Stereoselective cyclopropanation of unsaturated acetals, using carbohydrates with d-gluco, l-rhamno and d-xylo configurations as chiral auxiliaries

Article abstract of DOI:10.1016/j.tetasy.2008.06.018

The stereoselective synthesis of (2-phenylcyclopropyl)methylidene acetals of sugar derivatives from methyl d-glucopyranoside, dodecyl N-acetyl-2-amino-2-deoxy-d-glucopyranoside, 1,2-O-isopropylidene-d-glucofuranose, methyl l-rhamnopyranoside and 1,2-O-isopropylidene-d-xylofuranose, as a chiral auxiliary, is described. The cyclopropanation reaction of the corresponding alkenylidene derivatives with CH₂I₂/ZnEt₂ took place with different stereoselectivity, depending on the configuration on the acetal carbon, the size of the acetal ring, the sugar configuration, the protecting group of the hydroxyl groups of the sugar and the substitution of the unsaturated system. The stereochemistry of the new stereogenic centres was then determined by acid hydrolysis of the cyclopropane moiety of the chiral auxiliary, which was also recovered.

Full text of DOI:10.1016/j.tetasy.2008.06.018

Tetrahedron: Asymmetry 19 (2008) 1720–1729
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Tetrahedron: Asymmetry
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Stereoselective cyclopropanation of unsaturated acetals, using carbohydrates
with D-gluco, L-rhamno and D-xylo configurations as chiral auxiliaries
*
*
José M. Vega-Pérez , Ignacio Periñán, Margarita Vega, Fernando Iglesias-Guerra
Departamento de Química Orgánica y Farmacéutica, 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:
The stereoselective synthesis of (2-phenylcyclopropyl)methylidene acetals of sugar derivatives from
methyl -glucopyranoside, dodecyl N-acetyl-2-amino-2-deoxy- -glucopyranoside, 1,2-O-isopropyli-
dene- -glucofuranose, methyl -rhamnopyranoside and 1,2-O-isopropylidene- -xylofuranose, as a chiral
auxiliary, is described. The cyclopropanation reaction of the corresponding alkenylidene derivatives with
CH2I2/ZnEt2 took place with different stereoselectivity, depending on the configuration on the acetal car-
bon, the size of the acetal ring, the sugar configuration, the protecting group of the hydroxyl groups of the
sugar and the substitution of the unsaturated system. The stereochemistry of the new stereogenic centres
was then determined by acid hydrolysis of the cyclopropane moiety of the chiral auxiliary, which was
also recovered.
Received 2 June 2008
Accepted 16 June 2008
Available online 12 July 2008
D
D
D
L
D
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
which the chiral auxiliary is linked to the olefin moiety via a glyco-
sidic bond, making the final separation difficult.
The importance of chiral, non-racemic cyclopropane moieties in
a number of natural and synthetic compounds, as well as in mole-
cules used to probe biological and pharmacological processes, has
led to intensive efforts to develop efficient methods for their con-
struction.1–10 Cyclopropanes have also been used as versatile syn-
thetic intermediates in the synthesis of more-functionalised
cycloalkanes and acyclic compounds.11–13
General methods have been used for building the cyclopropane
ring, and have been reviewed recently.5,11 The enantioselective
methylenative cyclopropanation methods for prochiral alkenes
can be classified in to two categories: (a) a synthetic strategy
involving the stereoselective addition of a methylene group to
In view of the scarcity of the antecedents found on the use of
sugars as chiral auxiliaries in the Simmons–Smith cyclopropana-
tion reaction, and because of our interest and experience in carbo-
hydrate chemistry,30–40 we proposed to use new carbohydrate
derivatives as chiral auxiliaries in the stereoselective synthesis of
cyclopropanes.
In this paper, we have studied the cyclopropanation reaction,
with the diiodomethane/diethylzinc system, of the double bond
of acetals of trans-cinnamaldehyde and
dehyde with different monosaccharide derivatives of alkyl
pyranoside, alkyl 2-acetamido-2-deoxy- -glucopyranoside, 1,2-O-
isopropylidene- -glucofuranose, alkyl rhamnopyranoside and 1,2-
O-isopropylidene- -xylofuranose. In order to find the substrate
a-methyl-trans-cinnamal-
D-gluco-
D
D
substituted allylic alcohols or
a,b-unsaturated carbonyl com-
D
pounds linked to different chiral auxiliaries;14–16 and (b) the use
of chiral catalysts in the enantioselective cyclopropanation of achi-
ral alkenes.17–20
giving the best yields and diastereomeric excesses, we have diver-
sified the chiral substrate, varying the carbohydrate configuration,
the protection of the hydroxyl groups and the size of the sugar and
acetal rings. The union of the olefin to the carbohydrate across an
acetal function allowed easy separation of the new chiral cyclopro-
pane fragment from the chiral auxiliary by acid hydrolysis.
Carbohydrates are used as tools in stereochemical differentia-
tions: as starting materials in the syntheses of interesting enantio-
pure compounds;21 as chiral templates in asymmetric
transformations;22 and as chiral auxiliaries in stereoselective syn-
theses.23,24 However, there are only few precedents of the use of
carbohydrates as chiral auxiliaries in the asymmetric cyclopropa-
nation reaction of olefins,25–29 the most important being those in
2. Results and discussion
The synthesis of the alkenylidene acetals, substrates of the
cyclopropanation reaction, has been carried out from commer-
cial compounds or compounds previously described by us.39,40
Methyl 2,3-O-(E-3-phenyl-2-propenylidene)-
sides 4 and 5 were obtained by reaction of methyl
anoside 1 and trans-cinnamaldehyde dimethyl acetal41 2 in good
a
-
L
-rhamnopyrano-
* Corresponding authors. Tel./fax: +34 95 4556737 (J.M.V.-P).
E-mail addresses: vega@us.es (J. M. Vega-Pérez), iglesias@us.es (F. Iglesias-
Guerra).
a-L-rhamnopyr-
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.06.018

J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 19 (2008) 1720–1729
1721
OMe
OMe
R
MeCN
CSA
Ph
OMe
OMe
O
O
R
+
HO
HO
HO
O
OH
O
2 R = H
3 R = Me
1
Ph
4 and 5 R = H
6 and 7 R = Me
Scheme 1.
yields, using the procedure described by Murphy et al.42 for the
formation of acetals using aldehyde dimethyl acetal as reagent.
Compounds 4 and 5 were obtained as a diastereomeric mixture
in a 1:1 ratio, as their NMR spectra showed. The same method
was used for the preparation of methyl 2,3-O-(E-2-methyl-3-phen-
and 29–37 were isolated and purified by flash chromatography
on silica gel. When the starting compounds were 9, 14 and 15,
the cyclopropanation reactions gave the lowest yields of com-
pounds 28, 25 and 26, which were detected by 1H NMR but not
isolated.
yl-2-propenylidene)-
a
Compounds 6 and 7 were obtained as a diastereomeric mixture
in a 2.2:1 ratio. The NMR spectra for mixtures 4 and 5, and 6 and
7 showed signals corresponding to the olefin moiety incorporated
a
-
L
-rhamnopyranosides 6 and 7 from 1 and
The diastereomeric excess (de) in each case was determined by
1H NMR, and is shown in Table 1. The starting propylidene acetals
have been classified into two groups, depending on the acetal ring
size. The first group comprises compounds with an acetal ring of
five members (Scheme 3); they are listed as a function of the car-
-methyl-trans-cinnamaldehyde dimethyl acetal39 3 (Scheme 1).
into the methyl
reaction.
a-L
-rhamnopyranoside molecule in the acetalation
bohydrate configuration:
a-L-rhamnopyranose for compounds 12
and 13, and -glucofuranose for compounds 8, 9, 16 and 17.
a-D
Compounds 4–11 were transformed into their O-benzyl deriva-
tives 12–19 with benzyl bromide and 18-crown-6 as a catalyst
(Scheme 2). The two diastereoisomers 12 and 13, obtained from
the mixture of 4 and 5, were separated by column chromatogra-
phy. Compounds 14 and 15 were obtained as two diastereoisomers
from a mixture of 6 and 7, and were separated by column chroma-
tography. In each case, 2D-NOESY experiments established, at the
acetal carbon, an (S)-configuration for the major isomers 12 and
14, and an (R)-configuration for the minor isomers 13 and 15.
The cyclopropanation reactions of compounds 8–22 were car-
ried out using the CH2I2/ZnEt2 system as a reagent and dichloro-
methane as a solvent (Schemes 3 and 4). Compounds 23, 24, 27
The second group comprises compounds with acetal ring of six
members (Scheme 4); they are also listed in the order of the carbo-
hydrate configuration:
a-D-glucopyranose for compounds 10, 11
and 18–20, and -xylofuranose for compounds 21 and 22. Within
a-D
the two groups, the compounds differ in the acetal carbon config-
uration, in the degree of substitution of the double bond and in the
presence of a free hydroxyl group or a blocked hydroxyl group.
With regard to the degree of substitution of the double bond of
the starting propylidene acetals, the experimental data show that
the diastereomeric excesses (des) obtained from trans-cinnamalde-
hyde acetals (entries 1–4, 6, 8, 10 and 11) are higher than those
from
a-methyl-trans-cinnamaldehyde acetals (entries 5, 7, 9 and
OMe
OMe
OMe
O
O
O
HO
BnO
BnO
BnBr / KOH
O
O
O
O
O
O
18-crown-6 / THF
+
R
R
R
Ph
Ph
Ph
13 R = H
12 R = H
4 and 5 R = H
15 R = Me
14 R = Me
6 and 7 R = Me
O
O
H
H
H
H
R
R
O
O
BnBr / KOH
O
O
O
O
18-crown-6 / THF
Ph
Ph
Ph
O
O
HO
BnO
H
H
8 R = H
9 R = Me
16 R = H
17 R = Me
O
O
O
Ph
BnBr / KOH
O
O
O
HO
BnO
R
R
18-crown-6 / THF
HO
BnO
OMe
OMe
10 R = H
11 R = Me
18 R = H
19 R = Me
Scheme 2.

1722
J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 19 (2008) 1720–1729
OMe
OMe
O
O
R
BnO
BnO
O
O
CH2I2 / ZnEt2
O
O
CH2Cl2
R
Ph
12
Ph
23
R = H
R = H
14 R = Me
25 R = Me
OMe
OMe
O
O
BnO
BnO
O
O
O
O
CH2I2 / ZnEt2
CH2Cl2
R
R
Ph
Ph
13
15
24
26
R = H
R = Me
R = H
R = Me
O
O
H
H
H
H
R
R
R
R
O
O
O
CH2I2 / ZnEt2
CH2Cl2
O
O
O
O
O
O
Ph
Ph
Ph
Ph
O
O
HO
HO
H
H
H
H
8 R = H
9 R = Me
27 R = H
28 R = Me
O
O
H
H
H
H
O
CH2I2 / ZnEt2
CH2Cl2
O
O
O
O
BnO
BnO
16 R = H
17 R = Me
29 R = H
30 R = Me
Scheme 3.
