz, J3,4¼J3,OH 9.4 Hz, H-3), 3.78 (3H, m, H-4,
H-5, H-6a), 3.63 (1H, dd, J1,2 1.2 Hz, J2,3 4.0 Hz, H-2), 3.43 [1H, m,
OCHAHBCH(CH3)2], 3.39 (3H, s, OCH3), 3.31 [1H, m,
OCHAHBCH(CH3)2], 2.38 (1H, d, J3,OH 9.7 Hz, OH), 1.92 [1H, m,
OCH2CH(CH3)2], 0.94 [6H, m, OCH2CH(CH3)2]; 13C NMR (125 MHz,
4.3. Synthesis of methyl 2-O-alkyl-4,6-O-(R)-benzylidene-
a-D-
mannopyranosides 14e1721
CDCl3): d 137.3e126.3 (Ph), 102.1 (PhCH), 98.9 (C-1), 79.6 (C-4), 79.1
(C-2), 78.4 [OCH2CH(CH3)2], 68.8 (C-6), 68.5 (C-3), 63.2 (C-5), 54.9
(OCH3), 28.7 [OCH2CH(CH3)2], 19.2 [OCH2CH(CH3)2]; MS (CI): m/z
339 (50%, [MþH]þ); HRMS (CI): [MþH]þ, found 339.1808. C18H27O6
requires 339.1807.
To a solution of methyl 4,6-O-(R)-benzylidene-a-D-mannopyr-
anoside 13 (1.0 mmol) in dry CH2Cl2 (10 mL) were added tetrabu-
tylammonium hydrogen sulfate catalytic (20e25 mg), sodium
hydroxide (1.5 mmol), and the appropriate alkyl iodide (1.5 mmol).
The reaction mixture was stirred and heated at 45 ꢁC for 3 h. Then
diluted with dichloromethane (20 mL), washed with water, dried
(MgSO4), filtered, and the filtrate evaporated to dryness.
4.4. Synthesis of methyl 2-O-alkyl-4,6-O-(R)-benzylidene-
arabino-hexopyranoside-3-uloses 18e22
a-D-
To a solution of the appropriate methyl 2-O-alkyl-4,6-O-(R)-
benzylidene- -hexopyranoside 12, 14e17 (1.0 mmol) in dry
4.3.1. Methyl 4,6-O-(R)-benzylidene-2-O-ethyl-
a
-
D
-mannopyrano-
a-D
side (14)31. The syrupobtainedwaspurifiedbyflashchromatography
dichloromethane (20 mL) were added pyridinium chlorochromate
ꢁ
on silica gel (2:1 hexaneeethyl acetate) to give compound 14 (0.15 g,
(2.0 mmol) and molecular sieves 3 A (5 g). The reaction mixture was
50%) as a pale yellow syrup; 1H NMR (500 MHz, CDCl3):
d
7.36e7.33
stirred overnight at room temperature. After TLC showed that the
reaction was finished, the mixture was diluted with diethylether
(20 mL) and filtered through a column with silicaeCaSO4 (10%).
(5H, m, Ph), 5.57 (1H, s, PhCH), 4.77 (1H, d, J1,2 1.0 Hz, H-1), 4.26 (1H,
dd, J5,6e 4.7 Hz, J6e,6a 10.1 Hz, H-6e), 4.03 (1H, dt, J2,3 4.0 Hz, J3,4¼J3,OH
9.4 Hz, H-3), 3.80 (4H, m, H-4, H-5, H-6a, OCHAHBCH3), 3.66 (1H, dd,
J1,2 1.3 Hz, J2,3 4.0 Hz, H-2), 3.61 (1H, m, OCHAHBCH3), 3.39 (3H, s,
4.4.1. Methyl 4,6-O-(R)-benzylidene-2-O-methyl-a-D-arabino-hexo-
OCH3), 2.39 (1H, d, J3,OH 8.9 Hz, OH),1.26 (1H, t, J 7.0 Hz, OCH2CH3); 13
C
pyranoside-3-ulose (18)22. The filtrate was evaporated to dryness to
NMR (125 MHz, CDCl3): d 137.3e126.3 (Ph), 102.1 (PhCH), 99.2 (C-1),
give compound 18 (0.25 g, 84%) as a pale yellow syrup; 1H NMR
79.5 (C-4), 79.8 (C-2), 68.7 (C-6), 68.3 (C-3), 67.2 (OCH2CH3), 63.2 (C-
5), 54.4 (OCH3), 15.2 (OCH2CH3); MS (CI): m/z 311 (90%, [MþH]þ);
HRMS (CI): [MþH]þ, found 311.1495. C16H23O6 requires 311.1495.
