The use of 1,2-O-isopropylidene-α-d-xylofuranose as a chiral auxiliary in asymmetric cyclopropanation reactions

Article abstract of DOI:10.1016/j.tetasy.2009.02.062

The stereoselective synthesis of cyclopropylmethylidene acetals derived from 1,2-O-isopropylidene-d-xylofuranose, as a chiral auxiliary, is described. The Simmons-Smith cyclopropanation reaction of the corresponding alkenylidene derivatives with CH_2<

Full text of DOI:10.1016/j.tetasy.2009.02.062

Tetrahedron: Asymmetry 20 (2009) 1065–1072
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Tetrahedron: Asymmetry
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The use of 1,2-O-isopropylidene-
a-D-xylofuranose as a chiral auxiliary
in asymmetric cyclopropanation reactions
*
*
José M. Vega-Pérez , Ignacio Periñán, 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 cyclopropylmethylidene acetals derived from 1,2-O-isopropylidene-D-
Received 4 February 2009
Accepted 23 February 2009
Available online 7 May 2009
xylofuranose, as a chiral auxiliary, is described. The Simmons–Smith cyclopropanation reaction of the
corresponding alkenylidene derivatives with CH2I2/ZnEt2, in different reaction conditions, took place with
high stereoselectivity. The diastereomeric excess in each case depended on the solvent and the temper-
ature used in the reaction. The absolute configuration of the new stereogenic centres formed was deter-
mined by acid hydrolysis of the cyclopropane moiety of the chiral auxiliary, which was also recovered.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
ever, there are few precedents for the use of carbohydrates as chi-
ral auxiliaries in the asymmetric cyclopropanation reaction of
The importance of chirality is well recognised, mainly in connec-
tion with the fact that nearly all natural products are chiral and their
physiological or pharmacological properties depend upon their rec-
ognition by chiral receptors, which will interact only with molecules
of the proper absolute configuration. At the same time, the chiral
cyclopropane moiety is present in a number of natural and synthetic
compounds, as well as in molecules used to probe biological and
pharmacological processes;1–6 thus, optically active 2-substituted
1-cyclopropanecarboxylates, especially 2-phenyl-1-cyclopropane-
carboxylates, are very useful intermediates in the synthesis of chiral
compounds, and are present in many biologically important sub-
stances.7,8 Compounds containing cyclopropanes have been used
extensively as a probe to solve mechanistic problems.9,10 In the last
few years, efforts have been made to develop new and more efficient
methods for the preparation of these entities in enantiomerically
pure form. General methods for the stereoselective synthesis of
the cyclopropane ring have been reviewed recently.2,11–13 Enantio-
selective methylenation cyclopropanation methods for prochiral al-
kenes have been carried out using chiral auxiliaries9,14–16 or chiral
catalysts.17–20 Cyclopropanes have also been used as versatile syn-
thetic intermediate in the synthesis of more functionalised cycloal-
kanes and acyclic compounds.13,21,22
olefins,38–42 the most important being those in which the chiral
auxiliary is linked to the olefin moiety via a glycosidic bond, mak-
ing the final separation difficult.
In a previous paper43 we used sugar derivatives as chiral auxilia-
ries in the Simmons–Smith cyclopropanation reaction. We studied
the cyclopropanation reaction, using the diiodomethane/diethyl-
zinc system, of the double bond of acetals of trans-cinnamaldehyde
and
ride derivatives of alkyl
deoxy- -glucopyranoside, 1,2-O-isopropylidene-
alkyl rhamnopyranoside and 1,2-O-isopropylidene-
a
-methyl-trans-cinnamaldehyde with different monosaccha-
-glucopyranoside, alkyl 2-acetamido-2-
-glucofuranose,
-xylofuranose.
D
D
D
D
In order to find the substrate giving the best yields and diastereo-
meric excesses, we diversified the chiral substrate, varyied the
carbohydrate configuration, protected the hydroxyl groups and
the size of the sugar and acetal rings. We found that the best diaste-
reomeric excesses were obtained when 1,2-O-isopropylidene-
D-xylofuranose was used as a chiral auxiliary.
For this reason, we have chosen 1,2-O-isopropylidene-D-xylof-
uranose as a chiral auxiliary for the optimisation of the Sim-
mons–Smith cyclopropanation with a wide range of alkenes,
under different experimental conditions of solvents and tempera-
tures. The results obtained are reported in this paper. It is impor-
tant to point out that the union of the olefin to the carbohydrate
across an acetal function allowed easy separation of the new chiral
cyclopropane fragment and the chiral auxiliary by acid hydrolysis,
obtaining functionalised chiral cyclopropanes which can be used as
building blocks in different synthetic routes.
Carbohydrates contain several functional groups and stereo-
genic centres in one molecular unit, which allows the use of car-
bohydrates as tools in stereochemical differentiations, as the
starting materials in syntheses of interesting enantiopure com-
pounds,23–26 as chiral templates in asymmetric transformations27
and as chiral auxiliaries in stereoselective syntheses.28–37 How-
2. Results and discussion
The synthesis of the new alkenylidene acetals 13–24, substrates
* Corresponding authors. Tel./fax: +34 95 4556737.
for the cyclopropanation reaction, has been carried out by reaction
E-mail addresses: vega@us.es (J.M. Vega-Pérez), iglesias@us.es (F. Iglesias-Guerra).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.062

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J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 20 (2009) 1065–1072
of 1,2-O-isopropylidene-
D
-xylofuranose 1 and the corresponding
(R1 = H, entry 12) was obtained with 100% de, while 34 (R1 – H, en-
try 20) was obtained with 67% de; (c) the des obtained from pro-
pylidene acetals with hindered substituents on carbon three
were higher than those obtained from acetals with smaller substit-
uents on carbon three; thus, compounds 27 (R3 = o-MeOC6H4) and
30 (R3 = n-C7H15) were obtained with des of 77% (entry 7) and 100%
(entry 12), while compounds 28 (R3 = p-MeOC6H4) and 29
(R3 = CH3) were obtained with des of 46% (entry 8) and 60% (entry
10); (d) the des obtained from propylidene acetals with two sub-
stituents on carbon three were higher than those obtained from
acetals with one substituent on carbon three; thus, compound 31
(R2 = R3 = Ph) gave 100% de (entry 15) while compound 25
(R2 = H, R3 = Ph) gave 82% de (entry 2).
unsaturated aldehyde dimethyl acetals 2–12 in good yields,
employing the procedure described by Murphy et al.44 for the for-
mation of acetals using the aldehyde dimethyl acetal as a reagent
(Scheme 1). Compounds 13–24 were obtained as only one stereo-
isomer, in all cases with an (S)-configuration at the acetal carbon,
established by 2D-NOESY experiments in each case. The reaction
of 1 with
a-hexylcinnamaldehyde dimethyl acetal (11E + 11Z)
gave two compounds 22 and 23 as a stereoisomeric mixture. Col-
umn chromatography was used to separate compounds 22 and
23, whose configurations E and Z, respectively, were determined
by 2D-NOESY experiments.
The cyclopropanation reactions of compounds 13–16, 18–22
and 24 were carried out using the CH2I2/ZnEt2 system as a reagent
and different solvents and reaction temperatures, giving com-
pounds 25–34 (Scheme 2), which were isolated and purified by
flash chromatography on silica gel. The compound obtained from
17 was not recovered, it is assumed that it partitioned into the
aqueous layer on work-up when aqueous ammonium chloride
was added. However, subsequent extraction after this layer had
been made alkaline with sodium hydroxide did not provide any
appreciable amount of material. When the starting compound
was 23, the reaction gave a complex mixture of cyclopropanes de-
tected by 1H NMR but not isolated. The diastereomeric excess (de)
in each case was determined by 1H NMR, and is shown in Table 1.