12). Thus, compounds 29, 31, 33 and 36 were obtained with des of
4.8%, 20%, 33% and 80%, respectively, while compounds 30, 32, 34
and 37 were obtained with des of 0%, 4.8%, 4.8% and 50%,
respectively.
In the group of compounds with an acetal ring of five members
(Scheme 3), we can observe that in those with a-L-rhamnopyranose
configuration, 23 and 24, the des depend on the configuration of
the acetal carbon; thus, compound 23, with an (S)-configuration
on the acetal carbon, was obtained in 26% de, whereas 24, with
an (R)-configuration on the acetal carbon, was obtained in 57%
In order to assign the configuration at the stereogenic centres in
the cyclopropane ring formed in the cyclopropanation reaction, we
proceeded to the separation of the chiral auxiliary by hydrolysis
with 80% acetic acid and subsequent reduction with sodium boro-
hydride to give the corresponding hydroxymethylcyclopropane
and recovery of the carbohydrate derivative (Scheme 5). The abso-
lute stereochemistry of the cyclopropane ring, (2R,3R) for 23,
(2S,3S) for 24, (2R,3S) for 32, (2R,3R) for 36 and (2R,3S) for 37,
was deduced by correlation with (1R,2R)-trans-1-hydroxymethyl-
2-phenylcyclopropane29,43 (ꢀ)-38 obtained from 23 or 36, by cor-
relation with (1S,2S)-trans-1-hydroxymethyl-2-phenylcyclopro-
pane25,44 (+)-38 obtained from 24, and by correlation with
(1R,2S)-E-1-hydroxymethyl-1-methyl-2-phenylcyclopropane45,46
(ꢀ)-40 obtained from 32 or 37. The configuration of the other
cyclopropanes listed in Table 1 was established on the basis of
the analysis of the chemical shifts of the protons and the carbons
corresponding to the cyclopropane acetal system in the NMR spec-
tra. For cyclopropanes derived from trans-cinnamaldehyde, the sig-
nal corresponding to H-10 is easily identifiable in the 1H NMR
spectra at approximately 5.0–4.4 ppm as a doublet, and the signals
for C-10, C-20, C-30 and C-40 are identifiable in the 13C NMR spectra
at approximately 107–96, 25, 19 and 12 ppm, respectively. Com-
pound 29 showed the same profile in H-10, C-10, C-20 and C-30 as
that of compound 24, so that we assigned (2S,3S) for the major iso-
mer of compound 29. Compound 27 showed the same profile in H-
10 as 23 and a different profile to that of 24 and 29; moreover, com-
de. The des of the compounds with a-D-glucofuranose configuration
27, 29 and 30 were very different (Table 1, entries 3, 4 and 5)
depending on the functionalisation on carbon 3 of the carbohy-
drate; compound 27, with the 3-hydroxyl group free, was obtained
in 49% de, whereas compounds 29 and 30, with the 3-hydroxyl
group blocked, were obtained with des of 4.8% and 0%, respec-
tively. In the group of compounds with acetal ring of six members
(Scheme 4), the des depended on the configuration of the carbohy-
drate moiety. The results show that the compounds 36 and 37
(with
a
-
D
-xylofuranose configuration) (entries 11 and 12) present
-glucopyranose con-
des higher than the compounds 31–35 (with
D
figuration) (entries 6–10). Thus, compounds 31, 33, 35 and 36, ob-
tained from trans-cinnamaldehyde acetal derivatives, showed des
of 20%, 33%, 46% and 80%, respectively. Equally, cyclopropanes
32, 34 and 37, obtained from
a-methyl-trans-cinnamaldehyde ace-
tal derivatives, showed des of 4.8%, 4.8% and 50%, respectively.

J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 19 (2008) 1720–1729
1723
O
O
Ph
Ph
Ph
Ph
CH2I2 / ZnEt2
CH2Cl2
O
O
O
O
HO
HO
R
R
HO
HO
OMe
OMe
10 R = H
11 R = Me
31 R = H
32 R = Me
O
O
Ph
CH2I2 / ZnEt2
CH2Cl2
O
O
O
O
BnO
BnO
R
R
BnO
BnO
OMe
OMe
18 R = H
19 R = Me
33 R = H
34 R = Me
O
O
Ph
O
O
CH2I2 / ZnEt2
CH2Cl2
O
O
O
O
BnO
BnO
( )11
( )11
NHAc
NHAc
20
35
H
H
H
O
H
O
O
O
O
O
R
R
CH2I2 / ZnEt2
CH2Cl2
O
O
Ph
Ph
O
O
H
H
H
H
21 R = H
36 R = H
22 R = Me
37 R = Me
Scheme 4.
Table 1
Cyclopropanation of 3-phenylpropenylidene derivatives 8–22 in CH2Cl2
compounds with gluco and xylo configuration, whereas the com-
pounds with rhamno configuration present the Re,Re or Si,Si face
as the more reactive, depending on the configuration of the acetal
carbon; (b) the diastereomeric excesses (des) found depend on
the carbohydrate configuration; (c) we have not found a direct
relationship between the reactivity (de) and the protection (or
not) of the hydroxyl groups of the sugar; (d) of the sugars used as
chiral auxiliaries in this work, the best (best de) was 1,2-O-isopro-
Entry
Starting
compound
Reaction
product
Yielda
(%)
deb
(%)
Major cyclopropane
configuration
1
2
3
4
5
6
7
8
9
12
13
8
23
24
27
29
30
31
32
33
34
35
36
37
81
75
66
64
60
65
62
66
74
76
85
87
26
56.5
49
4.8
0
20
4.8
33
4.8
46
80
50
(2R,3R)
(2S,3S)
(2R,3R)
(2S,3S)
—
(2R,3R)
(2R,3S)
(2R,3R)
(2R,3S)
(2R,3R)
(2R,3R)
(2R,3S)
16
17
10
11
18
19
20
21
22
pylidene-a-D-xylofuranose. We have chosen this chiral auxiliary for
the optimisation of the cyclopropanation reaction in a wide range of
alkenes, whose results will be reported in forthcoming articles.
10
11
12
4. Experimental
4.1. General
a
Yields refer to compounds obtained in each reaction after isolation and
purification.
b
Determined by integration in 1H NMR spectra of reaction mixtures.
Evaporations were conducted under reduced pressure. Prepara-
tive chromatography was performed on Silica Gel 60 (E. Merck).
Kieselgel 60 F254 (E. Merck) was used for TLC. Melting points were
obtained on a Stuart Melting Point Apparatus SMP 10 and are
uncorrected. Optical rotations were obtained on a Perkin Elmer
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. 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 ppm on the
d scale relative to TMS. COSY, DEPT, HSQC and NOESY experiments
were performed to assign the signals in the NMR spectra.
pounds 27 and 29 present a different sign for [a]D. We assigned
(2R,3R) for the major isomer of compound 27. Compounds 31
and 33 showed the same profiles as 23, so that the same configu-
rations have been assigned to them. For cyclopropanes derived
from
a-methyl-trans-cinnamaldehyde, the signal corresponding
to H-10 is easily identifiable in the 1H spectra at approximately
4.7–4.2 ppm as a singlet, and the signals for C-10, C-30 and C-40
are identifiable in the 13C NMR spectra at approximately 106–
103, 25 and 14 ppm, respectively. Compound 34 showed the same
profile in H-10, C-10, C-30 and C-40 as that of compounds 32 and 37,
so we assigned (2R,3S) for the major isomer of compound 34.
4.2. General procedure for synthesis of a,b-unsaturated acetals
3. Conclusion
To
a solution of methyl a-L-rhamnopyranoside 1 (0.89 g,
In conclusion, in the cyclopropanation reaction of propylidene
5.0 mmol) in acetonitrile (30 mL), the aldehyde dimethylacetal
acetals presented here, (a) the Re,Re face is the more reactive in

1724
J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 19 (2008) 1720–1729
OMe
O
BnO
(R)
O
O
AcOH 80%
NaBH4
Ph
Ph
OH
O
(R)
(−)-38
Ph
23
OMe
O
BnO
(S)
O
O
AcOH 80%
NaBH4
Ph
Ph
OH
O
(S)
(+)-38
Ph
24
H
H
O
O
(R)
O
O
AcOH 80%
AcOH 80%
AcOH 80%
NaBH4
Ph
Ph
Ph
Ph
OH
OH
OH
O
(R)
Ph
Ph
O
H
H
(−)-38
36
O
O
(R)
(R)
O
O
NaBH4
Ph
HO
(S)
(S)
HO
OMe
O
39
(−)-40
32
H
H
O
O
(R)
(R)
O
O
NaBH4
Ph
(S)
(S)
Ph
O
H
H
39
(−)-40
37
Scheme 5.
241 or 339 (10.0 mmol) and camphorsulfonic acid (10 mg) were
added. The mixture was stirred at room temperature until a check
by TLC showed that all the starting material had reacted. Then, tri-
ethylamine was added until pH 7. The reaction mixture was evap-
orated, and a syrup was obtained. Column chromatography gave
the compounds 4 and 5 or 6 and 7, in good yields.
128.6–127.0 (Ph), 125.3, 125.2 (PhCH@CHCH), 104.5, 103.3
(PhCH@CHCH), 98.1, 97.8 (C-1), 79.1, 77.9 (C-3), 77.6, 75.3 (C-2),
74.9, 72.0 (C-4), 65.8, 65.4 (C-5), 55.0, 54.9 (OCH3), 17.5, 17.4 (C-
6). HRMS (EI): [M]+Å, found 292.130072. C16H20O5 requires
292.131074. Anal. Calcd for C16H20O5: C, 65.74; H, 6.90. Found: C,
65.80; H, 7.14.
4.2.2. Methyl 2,3-O-(E-2-methyl-3-phenyl-2-propenylidene)-
-rhamnopyranoside 6 and 7
Two stereoisomers were obtained in a 22:10 ratio (37.5% de).