(500 MHz, CDCl3): d 7.52e7.36 (5H, m, Ph), 5.60 (1H, s, PhCH), 4.99
(1H, d, J1,2 1.0 Hz, H-1), 4.80 (1H, d, J4,5 9.7 Hz, H-4), 4.38 (1H, dd,
J5,6e 4.7 Hz, J6e,6a 10.1 Hz, H-6e), 4.10 (1H, dt, J5,6e 4.7 Hz, J4,5¼J5,6a
9.8 Hz, H-5), 4.00 (1H, t, J5,6a¼J6e,6a 10.2 Hz, H-6a), 3.66 (1H, d, J1,2
1.0 Hz, H-2), 3.42 (3H, s, OCH3), 3.40 (3H, s, OCH3); 13C NMR
4.3.2. Methyl 2-O-benzyl-4,6-O-(R)-benzylidene-a-D-mannopyrano-
side (15)31. The solid was purified by flash chromatography on silica
gel (6:1 hexaneeethyl acetate) to give compound 15 (0.17 g, 45%) as
(125 MHz, CDCl3): d 198.1 (C]O), 136.5e126.3 (Ph), 103.1 (C-1),
102.2 (PhCH), 85.2 (C-2), 80.9 (C-4), 69.3 (C-6), 66.3 (C-5), 58.0
(OCH3), 55.1 (OCH3); MS (CI): m/z 295 (50%, [MþH]þ). HRMS (CI):
[MþH]þ, found 295.1183. C15H19O6 requires 295.1182.
a white solid; 1H NMR (500 MHz, CDCl3):
d 7.35e7.26 (10H, m, 2Ph),
5.57 (1H, s, PhCH), 4.76 (1H, d, Jgem 11.6 Hz, OCHAHBPh), 4.75 (1H, d,
J1,2 1.4 Hz, H-1), 4.70 (1H, d, Jgem 11.6 Hz, OCHAHBPh), 4.26 (1H, dd,
J5,6e 4.4 Hz, J6e,6a 9.8 Hz, H-6e), 4.08 (1H, m, H-3), 3.91 (1H, t,
J5,6e¼J6e,6a 9.8 Hz, H-6a), 3.81 (3H, m, H-2, H-4, H-5), 3.36 (3H, s,
OCH3), 2.36 (1H, d, J3,OH 8.5 Hz, OH); 13C NMR (125 MHz, CDCl3):
4.4.2. Methyl
4,6-O-(R)-benzylidene-2-O-ethyl-a-D-arabino-hexo-
pyranoside-3-ulose (19). The filtrate was evaporated to dryness to
give compound 19 (0.2 g, 65%) as a pale yellow syrup; ½a D25
þ71.4 (c
ꢃ
d
137.7e126.3 (2Ph), 102.1 (PhCH), 99.4 (C-1), 79.5 (C-2), 78.5 (C-4),
1.0, CH2Cl2); 1H NMR(500 MHz, CDCl3):
d 7.52e7.35 (5H, m, Ph),
73.7 (OCH2Ph), 68.8 (C-6), 68.7 (C-3), 63.3 (C-5), 54.9 (OCH3); MS
(CI): m/z 373 (60%, [MþH]þ); HRMS (CI): [MþH]þ, found 373.1639.
C21H25O6 requires 373.1651.