The data shown in the table indicate that the diastereomeric ex-
cesses (des) obtained in the cyclopropanation of the compounds
studied are different depending on the solvent and temperature
used in the reaction. The des are higher when lower temperatures
are used. At temperatures below À20 °C, the solubility of the start-
ing material is low and the times of reaction are considerably long-
er. With regard to solvent, the experimental data show that the des
obtained in 1,2-dichloroethane or toluene are higher than those
from dichloromethane. The combined use of low temperature
and 1,2-dichloroethane as a solvent gave the best result in des:
compounds 30 and 31 were both obtained with 100% de using
these temperature and solvent conditions. With regard to the de-
gree of substitution of the double bond in the starting propylidene
acetals, the experimental data show that (a) the de obtained
from trans-cinnamaldehyde acetal (R1 = H, entry 2) was higher
In order to assign the configuration of the stereogenic centres
in the cyclopropane ring formed during the cyclopropanation
reaction, we proceeded to separate the chiral auxiliary by hydro-
lysis with 80% acetic acid and subsequent reduction with sodium
borohydride to give the corresponding hydroxymethylcyclopro-
pane, with recovery of the carbohydrate derivative (Scheme 3).
The absolute stereochemistry of the cyclopropane ring, (2R,3R)
for 25, 26 and 30, (2R) for 31, and (2R,3S) for 32, was deduced
by correlation with (1R,2R)-trans-1-hydroxymethyl-2-phenylcy-
clopropane45 (À)-35 obtained from 25, by correlation with
(1R,2R)-trans-1-hydroxymethyl-2-(o-nitrophenyl)cyclopropane46
(+)-36 obtained from 26, by correlation with (1R)-1-hydroxy-
methyl-2,2-diphenyclopropane46,47 (+)-38 obtained from 31,
and by correlation with (1R,2S)-E-1-hydroxymethyl-1-methyl-
2-phenylcyclopropane48 (À)-39 obtained from 32. The configura-
tion of the other cyclopropanes listed in Table 1 was established
from the analysis of the chemical shifts of the protons and the
carbons corresponding to the cyclopropane acetal system in
the NMR spectra.
3. Conclusion
In conclusion, in the cyclopropanation reaction of propylidene
acetals derived from 1,2-O-isopropylidene-D-xylofuranose pre-
sented here, (a) in all cases studied the more reactive face is always
the same one; its notation being Re,Re in compounds with one aro-
matic substituent on carbon three, Re when the compound has two
substituents on carbon three, and Re,Si in compounds with one al-
kyl substituent on carbon three; (b) the diastereomeric excesses
(des) were found to depend on the solvent and the reaction tem-
perature, the best des being obtained when 1,2-dichloroethane
than those obtained from
a-alkyl-trans-cinnamaldehyde acetal
(R1 – H, entries 18 and 19); thus, compound 25 was obtained with
82% de, while compounds 32 and 33 were obtained with des of 76%
and 66%, respectively; (b) in this same aspect, compound 30
H
R1
H
O
O
HO
HO
R1
O
O
R3
OMe
+
MeCN
CSA
O
O
R3
O
R2
OMe
2−12
H
O
H
R2
1
13−23
2 and 13 R1 = H , R2 = H, R3 = Ph
OMe
OMe
3 and 14 R1 = H , R2 = H, R3 = o-NO2C6H4
4 and 15 R1 = H , R2 = H, R3 = o-MeOC6H4
5 and 16 R1 = H , R2 = H, R3 = p-MeOC6H4
6 and 17 R1 = H , R2 = H, R3 = p-Me2NC6H4
7 and 18 R1 = H , R2 = H, R3 = Me
MeCN
CSA
12
H
H
O
8 and 19 R1 = H , R2 = H, R3 = n-C7H15
9 and 20 R1 = H , R2 = Ph, R3 = Ph
O
O
O
10 and 21 R1 = Me , R2 = H, R3 = Ph
O
11E and 22 R1 = n-C6H13 , R2 = H, R3 = Ph
11Z and 23 R1 = n-C6H13 , R2 = Ph, R3 = H
H
H
24
Scheme 1.

J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 20 (2009) 1065–1072
1067
H
H
H
O
H
O
O
O
R1
R2
R1
O
O
CH2I2 / ZnEt2
CH2Cl2
O
O
R3
O
R3
O
H
H
H
H
R2
13−16, 18−22, 24
25 R1 = H , R2 = H, R3 = Ph
26 R1 = H , R2 = H, R3 =
27 R1 = H , R2 = H, R3 =
28 R1 = H , R2 = H, R3 =
o
o
p
-NO2C6H4
-MeOC6H4
-MeOC6H4
CH2I2 / ZnEt2 / CH2Cl2
H
29 R1 = H , R2 = H, R3 = Me
H
O
30 R1 = H , R2 = H, R3 =
n
-C7H15
O
O
31 R1 = H , R2 = Ph, R3 = Ph
32 R1 = Me , R2 = H, R3 = Ph
O
O
n
33 R1 = -C6H13 , R2 = H, R3 = Ph
H
H
34
Scheme 2.
Table 1
Cyclopropanation of a,b-unsaturated acetal derivatives 13–24
Entry
Starting compound
Reaction product
Solvent
Temp (°C)
Yielda (%)
Deb (%)
Major cyclopropane configuration
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
13
13
14
14
14
15
15
16
18
18
18
19
20
20
20
20
21
21
22
24
25c
25
26
26
26
27
27
28
29
29
29
30
31
31
31
31
32c
32
33
34
CH2Cl2
ClCH2CH2Cl
CH2Cl2
PhMe
ClCH2CH2Cl
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
À15
85
77
80
82
75
75
78
33
77
46
56
65
60
100
82
85
100
20
50
76
66
67
(2R,3R)
(2R,3R)
(2R,3R)
(2R,3R)
(2R,3R)
(2R,3R)
(2R,3R)
(2R,3R)
(2R,3R)
(2R,3R)
(2R,3R)
(2R,3R)
(2R)
(2R)
(2R)
(2R)
(2R,3S)
(2R,3S)
(2R,3S)
(2R,3R)
À20 to 0
À20 to 0
À20 to 0
À20 to 0
À20 to 0
À30
84
86
77
À30
À20 to 0
À20 to 0
À20 to 0
À20 to 0
À20 to 0
À20 to 0
À20 to 0
20
PhMe
76
74
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
PhMe
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
69
À15
87
75
72
79
À20 to 0
À20 to 0
À20 to 0
a
Yields refer to compounds obtained in each reaction after isolation and purification.
Determined by integration in 1H NMR spectra of reaction mixtures.
Ref. 43.
b
c
H
H
O
O
R1
O
O
R3
O
H
H
R2
i
i
25, 26, 30−32
(R)
(R)
Ph
OH
Ph
OH
(S)
(R)
i
i
i
(−)-35
(−)-39
(R)
OH
(R)
(R)
(R)
Ph
Ph
OH
OH
(−)-37
(R)
NO2
(+)-38
(+)-36
Scheme 3. Reagents: (i) 1. AcOH 80%; 2. NaBH4.

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J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 20 (2009) 1065–1072
and the lowest temperature are used; (c) 1,2-O-isopropylidene-
xylofuranose is a good chiral auxiliary in the reaction of cycloprop-
anation of propylidene acetals.
D
-
HRMS (CI): [M+H]+, found 335.1492. C18H23O6 requires 335.1495.
Anal. Calcd for C18H22O6: C, 64.66; H, 6.63. Found: C, 64.65; H, 6.77.
4.2.3. 1,2-O-Isopropylidene-3,5-O-[(S,E)-3-(4-methoxyphenyl)-
2-propenylidene]-a-D-xylofuranose 16
4. Experimental
4.1. General
The solid was purified by column chromatography, using hex-
ane–ethyl acetate (4:1) as eluent. Yield 1.39 g (83%); mp 164–
166 °C, [a]
D = +13.0 (c 1.0, CH2Cl2); MS (EI): m/z 334 (85%) [M]+Å.