The pure diastereomeric mixture was obtained as a syrup by col-
umn chromatography, using hexane–ethyl acetate (10:1) as eluent.
a-
4.2.1. Methyl 2,3-O-(E-3-phenyl-2-propenylidene)-a-L-
rhamnopyranoside 4 and 5
Two stereoisomers were obtained in a 1:1 ratio. The pure dia-
stereomeric mixture was obtained as a solid by column chroma-
tography, using hexane–ethyl acetate (6:1) as eluent. Yield 1.15 g
L
Yield 1.40 g (92%); [
a
]
D = ꢀ6.8 (c 1.6, CH2Cl2); MS (CI): m/z 307
(79%); mp 136–138 °C; [
a
]
D = ꢀ13.0 (c 1.1, CH2Cl2); MS (EI): m/z
(98%) [M+H]+. 1H NMR (500 MHz, CDCl3): d 7.4–7.2 (m, 10H, Ph),
6.74 [s, 0.31H, PhCH@C(CH3)CH minor], 6.66 [s, 0.69H,
PhCH@C(CH3)CH major], 5.59 [s, 0.69H, PhCH@C(CH3)CH major],
5.36 [d, 0.31H, 4J 0.5 Hz, PhCH@C(CH3)CH minor], 4.94 (s, 0.31H,
H-1 minor), 4.91 (s, 0.69H, H-1 major), 4.34 (dd, 0.69H, J2,3
5.5 Hz, J3,4 7.4 Hz, H-3 major), 4.19 (t, 0.31H, J2,3 = J3,4 6.5 Hz, H-3
minor), 4.12 (m, 1H, H-2), 3.71 (m, 1H, H-5), 3.50 (m, 1H, H-4),
3.42 (s, 0.93H, OCH3 minor), 3.40 (s, 2.07H, OCH3 major), 2.40
(m, 0.31H, J4,OH 5.0 Hz, OH minor), 2.34 (m, 0.69H, J4,OH 4.4 Hz,
OH major), 1.94 [d, 0.93H, 4J 1.5 Hz, PhCH@C(CH3)CH minor],
1.86 (d, 2.07H, 4J 1.4 Hz, PhCH@C(CH3)CH A), 1.35 [d, 2.07H, J5,6
6.3 Hz, CH3 major], 1.32 (d, 0.93H, J5,6 6.3 Hz, CH3 minor). 13C
292 (30%) [M]+Å. 1H NMR (500 MHz, CDCl3): d 7.5–7.3 (m, 5H, Ph),
6.79 (d, 0.5H, Jtrans 16.0 Hz, PhCH@CHCH B), 6.73 (d, 0.5H, Jtrans
15.9 Hz, PhCH@CHCH A), 6.19 (dd, 0.5H, Jtrans 16.0 Hz, J 6.5 Hz,
PhCH@CHCH B), 6.13 (dd, 0.5H, Jtrans 15.9 Hz, J 6.0 Hz, PhCH@CHCH
A), 5.75 (d, 0.5H, J 6.0 Hz, PhCH@CHCH A), 5.53 (dd, 0.5H, J 6.5 Hz,
4J 0.6 Hz, PhCH@CHCH B), 4.94 (s, 0.5H, H-1 B), 4.91 (s, 0.5H, H-1
A), 4.28 (dd, 0.5H, J2,3 5.4 Hz, J3,4 7.5 Hz, H-3 A), 4.15 (dd, 0.5H,
J2,3 5.0 Hz, J3,4 7.0 Hz, H-3 B), 4.09 (m, 1H, H-2), 3.69 (m, 1H, H-
5), 3.44 (m, 1H, H-4), 3.41 (s, 1.5H, OCH3 B), 3.39 (s, 1.5H, OCH3
A), 2.40 (d, 0.5H, J4,OH 4.6 Hz, OH B), 2.38 (d, 0.5H, J4,OH 4.4 Hz,
OH A), 1.34 (d, 1.5H, J5,6 6.3 Hz, CH3 A), 1.32 (d, 1.5H, J5,6 6.3 Hz,
CH3 B). 13C NMR (125 MHz, CDCl3): d 135.8, 134.4 (PhCH@CHCH),

J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 19 (2008) 1720–1729
1725
NMR (125 MHz, CDCl3): d 136.6, 136.5 [PhCH@C(CH3)CH], 131.0,
129.9 [PhCH@C(CH3)CH], 129.1–127.1 (Ph), 107.8, 106.9
[PhCH@C(CH3)CH], 98.3, 98.2 (C-1), 79.5, 77.7 (C-3), 77.3, 76.2
(C-2), 74.1, 71.6 (C-4), 66.2, 65.3 (C-5), 55.0, 54.9 (OCH3), 17.7,
17.5 (C-6), 12.3, 12.0 [PhCH@C(CH3)CH]. HRMS (CI): [M+H]+, found
307.154013. C17H23O5 requires 307.15455.
4.3.2.1. Methyl 4-O-benzyl-2,3-O-[(S,E)-2-methyl-3-phenyl-2-
propenylidene]-a-L-rhamnopyranoside 14 (major Rf). [a] =
D
ꢀ43.8 (c 1.2, CH2Cl2); MS (CI): m/z 397 (15%) [M+H]+. 1H NMR
(500 MHz, CDCl3):
d 7.4–7.2 (m, 10H, Ph), 6.66 [s, 1H,
PhCH@C(CH3)CH], 5.49 [s, 1H, PhCH@C(CH3)CH], 4.95 (d, 1H, Jgem
11.6 Hz, PhCHAHBO), 4.90 (s, 1H, H-1), 4.72 (d, 1H, Jgem 11.6 Hz,
PhCHAHBO), 4.53 (dd, 1H, J2,3 5.5 Hz, J3,4 7.2 Hz, H-3), 4.09 (d, 1H,
J2,3 5.5 Hz, H-2), 3.72 (m, 1H, H-5), 3.38 (s, 3H, OCH3), 3.27 (dd,
1H, J3,4 7.2 Hz, J4,5 9.7 Hz, H-4), 1.89 [d, 3H, 4J 1.4 Hz,
PhCH@C(CH3)CH], 1.34 (d, 3H, J5,6 6.2 Hz, CH3). 13C NMR
(125 MHz, CDCl3): d 138.1–127.1 (Ph), 136.6 [PhCH@C(CH3)CH],
130.0 [PhCH@C(CH3)CH], 106.8 [PhCH@C(CH3)CH], 98.1 (C-1),
79.7 (C-4), 77.3 (C-3), 76.3 (C-2), 73.0 (PhCH2O), 64.1 (C-5), 54.9
(OCH3), 17.8 (C-6), 12.0 [PhCH@C(CH3)CH]. HRMS (CI): [M+H]+,
found 397.198103. C24H29O5 requires 397.201499.
4.3. O-Benzyl derivatives 12–19
To a cooled solution (5 °C) of sugar derivatives 4–11 (3.0 mmol)
in freshly distilled THF (20 mL) were added, successively, freshly
powdered potassium hydroxide (1.0 g, 11.9 mmol), 18-crown-6
(60 mg, 0.2 mmol) and benzyl bromide (4.8 mmol for each hydro-
xyl group in 4–11). The reaction mixture was stirred at this tem-
perature for 3 h, and left overnight at room temperature, then
diluted with dichloromethane (30 mL) and washed successively
with water and an aqueous saturated solution of sodium bicarbon-
ate, dried (MgSO4) and filtered, and the filtrate evaporated to
dryness.
4.3.2.2. Methyl
4-O-benzyl-2,3-O-[(R,E)-2-methyl-3-phenyl-
2-propenylidene]-a-L-rhamnopyranoside 15 (minor Rf). [a] =
D
ꢀ6.0 (c 0.6, CH2Cl2); MS (CI): m/z 397 (20%) [M+H]+. 1H NMR
(500 MHz, CDCl3):
d 7.4–7.2 (m, 10H, Ph), 6.77 [s, 1H,
PhCH@C(CH3)CH], 5.38 [d, 1H, 4J 0.6 Hz, PhCH@C(CH3)CH], 4.97
(s, 1H, H-1), 4.93 (d, 1H, Jgem 11.6 Hz, PhCHAHBO), 4.64 (d, 1H, Jgem
11.6 Hz, PhCHAHBO), 4.37 (t, 1H, J2,3 = J3,4 6.6 Hz, H-3), 4.15 (dd, 1H,
J2,3 6.6 Hz, 4J 0.6 Hz, H-2), 3.74 (m, 1H, H-5), 3.40 (s, 3H, OCH3), 3.33
(dd, 1H, J3,4 6.6 Hz, J4,5 9.8 Hz, H-4), 1.93 [d, 3H, 4J 1.4 Hz,
PhCH@C(CH3)CH], 1.33 (d, 3H, J5,6 6.2 Hz, CH3). 13C NMR
(125 MHz, CDCl3): d 138.3–127.1 (Ph), 136.6 [PhCH@C(CH3)CH],
130.8 [PhCH@C(CH3)CH], 107.6 [PhCH@C(CH3)CH], 98.0 (C-1),
81.4 (C-4), 77.9 (C-2, C-3), 72.6 (PhCH2O), 64.2 (C-5), 54.7
(OCH3), 18.0 (C-6), 12.4 [PhCH@C(CH3)CH]. HRMS (CI): [M+H]+,
found 397.199113. C24H29O5 requires 397.201499.
4.3.1. From 4 and 5
Two stereoisomers were obtained in a 1:1 ratio. Both stereoiso-
mers were isolated as solid compounds by column chromatogra-
phy, using hexane–ethyl acetate (15:1) as eluent. Yield 1.09 g
(95%).
4.3.1.1. Methyl
4-O-benzyl-2,3-O-[(S,E)-3-phenyl-2-propenyl-
idene]-a-L-rhamnopyranoside 12 (major Rf). Mp 79–80 °C;
[
a
]
D = ꢀ63.2 (c 1.2, CH2Cl2); MS (CI): m/z 383 (10%) [M+H]+. 1H
NMR (500 MHz, CDCl3): d 7.5–7.3 (m, 10H, Ph), 6.76 (d, 1H, Jtrans
15.9 Hz, PhCH@CHCH), 6.15 (dd, 1H, Jtrans 15.9 Hz,
J 6.1 Hz,
PhCH@CHCH), 5.67 (d, 1H, J 6.1 Hz, PhCH@CHCH), 4.94 (d, 1H, Jgem
11.6 Hz, PhCHAHBO), 4.89 (s, 1H, H-1), 4.70 (d, 1H, Jgem 11.6 Hz,
PhCHAHBO), 4.48 (dd, 1H, J2,3 5.6 Hz, J3,4 7.0 Hz, H-3), 4.08 (d, 1H,
J2,3 5.5 Hz, H-2), 3.72 (m, 1H, H-5), 3.37 (s, 3H, OCH3), 3.25 (dd,
1H, J3,4 7.1 Hz, J4,5 9.7 Hz, H-4), 1.33 (d, 3H, J5,6 6.3 Hz, CH3). 13C
NMR (125 MHz, CDCl3): d 138.2–127.0 (Ph), 135.7 (PhCH@CHCH),
125.4 (PhCH@CHCH), 103.1 (PhCH@CHCH), 98.0 (C-1), 79.3 (C-3),
78.0 (C-4), 75.4 (C-2), 73.0 (PhCH2O), 64.2 (C-5), 54.9 (OCH3),
17.8 (C-6). HRMS (EI): [M]+Å, found 382.178694. C23H26O5 requires
382.178024. Anal. Calcd for C23H26O5: C, 72.23; H, 6.85. Found: C,
72.54; H, 7.08.