5.61 (1H, s, PhCH), 4.98 (1H, d, J1,2 1.0 Hz, H-1), 4.83 (1H, d, J4,5
9.7 Hz, H-4), 4.38 (1H, dd, J5,6e 4.6 Hz, J6e,6a 10.2 Hz, H-6e), 4.08 (1H,
dt, J5,6e 4.6 Hz, J4,5¼J5,6a 10.0 Hz, H-5), 4.00 (1H, t, J5,6a¼J6e,6a 10.2 Hz,
H-6a), 3.77 (1H, d, J1,2 1.0 Hz, H-2), 3.57 (2H, m, OCH2CH3), 3.40 (3H,
s, OCH3), 1.24 (3H, t, J 7.0 Hz, OCH2CH3); 13C NMR (125 MHz, CDCl3):
4.3.3. Methyl 4,6-O-(R)-benzylidene-2-O-isopropyl-
a-D-mannopyr-
anoside (16). The solid was purified by flash chromatography on
d
198.5 (C]O), 136.1e126.3 (Ph), 103.3 (C-1), 102.1 (PhCH), 83.6

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J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 7057e7065
7063
(C-2), 80.9 (C-4), 69.3 (OCH2CH3), 66.3 (C-6), 66.2 (C-5), 55.1
4.6. Synthesis of methyl 4,6-O-(R)-benzylidene-2-deoxy-
a-D-
(CH3O), 15.1 (OCH2CH3); MS (CI): m/z 309 (100%, [MþH]þ). HRMS
erythro-hexopyranoside-3-ulose 2432
(CI): [MþH]þ, found 309.1338. C16H21O6 requires 309.1336.
To a solution of methyl 2,3-anhydro-4,6-O-(R)-benzylidene a-D-
4.4.3. Methyl 2-O-benzyl-4,6-O-(R)-benzylidene-
a
-
D
-arabino-hexo-
allopyranoside 11 (1.0 mmol) in THF (20 mL) was added LiAlH4
(3.0 mmol). The mixture was heated at reflux for 8 h and cooled to
room temperature. A saturated solution of sodium sulfate was
added (3ꢂ0.3 mL), filtered and the filtrate was evaporated to dry-
ness yielding compound 24 (0.25 g, 70%) as a white solid, that was
used in the epoxidation reaction (see Section 4.4) without purifi-
pyranoside-3-ulose (20). The filtrate was evaporated to dryness to
give compound 20 (0.3 g, 80%) as a white solid; [Found: C, 68.02; H,
6.22. C21H23O6 requires C, 68.10; H, 5.99%]; mp 105e106 ꢁC; ½a D25
ꢃ
þ48.1 (c 0.5, CH2Cl2); 1H NMR (500 MHz, CDCl3)
d 7.71e7.66 (10H,
m, 2Ph), 5.60 (1H, s, PhCH), 4.99 (1H, d, J1,2 1.1 Hz, H-1), 4.87 (1H, d,
J4,5 9.6 Hz, H-4), 4.67 (1H, d, Jgem 11.8 Hz, OCHAHBPh), 4.50 (1H, d,
Jgem 11.8 Hz, OCHAHBPh), 4.38 (1H, dd, J5,6e 4.7 Hz, J6e,6a 10.2 Hz, H-
6e), 4.10 (1H, dt, J5,6e 4.6 Hz, J4,5¼J5,6a 9.8 Hz, H-5), 3.99 (1H, t,
J5,6a¼J6e,6a 9.9 Hz, H-6a), 3.87 (1H, d, J1,2¼1.3 Hz, H-2), 3.38 (3H, s,
cation; 1H NMR (500 MHz, CDCl3):
d 7.49e7.33 (5H, m, Ph), 5.56
(1H, s, PhCH), 5.11 (1H, dd, J1,2a 4.7 Hz, H-1), 4.35 (1H, dd, J5,6e
4.8 Hz, J6e,6a 10.3 Hz, H-6e), 4.35 (1H, dd, J4,5 9.9 Hz, 4J2a,4 1.1 Hz, H-
4), 4.12 (1H, dt, J5,6e 4.8 Hz, J4,5¼J5,6a 10.0 Hz, H-5), 3.89 (1H, t,
J5,6a¼J6e,6a 10.5 Hz, H-6a), 3.36 (3H, s, OCH3), 2.81 (1H, ddd, J1,2a
OCH3); 13C NMR (125 MHz, CDCl3)
d 198.0 (C]O), 136.5e126.3
4
(2Ph), 103.1 (C-1), 102.1 (PhCH), 82.6 (C-2), 81.0 (C-4), 72.2
(OCH2Ph), 69.3 (C-6), 66.3 (C-5), 55.0 (OCH3); MS (CI): m/z 371 (30%,
[MþH]þ); HRMS (CI): [MþH]þ, found 371.1486. C21H22O6 requires
371.1495.