1H NMR (500 MHz, CDCl3): d 7.3–6.8 (m, 4H, Ar), 6.72 [d, 1H, Jtrans
16.1 Hz, ArCH@CHCH], 6.07 (d, 1H, J1,2 3.7 Hz, H-1), 6.03 [dd, 1H,
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 at
125 MHz for 13C. The chemical shifts are reported in ppm on the
d scale relative to TMS. COSY, HSQC and NOESY experiments were
performed to assign the signals in the NMR spectra.
Jtrans 16.1 Hz,
J 5.0 Hz, ArCH@CHCH], 5.08 [d, 1H, J 5.0 Hz,
ArCH@CHCH], 4.62 (d, 1H, J1,2 3.7 Hz, H-2), 4.39 (d, 1H, J5e,5a
13.2 Hz, H-5e), 4.33 (d, 1H, J3,4 1.7 Hz, H-3), 4.09 (m, 1H, H-4),
4.06 (dd, 1H, J4,5a 1.8 Hz, J5e,5a 13.2 Hz, H-5a), 3.80 (s, 3H, OCH3),
1.51, 1.34 [2s, 6H, C(CH3)2]. 13C NMR (125 MHz, CDCl3): d 159.8–
113.9 (Ar), 133.6 [ArCH@CHCH], 122.2 [ArCH@CHCH], 111.8
[C(CH3)2], 105.6 (C-1), 99.1 [ArCH@CHCH], 83.8 (C-2), 78.6 (C-3),
72.2 (C-4), 66.4 (C-5), 55.2 (OCH3), 26.7, 26.1 [C(CH3)2]. HRMS
(EI): [M]+Å, found 334.1406. C18H22O6 requires 334.1416. Anal.
Calcd for C18H22O6: C, 64.66; H, 6.63. Found: C, 64.37; H, 6.59.
4.2.4. 3,5-O-[(S,E)-3-(4-Dimethyaminophenyl)-2-propenylid-
ene]-1,2-O-isopropylidene-
The syrup was purified by column chromatography, using hex-
ane–ethyl acetate (4.5:1) as eluent. Yield 1.53 g (88%); [ D = +19.3
(c 1.0, CH2Cl2); MS (CI): m/z 348 (65%) [M+H]+. 1H NMR (500 MHz,
CDCl3): 7.3–6.8 (m, 4H, Ar), 6.69 [d, 1H, Jtrans 16.2 Hz,
ArCH@CHCH], 6.07 (d, 1H, J1,2 3.7 Hz, H-1), 5.97 [dd, 1H, Jtrans
16.2 Hz, J 5.2 Hz, ArCH@CHCH], 5.07 [dd, 1H, J 5.2 Hz, 4J 1.0 Hz,
ArCH@CHCH], 4.61 (d, 1H, J1,2 3.7 Hz, H-2), 4.38 (d, 1H, J5e,5a
13.2 Hz, H-5e), 4.32 (d, 1H, J3,4 1.9 Hz, H-3), 4.08 (m, 1H, H-4),
4.05 (dd, 1H, J4,5a 2.0 Hz, J5e,5a 13.1 Hz, H-5a), 2.96 [s, 6H,
N(CH3)2], 1.51, 1.34 [2s, 6H, C(CH3)2]. 13C NMR (125 MHz, CDCl3):
d 134.3 [ArCH@CHCH], 128.0–112.1 (Ar), 120.0 [ArCH@CHCH],
111.8 [C(CH3)2], 105.7 (C-1), 99.7 [ArCH@CHCH], 83.9 (C-2), 78.7
(C-3), 72.2 (C-4), 66.4 (C-5), 40.3 [(NCH3)2], 26.7, 26.2 [C(CH3)2].
HRMS (EI): [M]+Å, found 347.1723. C19H25NO5 requires 347.1733.
Anal. Calcd for C19H25NO5: C, 65.69; H, 7.25; N, 4.03. Found: C,
65.35; H, 7.17; N, 4.15.
a-D-xylofuranose 17
4.2. General procedure for synthesis of
a
,b-unsaturated acetals
a]
To solution of 1,2-O-isopropylidene-
a
a-D
-xylofuranose
1
(0.95 g, 5.0 mmol) in acetonitrile (30 mL), the aldehyde dimethy-
lacetals 2–12 (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 the product obtained was chromatographed, giving
compounds 13–23 in good yields.
d
4.2.1. 1,2-O-Isopropylidene-3,5-O-[(S,E)-3-(2-nitrophenyl)-2-
propenylidene]-a-D-xylofuranose 14
The solid was purified by column chromatography, using hex-
ane–ethyl acetate (4:1) as eluent. Yield 1.57 g (90%); mp 70–71 °C,
[
a
]
D = À12.5 (c 0.6, CH2Cl2); MS (CI): m/z 350 (100%) [M+H]+. 1H
NMR (500 MHz, CDCl3): d 7.9–7.4 (m, 4H, Ar), 7.21 (d, 1H, Jtrans
15.9 Hz, ArCH@CHCH), 6.07 (dd, 1H, Jtrans 15.9 Hz,
J 4.6 Hz,
4.2.5. 3,5-O-[(S,E)-2-Butenylidene]-1,2-O-isopropylidene-a-D-
ArCH@CHCH), 6.00 (d, 1H, J1,2 3.7 Hz, H-1), 5.12 (d, 1H, J 4.5 Hz,
ArCH@CHCH), 4.56 (d, 1H, J1,2 3.7 Hz, H-2), 4.34–4.31 (m, 2H, H-3,
H-5e), 4.06–4.03 (m, 2H, H-4, H-5a), 1.45, 1.28 [2s, 6H, C(CH3)2].
13C NMR (125 MHz, CDCl3): d 148.0–124.6 (Ar), 129.7 (ArCH@
CHCH), 129.4 (ArCH@CHCH), 111.9 [C(CH3)2], 105.6 (C-1), 98.1
(ArCH@CHCH), 83.7 (C-2), 78.6 (C-3), 72.1 (C-4), 66.4 (C-5), 26.7,
26.1 [C(CH3)2]. HRMS (CI): [M+H]+, found 350.123545, C17H20NO7
requires 350.123977. Anal. Calcd for C17H19NO7: C, 58.45; H, 5.48;
N, 4.01. Found: C, 58.48; H, 5.46; N, 4.25.
xylofuranose 18
The compound was purified by column chromatography, using
hexane–ethyl acetate (7:1) as eluent, obtaining a syrup. Yield
0.93 g (77%); [
a
]
D = À6.2 (c 1.1, CH2Cl2); MS (CI): m/z 243 (100%)
[M+H]+. 1H NMR (500 MHz, CDCl3): d 6.01 (d, 1H, J1,2 3.6 Hz, H-
1), 5.91 (m, 1H, CH3CH@CHCH), 5.48 (m, 1H, CH3CH@CHCH), 4.85
(d, 1H, J 5.3 Hz, CH3CH@CHCH), 4.54 (d, 1H, J1,2 3.6 Hz, H-2), 4.30
(d, 1H, J5e,5a 13.3 Hz, H-5e), 4.23 (d, 1H, J3,4 1.7 Hz, H-3), 4.01 (m,
1H, H-4), 3.97 (dd, 1H, J4,5a 1.9 Hz, J5e,5a 13.2 Hz, H-5a), 1.70 (dd,
3H, 4J 1.1 Hz,
J 6.6 Hz, CH3CH@CHCH), 1.46, 1.29 [2s, 6H,
C(CH3)2]. 13C NMR (125 MHz, CDCl3): d 131.4 (CH3CH@CHCH),
127.2 (CH3CH@CHCH), 111.6 [C(CH3)2], 105.5 (C-1), 99.2
(CH3CH@CHCH), 83.7 (C-2), 78.4 (C-3), 72.0 (C-4), 66.2 (C-5),
26.6, 26.0 [C(CH3)2], 17.5 (CH3CH@CHCH). HRMS (CI): [M+H]+,
found 243.123087. C12H19O5 requires 243.123249.