4.3.3. 3-O-Benzyl-5,6-O-[(S,E)-3-phenyl-2-propenylidene]-1,2-
O-isopropylidene-a-D-glucofuranose 16
The syrup obtained was purified by flash chromatography on
silica gel, using hexane–ethyl acetate (5:1) as eluent. Yield 0.92 g
(72%); [
a
]
D = ꢀ4.7 (c 0.8, CH2Cl2); MS (CI): m/z 425 (40%) [M+H]+.
1H NMR (500 MHz, CDCl3): d 7.4–7.2 (m, 10H, Ph), 6.80 (d, 1H, Jtrans
16.0 Hz, PhCH@CHCH), 6.20 (dd, 1H, Jtrans 16.1 Hz,
J 5.0 Hz,
PhCH@CHCH), 6.09 (d, 1H, J1,2 3.8 Hz, H-1), 5.71 (d, 1H, J 5.0 Hz,
PhCH@CHCH), 4.68 (d, 1H, J1,2 3.6 Hz, H-2), 4.65, 4.60 (2d, 2H, Jgem
12.2 Hz, PhCH2O), 4.52 (d, 1H, J3,4 2.3 Hz, H-3), 4.39 (t, 1H,
J5,6A = J5,6B 4.2 Hz, H-5), 4.19 (m, 1H, H-4), 3.95 (dd, 1H, J5,6A
4.2 Hz, J6A,6B 10.5 Hz, H-6A), 3.81 (dd, 1H, J5,6B 4.2 Hz, J6A,6B
10.5 Hz, H-6B), 1.58, 1.38 [2s, 6H, C(CH3)2]. 13C NMR (125 MHz,
4.3.1.2. Methyl 4-O-benzyl-2,3-O-[(R,E)-3-phenyl-2-propenyl-
idene]-a-L-rhamnopyranoside 13 (minor Rf). Mp 116–118 °C;
CDCl3):
d
135.7–126.9 (Ph), 133.7 (PhCH@CHCH), 126.7
[
a
]
D = ꢀ36.0 (c 0.7, CH2Cl2); MS (CI): m/z 383 (15%) [M+H]+. 1H
(PhCH@CHCH), 111.6 [C(CH3)2], 104.7 (C-1), 94.85 (PhCH@CHCH),
83.9 (C-2), 76.7 (C-3), 73.4 (C-5), 73.5 (C-4), 73.5 (PhCH2O), 71.4
(C-6), 26.6, 26.0 [C(CH3)2]. HRMS (EI): [M]+Å, found 424.183759.
NMR (500 MHz, CDCl3): d 7.5–7.2 (m, 10H, Ph), 6.80 (d, 1H, Jtrans
16.0 Hz, PhCH@CHCH), 6.13 (dd, 1H, Jtrans 16.0 Hz,
J 6.6 Hz,
PhCH@CHCH), 5.53 (d, 1H, J 6.6 Hz, PhCH@CHCH), 4.94 (s, 1H, H-
1), 4.89 (d, 1H, Jgem 11.7 Hz, PhCHAHBO), 4.67 (d, 1H, Jgem 11.7 Hz,
PhCHAHBO), 4.33 (t, 1H, J2,3 = J3,4 6.5 Hz, H-3), 4.09 (dd, 1H, J2,3
6.0 Hz, 4J 0.6 Hz, H-2), 3.73 (m, 1H, H-5), 3.39 (s, 3H, OCH3), 3.24
(dd, 1H, J3,4 6.9 Hz, J4,5 9.9 Hz, H-4), 1.31 (d, 3H, J5,6 6.2 Hz, CH3).
C18H22O6 requires 424.188589.
4.3.4. 3-O-Benzyl-5,6-O-[(S,E)-2-methyl-3-phenyl-2-
propenylidene]-1,2-O-isopropylidene- -glucofuranose 17
a
-D
13C NMR (125 MHz, CDCl3):
d
138.2–127.1 (Ph), 135.6
The syrup obtained was purified by flash chromatography on
(PhCH@CHCH), 125.7 (PhCH@CHCH), 104.5 (PhCH@CHCH), 97.7
(C-1), 81.0 (C-4), 78.2 (C-3), 77.9 (C-2), 72.7 (PhCH2O), 64.5 (C-5),
54.8 (OCH3), 17.8 (C-6). HRMS (EI): [M]+Å, found 382.179407.
silica gel, using hexane–ethyl acetate (12.5:1) as eluent. Yield
0.90 g (71%); [
a
]D = ꢀ10.7 (c 0.8, CH2Cl2); MS (CI): m/z 439 (25%)
[M+H]+. 1H NMR (500 MHz, CDCl3): d 7.3–7.2 (m, 10H, Ph), 6.64
[s, 1H, PhCH@C(CH3)CH], 6.04 (d, 1H, J1,2 3.7 Hz, H-1), 5.46 [s, 1H,
PhCH@C(CH3)CH], 4.64 (d, 1H, J1,2 3.7 Hz, H-2), 4.61, 4.58 (2d, 2H,
Jgem 12.2 Hz, PhCH2O), 4.48 (d, 1H, J3,4 2.0 Hz, H-3), 4.36 (t, 1H,
J5,6A = J5,6B 4.0 Hz, H-5), 4.15 (m, 1H, H-4), 3.92 (dd, 1H, J5,6A
4.0 Hz, J6A,6B 10.4 Hz, H-6A), 3.78 (dd, 1H, J5,6B 4.0 Hz, J6A,6B
10.4 Hz, H-6B), 1.90 [d, 3H, 4J 1.5 Hz, PhCH@C(CH3)CH], 1.54, 1.35
[2s, 6H, C(CH3)2]. 13C NMR (125 MHz, CDCl3): d 136.7–128.1 (Ph),
C23H26O5 requires 382.178024. Anal. Calcd for C23H26O5: C,
72.23; H, 6.85. Found: C, 72.15; H, 6.88.
4.3.2. From 6 and 7
Two stereoisomers were obtained in a 22:10 ratio. Both stereo-
isomers were isolated as syrups by column chromatography, using
hexane–ethyl acetate (21:1) as eluent. Yield 1.06 (89%).

1726
J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 19 (2008) 1720–1729
134.1 [PhCH@C(CH3)CH], 127.0 [PhCH@C(CH3)CH], 111.9
[C(CH3)2], 105.0 (C-1), 97.3 [PhCH@C(CH3)CH], 84.0 (C-2), 77.7
(C-3), 73.9 (C-5), 73.6 (PhCH2O), 73.0 (C-4), 61.8 (C-6), 26.8, 26.2
[C(CH3)2], 12.9 [PhCH@C(CH3)CH]. HRMS (EI): [M]+Å, found
438.202348. C19H24O6 requires 438.204239.
(45%) [M+H]+. 1H NMR (500 MHz, CDCl3): d 7.4–7.1 (m, 10H, Ph),
4.99 [d, 0.63H, J 5.0 Hz, PhCH(CH2)CHCH major], 4.95 [d, 0.37H, J
5.2 Hz, PhCH(CH2)CHCH minor], 4.90 (2d, 1H, Jgem 11.7 Hz,
PhCHAHBO), 4.86 (s, 0.63H, H-1 major), 4.85 (s, 0.37H, H-1 minor),
4.69 (2d, 1H, Jgem 11.7 Hz, PhCHAHBO), 4.44 (m, 1H, H-3), 4.03 (m,
1H, H-2), 3.69 (m, 1H, H-5), 3.37 (s, 1.89H, OCH3 major), 3.36 (s,
1.11H, OCH3 minor), 3.17 (dd, 1H, J3,4 7.2 Hz, J4,5 9.8 Hz, H-4),
2.05 [m, 1H, PhCH(CH2)CHCH], 1.45 [m, 1H, PhCH(CH2)CHCH],
1.32 (d, 3H, J5,6 6.3 Hz, CH3), 1.15 [m, 1H, PhCH(CHAHB)CHCH],
0.98 [m, 1H, PhCH(CHAHB)CHCH]. 13C NMR (125 MHz, CDCl3):
4.3.5. Methyl 2,3-di-O-benzyl-4,6-O-[(R,E)-3-phenyl-2-propenyl-
idene]-a-D-glucopyranoside 18
The syrup obtained was purified by flash chromatography on
silica gel, using hexane–ethyl acetate (8:1) as eluent. Yield 1.17 g
a]
D = +6.8 (c 0.9, CH2Cl2); MS (CI): m/z 489 (10%) [M+H]+.
d
141.7–125.8 (Ph), 105.0 [PhCH(CH2)CHCH minor], 104.7
(80%); [
1H NMR (500 MHz, CDCl3): d 7.6–7.2 (m, 15H, Ph), 6.81 (d, 1H, Jtrans
16.1 Hz, PhCH@CHCH), 6.19 (dd, 1H, Jtrans 16.1 Hz, 4.3 Hz,
[PhCH(CH2)CHCH major], 98.0 (C-1), 79.2 (C-3), 77.3 (C-4 minor),
77.2 (C-4 major), 75.65 (C-2 major), 75.60 (C-2 minor), 72.9
(PhCH2O minor), 72.8 (PhCH2O major), 64.1 (C-5), 54.8 (OCH3),
25.7 [PhCH(CH2)CHCH minor], 25.5 [PhCH(CH2)CHCH major],
19.5 [PhCH(CH2)CHCH major], 19.2 [PhCH(CH2)CHCH minor],
17.8 (C-6), 11.6 [PhCH(CH2)CHCH minor], 11.2 [PhCH(CH2)CHCH
major]. HRMS (EI): [M]+Å, found 396.192959. C24H28O5 requires
396.193674.
J
PhCH@CHCH), 5.17 (dd, 1H, J 4.3 Hz, 4J 1.2 Hz, PhCH@CHCH),
4.9–4.7 (m, 4H, 2 PhCH2O), 4.59 (d, 1H, J1,2 3.7 Hz, H-1), 4.20 (dd,
1H, J5,6e 4.9 Hz, J6e,6a 10.2 Hz, H-6e), 4.01 (t, 1H, J2,3 = J3,4 9.3 Hz,
H-3), 3.6–3.5 (m, 3H, H-2, H-5, H-6a), 3.5 (m, 1H, H-4), 3.4 (s, 3H,
OCH3). 13C NMR (125 MHz, CDCl3): d 128.4–126.8 (Ph), 133.6
(PhCH@CHCH), 124.5 (PhCH@CHCH), 100.7 (PhCH@CHCH), 99.2
(C-1), 81.9 (C-4), 79.2 (C-2), 78.6 (C-3), 75.3, 73.7 (2 PhCH2O),
68.8 (C-6), 62.3 (C-5), 55.2 (OCH3). HRMS (CI): [M+H]+, found
489.226908. C30H33O6 requires 489.227714.
4.4.2. Methyl 4-O-benzyl-2,3-O-[(1R,2S,3S)-(2-phenylcyclo-
propyl)methylidene]-a-L-rhamnopyranoside 24
Two stereoisomers were obtained in a 36:10 ratio (57% de). The
pure diastereomeric mixture was obtained as a syrup by column
chromatography, using hexane–ethyl acetate (15:1) as eluent.