4.7 Hz, J2a,4 1.1 Hz, Jgem 14.5 Hz, H-2ax), 2.65 (1H, d, J1,2e 0.6, Jgem
14.5 Hz, H-2e); MS (EI): m/z 264 (60%, [M]þ$).
4.7. Reaction with alkyl triphenylphosphonium bromide
4.4.4. Methyl
4,6-O-(R)-benzylidene-2-O-isopropyl-
a
-
D
-arabino-
To a stirred solution of the appropriate alkyl triphenylphos-
phonium bromide (2 mmol) in THF (10 mL) under argon at
ꢀ78 ꢁC, was added butyllithium (2 mmol) dropwise and stirred
for 1 h at ꢀ40 ꢁC. Then a solution of ketone 31 (1 mmol) in THF
(5 mL) was added and kept with stirring at ꢀ40 ꢁC for 2 h. After,
the reaction mixture was diluted with ethyl acetate (20 mL) and
quenched with saturated ammonium chloride solution (15 mL).
The organic layer was dried (MgSO4), filtered, and evaporated to
dryness.
hexopyranoside-3-ulose (21). The filtrate was evaporated to dryness
to give compound 21 (0.25 g, 77%) as a pale yellow syrup; ½a D25
ꢃ
þ53.4 (c 1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d 7.50e7.26 (5H,
m, Ph), 5.61 (1H, s, PhCH), 4.91 (1H, d, J1,2 1.0 Hz, H-1), 4.85 (1H, d,
J4,5 9.6 Hz, H-4), 4.37 (1H, dd, J6e,6a 10.2 Hz, J5,6e 4.4 Hz, H-6e), 4.08
(1H, dt, J5,6e 4.4 Hz, J4,5¼J5,6a 10.0 Hz, H-5), 4.00 (1H, t, J4,5¼J5,6a
10.0 Hz, H-6a), 3.86 (1H, d, J1,2 1.4 Hz, H-2), 3.37 [1H, m, J 6.2 Hz,
CH(CH3)2], 3.39 (3H, s, OCH3), 1.19 [6H, m, OCH(CH3)2]; 13C NMR
(125 MHz, CDCl3):
d 198.8 (C]O), 139.6e126.4 (Ph), 103.8 (C-1),
102.1 (PhCH), 81.5 (C-2), 80.9 (C-4), 76.7 [OCH(CH3)2], 69.3 (C-6),
66.3(C-5), 55.0 (OCH3), 22.8, 21.5 [OCH(CH3)2]; MS (CI): m/z 323
(60%, [MþH]þ). HRMS (CI): [MþH]þ, found 323.1486. C17H23O6 re-
quires 323.1495.
4.7.1. 1-Benzyloxy-2-benzyloxymethyl-pent-2-ene (35). A syrup was
obtained after flash chromatography using a mixture of hex-
aneeethyl acetate (15:1) as eluent. (0.16 g, 55%). 1H NMR (500 MHz,
CDCl3):
d 7.37e7.29 (10H, m, 2Ph), 5.74 (1H, t, J 7.4 Hz, EtCH), 4.53,
4.52 (4H, 2br s, 2CH2OPh), 4.14, 4.09 (4H, 2br s, 2OCH2C), 2.17 (2H, q,
4.4.5. Methyl 4,6-O-(R)-benzylidene-2-O-isobutyl-
a-
D-arabino-hexo-
J 7.4 Hz, CH2), 1.04 (3H, t, J 7.4 Hz, CH3); 13C NMR (125 MHz, CDCl3):
pyranoside-3-ulose (22). The filtrate was evaporated to dryness to
d 138.6e127.5 (2Ph), 138.63 (2OCH2C), 132.4 (EtCH), 72.2, 72.1
give compound 22 (0.28 g, 83%) as a pale yellow syrup; ½a D25
ꢃ
þ70.9 (c
(2OCH2Ph), 72.9, 65.4 (2OCH2C), 20.9 (CH2), 14.3 (CH3); MS (CI): m/z
297 (20%, [MþH]þ). HRMS (CI): [MþH]þ, found 297.1863. C20H25O2
requires 297.1555.