4.2.2. 1,2-O-Isopropylidene-3,5-O-[(S,E)-3-(2-methoxyphenyl)-
2-propenylidene]-a-D-xylofuranose 15
The solid was purified by column chromatography, using hex-
ane–ethyl acetate (3.5:1) as eluent. Yield 1.34 g (80%); mp 168–
169 °C, [a]D = +5.4 (c 1.0, CH2Cl2); MS (CI): m/z 335 (100%)
[M+H]+. 1H NMR (500 MHz, CDCl3): d 7.4–6.8 (m, 4H, Ar), 7.08 [d,
1H, Jtrans 16.2 Hz, ArCH@CHCH], 6.22 [dd, 1H, Jtrans 16.2 Hz, J
5.1 Hz, ArCH@CHCH], 6.07 (d, 1H, J1,2 3.7 Hz, H-1), 5.10 [dd, 1H, J
5.0 Hz, 4J 1.0 Hz, ArCH@CHCH], 4.62 (d, 1H, J1,2 3.7 Hz, H-2), 4.39
(d, 1H, J5e,5a 13.1 Hz, H-5e), 4.33 (d, 1H, J3,4 1.9 Hz, H-3), 4.09 (m,
1H, H-4), 4.06 (dd, 1H, J4,5a 2.0 Hz, J5e,5a 13.1 Hz, H-5a), 3.84 (s,
3H, OCH3), 1.51, 1.34 [2s, 6H, C(CH3)2]. 13C NMR (125 MHz, CDCl3):
d 157.2–110.8 (Ar), 129.4 [ArCH@CHCH], 124.8 [ArCH@CHCH],
111.8 [C(CH3)2], 105.7 (C-1), 99.6 [ArCH@CHCH], 83.9 (C-2), 78.7
(C-3), 72.2 (C-4), 66.4 (C-5), 55.4 (OCH3), 26.7, 26.2 [C(CH3)2].
4.2.6. 3,5-O-[(S,E)-2-Decenylidene]-1,2-O-isopropylidene-a-D-
xylofuranose 19
The compound was purified by column chromatography, using
hexane–ethyl acetate (8:1) as eluent, obtaining a syrup. Yield
1.30 g (80%); [
a]
D = À3.6 (c 1.3, CH2Cl2); MS (EI): m/z 326 (20%)
[M+H]+. 1H NMR (500 MHz, CDCl3): d 6.04 (d, 1H, J1,2 3.7 Hz, H-
1), 5.93 (m, 1H, RCH2CH@CHCH), 5.49 (m, 1H, RCH2CH@CHCH),
4.88 (d, 1H, J 5.4 Hz, RCH2CH@CHCH), 4.58 (d, 1H, J1,2 3.7 Hz, H-
2), 4.33 (d, 1H, J5e,5a 13.2 Hz, H-5e), 4.26 (d, 1H, J3,4 1.8 Hz, H-3),

J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 20 (2009) 1065–1072
1069
4.04 (m, 1H, H-4), 3.99 (dd, 1H, J4,5a 1.9 Hz, J5e,5a 13.2 Hz, H-5a),
2.05 (m, 2H, RCH2CH@CHCH), 1.49, 1.32 [2s, 6H, C(CH3)2], 1.4–
1.2 [m, (CH2)5], 0.87 (t, 3H, J 6.9 Hz, CH3). 13C NMR (125 MHz,
CDCl3): d 136.8 (RCH2CH@CHCH), 125.7 (RCH2CH@CHCH), 111.8
[C(CH3)2], 105.6 (C-1), 99.3 (RCH2CH@CHCH), 83.8 (C-2), 78.5 (C-
3), 72.1 (C-4), 66.3 (C-5), 32.0, 31.8, 29.2, 29.1, 28.5, 22.6
[(CH2)6], 26.7, 26.1 [C(CH3)2], 14.1 (CH3). HRMS (EI): [M]+Å, found
326.2085. C18H30O5 requires 326.2093.
1H, J1,2 3.7 Hz, H-2), 4.34 (d, 1H, J5e,5a 13.2 Hz, H-5e), 4.26 (d, 1H,
J3,4 1.9 Hz, H-3), 4.04 (m, 1H, H-4), 3.99 (dd, 1H, J4,5a 1.9 Hz, J5e,5a
13.2 Hz, H-5a), 2.06–2.04 (m, 4H, 2CH2), 1.63–1.59 (m, 4H, 2CH2),
1.49, 1.33 [2s, 6H, C(CH3)2]. 13C NMR (125 MHz, CDCl3): d 134.7
(CH@CCH), 126.7 (CH@CCH), 111.7 [C(CH3)2], 105.6 (C-1), 101.5
(CH@CCH), 83.9 (C-2), 78.6 (C-3), 72.2 (C-4), 66.5 (C-5), 26.7, 26.2
[C(CH3)2], 24.7, 23.0, 22.2, 22.1 (4CH2). HRMS (EI): [M]+Å, found
282.1457. C15H22O5 requires 282.1467. Anal. Calcd for C15H22O5:
63.81; H, 7.85. Found: 63.80; H, 7.93.
4.2.7. 3,5-O-[(S)-3,3-Diphenyl-2-propenylidene]-1,2-O-isopro-
pylidene-a-D-xylofuranose 20
4.3. General procedure for cyclopropanation of
acetals
a,b-unsaturated
The solid was purified by column chromatography, using
hexane–ethyl acetate (8:1) as eluent. Yield 1.80 g (94%); mp 188–
To a solution of the corresponding unsaturated acetals 13–16,
18–22 and 24 (1.0 mmol) in dry solvent (10–30 mL) at the corre-
sponding temperature (Table 1) were added 1.0 M diethylzinc in
hexane (5.0 mL, 5.0 mmol) and diiodomethane (0.8 mL,
10.0 mmol). The reaction mixture was stirred for 1 h at À5 °C,
and then kept at room temperature until a check by TLC showed
that all the starting material had reacted (ꢀ12 h). The reaction
mixture was diluted with dichloromethane and the reaction was
quenched with saturated ammonium chloride solution. The organ-
ic layer was dried (MgSO4), filtered and evaporated to dryness.
Compounds obtained were purified by flash chromatography on
silica gel. The diastereomeric excesses (des) were determined by
1H NMR, and are shown in Table 1.
189 °C, [
a
]
D = À53.7 (c 1.0, CH2Cl2); MS (EI): m/z 380 (100%)
[M]+Å. 1H NMR (500 MHz, CDCl3): d 7.4–7.2 (m, 10H, Ph), 6.08–6.07
(m, 2H, Ph2C@CHCH, H-1), 4.84 (d, 1H, J 7.3 Hz, Ph2C@CHCH), 4.61
(d, 1H, J1,2 3.7 Hz, H-2), 4.31 (d, 1H, J5e,5a 13.3 Hz, H-5e), 4.17 (d,
1H, J3,4 2.0 Hz, H-3), 3.98 (m, 1H, H-4), 3.87 (dd, 1H, J4,5a 2.0 Hz,
J5e,5a 13.3 Hz, H-5a), 1.48, 1.34 [2s, 6H, C(CH3)2]. 13C NMR
(125 MHz, CDCl3): d 147.1 (Ph2C@CHCH), 141.0–127.9 (2Ph), 123.8
(Ph2C@CHCH), 111.8 [C(CH3)2], 105.6 (C-1), 97.5 (Ph2C@CHCH],
83.9 (C-2), 78.2 (C-3), 72.0 (C-4), 66.1 (C-5), 26.7, 26.2 [C(CH3)2].