4.3.6. Methyl 2,3-di-O-benzyl-4,6-O-[(R,E)-2-methyl-3-phenyl-
2-propenylidene]-a-D-glucopyranoside 19
Yield 0.30 g (75%); [
a
]
D = ꢀ15.3 (c 1.2, CH2Cl2); MS (EI): m/z 396
The syrup obtained was purified by flash chromatography on
(15%) [M]+Å. 1H NMR (500 MHz, CDCl3): d 7.4–7.1 (m, 10H, Ph),
4.95 (s, 0.78H, H-1 major), 4.94 (s, 0.22H, H-1 minor), 4.92 (d,
0.22H, Jgem 11.7 Hz, PhCHAHBO minor), 4.88 (d, 0.78H, Jgem
silica gel, using hexane–ethyl acetate (8:1) as eluent. Yield 1.11 g
(74%); [a]
D = +29.2 (c 1.1, CH2Cl2); MS (CI): m/z 503 (5%) [M+H]+.
1H NMR (500 MHz, CDCl3): d 7.5–7.3 (m, 15H, Ph), 6.70 [s, 1H,
PhCH@C(CH3)CH], 4.98 [s, 1H, PhCH@C(CH3)CH], 4.91(d, 1H, Jgem
11.3 Hz, PhCHAHBO), 4.9–4.8 (2d, 2H, Jgem 12.3 Hz, Jgem 11.3 Hz,
PhCHDHEO, PhCHAHBO), 4.71 (d, 1H, Jgem 12.2 Hz, PhCHDHEO),
4.59 (d, 1H, J1,2 3.70 Hz, H-1), 4.21 (dd, 1H, J5,6e 4.9 Hz, J6e,6a
10.2 Hz, H-6e), 4.02 (t, 1H, J2,3 = J3,4 9.3 Hz, H-3), 3.77 (dt, 1H, J5,6e
4.5 Hz, J4,5 = J5,6a 10.0 Hz, H-5), 3.62 (t, 1H, J5,6a 10.3 Hz, H-6a),
3.54 (dd, 1H, J1,2 3.7 Hz, J2,3 9.3 Hz, H-2), 3.50 (dd, 1H, J3,4
9.30 Hz, J4,5 10.0 Hz, H-4), 3.40 (s, 3H, OCH3), 1.94 [d, 3H, 4J
2.4 Hz, PhCH@C(CH3)CH]. 13C NMR (125 MHz, CDCl3): d 128.1–
127.5 (Ph), 129.1 [PhCH@C(CH3)CH], 128.3 [PhCH@C(CH3)CH],
104.2 [PhCH@C(CH3)CH], 99.2 (C-1), 81.9 (C-4), 79.2 (C-2), 78.5
(C-3), 75.3, 73.8 (2 PhCH2O), 68.9 (C-6), 62.4 (C-5), 55.3 (OCH3),
13.5 [PhCH@C(CH3)CH]. HRMS (CI): [M+H]+Å, found 503.241457.
11.7 Hz, PhCHAHBO major), 4.85 [d, 0.22H,
J
6.0 Hz,
PhCH(CH2)CHCH minor], 4.79 [d, 0.78H, J 6.0 Hz, PhCH(CH2)CHCH
major], 4.66 (2d, 1H, Jgem 11.7 Hz, PhCHAHBO), 4.30 (m, 1H, H-3),
4.06 (m, 1H, H-2), 3.73 (m, 1H, H-5), 3.41 (s, 2.34H, OCH3 major),
3.40 (s, 0.66H, OCH3 minor), 3.27 (dd, 0.22H, J3,4 6.8 Hz, J4,5
9.9 Hz, H-4 minor), 3.22 (dd, 0.78H, J3,4 6.8 Hz, J4,5 9.9 Hz, H-4 ma-
jor), 2.12 [m, 1H, PhCH(CH2)CHCH], 1.49 [m, 1H, PhCH(CH2)CHCH],
1.35 (d, 0.66H, J5,6 6.3 Hz, CH3 minor), 1.30 (d, 2.34H, J5,6 6.3 Hz,
CH3 major), 1.20 [m, 0.22H, PhCH(CHAHB)CHCH minor], 1.15 [m,
0.78H, PhCH(CHAHB)CHCH major], 0.98 [m, 1H, PhCH(CHAHB)-
CHCH]. 13C NMR (125 MHz, CDCl3): d 141.6–125.9 (Ph), 106.9
[PhCH(CH2)CHCH major], 106.2 [PhCH(CH2)CHCH minor], 97.8
(C-1), 81.0 (C-4 minor), 80.9 (C-4 major), 78.0 (C-3 major), 77.9
(C-3 minor), 77.8 (C-2 major), 77.7 (C-2 minor), 72.7 (PhCH2O min-
or), 72.5 (PhCH2O major), 64.5 (C-5 minor), 64.3 (C-5 major), 54.8
(OCH3), 25.5 [PhCH(CH2)CHCH major], 25.2 [PhCH(CH2)CHCH min-
or], 19.9 [PhCH(CH2)CHCH major], 19.7 [PhCH(CH2)CHCH minor],
17.9 (C-6), 12.0 [PhCH(CH2)CHCH minor], 11.7 [PhCH(CH2)CHCH
major]. HRMS (EI): [M]+Å, found 396.193339. C24H28O5 requires
396.193674.
C31H35O6 requires 503.243364.
4.4. General procedure for cyclopropanation of
acetals
a,b-unsaturated
To a solution of the corresponding unsaturated acetal 8–22
(1.0 mmol) in dry dichloromethane (10–30 mL) at ꢀ15 °C were
added 1.0 M diethylzinc in hexane (5.0 mL, 5.0 mmol) and diiodo-
methane (0.8 mL, 10.0 mmol). The reaction mixture was stirred for
1 h at ꢀ15 °C, and then left at room temperature until TLC showed
that all the starting material had reacted (ꢁ12 h). The reaction was
diluted with dichloromethane and quenched with saturated
ammonium chloride solution. The organic layer was dried (MgSO4),
filtered and evaporated to dryness. Compounds obtained were
purified by flash chromatography on silica gel. The diastereomeric
excess (de) was determined by 1H NMR.
4.4.3. 1,2-O-Isopropylidene-5,6-O-[(1S,2R,3R)-(2-phenylcyclo-
propyl)methylidene]-a-D-glucofuranose 27
Two stereoisomers were obtained in a 29:10 ratio (49% de). The
pure diastereomeric mixture was obtained as a syrup by column
chromatography, using hexane–ethyl acetate (5:1) as eluent. Yield
0.23 g (66%); [
a
]
D = ꢀ6.3 (c 1.1, CH2Cl2); MS (EI): m/z 348 (10%)
[M]+Å. 1H NMR (500 MHz, CDCl3): d 7.6–7.1 (m, 5H, Ph), 5.97 (d,
J1,2 3.7, H-1 minor), 5.95 (d, J1,2 3.60, H-1 major), 4.88 [d, 0.74H, J
5.5, PhCH(CH2)CHCH major], 4.73 [d, 0.26H, J 5.5, PhCH(CH2)CHCH
minor], 4.63 (d, 0.26H, J1,2 3.7 Hz, H-2 minor), 4.53 (d, 0.74H, J1,2
3.6 Hz, H-2 major), 4.48 (d, 0.26H, J3,4 2.5 Hz, H-3 minor), 4.36 (d,
0.74H, J3,4 2.7 Hz, H-3 major), 4.28 (dd, 1H, J4,5 8.0 Hz, J5,6A
6.4 Hz, H-5), 4.18 (dd, 1H, J3,4 2.7 Hz, J4,5 8.0 Hz, H-4), 3.95 (dd,
1H, J5,6A 6.4 Hz, Jgem 8.6 Hz, H-6A), 3.82 (d, 1H, Jgem 8.6 Hz, H-6B),
2.06 [m, PhCH(CH2)CHCH major], 1.95 [m, PhCH(CH2)CHCH min-
or], 1.48 [m, 1H, PhCH(CH2)CHCH], 1.21 [m, PhCH(CHAHB)CHCH
4.4.1. Methyl 4-O-benzyl-2,3-O-[(1S,2R,3R)-(2-phenylcyclo-
propyl)methylidene]-a-L-rhamnopyranoside 23
Two stereoisomers were obtained in a 17:10 ratio (26% de). The
pure diastereomeric mixture was obtained as a syrup by column
chromatography, using hexane–ethyl acetate (15:1) as eluent.
Yield 0.32 g (81%); [
a
]D = ꢀ17.8 (c 1.0, CH2Cl2); MS (CI): m/z 397

J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 19 (2008) 1720–1729
1727
minor], 1.12 [m, PhCH(CHAHB)CHCH major], 1.03 [m, 1H,
PhCH(CHAHB)CHCH]. HRMS (EI): [M]+Å, found 348.157228.
(OCH3), 24.8 [PhCH(CH2)CHCH], 19.4 [PhCH(CH2)CHCH], 11.8
[PhCH(CH2)CHCH]. HRMS (EI): [M]+Å, found 322.142677. C17H22O6
requires 322.141639.
C19H24O6 requires 348.157289.
4.4.4. 3-O-Benzyl-1,2-O-isopropylidene-5,6-O-[(1S,2S,3S)-(2-
phenylcyclopropyl)methylidene]- -glucofuranose 29
4.4.7. Methyl 4,6-O-[(1R,2R,3S)-(1-methyl-2-phenylcyclo-
propyl)methylidene]-a-D-glucopyranoside 32
a-D
Two stereoisomers were obtained in an 11:10 ratio (4.8% de).
The pure diastereomeric mixture was obtained as a syrup by col-
umn chromatography, using hexane–ethyl acetate (7:1) as eluent.
Two stereoisomers were obtained in an 11:10 ratio (4.8% de).
The pure diastereomeric mixture was obtained as a syrup by col-
umn chromatography, using hexane–ethyl acetate (6:1) as eluent.