1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d 7.52e7.36 (5H, m, Ph), 5.6
(1H, s, PhCH), 4.99 (1H, d, J1,2 1.2 Hz, H-1), 4.78 (1H, d, J4,5 9.6 Hz, H-4),
4.37 (1H, dd, J5,6e 4.6 Hz, J6e,6a 10.0 Hz, H-6e), 4.08 (1H, dt, J5,6e 4.6 Hz,
J4,5¼J5,6a 9.6 Hz, H-5), 4.08 (1H, t, J4,5¼J5,6a 10.0 Hz, H-6a), 3.74 (1H, d,
J1,2 1.2 Hz, H-2), 3.40 (3H, s, OCH3), 3.26 [2H, m, OCH2CH(CH3)2],1.89
[1H, m, OCH2CH(CH3)2], 0.92 [6H, m, OCH2CH(CH3)2]; 13C NMR
4.7.2. 1-Benzyloxy-2-benzyloxymethyl-tetradec-2-ene (36). A syrup
was obtained after flash chromatography using a mixture of hex-
aneeethyl acetate (40:1) as eluent. (0.23 g, 55%).
d 7.39e7.29 (10H,
(125 MHz, CDCl3):
d
198.3 (C]O), 136.5e126.3 (Ph), 103.2 (C-1),
m, 2Ph), 5.74 (1H, t, J 7.4 Hz, CH3(CH2)10CH), 4.45 (4H, br s,
2CH2OPh), 4.14, 4.09 (4H, 2br s, 2OCH2C), 2.12 (2H, c, J 7.4 Hz, CH2),
1.42e1.29 [m, 18H, (CH2)9], 0.92 (3H, t, J 7.1 Hz, CH3); 13C NMR
102.2 (PhCH), 83.9 (C-2), 81.0 (C-4), 77.2 [OCH2CH(CH3)2], 69.4 (C-6),
66.3 (C-5), 55.0 (OCH3), 28.3 [OCH2CH(CH3)2],19.1 [OCH2CH(CH3)2];
MS (CI): m/z 337 (10%, [MþH]þ). HRMS (EI): [M]þ$, found 336.1574.
C18H24O6 requires 336.1573.
(125 MHz, CDCl3):
d 138.6e127.5 (2Ph), 138.63 (2OCH2C),132.8
[CH3(CH2)10CH], 72.2, 71.9 (2OCH2Ph), 72.9, 65.4 (2OCH2C),
31.9e27.6 [(CH2)9], 20.9 (CH2CH), 14.1 (CH3); MS (EI): m/z 422 (30%,
[M]þꢄ). HRMS (EI): [M]þꢄ, found 422.3183. C29H42O2 requires
422.3185.
4.5. Synthesis of methyl 4,6-O-(R)-benzylidene-2-O-methyl-a-
D
-ribo-hexopyranoside-3-ulose 2323
To a solution of methyl 4,6-O-(R)-benzylidene-2-O-methyl-
a-
D-
4.8. General procedure for the enantioselective epoxidation
arabino-hexopyranoside-3-ulose 18, (1.0 mmol) in ethanol (60 mL)
was added triethylamine (3.0 mmol). The reaction mixture was
heated at reflux for 5 h. Then, the solution was poured into water
(150 mL) and extracted with dichloromethane (3ꢂ20 mL). The or-
ganic layer was dried (MgSO4) and evaporated to dryness to give
compound 23 (0.28 g, 70%) as a white solid; 1H NMR (500 MHz,
To a solution of the alkene (25e33) (0.2 mmol) in 1,2-
dimethoxyethane (5 mL) were added chiral ketones 18e24
(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 4ꢂ10ꢀ4 M (2 mL), and NaHCO3
CDCl3):
d
7.50e7.33 (5H, m, Ph), 5.53 (1H, s, PhCH), 5.19 (1H, dd, J1,2
(1.2 mmol) was dissolved in a solution of Na2EDTA 4ꢂ10ꢀ4
M
4.3 Hz, 4J 0.3 Hz, H-1), 4.39 (1H, dd, J5,6e 4.7 Hz, J6e,6a 10.3 Hz, H-6e),
(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 (2e3 h), and
4
4.24 (1H, dd, J4,5 9.8 Hz, J2,4 1.4 Hz, H-4), 4.06 (1H, dt, J5,6e 4.7 Hz,
J4,5¼J5,6a 10.0 Hz, H-5), 4.02 (1H, dd, J1,2 4.2 Hz, 4J2,4 1.4 Hz, H-2), 3.90
(1H, t, J5,6a¼J6e,6a 10.3 Hz, H-6a), 3.54 (3H, s, OCH3), 3.44 (3H, s,
OCH3); MS (CI): m/z 295 (60%, [MþH]þ).