HRMS (EI): [M]+Å, found 380.1616. C23H24O5 requires 380.1624. Anal.
Calcd for C23H24O5: C, 72.61; H, 6.36. Found: C, 72.59; H, 6.38.
4.2.8. 3,5-O-[(S,E)-2-Hexyl-3-phenyl-2-propenylidene]-1,2-O-
isopropylidene-
The syrup was purified by column chromatography, using hex-
ane–ethyl acetate (8:1) as eluent. Yield 1.40 g (72%); [ D = +15.0
a-D-xylofuranose 22
4.3.1. 1,2-O-Isopropylidene-3,5-O-[(1S,2R,3R)-(2-phenylcyclo-
propyl)methylidene]-a-D-xylofuranose 25
a
]
Two stereoisomers were obtained in a 10:1 ratio (82% de), using
1,2-dichloroethane as the reaction solvent. The solid was purified
by column chromatography, using hexane–ethyl acetate (8:1) as
(c 1.0, CH2Cl2); MS (CI): m/z 389 (80%) [M+H]+. 1H NMR (500 MHz,
CDCl3): d 7.4–7.2 (m, 5H, Ph), 6.71 [s, 1H, PhCH@C(C6H13)CH], 6.06
(d, 1H, J1,2 3.7 Hz, H-1), 4.96 [d, 1H, 4J 0.9 Hz, PhCH@C(C6H13)CH],
4.63 (d, 1H, J1,2 3.7 Hz, H-2), 4.41 (d, 1H, J5e,5a 13.2 Hz, H-5e), 4.33
(d, 1H, J3,4 2.0 Hz, H-3), 4.10 (m, 1H, H-4), 4.05 (dd, 1H, J4,5a 2.0 Hz,
J5e,5a 13.2 Hz, H-5a), 2.31 [m, 2H, PhCH@C(CH2R)CH], 1.52, 1.35
[2s, 6H, C(CH3)2], 1.3–1.2 [m, (CH2)4], 0.87 (t, 3H, J 7.1 Hz, CH3).
13C NMR (125 MHz, CDCl3): d 138.5 [PhCH@C(C6H13)CH], 136.9–
128.1 (Ph), 126.8 [PhCH@C(C6H13)CH], 111.8 [C(CH3)2], 105.7 (C-
1), 101.3 [PhCH@C(C6H13)CH], 84.0 (C-2), 78.9 (C-3), 72.3 (C-4),
66.7 (C-5), 31.5, 29.5, 28.7, 27.6, 22.6 [(CH2)5], 26.8, 26.2 [C(CH3)2],
14.0 (CH3). HRMS (CI): [M+H]+, found 389.2313. C23H33O5 requires
389.2328.
eluent. Yield 0.25 g (77%); [
a
]
D = À61.7 (c 1.0, CH2Cl2). {lit.43
[a
]D = À60.4 (c 1.0, CH2Cl2 as 80% de)}.
4.3.2. 1,2-O-Isopropylidene-3,5-O-{(1S,2R,3R)-2-[(2-nitrophen-
yl)cyclopropyl]methylidene}- -xylofuranose 26
a-D
Two stereoisomers were obtained in an 8.1:1 ratio (78% de), using
1,2-dichloroethane as the reaction solvent. The syrup was purified
by column chromatography, using hexane–ethyl acetate (5:1) as
eluent. Yield 0.30 g (84%); [
a]
D = À42.8 (c 0.9, CH2Cl2); MS (EI): m/z
363 (5%) [M]+Å. 1H NMR (500 MHz, CDCl3): d 7.8–7.2 (4H, Ar), 6.06
(d, 0.89H, J1,2 3.7 Hz, H-1 major), 6.03 (d, 0.11H, J1,2 3.7 Hz, H-1 min-
or), 4.59 (d, 1H, J1,2 3.7 Hz, H-2), 4.54 [d, 0.89H,
J 4.3 Hz,
4.2.9. 3,5-O-[(S,Z)-2-Hexyl-3-phenyl-2-propenylidene]-1,2-O-
ArCH(CH2)CHCH major], 4.52 [s, 0.11H, J 4.3 Hz, ArCH(CH2)CHCH
minor], 4.32 (d, 1H, J5e,5a 13.2 Hz, H-5e), 4.24 (d, 1H, J3,4 1.9 Hz, H-
3), 4.05 (m, 1H, H-4), 3.96 (dd, 1H, J4,5a 2.0 Hz, J5e,5a 13.2 Hz, H-5a),
2.55 [m, 1H, ArCH(CH2)CHCH], 1.50, 1.34 [2s, 6H, C(CH3)2], 1.46
[m, 1H, ArCH(CH2)CHCH], 1.27 [m, 1H, ArCH(CHAHB)CHCH], 0.92
[m, 1H, ArCH(CHAHB)CHCH]. 13C NMR (500 MHz, CDCl3): d 150.9–
124.2 (Ar), 111.8 [C(CH3)2], 105.7 (C-1), 99.6 [ArCH(CH2)CHCH min-
or], 99.2 [ArCH(CH2)CHCH major], 83.9 (C-2), 78.7 (C-3 minor), 78.5
(C-3 mayor), 72.3 (C-4), 66.4 (C-5), 26.7, 26.2 [C(CH3)2], 24.5
[ArCH(CH2)CHCH], 16.6 [ArCH(CH2)CHCH minor], 16.4 [ArCH
(CH2)CHCH major], 10.1 [ArCH(CH2)CHCH minor], 9.8 [ArCH(CH2)
CHCH major]. HRMS (EI): [M]+Å, found 363.133598. C18H21NO7
requires 363.131802.
isopropylidene-
The syrup was purified by column chromatography, using hex-
ane–ethyl acetate (8:1) as eluent. Yield 0.40 g (21%); [
a-D-xylofuranose 23
a]
D = À52.9 (c
1.2, CH2Cl2); MS (CI): m/z 389 (65%) [M+H]+. 1H NMR (500 MHz,
CDCl3): d 7.4–7.2 (m, 5H, Ph), 6.51 [s, 1H, PhCH@C(C6H13)CH],
6.04 (d, 1H, J1,2 3.7 Hz, H-1), 5.15 [s, 1H, PhCH@C(C6H13)CH], 4.58
(d, 1H, J1,2 3.7 Hz, H-2), 4.31 (d, 1H, J5e,5a 13.2 Hz, H-5e), 4.23 (d,
1H, J3,4 2.0 Hz, H-3), 4.01 (m, 1H, H-4), 3.92 (dd, 1H, J4,5a 2.0 Hz,
J5e,5a 13.2 Hz, H-5a), 2.30 [m, 2H, PhCH@C(CH2R)CH], 1.6–1.2 [m,
(CH2)4], 1.49, 1.34 [2s, 6H, C(CH3)2], 0.90 (t, 3H,
J 7.0 Hz,
CH3). HRMS (CI): [M+H]+, found 389.2316. C23H33O5 requires
389.2328.