Yield 0.28 g (64%); [
a
]
D = +12.9 (c 1.2, CH2Cl2); MS (CI): m/z 439
Yield 0.21 g (62%); [a]D = +94.0 (c 1.0, CH2Cl2); MS (CI): m/z 337
(5%) [M+H]+. 1H NMR (500 MHz, CDCl3): d 7.6–7.1 (m, 10H, Ph),
6.02 (d, 0.48H, J1,2 4.0 Hz, H-1 minor), 6.00 (d, 0.52H, J1,2 4.0 Hz,
H-1 major), 4.91 [d, 0.48H, J 5.0 Hz, PhCH(CH2)CHCH minor], 4.86
[d, 0.52H, J 5.0 Hz, PhCH(CH2)CHCH major], 4.59 (2d, 1H, J1,2
4.1 Hz, H-2), 4.56 (s, 2H, PhCH2O), 4.36 (d, 1H, J3,4 2.1 Hz, H-3),
4.28 (m, 1H, H-5), 4.09 (m, 1H, H-4), 3.83 (m, 1H, H-6A), 3.70 (m,
1H, H-6B), 2.01 [m, 1H, PhCH(CH2)CHCH], 1.49, 1.33 [2s, 6H,
C(CH3)2], 1.45 [m, 1H, PhCH(CH2)CHCH], 1.12 [m, 1H,
PhCH(CHAHB)CHCH], 0.90 [m, 1H, PhCH(CHAHB)CHCH]. 13C NMR
(125 MHz, CDCl3): d 136.7–128.1 (Ph), 111.6 [C(CH3)2], 104.7 (C-
1), 96.7 [PhCH(CH2)CHCH major], 96.4 [PhCH(CH2)CHCH minor],
84.0 (C-2), 77.8 (C-3 major), 77.7 (C-3 minor), 73.5 (C-4), 73.4
(PhCH2O), 72.3 (C-5), 71.3 (C-6), 26.6, 26.0 [C(CH3)2], 25.5
[PhCH(CH2)CHCH major], 25.4 [PhCH(CH2)CHCH minor], 19.3
[PhCH(CH2)CHCH major], 19.1 [PhCH(CH2)CHCH minor], 11.8
[PhCH(CH2)CHCH major], 11.7 [PhCH(CH2)CHCH minor]. HRMS
(CI): [M+H]+, found 439.213282. C26H31O6 requires 439.212064.
(50%) [M+H]+. 1H NMR (500 MHz, CDCl3): d 7.6–7.1 (m, 5H, Ph),
4.8 (d, 1H, J1,2 3.8 Hz, H-1), 4.36 [s, 0.60H, PhCH(CH2)C(CH3)CH
major], 4.26 [s, 0.40H, PhCH(CH2)C(CH3)CH minor], 4.20 (m, 1H,
H-6e), 3.93 (m, 1H, H-3), 3.7–3.6 (m, 2H, H-2, H-5), 3.56 (m, 1H,
H-6a), 3.46 (1s, 3H, OCH3), 3.31 (m, 1H, H-4), 2.33 [dd, 0.60H, J
8.8 Hz, J 6.7 Hz, PhCH(CH2)C(CH3)CH major], 2.31 [dd, 0.40H, J
8.8 Hz,
J 6.5 Hz, PhCH(CH2)C(CH3)CH minor], 1.30 [m, 1H,
PhCH(CHAHB)C(CH3)CH], 0.90 [m, 1H, PhCH(CHAHB)C(CH3)CH],
0.87 [s, 1.80H, PhCH(CH2)C(CH3)CH major], 0.86 [s, 1.20H,
PhCH(CH2)C(CH3)CH minor]. 13C NMR (500 MHz, CDCl3): d 136.7–
128.1 (Ph), 105.9 [PhCH(CH2)C(CH3)CH minor], 105.0 [PhCH-
(CH2)C(CH3)CH major], 99.1 (C-1), 81.9 (C-4 minor), 81.7 (C-4 ma-
jor), 78.9 (C-2), 78.4 (C-3 major), 78.3 (C-3 minor), 75.1, 73.3 (2
PhCH2O), 68.7 (C-6 major), 68.6 (C-6 minor), 62.4 (C-5 major),
62.3 (C-5 minor), 55.3 (OCH3), 25.1 [PhCH(CH2)C(CH3)CH minor],
24.9 [PhCH(CH2)C(CH3)CH major], 24.8 [PhCH(CH2)C(CH3)CH],
14.5 [PhCH(CH2)C(CH3)CH major], 14.0 [PhCH(CH2)C(CH3)CH min-
or], 13.8 [PhCH(CH2)C(CH3)CH minor], 13.6 [PhCH(CH2)C(CH3)CH
major]. HRMS (EI): [M]+Å, found 337.165533. C18H24O6 requires
337.165114.
4.4.5. 3-O-Benzyl-1,2-O-isopropylidene-5,6-O-[(1S,2R,3S)-(1-
methyl-2-phenylcyclopropyl)methylidene]-
a-D-glucofuranose
30
Two stereoisomers were obtained in a 1:1 ratio. The pure dia-
stereomeric mixture was obtained as a syrup by column chroma-
tography, using hexane–ethyl acetate (12.5:1) as eluent. Yield
4.4.8. Methyl 2,3-di-O-benzyl-4,6-O-[(1R,2R,3R)-(2-phenyl-
cyclopropyl)methylidene]-a-D-glucopyranoside 33
Two stereoisomers were obtained in a 2:1 ratio (33% de). The
pure diastereomeric mixture was obtained as a syrup by column
chromatography, using hexane–ethyl acetate (8:1) as eluent. Yield
0.27 g (60%); [a]D = +16.6 (c 2.7, CH2Cl2); MS (CI): m/z 453 (5%)
[M+H]+. 1H NMR (500 MHz, CDCl3): d 7.4–7.1 (m, 10H, Ph), 6.00,
5.99 (2d, 1H, J1,2 4.0 Hz, H-1), 4.74 [s, 0.5H, PhCH(CH2)C(CH3)CH],
4.67 [s, 0.5H, PhCH(CH2)CHCH], 4.62, 4.60 (2d, 1H, J1,2 4.1 Hz, H-
2), 4.57 (s, 2H, PhCH2O), 4.36 (d, 1H, J3,4 2.1 Hz, H-3), 4.30 (m,
1H, H-5), 4.09 (m, 1H, H-4), 3.82 (m, 1H, H-6A), 3.73 (m, 1H, H-
6B), 2.19 [m, 1H, PhCH(CH2)C(CH3)CH], 1.53, 1.35 [2s, 6H,
C(CH3)2], 1.11 [dd, 0.5H, Jgem 5.0 Hz, J 8.9 Hz, PhCH(CHAHB)-
C(CH3)CH], 1.06 [dd, 0.5H, Jgem 5.0 Hz, J 8.9 Hz, PhCH(CHAHB)-
C(CH3)CH], 0.80 [m, 4H, PhCH(CHAHB)C(CH3)CH]. 13C NMR
(125 MHz, CDCl3): d 138.6–125.8 (Ph), 111.7, 11.6 [C(CH3)2],
104.8 (C-1), 99.2, 98.7 [PhCH(CH2)C(CH3)CH], 84.1 (C-2), 77.8,
77.7 (C-3), 73.5 (PhCH2O), 73.44, 73.39 (C-4), 72.3, 72.2 (C-5),
0.33 g (66%); [a]D = +79.9 (c 0.8, CH2Cl2); MS (EI): m/z 502 (50%)
[M]+Å. 1H NMR (500 MHz, CDCl3): d 7.6–7.1 (m, 15H, Ph), 5.0–4.7
(m, 4H, 2PhCH2O), 4.63 [d, 0.67H, J 4.2 Hz, PhCH(CH2)CHCH major],
4.61 (d, 1H, J1,2 3.7 Hz, H-1), 4.51 [d, 0.33H,
J 4.7 Hz,
PhCH(CH2)CHCH minor], 4,16 (dd, 1H, J5,6e 4.9 Hz, J6e,6a 10.2 Hz,
H-6e), 4.00 (t, 1H, J2,3 = J3,4 9.3 Hz, H-3), 3.72 (dt, 1H, J5,6e 4.8 Hz,
J4,5 = J5,6a 9.7 Hz, H-5), 3.6–3.5 (m, 2H, H-2, H-6a), 3.43 (s, 3H,
OCH3), 3.40 (t, 1H, J3,4 9.4 Hz, H-4), 2.21 [m, 0.33H,
PhCH(CH2)CHCH minor], 2.12 [m, 0.67H, PhCH(CH2)CHCH major],
1.51 [m, 1H, PhCH(CH2)CHCH], 1.25 [m, 0.67H, PhCH(CHAHB)CHCH
major], 1,03 [m, 0.33H, PhCH(CHAHB)CHCH minor], 0.97 [m, 1H,
PhCH(CHAHB)CHCH]. 13C NMR (125 MHz, CDCl3): d 136.7–128.1
(Ph), 102.8 [PhCH(CH2)CHCH minor], 101.9 [PhCH(CH2)CHCH
major], 99.2 (C-1), 81.9 (C-4 minor), 81.7 (C-4 major), 79.2 (C-2),
78.5 (C-3 major), 78.4 (C-3 minor), 75.2, 73.7 (2 PhCH2O), 68.7
(C-6), 62.3 (C-5), 55.3 (OCH3), 25.1 [PhCH(CH2)CHCH minor], 25.0
[PhCH(CH2)CHCH major], 19.5 [PhCH(CH2)CHCH major], 19.3
[PhCH(CH2)CHCH minor], 11.7 [PhCH(CH2)CHCH minor], 11.4
[PhCH(CH2)CHCH major]. HRMS (EI): [M]+Å, found 502.234491.
71.2,
71.1
(C-6),
26.7,
26.1
[C(CH3)2],
25.3,
25.2
[PhCH(CH2)C(CH3)CH], 24.9, 24.6 [PhCH(CH2)C(CH3)CH], 13.7,
13.3 [PhCH(CH2)C(CH3)CH], 13.6 [PhCH(CH2)C(CH3)CH]. HRMS
(CI): [M+H]+, found 453.227332. C27H33O6 requires 453.227714.
4.4.6. Methyl 4,6-O-[(1R,2R,3R)-(2-phenylcyclopropyl)-
methylidene]-a-D-glucopyranoside 31
Two stereoisomers were obtained in a 15:10 ratio (20% de). Col-
umn chromatography, using dichloromethane–methanol (30:1) as
eluent, gave the major diastereoisomer separated as a syrup. Yield
C31H34O6 requires 502.235539.
0.21 g (65%); [
a
]
D = +82.8 (c 1.0, CH2Cl2); MS (CI): m/z 323 (65%)
4.4.9. Methyl 2,3-di-O-benzyl-4,6-O-[(1R,2R,3S)-(1-methyl-2-
phenylcyclopropyl)methylidene]- -glucopyranoside 34
Two stereoisomers were obtained in an 11:10 ratio (4.8% de).