ꢀ
J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 7057e7065
7064
then diluted with water (10 mL). The solution was extracted with
dichloromethane (3ꢂ10 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 methylindene), to afford the pure alkene
epoxide. The eluent was changed to a mixture of hexaneeethyl
acetate (2.5:1 for ketones 18 and 19, 4.5:1 for 20, 4:1 for 21 and 22,
1:3.5 for 23, 1.5:1 for 24) and the chiral ketone was recovered in
70e75%.
(EI): m/z 438 (20%, [M]þꢄ). HRMS (EI): [M]þꢄ, found 431.3130.
C29H42O3 requires 438.3134.
Acknowledgements
We thank the Junta de Andalucía and the Ministerio de Educa-
cion (Spain), and the FEDER program, for financial support (P06-
ꢀ
FQM-01885 and CTQ2007-61185). I.P. thanks Junta de Andalucía
for a predoctoral grant. C.P.-N. thanks Junta de Andalucía for fi-
nancial support (P09-AGR4597) and Ministerio de Asuntos Exteri-
4.8.1. (þ)-(1R,2R)-trans-Stilbene oxide10,28
.
1H NMR (500 MHz,
ꢀ
ores y Cooperacion (AECID A/023577/09). The help of Dr. M. Angulo
in 1H NMR spectra recording is gratefully acknowledged.
CDCl3):
d 7.4e7.3 (10H, m, 2Ph), 3.88 [2H, s, 2CH(O)].
4.8.2. (þ)-(1R,2R)-trans-
a
-Methylstilbene
oxide10,29
.
1H
NMR
Supplementary data
(500 MHz, CDCl3):
(3H, s, CH3).
d 7.4e7.3 (10H, m, 2Ph), 3.96 [1H, s, CH(O)], 1.46
These data include 1H and 13C spectra of the precursors (14e17),
the chiral ketones (18e24), the new alkyl olefins (35 and 36) and
their epoxides (37 and 38). 1H NMR spectra used for the de-
termination of enantiomeric excesses in the epoxidation reactions
of alkenes are also included. Supplementary data associated with
this article can be found, in the online version, at doi:10.1016/
j.tet.2011.07.014. These data include MOL files and InChIKeys of the
most important compounds described in this article.
4.8.3. (ꢀ)-(R)-Triphenylethylene oxide10,28,29
.
1H NMR (500 MHz,
d 7.4e7.1 (15H, m, 3Ph), 4.32 [1H, s, CH(O)].
CDCl3):
4.8.4. (þ)-(R)-1,1-Dimethyl-2-phenylethylene oxide4b,17
.
1H NMR
(500 MHz, CDCl3):
d 7.4e7.3 (5H, m, Ph), 3.85 [1H, s, CH(O)], 1.47
(3H, s, CH3), 1.06 (3H, s, CH3).
4.8.5. (þ)-(1R,2R)-1-Phenylcyclohexene
oxide9,28,29
.
1H
NMR
References and notes
(500 MHz, CDCl3): d 7.4e7.3 (5H, m, Ph), 3.5 [1H, m, CH(O)], 2.3e2.2
(1H, m, CHAHB), 2.2e2.0 (1H, m, CHAHB), 2.0e1.9 (2H, m, CH2),
1.5e1.4 (1H, m, CHAHB), 1.3e1.2 (1H, m, CHAHB).
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8201e8205; (d) Furutani, T.; Imashiro, R.; Hatsuda, M.; Seki, M. J. Org. Chem.
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1H NMR (500 MHz,
d 7.5e7.2 (9H, m, 2Ph), 4.33 [1H, dd, J 0.45, 1.3 Hz, CH(O)],
CDCl3):
3.57 (1H, d, Jgem 17.7 Hz, CHAHB), 3.41 (1H, d, Jgem 17.7 Hz, CHAHB).
4.8.7. (þ)-(1R,2R)-2-Methylindene oxide24,30
.
1H NMR (500 MHz,
d 7.4e7.2 (4H, m, Ar), 4.04 [1H, s, CH(O)C(CH3)CH2], 3.17
CDCl3):
3. Curci, R.; Fiorentino, M.; Serio, M. R. J. Chem. Soc., Chem. Commun. 1984,
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React.; John Wiley & Sons Inc.: New York, NY, 2007; 69; ISBN 978-0-470-22397-
4.8.8. Dihydronaphtalene oxide28,30 1H NMR (500 MHz, CDCl3):
.