4.2.10. 3,5-O-[(S)-(1-Cyclohexenyl)methylidene]-1,2-O-isopro-
pylidene-a-D-xylofuranose 24
4.3.3. 1,2-O-Isopropylidene-3,5-O-{(1S,2R,3R)-2-[(2-methoxy-
phenyl)cyclopropyl]methylidene}-a-D-xylofuranose 27
The compound was purified by column chromatography, using
Two stereoisomers were obtained in a 7.7:1 ratio (77% de), using
1,2-dichloroethane as the reaction solvent. The syrup was purified
by column chromatography using hexane–ethyl acetate (4:1) as elu-
hexane–ethyl acetate (10:1) as eluent, obtaining a solid. Yield
1.33 g (94%); mp 94–95 °C, [
a]
D = À2.8 (c 1.0, CH2Cl2); MS (EI): m/z
282 (100%) [M]+Å. 1H NMR (500 MHz, CDCl3): d 6.03 (d, 1H, J1,2
3.7 Hz, H-1), 5.91 (s, 1H, CH@CCH), 4.74 (s, 1H, CH@CCH), 4.58 (d,
ent. Yield 0.30 g (86%); [a]D = À60.6 (c 1.0, CH2Cl2); MS (EI): m/z 348

1070
J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 20 (2009) 1065–1072
(70%) [M]+Å. 1H NMR (500 MHz, CDCl3): d 7.2–6.8 (4H, Ar), 6.04 (d,
1H, J1,2 3.7 Hz, H-1), 4.60 (d, 1H, J1,2 3.7 Hz, H-2), 4.40 [d, 0.88H, J
5.0 Hz, ArCH(CH2)CHCH major], 4.37 [s, 0.12H, J 5.0 Hz, ArCH
(CH2)CHCH minor], 4.32 (d, 1H, J5e,5a 13.2 Hz, H-5e), 4.23 (d, 1H,
J3,4 1.9 Hz, H-3), 4.05 (m, 1H, H-4), 3.95 (2dd, 1H, J4,5a 2.0 Hz,
J5e,5a 13.3 Hz, H-5a), 3.85 (s, 0.36H, OCH3 minor), 3.84 (s, 2.64H,
OCH3 major), 2.27 [m, 1H, ArCH(CH2)CHCH], 1.54 [m, 1H,
ArCH(CH2)CHCH], 1.50, 1.33 [2s, 6H, C(CH3)2], 1.13 [m, 1H, ArCH
(CHAHB)CHCH], 0.85 [m, 1H, ArCH(CHAHB)CHCH]. 13C NMR
(500 MHz, CDCl3): d 158.1, 129.9, 126.7, 125.7, 120.5, 110.3 (Ar),
111.8 [C(CH3)2], 105.7 (C-1), 101.0 [ArCH(CH2)CHCH minor], 100.9
[ArCH(CH2)CHCH major], 83.8 (C-2), 78.7 (C-3 minor), 78.6 (C-3 ma-
jor), 72.3 (C-4), 66.4 (C-5), 55.5 (OCH3), 26.7, 26.1 [C(CH3)2], 23.6
[ArCH(CH2)CHCH minor], 23.5 [ArCH(CH2)CHCH major], 13.9
[ArCH(CH2)CHCH], 11.0 [ArCH(CH2)CHCH minor], 10.9 [ArCH(CH2)
CHCH major]. HRMS (EI): [M]+Å, found 348.1573. C19H24O6 requires
348.1573.
4.3.6. 3,5-O-[(1S,2R,3R)-(2-Heptylcyclopropyl)methylidene]-
1,2-O-isopropylidene- -xylofuranose 30
Only one stereoisomer was obtained (100% de). The syrup was
purified by column chromatography, using hexane–ethyl acetate
a
-D
(10:1) as eluent. Yield 0.25 g (74%); [
a]
D = À26.7 (c 1.0, CH2Cl2);
MS (CI): m/z 341 (30%) [M+H]+. 1H NMR (500 MHz, CDCl3): d 6.02
(d, 1H, J1,2 3.7 Hz, H-1), 4.56 (d, 1H, J1,2 3.7 Hz, H-2), 4.29 (d, 1H,
J5e,5a 13.2 Hz, H-5e), 4.16 (d, 1H, J 1.9 Hz, H-3), 4.05 [d, 1H, J
5.8 Hz, RCH2CH(CH2)CHCH], 4.00 (m, 1H, H-4), 3.89 (dd, 1H, J4,5a
1.9 Hz, J5e,5a 13.2 Hz, H-5a), 1.48, 1.31 [2s, 6H, C(CH3)2], 1.4–1.1
[m, (CH2)6], 0.87 [m, 4H, CH3(CH2)5CH2CH(CH2)CHCH], 0.80 [m,
1H, RCH2CH(CH2)CHCH], 0.55 [m, 1H, RCH2CH(CHAHB)CHCH],
0.32 [m, 1H, RCH2CH(CHAHB)CHCH]. 13C NMR (125 MHz, CDCl3):
d 111.7 [C(CH3)2], 105.6 (C-1), 102.2 [RCH2CH(CH2)CHCH], 83.8
(C-2), 78.5 (C-3), 72.2 (C-4), 66.4 (C-5), 33.3, 31.9, 29.3, 29.2, 22.6
[(CH2)6]. 26.7, 26.1 [C(CH3)2], 21.7 [RCH2CH(CH2)CHCH], 15.3
[RCH2CH(CH2)CHCH], 14.1 (CH3), 8.4 [RCH2CH(CH2)CHCH],]. HRMS
(CI): [M+H]+, found 341.2320. C19H33O5 requires 341.2328.
4.3.4. 1,2-O-Isopropylidene-3,5-O-{(1S,2R,3R)-2-[(4-methoxy-
phenyl)cyclopropyl]methylidene}-a-D-xylofuranose 28
Two stereoisomers were obtained in a 2:1 ratio (46% de), using
1,2-dichloroethane as the reaction solvent. The syrup was purified
by column chromatography, using hexane–ethyl acetate (3:1) as
4.3.7. 3,5-O-[(1S,2R)-(2,2-Diphenylcyclopropyl)methylidene]-
1,2-O-isopropylidene-a-D-xylofuranose 31
Only one stereoisomer was obtained (100% de), using 1,2-
dichloroethane as the reaction solvent. The syrup was purified by
column chromatography, using hexane–ethyl acetate (6:1) as elu-
eluent. Yield 0.27 g (77%); [
a
]D = À36.9 (c 1.0, CH2Cl2); MS (EI):
m/z 348 (65%) [M]+Å. 1H NMR (500 MHz, CDCl3): d 7.1–6.7 (4H,
Ar), 6.04 (m, 1H, H-1), 4.58 (d, 1H, J1,2 3.7 Hz, H-2), 4.35 [d,
0.67H, J 5.0 Hz, ArCH(CH2)CHCH major], 4.37 [s, 0.33H, J 5.0 Hz,
ArCH(CH2)CHCH minor], 4.32 (2d, 1H, J5e,5a 13.2 Hz, H-5e), 4.24
(d, 1H, J3,4 1.8 Hz, H-3), 4.04 (m, 1H, H-4), 3.94 (2dd, 1H, J4,5a
2.0 Hz, J5e,5a 13.3 Hz, H-5a), 3.77 (s, 1.00H, OCH3 minor), 3.77 (s,
2.00H, OCH3 major), 2.00 [m, 1H, ArCH(CH2)CHCH], 1.50, 1.33
[2s, 6H, C(CH3)2], 1.41 [m, 1H, ArCH(CH2)CHCH], 1.09 [m, 1H,
ArCH(CHAHB)CHCH], 0.85 [m, 1H, ArCH(CHAHB)CHCH]. 13C NMR
(500 MHz, CDCl3): d 157.8–127.3 (Ar), 113.7 [C(CH3)2], 105.6 (C-
1), 100.7 [ArCH(CH2)CHCH minor], 100.6 [ArCH(CH2)CHCH major],
83.8 (C-2), 78.7 (C-3 minor), 78.6 (C-3 major), 72.2 (C-4), 66.4 (C-
5), 55.3 (OCH3), 26.7, 26.1 [C(CH3)2], 24.9 [ArCH(CH2)CHCH minor],
24.7 [ArCH(CH2)CHCH major], 18.6 [ArCH(CH2)CHCH minor], 18.5
[ArCH(CH2)CHCH major], 11.3 [ArCH(CH2)CHCH minor], 11.2
[ArCH(CH2)CHCH major]. HRMS (EI): [M]+Å, found 348.1561.