The pure diastereomeric mixture was obtained as a syrup by col-
umn chromatography, using dichloromethene–methanol (60:1)
[M+H]+. 1H NMR (500 MHz, CDCl3): d 7.5–7.1 (m, 5H, Ph), 4.79 (d,
1H, J1,2 3.9 Hz, H-1), 4.59 [d, 1H, J 3.9 Hz, PhCH(CH2)CHCH], 4.17
(dd, 1H, J5,6e 4.9 Hz, J6e,6a 10.2 Hz, H-6e), 3.90 (t, 1H, J2,3 = J3,4
9.3 Hz, H-3), 3.7–3.5 (m, 3H, H-2, H-5, H-6a), 3.46 (s, 3H, OCH3),
3.31 (t, 1H, J3,4 = J4,5 9.4 Hz, H-4), 2.10 [m, 1H, PhCH(CH2)CHCH],
1.55, 1.20, 0.90 [3m, 3H, PhCH(CH2)CHCH]. 13C NMR (500 MHz,
CDCl3): d 128.3–125.7 (Ph), 102.2 [PhCH(CH2)CHCH], 99.7 (C-1),
80.4 (C-4), 72.8 (C-2), 71.8 (C-3), 68.4 (C-6), 62.3 (C-5), 55.5
a-D
as eluent. Yield 0.38 g (74%); [a]D = +31.4 (c 0.9, CH2Cl2); MS (EI):
m/z 516 (5%) [M]+Å. 1H NMR (500 MHz, CDCl3): d 7.6–7.1 (m, 15H,
Ph), 5.0–4.7 (m, 4H, 2CH2Ph), 4.62 (d, 1H, J1,2 3.6 Hz, H-1), 4.45
[s, 0.52H, PhCH(CH2)C(CH3)CH major], 4.32 [s, 0.42H,

1728
J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 19 (2008) 1720–1729
PhCH(CH2)C(CH3)CH minor], 4.18 (m, 1H, H-6e), 4.02 (m, 1H, H-3),
3.70 (m, 1H, H-5), 3.52 (m, 1H, H-2), 3.45 (m, 2H, H-4, H-6a), 3.43
(2s, 6H, OCH3 major, OCH3 minor), 2.37 [dd, 0.52H, Jcis 8.8 Hz, Jtrans
6.5 Hz, PhCH(CH2)C(CH3)CH major], 2.31 [dd, 0.42H, Jcis 8.8 Hz, Jtrans
6.5 Hz, PhCH(CH2)C(CH3)CH minor], 1.23 [dd, 0.52H, Jgem 5.0 Hz, Jcis
8.9 Hz, PhCH(CHcisHtrans)C(CH3)CH major], 1.19 [dd, 0.42 H, Jgem
5.0 Hz, J 9.0 Hz, PhCH(CHcisHtrans)C(CH3)CH minor], 0.90 [m, 4H,
PhCH(CHAHB)C(CH3)CH]. 13C NMR (500 MHz, CDCl3): d 136.7–
1H, J4,5a 2.2 Hz, J5e,5a 13.2 Hz, H-5a), 2.26 [dd, 0.75H, Jcis 8.9 Hz, Jtrans
6.4 Hz, PhCH(CH2)C(CH3)CH major], 2.23 [dd, 0.25H, Jcis 8.9 Hz, Jtrans
6.4 Hz, PhCH(CH2)C(CH3)CH minor], 1.51, 1.34 [2s, 6H, C(CH3)2],
1.14 [dd, 1H, Jgem 5.1 Hz, Jcis 8.9 Hz, PhCH(CHcisHtrans)C(CH3)CH],
0.81 [s, 3H, PhCH(CH2)C(CH3)CH], 0.79 [m, 1H, PhCH(CHcis
-
Htrans)C(CH3)CH]. 13C NMR (500 MHz, CDCl3): d 138.5–125.9 (Ph),
111.8 [C(CH3)2], 105.7 (C-1), 103.4 [PhCH(CH2)C(CH3)CH minor],
103.1 [PhCH(CH2)C(CH3)CH major], 84.0 (C-2), 78.7 (C-3 minor),
78.6 (C-3 major), 72.4 (C-4), 66.5 (C-5), 26.8, 26.2 [C(CH3)2], 25.2
[PhCH(CH2)C(CH3)CH], 24.8 [PhCH(CH2)C(CH3)CH minor], 24.7
[PhCH(CH2)C(CH3)CH major], 14.0 [PhCH(CH2)C(CH3)CH], 13.7
[PhCH(CH2)C(CH3)CH]. HRMS (CI): [M+H]+, found 333.169907.
128.1
(Ph),
105.9
[PhCH(CH2)C(CH3)CH
minor],
105.0
[PhCH(CH2)C(CH3)CH major], 99.1 (C-1), 81.9 (C-4 minor), 81.7
(C-4 major), 78.9 (C-2), 78.4 (C-3 major), 78.3 (C-3 minor), 75.1,
73.3 (2 PhCH2O), 68.6 (C-6 minor), 68.7 (C-6 major), 62.4 (C-5 ma-
jor), 62.3 (C-5 minor), 55.3 (OCH3 minor), 55.2 (OCH3 major), 25.1
[PhCH(CH2)C(CH3)CH minor], 24.9 [PhCH(CH2)C(CH3)CH major],
24.8 [PhCH(CH2)C(CH3)CH], 14.5 [PhCH(CH2)C(CH3)CH major],
14.0 [PhCH(CH2)C(CH3)CH minor], 13.8 [PhCH(CH2)C(CH3)CH min-
or], 13.6 [PhCH(CH2)C(CH3)CH major]. HRMS (EI): [M]+Å, found
516.248457. C32H36O6 requires 516.251189.
C19H25O5 requires 333.170199. Anal. Calcd for C19H24O5: C,
68.66; H, 7.28. Found: C, 68.48; H, 7.21.
4.5. Separation of chiral auxiliary
A solution of the cyclopropylmethylidene acetal 23, 24, 32, 36
or 37 (0.4 mmol) in 80% acetic acid in water (20 mL) was heated
at 60 °C, and the reaction was monitored until TLC showed that
all the starting material had reacted (0.5 h). Then, the reaction mix-
ture was cooled to room temperature. The pH of the solution was
adjusted to 7.5 with saturated aqueous sodium bicarbonate solu-
tion, and the aqueous solution was extracted with ethyl acetate.
The organic layer was washed with water and saturated aqueous
sodium chloride solution, dried over MgSO4 and concentrated un-
der reduced pressure. The residue was purified by flash chromatog-
raphy on silica gel, using hexane–ethyl acetate (7:1) as eluent. The
sugar was recovered in good yield (70–85%) by elution with dichlo-
romethane–methanol mixture.
The aldehyde obtained was dissolved in ethanol (5 mL), and so-
dium borohydride (22 mg, 0.58 mmol) was added at room tempera-
ture. The reaction mixture was stirred for 1.5 h at room temperature,
and the reaction was quenched with saturated aqueous ammonium
chloride solution. After evaporation of the solvent, the solution was
diluted with water and tert-butyl methyl ether. The organic layer
was washed with water and saturated aqueous sodium chloride
solution, dried (MgSO4) and concentrated under reduced pressure.
The compound obtained was purified by flash chromatography on
silica gel, using hexane–ethyl acetate (4:1) as eluent.
4.4.10. 1-Dodecyl 2-acetamido-3-O-benzyl-2-deoxy-4,6-O-
[(1R,2R,3R)-(2-phenylcyclopropyl)methylidene]-b-D-
glucopyranoside 35
Two stereoisomers were obtained in a 27:10 ratio (46% de). The
pure diastereomeric mixture was obtained as a syrup by column
chromatography, using dichloromethane–methanol (80:1) as elu-
ent. Yield 0.46 g (76%); [a]D = +4.0 (c 4.6, CH2Cl2); MS (CI): m/z
608 (45%) [M+H]+. 1H NMR (500 MHz, CDCl3): d 7.6–7.1 (m, 10H,
Ph), 5.55 (d, 1H, J2,NH 7.2 Hz, NH), 4.90 (d, 1H, J1,2 8.3 Hz, H-1),
4.8–4.5 [m, 3H, PhCH(CH2)CHCH, PhCH2O], 2.10 [m, 1H,
PhCH(CH2)CHCH], 1.90 (s, 2.19H, CH3CON major), 1.83 (s, 0.81H,
CH3CON minor), 1.48 [m, 1H, PhCH(CH2)CHCH], 1.4–1.2 [m, 20H,
(CH2)10], 1.17 [m, 1H, PhCH(CHAHB)CHCH], 0.98 [m, 1H,
PhCH(CHAHB)CHCH], 0.90 (t, 3H,
J 6.8 Hz, CH3). HRMS (CI):
[M+H]+, found 607.38806. C37H54NO6 requires 607.38729.
4.4.11. 1,2-O-Isopropylidene-3,5-O-[(1S,2R,3R)-(2-phenyl-
cyclopropyl)methylidene]-a-D-xylofuranose 36
Two stereoisomers were obtained in a 9:1 ratio (80% de). Col-
umn chromatography, using hexane–ethyl acetate (8:1) as eluent,
gave the major diastereoisomer separated as a solid. Yield 0.27 g
(85%); mp 108–110 °C; [
319 (40%) [M+H]+. 1H NMR (500 MHz, CDCl3): d 7.4–7.1 (m, 5H,
Ph), 6.03 (d, 1H, J1,2 3.7 Hz, H-1), 4.42 [d, 1H, 4.7 Hz,
a
]
D = ꢀ60.4 (c 1.0, CH2Cl2); MS (CI): m/z
4.5.1. (1R,2R)-trans-1-Hydroxymethyl-2-phenylcyclo-
propane29,43 (ꢀ)-38
J
PhCH(CH2)CHCH], 4.58 (d, 1H, J1,2 3.7 Hz, H-2), 4.32 (d, 1H, J5e,5a
13.3 Hz, H-5e), 4.22 (d, 1H, J3,4 1.9 Hz, H-3), 4.04 (m, 1H, H-4),
4.32 (d, 1H, J5e,5a 13.3 Hz, H-5a), 2.07 [m, 1H, PhCH(CH2)CHCH],
1.50, 1.32 [2s, 6H, C(CH3)2], 1.45 [m, 1H, PhCH(CH2)CHCH], 1.14
[m, 1H, PhCH(CHAHB)CHCH], 0.92 [m, 1H, PhCH(CHAHB)CHCH].
13C NMR (125 MHz, CDCl3): d 141.8–125.7 (Ph), 111.7 [C(CH3)2],
105.6 (C-1), 100.3 [PhCH(CH2)CHCH], 83.8 (C-2), 78.5 (C-3), 72.2
(C-4), 66.4 (C-5), 26.7, 26.1 [C(CH3)2], 25.1 [PhCH(CH2)CHCH],
19.1 [PhCH(CH2)CHCH], 11.6 [PhCH(CH2)CHCH]. HRMS (CI):
[M+H]+, found 319.155503. C18H23O5 requires 319.15459. Anal.
Calcd for C18H22O5: C, 67.09; H, 6.62. Found: C, 66.80; H, 6.30.