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, 3.0 Hz, CH(O)CHCH2], 2.80 (1H, m), 2.55 (1H, dd, J 6.0,
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0, 1e346; (e) Adam, W.; Saha-Moller, C. R.; Zhao, C.-G. Dioxirane Epoxidation of
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0-471-27448-3, 219e516.
4.8.9. (ꢀ)-(R)-Styrene oxide4b,24,33
.
1H NMR (500 MHz, CDCl3):
7.4e7.3 (5H, m, Ph), 3.83 [1H, dd, Jcis 4.1 Hz, Jtrans 2.5 Hz, PhCH(O)
5. Bortolini, O.; Fantin, G.; Fogagnolo, M.; Mari, L. Tetrahedron 2006, 62,
4482e4490.
d
ꢀ
6. (a) Solladie-Cavallo, A.; Bouret, L. Tetrahedron: Asymmetry 2000, 11, 935e941;
CHAHB], 3.12 [1H, dd, J 5.8 Hz, Jcis 4.1 Hz, PhCH(O)CHAHB], 2.77 [1H,
dd, J 5.8 Hz, Jtrans 2.5 Hz, PhCH(O)CHAHB].
ꢀ
(b) Solladie-Cavallo, A.; Jierry, L.; Bouerat, L.; Taillasson, P. Tetrahedron: Asym-
metry 2001, 12, 883e891.
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8. Adam, W.; Saha-Moller, C. R.; Zhao, C.-G. Tetrahedron: Asymmetry 1999, 10,
2749e2755.
4.8.10. (ꢀ)-1-Benzyloxy-2-benzyloxymethyl-pent-2-ene
oxide
37. ½a D
ꢃ
ꢀ1.3 (c 0.5, CH2Cl2); 1H NMR (500 MHz, CDCl3):
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d
7.26e7.35 (10H, m, 2Ph), 4.59, 4.57, 4.54, 4.49 (4d, 4H, Jgem
12.0 Hz, 2OCH2Ph), 3.72, 3.71, 3.64, 3.60 [4d, 4H, Jgem 10.7 Hz,
2OCH2C(O)], 2.93 [1H, t, J 6.6 Hz, EtC(O)H], 1.56 (2H, m, CH2), 1.05
(3H, t, J 7.5 Hz, CH3); 13C NMR (125 MHz, CDCl3):
d 138.2e127.6
(2Ph), 138.1 [2OCH2C(O)], 73.5, 73.4 (2OCH2Ph), 71.0, 68.4
[2OCH2C(O)], 61.6 [EtCH(O)], 21.3 (CH2), 10.7 (CH3); MS (CI): m/z
313 (15%, [MþH]þ). HRMS (CI): [MþH]þ, found 313.1802. C20H25O3
requires 313.1804.
4.8.11. (ꢀ)-1-Benzyloxy-2-benzyloxymethyl-tetradec-2-ene
oxide
7.29e7.39
38. ½a D
ꢃ
ꢀ1.7 (c 0.5, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d
14. Boutureira, O.; McGouran, J. F.; Stafford, R. L.; Emmerson, D. P. G.; Davis, B. G.
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(10H, m, 2Ph), 4.64e4.51, (m, 4H, 2OCH2Ph), 3.74, 3.73, 3.67, 3.63
[4d, 4H, Jgem 10.7 Hz, 2OCH2C(O)], 2.93 [1H, t, J 6.6 Hz, CH2C(O)H],
2.49 [2H, m, CH2C(O)H], 1.48e1.29 [m, 18H, (CH2)9], 0.97 (3H, t, J
ꢀ
16. Recent contributions: (a) Vega-Perez, J. M.; Vega, M.; Blanco, E.; Iglesias-Guerra,
ꢀ
6.7 Hz, CH3); 13C NMR (125 MHz, CDCl3):
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138.63 (2OCH2C), 73.5, 71.1 (2OCH2Ph), 72.9, 68.2 (2OCH2C), 61.2
[CH3(CH2)10C(O)], 31.9e26.7 [(CH2)9], 22.7 (CH2CH), 14.2 (CH3); MS
ꢀ
~ꢀ

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J.M. Vega-Perez et al. / Tetrahedron 67 (2011) 7057e7065
7065
ꢀ
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