C19H24O6 requires 348.1573.
ent. Yield 0.27 g (69%); [a]D = +77.0 (c 1.1, CH2Cl2); MS (CI): m/z
395 (10%) [M+H]+. 1H NMR (500 MHz, CDCl3): d 7.5–7.1 (10H,
2Ph), 6.12 (d, 1H, J1,2 3.7 Hz, H-1), 4.69 (d, 1H, J1,2 3.7 Hz, H-2),
4.28 (d, 1H, J5e,5a 13.3 Hz, H-5e), 3.92 (m, 2H, H-3, H-4), 4.76 (dd,
1H, J4,5a 2.0 Hz, J5e,5a 13.3 Hz, H-5a), 3.62 [d, 1H,
J 7.8 Hz,
(Ph)2C(CH2)CHCH], 2.05 [m, 1H, (Ph)2C(CH2)CHCH], 1.53, 1.40
[2m, 2H, (Ph)2C(CH2)CHCH], 1.50, 1.38 [2s, 6H, C(CH3)2]. 13C NMR
(500 MHz, CDCl3): d 145.6–126.1 (2Ph), 111.7 [C(CH3)2], 105.7 (C-
1), 101.5 [(Ph)2C(CH2)CHCH], 83.9 (C-2), 78.5 (C-3), 72.1 (C-4),
66.5 (C-5), 34.9 [(Ph)2C(CH2)CHCH], 28.7 [(Ph)2C(CH2)CHCH],
26.7, 26.2 [C(CH3)2], 16.9 [(Ph)2C(CH2)CHCH]. HRMS (CI): [M+H]+,
found 395.1859. C24H27O5 requires 395.1858.
4.3.8. 1,2-O-Isopropylidene-3,5-O-[(1S,2R,3S)-(1-methyl-2-
phenylcyclopropyl)methylidene]-a-D-xylofuranose 32
Two stereoisomers were obtained in a 6.5:1 ratio (76% de),
using 1,2-dichloroethane as the reaction solvent. The solid was
purified by column chromatography, using hexane–ethyl acetate
(11:1) as eluent. Yield 0.25 g (75%); [
a
]
D = À17.8 (c 0.9, CH2Cl2).
4.3.5. 1,2-O-Isopropylidene-3,5-O-[(1S,2R,3R)-(2-methylcyclo-
propyl)methylidene]-a-D-xylofuranose 29
Two stereoisomers were obtained in a 4.7:1 ratio (65% de), using
toluene as the reaction solvent. The solid was purified by column
chromatography, using hexane–ethyl acetate (7:1) as eluent. Yield
{lit.43
[a]
D = À12.9 (c 0.9, CH2Cl2 as 50% de)}.
4.3.9. 3,5-O-[(1S,2R,3S)-(1-Hexyl-2-phenylcyclopropyl)meth-
ylidene]-1,2-O-isopropylidene- -xylofuranose 33
a-D
0.19 g (76%); mp 74–75 °C; [
a
]D = À21.2 (c 1.0, CH2Cl2); MS (CI): m/
Two stereoisomers were obtained in a 4.9:1 ratio (66% de), using
1,2-dichloroethane as the reaction solvent. The syrup was purified
by column chromatography, using hexane–ethyl acetate (18:1) as
z 257 (100%) [M+H]+. 1H NMR (500 MHz, CDCl3): d 6.03 (d, 1H, J1,2
3.6 Hz, H-1), 4.56 (d, 1H, J1,2 3.6 Hz, H-2), 4.30 (d, 1H, J5e,5a 13.2 Hz,
H-5e), 4.16 (m, 1H, H-3), 4.11 [d, 1H, J 5.0 Hz, CH3CH(CH2)CHCH min-
or], 4.04 [d, 1H, J 5.3 Hz, CH3CH(CH2)CHCH major], 4.01 (m, 1H, H-4),
3.89 (m, 1H, H-5a), 1.48, 1.32 [2s, 6H, C(CH3)2], 1.03 [m, 3H,
CH3CH(CH2)CHCH], 0.9–0.8 [m, 2H, CH3CH(CH2)CHCH], 0.59 [m,
1H, CH3CH(CHAHB)CHCH], 0.30 [m, 1H, CH3CH(CHAHB)CHCH]. 13C
NMR(125 MHz, CDCl3):d111.7[C(CH3)2 major], 111.6[C(CH3)2 min-
or], 105.6 (C-1), 102.2 [CH3CH(CH2)CHCH major], 101.8 [CH3
CH(CH2)CHCH minor], 83.8 (C-2), 78.6 (C-3 minor), 78.5 (C-3 major),
72.2 (C-4), 66.4 (C-5), 26.7, 26.1 [C(CH3)2], 22.9 [CH3CH-
(CH2)CHCH major], 22.7 [CH3CH(CH2)CHCH minor], 18.2 [CH3
CH(CH2)CHCH minor], 18.2 [CH3CH(CH2)CHCH major], 9.6 [CH3CH-
(CH2)CHCH], 9.4 [CH3CH(CH2)CHCH major], 9.3 [CH3CH(CH2)CHCH
minor]. HRMS (CI): [M+H]+, found 257.138960. C13H21O5 requires
257.138899. Anal. Calcd for C13H20O5: C, 60.92; H, 7.87. Found: C,
60.97; H, 7.93.
eluent. Yield 0.29 g (72%); [
a]
D = À16.9 (c 0.9, CH2Cl2); MS (CI): m/z
403 (50%) [M+H]+. 1H NMR (500 MHz, CDCl3): d 7.3–7.1 (5H, Ph),
6.02 (d, 0.82H, J1,2 3.7 Hz, H-1 major), 6.00 (d, 0.18H, J1,2 3.6 Hz, H-
1 minor), 4.59 (d, 0.82H, J1,2 3.7 Hz, H-2 major), 4.59 (d, 0.18H, J1,2
3.7 Hz, H-2 minor), 4.52 [s, 0.82H, PhCH(CH2)C(C6H13)CH major],
4.50 [s, 0.18H, PhCH(CH2)C(C6H13)CH minor], 4.33 (d, 1H, J5e,5a
13.2 Hz, H-5e), 4.23 (m, 1H, H-3), 4.05 (m, 1H, H-4), 3.94 (dd, 1H,
J4,5a 1.8 Hz, J5e,5a 13.2 Hz, H-5a), 2.35 [m, 1H, PhCH(CH2)C(C6H13)CH],
1.51, 1.34 [2s, 6H, C(CH3)2], 1.3–0.8 [m, 15H, PhHC(CH2)C(C6H13)CH].
13C NMR (500 MHz, CDCl3): d 138.7–125.7 (Ph), 111.8 [C(CH3)2],
105.7 (C-1), 101.0 [PhC(CH2)C(C6H13)CH minor], 100.8 [PhC(CH2)
C(C6H13)CH major], 84.0 (C-2), 78.7 (C-3 minor), 78.5 (C-3 major),
72.4 (C-4), 66.5 (C-5), 31.6–14.1 [PhCH(CH2)C(C6H13)CH], 26.8,
26.2 [C(CH3)2], 12.2 [PhCH(CH2)C(C6H13)CH]. HRMS (CI): [M+H]+,
found 403.2486. C24H35O5 requires 403.2484.