1H NMR (500 MHz, CDCl3): d 7.6–7.1 (m, 5H, Ph), 3.63 [dd,
2H, J 6.8 Hz, Jgem 11.3 Hz, PhCH(CH2)CHCH2OH], 1.84 [m, 1H,
PhCH(CH2)CHCH2OH], 1.47 [m, 1H, PhCH(CH2)CHCH2OH], 0.98
[m, 2H, PhCH(CH2)CHCH2OH]. 13C NMR (125 MHz, CDCl3): d
136.7–128.1 (Ph), 66.5 [PhCH(CH2)CHCH2OH], 25.2 [PhCH-
(CH2)CHCH2OH], 21.3 [PhCH(CH2)CHCH2OH], 13.7 [PhCH(CH2)-
CHCH2OH].
4.5.1.1. From 23. Yield 46 mg (77%); [
{lit.43
D = ꢀ92 (c 1.23, EtOH)}.
a]D = ꢀ22.1 (c 1.0, CH2Cl2).
[a]
4.5.1.2. From 36. Yield 50 mg (84%); [
a]
D = ꢀ75.6 (c 1.0, CH2Cl2).
4.4.12. 1,2-O-Isopropylidene-3,5-O-[(1S,2R,3S)-(1-methyl-2-
phenylcyclopropyl)methylidene]-
a
-
D
-xylofuranose 37
4.5.2. (1S,2S)-trans-1-Hydroxymethyl-2-phenylcyclo-
Two stereoisomers were obtained in a 3:1 ratio (50% de). Col-
umn chromatography, using hexane–ethyl acetate (11:1) as eluent,
gave the major diastereoisomer separated as a solid. Yield 0.29 g
propane25,44 (+)-38
4.5.2.1. From 24. Yield 45 mg (75%); [
a]D = +46.0 (c 1.0, CH2Cl2).
{lit.44
[a]
D = +18.0 (c 0.84, CHCl3 as 39% ee)}.
(87%); mp 112–114 °C; [
a
]
D = ꢀ12.9 (c 0.9, CH2Cl2); MS (CI): m/z
333 (40%) [M+H]+. 1H NMR (500 MHz, CDCl3): d 7.4–7.1 (m, 5H,
Ph), 6.03 (d, 1H, J1,2 3.7 Hz, H-1), 4.59 (d, 1H, J1,2 3.8 Hz, H-2),
4.34 (d, 1H, J5e,5a 13.2 Hz, H-5e), 4.26 [s, 0.75H,
PhCH(CH2)C(CH3)CH major], 4.24 (d, 1H, J3,4 2.1 Hz, H-3), 4.21 [s,
0.25H, PhCH(CH2)C(CH3)CH minor], 4.05 (m, 1H, H-4), 3.95 (dd,
4.5.3. (1R,2S)-E-1-Methyl-2-phenylcyclopropanecarbo-
xaldehyde16 39
Yield 40 mg (63%) from 37. 1H NMR (500 MHz, CDCl3): d 8.50 [s,
1H, PhCH(CH2)C(CH3)CHO], 7.6–7.1 (m, 5H, Ph), 2.73 [dd, 1H,
Jcis 9.2 Hz, Jtrans 7.2 Hz, PhCH(CH2)C(CH3)CHO], 1.68 [dd, 1H,

J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 19 (2008) 1720–1729
1729
11. Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977–
1050.
12. Davies, H. M. L. Tetrahedron 1993, 49, 5203–5223.
13. Corsaro, A.; Pistarà, V.; Catelani, G.; D’Andrea, F.; Adamo, R.; Chiacchio, M. A.
Tetrahedron Lett. 2006, 47, 6591–6594.
14. Mash, E. A.; Nelson, K. A. Tetrahedron 1987, 43, 679–692.
15. Vallgarda, J.; Hacksell, U. Tetrahedron Lett. 1991, 32, 5625–5628.
16. Dubs, M.; Dieks, H.; Günther, W.; Kötteritzsch, M.; Poppitz, W.; Schönecker, B.
Tetrahedron Lett. 2002, 43, 2499–2503.
Jgem 5.3 Hz, Jcis 9.3 Hz, PhCH(CHcisHtrans)C(CH3)CHO], 1.43 [dd, 1H,
Jgem 5.4 Hz, Jtrans 7.2 Hz, PhCH(CHcisHtrans)C(CH3)CHO], 0.98 [s, 3H,
PhCH(CH2)C(CH3)CHO]. 13C NMR (125 MHz, CDCl3):
d 201.7
[PhCH(CH2)C(CH3)CHO], 136.7–128.1 (Ph), 34.3 [PhCH(CH2)-
C(CH3)CHO], 29.9 [PhCH(CH2)C(CH3)CHO], 17.7 [PhCH(CH2)C-
(CH3)CHO], 11.5 [PhCH(CH2)C(CH3)CHO].
17. Balsells, J.; Walsh, P. J. J. Org. Chem. 2000, 65, 5005–5008.
18. Charette, A. B.; Janes, M. K.; Lebel, H. Tetrahedron: Asymmetry 2003, 14, 867–
872.
19. Long, J.; Du, H.; Li, K.; Shi, Y. Tetrahedron Lett. 2005, 46, 2737–2740.
20. Du, H.; Long, J.; Shi, Y. Org. Lett. 2006, 2827–2829.
21. Hollingsworth, R. I.; Wang, G. Chem. Rev. 2000, 100, 4267–4282.
22. Kunz, H.; Rück, K. Angew. Chem., Int. Ed. Engl. 1993, 32, 336–358.
23. Adam, W.; Zhang, A. Synlett 2005, 1047–1072.
24. Pleuss, N.; Zech, G.; Furman, B.; Kunz, H. In Sugars as Chiral Auxiliaries; Levy, D.
E., Fügedi, P., Eds.; The Organic Chemistry of Sugars; Taylor & Francis Group:
Boca Raton, 2006; pp 427–488.
25. Charette, A. B.; Côté, B.; Marcoux, J.-F. J. Am. Chem. Soc. 1991, 113, 8166–8167.
26. Charette, A. B.; Côté, B. J. Org. Chem. 1993, 58, 933–936.
27. Charette, A. B.; Turcotte, N.; Marcoux, J.-F. Tetrahedron Lett. 1994, 35, 513–
516.
4.5.4. (1R,2S)-E-1-Hydroxymethyl-1-methyl-2-phenyl-
cyclopropane45,46(ꢀ)-40
1H NMR (500 MHz, CDCl3): d 7.3–7.1 (m, 5H, Ph), 3.56 [d, 2H,
Jgem 11.0 Hz, PhCH(CH2)C(CH3)CH2OH], 2.05 [dd, 1H, Jcis 8.7 Hz, Jtrans
6.0 Hz, PhCH(CH2)C(CH3)CH2OH], 1.52 (s, 1H, OH), 0.94 [dd, 1H,
Jgem 5.0 Hz, Jcis 8.8 Hz, PhCH(CHcisHtrans)C(CH3)CH2OH], 0.89 [s, 3H,
PhCH(CH2)C(CH3)CH2OH], 0.86 [m, 1H, PhCH(CHcisHtrans)C(CH3)-
CH2OH]. 13C NMR (125 MHz, CDCl3): d 136.7–128.1 (Ph), 71.7
[PhCH(CH2)C(CH3)CH2OH], 29.7 [PhCH(CH2)C(CH3)CH2OH], 26.8
[PhCH(CH2)C(CH3)CH2OH], 15.7 [PhCH(CH2)C(CH3)CH2OH], 15.1
[PhCH(CH2)C(CH3)CH2OH].
28. Ferreira, V. F.; Leao, R. A. C.; Silva, F. C.; Pinheiro, S.; Lhoste, P.; Sinou, D.
Tetrahedron: Asymmetry 2007, 18, 1217–1223.
29. Kang, J.; Lim, G. J.; Yoon, S. K.; Kim, M. Y. J. Org. Chem. 1995, 60, 564–577.
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1998, 308, 57–62.
4.5.4.1. From 32. Yield 35 mg (89%); [
a
]
D = ꢀ6.1 (c 1.1, CH2Cl2).
{lit.45
[a]D = ꢀ1.4 (c 5.00, CHCl3 as 5% ee)}.
31. Iglesias-Guerra, F.; Candela, J. I.; Bautista, J.; Alcudia, F.; Vega-Pérez, J. M.
Carbohydr. Res. 1999, 316, 71–84.
32. Iglesias-Guerra, F.; Candela, J. I.; Blanco, E.; Alcudia, F.; Vega-Pérez, J. M.
Chirality 2002, 14, 199–203.
4.5.4.2. From 37. Yield 32 mg (80%); [
a]
D = ꢀ16.6 (c 1.0, CH2Cl2).
{lit.46
D = ꢀ15.1 (c 0.12, CHCl3)}.
[a]
Acknowledgments
33. Vega-Pérez, J. M.; Candela, J. I.; Blanco, E.; Iglesias-Guerra, F. Tetrahedron 1999,
55, 9641–9650.
34. Vega-Pérez, J. M.; Candela, J. I.; Iglesias-Guerra, F. J. Org. Chem. 1997, 62, 6608–
6611.
35. Vega-Pérez, J. M.; Vega, M.; Blanco, E.; Iglesias-Guerra, F. Tetrahedron:
Asymmetry 2001, 12, 135–147.
36. Vega-Pérez, J. M.; Candela, J. I.; Romero, I.; Blanco, E.; Iglesias-Guerra, F. Eur. J.
Org. Chem. 2000, 3949–3956.
We thank Junta de Andalucía and Ministerio de Educación y
Ciencia (Spain), and the FEDER programme, for financial support
(P06-FQM-01885 and CTQ2007-61185). Ignacio Periñán thanks
Junta de Andalucía for a predoctoral grant.
37. Vega-Pérez, J. M.; Candela, J. I.; Blanco, E.; Iglesias-Guerra, F. Tetrahedron:
Asymmetry 2002, 13, 2471–2483.
38. Vega-Pérez, J. M.; Vega, M.; Blanco, E.; Iglesias-Guerra, F. Tetrahedron:
Asymmetry 2001, 12, 3189–3203.
39. Vega-Pérez, J. M.; Vega, M.; Blanco, E.; Iglesias-Guerra, F. Tetrahedron:
Asymmetry 2004, 15, 3617–3633.
40. Vega-Pérez, J. M.; Vega, M.; Blanco, E.; Iglesias-Guerra, F. Tetrahedron:
Asymmetry 2007, 18, 1850–1867.
41. Padwa, A.; Blacklock, T.; Tremper, A. Org. Synth. 1988, 6, 893–896.
42. Murphy, P. V.; O’Brien, J. L.; Gorey-Feret, L. J.; Smith, A. B. Tetrahedron 2003, 59,
2259–2271.
43. Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991,
113, 726–728.
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