J. M. Vega-Pérez et al. / Tetrahedron: Asymmetry 20 (2009) 1065–1072
1071
4.3.10. 1,2-O-Isopropylidene-3,5-O-[(1S,2R,3R)-(1,2-methyli-
denecyclohexyl)methylidene]- -xylofuranose 34
Two stereoisomers were obtained in a 5:1 ratio (67% de), using
1,2-dichloroethane as the reaction solvent. The syrup was purified
by column chromatography, using hexane–ethyl acetate (10:1) as
d 7.9–7.2 (m, 4H, Ar), 3.75 [dd, 1H, J 5.8 Hz, Jgem 11.4 Hz, ArCH
(CH2)CHCHAHBOH], 3.55 [dd, 1H, J 7.4 Hz, Jgem 11.4 Hz, ArCH
(CH2)CHCHAHBOH], 2.30 [m, 1H, ArCH(CH2)CHCH2OH], 1.88 (s,
1H, OH), 1.35 [m, 1H, ArCH(CH2)CHCH2OH], 1.08, 0.90 [2 m, 2H,
ArCH(CH2)CHCH2OH]. 13C NMR (125 MHz, CDCl3): d 150.7, 136.6,
132.9, 128.6, 126.8, 124.4 (Ar), 66.2 [ArCH(CH2)CHCH2OH], 24.7
[ArCH(CH2)CHCH2OH], 19.1 [ArCH(CH2)CHCH2OH], 11.1 [ArCH
(CH2)CHCH2OH]. HRMS (CI): [M+H]+, found 194.0817. C10H12NO3
requires 194.0817.
a-D
eluent. Yield 0.23 g (79%); [
a
]
D = À10.0 (c 1.0, CH2Cl2); MS (CI): m/z
297 (15%) [M+H]+. 1H NMR (500 MHz, CDCl3): d 6.00 (d, 1H, J1,2
3.7 Hz, H-1), 4.56 (d, 0.18H, J1,2 3.7 Hz, H-2 minor), 4.54 (d, 0.82H,
J1,2 3.7 Hz, H-2 major), 4.30, 4.28 (2d, 1H, J5e,5a 13.2 Hz, H-5e), 4.16
(d, 0.18H, J 1.9 Hz, H-3 minor), 4.15 (d, 0.82H, J 1.9 Hz, H-3 major),
3.98 [m, 0.18H, CH(CH2)CCH minor], 3.93 [m, 0.82H, CH(CH2)CCH
major], 3.90–3.85 (m, 2H, H-4, H-5a), 2.0–1.0 (m, 8H, 4CH2 cyclo-
hexyl), 1.48, 1.32 [2s, 6H, C(CH3)2], 0.98 [m, 1H, CH(CH2)CCH], 0.69
[m, 1H, CH(CHAHB)CCH], 0.26 [dd, 0.82H, Jgem 4.6 Hz, J 5.8 Hz,
CH(CHAHB)CCH major], 0.22 [dd, 0.18H, Jgem 4.6 Hz, J 5.8 Hz,
4.4.3. (1R,2R)-trans-1-Heptyl-2-hydroxymethylcyclopropane
(À)-37
A syrup was obtained. Yield 59 mg (87%); [
a
]
D = À17.6 (c 0.5,
CH2Cl2); MS (CI): m/z 171 (5%) [M+H]+. 1H NMR (500 MHz, CDCl3):
d 3.43 [m, 2H, CH3(CH2)6CH(CH2)CHCH2OH], 1.42–1.15 [m, 13H,
CH3(CH2)6CH(CH2)CHCH2OH], 0.88 [t, 3H, J 7.0 Hz, CH3(CH2)6-
CH(CH2)CHCH2OH], 0.83 [m, 1H, CH3(CH2)6CH(CH2)CHCH2OH],
0.59 [m, 1H, CH3(CH2)6CH(CH2)CHCH2OH], 0.36, 0.30 [2m, 2H,
CH3(CH2)6CH(CH2)CHCH2OH]. 13C NMR (125 MHz, CDCl3): d 67.3
[CH3(CH2)6CH(CH2)CHCH2OH], 33.6, 31.9, 29.6, 29.4, 29.3, 22.7
[CH3(CH2)6CH(CH2)CHCH2OH], 21.2 [CH3(CH2)6CH(CH2)CHCH2OH],
17.4 [CH3(CH2)6CH(CH2)CHCH2OH], 14.1 [CH3(CH2)6CH(CH2)-
CHCH2OH], 9.9 [CH3(CH2)6CH(CH2)CHCH2OH].
CH(CHAHB)CCH minor]. 13C NMR (125 MHz, CDCl3):
d 111.7
[C(CH3)2], 105.7 (C-1), 104.8 [CH(CH2)CCH major], 104.5 [CH(CH2)
CCH minor], 83.9 (C-2), 78.6 (C-3 minor), 78.5 (C-3 major), 72.3 (C-
4), 66.5 (C-5 minor), 66.4 (C-5 major), 26.7, 26.1 [C(CH3)2], 23.8,
23.1, 22.0, 21.5, 21.0 (cyclohexyl), 14.1 [CH(CH2)CCH major], 14.0
[CH(CH2)CCH minor], 13.7 [CH(CH2)CCH major], 13.6 [CH(CH2)CCH
minor]. HRMS (CI): [M+H]+, found 297.1689. C16H25O5 requires
297.1702.
4.4.4. (1R)-1,1-Diphenyl-2-hydroxymethylcyclopropane46,47 (+)-
38
4.4. Separation of the chiral auxiliary
A syrup was obtained. Yield 76 mg (85%); [
a]D = +21.1 (c 0.5,
A solution of the cyclopropylmethylidene acetals 25, 26 and 30–
32 (0.4 mmol) in 80% acetic acid in water (20 mL) was heated at
60 °C, and the reaction was monitored until a check by TLC showed
that all the starting material had reacted (0.5 h). Then, the reaction
mixture was cooled to room temperature, the pH of the solution
was adjusted to 7.5 with saturated aqueous sodium bicarbonate
solution, and the aqueous solution was extracted with ethyl ace-
tate. The organic layer was washed with water and saturated aque-
ous sodium chloride solution, dried (MgSO4) and concentrated
under reduced pressure. The residue was purified by flash chroma-
tography on silica gel, using hexane–ethyl acetate (7:1) as eluent.
The sugar was recovered in good yield (70–85%) by elution with
dichloromethane-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 mixture as eluent.
CH2Cl2), {lit.47
[a]D = +167 (c 0.30, CHCl3)}; MS (CI): m/z 225 (40%)
[M+H]+. 1H NMR (500 MHz, CDCl3): d 7.5–7.2 (m, 10H, 2Ph), 3.67
[m, 2H, Ph2C(CH2)CHCH2OH], 3.10 (s, 1H, OH), 2.43 [m, 1H, Ph2C-
(CH2)CHCH2OH], 1.60 [m, 2H, Ph2C(CH2)CHCH2OH]. 13C NMR
(125 MHz, CDCl3): d 147.1, 128.1, 126.8, 126.1 (2Ph), 77.9 [Ph2C-
(CH2)CHCH2OH], 63.2 [Ph2C(CH2)CHCH2OH], 38.9 [Ph2C(CH2)-
CHCH2OH], 27.2 [Ph2C(CH2)CHCH2OH]. HRMS (CI): [M+H]+, found
225.1285. C16H17O requires 225.1279.
4.4.5. (1R,2S)-E-1-Hydroxymethyl-1-methyl-2-phenylcyclo-
propane48 (À)-39
Yield 32 mg (80%); [
a]
D = À23.7 (c 1.0, CH2Cl2), {lit.48
[a]
D = À15.1
(c 0.12, CHCl3)}; MS (CI): m/z 163 (20%) [M+H]+. 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].
Acknowledgements
4.4.1. (1R,2R)-trans-1-Hydroxymethyl-2-phenylcyclopropane45
(À)-35
We thank the Junta de Andalucía and the Ministerio de Educa-
ción y Ciencia (Spain), and the FEDER programme, for financial
support (P06-FQM-01885 and CTQ2007-61185). Ignacio Periñán
thanks the Junta de Andalucía for a predoctoral grant.
A syrup was obtained. Yield 48 mg (81%); [
a]
D = À78.2 (c 1.1,
CH2Cl2), {lit.45
[a
]D = À92 (c 1.23, EtOH)}; MS (CI): m/z 149 (20%)
[M+H]+. 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].
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