Comparison of the conformational properties of carbasugars and glycosides: The role of the endocyclic oxygen

Article abstract of DOI:10.1016/j.carres.2012.02.018

A series of carbasugars were prepared and their conformational properties studied by means of NMR spectroscopy. The results were compared to those previously found for O-, S-, and C-β-glycoside analogs. While the rotational populations of the hydroxymethy

Full text of DOI:10.1016/j.carres.2012.02.018

Carbohydrate Research 352 (2012) 101–108
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Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Comparison of the conformational properties of carbasugars and glycosides:
the role of the endocyclic oxygen
⇑
⇑
Carlos Mayato, Rosa L. Dorta , José M. Palazón, Jesús T. Vázquez
Instituto Universitario de Bio-Orgánica ‘Antonio González’, Departamento de Química Orgánica, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez, 2, 38206 La Laguna,
Tenerife, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of carbasugars were prepared and their conformational properties studied by means of NMR
spectroscopy. The results were compared to those previously found for O-, S-, and C-b-glycoside analogs.
While the rotational populations of the hydroxymethyl group in O-, S-, and C-glycosides are known to
depend on the structural nature of their aglycon, in carbasugars it proved to be independent of the
pseudo-aglycon. This result confirms that endocyclic oxygen is necessary for the observed relationship
between the structure of the aglycon and the rotational populations of the hydroxymethyl group, and
indicates that the stereoelectronic exo-anomeric effect is mainly responsible for such conformational
dependence.
Received 22 November 2011
Received in revised form 18 February 2012
Accepted 20 February 2012
Available online 3 March 2012
Keywords:
Carbasugars
Conformational analysis
Stereoelectronic effects
Glycosides
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
endo
O
O
Recent studies on the reactivity of glycosides have revealed an
extremely interesting relationship between the populations of
the hydroxymethyl group, namely of the gg, gt, and tg rotamers,
and the reactivity at the anomeric carbon.1 This observation is
coherent with our previous conformational studies, on the rota-
tional dependence of the hydroxymethyl group on the structure
of the aglycon in O-,2 S-,3 and C-glycosides.4 The stereoelectronic
exo- and endo-anomeric effects (Fig. 1),5–7 in O- and S-glycosides,
and the exo-deoxoanomeric effect,8 in C-glycosides, may well be
involved in these conformational relationships, non-bonded inter-
actions between these groups being excluded.
Carbasugars, carbohydrates in which the ring oxygen is re-
placed by a methylene group, are attractive carbohydrate mimics
because of their chemical stability and biological properties.9,10
Moreover, in these analogs the exo-and endo-anomeric effects can-
not be present. If these stereoelectronic effects are involved in the
above-mentioned conformational dependence in glycosides, and
assuming that non-bonded interactions between the hydroxy-
methyl group and the aglycon do not operate, the rotameric popu-
lation about the hydroxymethyl group should be independent of
the aglycon nature in the case of carbasugars. In other words, the
Φ O
R
exo
R
exo
O
β-anomers
α-anomers
Figure 1. Alkyl b-D- and a-D-glucopyranosides showing the orbitals involved in the
exo- and endo-anomeric effects.
To test our hypothesis and gain further insight into the factors
influencing the conformational preferences of the hydroxymethyl
group in glycosides, a simple, readily accessible set of conveniently
substituted carbocycles were synthesized and conformationally
analyzed in solution by NMR spectroscopy. The results were com-
pared to those previously found for O-, S-, and C-b-glycoside
analogues.
2. Results and discussion
2.1. Synthesis
There are a plethora of different approaches for the synthesis of
carbapyranosides.12 To obtain a set of them with the appropriate
substituent for comparison with the O- and C-glycosides, the syn-
thetic approach shown in Scheme 1 was envisioned. The carbasug-
ar analogs were prepared through Yu’s protocol,13 starting from a
non-carbohydrate starting material, the commercially available
( )-3-cyclohexene carboxylic acid.
populations of the hydroxymethyl group (torsion angle
x,
Fig. 2)11 in carbasugars will be completely independent of the
structure of the pseudo-anomeric aglycon.
⇑
Corresponding authors. Tel.: +34 922318581; fax: +34 922318571.
E-mail address: jtruvaz@ull.es (J.T. Vázquez).
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.02.018

102
C. Mayato et al. / Carbohydrate Research 352 (2012) 101–108
was 81% and 91%, respectively; only in the case of cyclohexyl
(a) 6
7
ω
ω
derivative 2c was it low (31%). In addition, the silyl derivative 2e
was obtained with a 96% yield by the conventional procedure using
tert-butylsilyl chloride and imidazole.
4
5
4
O
6
Y
O
R
R
1
3
H
H
Reduction of the ester derivatives by LiAlH4 afforded the
corresponding primary alcohols 3a–e, in excellent yields (86–96%).
Catalytic osmylation of the olefins, using OsO4 and N-methyl-
glc, gal, man
Y = O, CH2, S
R = Me, iPr, Cy, tBu, TBS
carbapyranosides
15
morpholine N-oxide in acetone–water (6:1), resulted in the
cis-hydroxylation on the opposite face from the neighboring ether
group. Then the compounds were acetylated to give the corre-
sponding alkyl b-deoxocarbapyranosides 4a–e in good yields
(78–98%). In addition, the silyl compound 4e was deprotected by
adding Py–HF to give 5 in 84% yield. Treatment of 5 with acetic
anhydride and pyridine led to compound 6 in 97% yield. The 4-
deoxysugar 7 was prepared as described by Hirota et al.,16 in order
to compare its conformational properties with those of our model
carbasugars. Compounds 11a and 12 were obtained from com-
pounds 3a and 3d by treating them first with m-CPBA in CH2Cl2
at room temperature overnight to give compounds 10a and 10d,
respectively, and then by opening the epoxides with acetic anhy-
dride and a catalytic amount of H2SO4.
(b)
H7R
H7S
C6
H7R
C4
C6
C4
C6
C4
H7S
H7S
H7R
H5
H5
H5
gg
gt
tg
Figure 2. (a) Molecular structure of glycopyranosides (left) and carbapyranosides
(right), blue color showing identical structural pattern (upper line). (b) Rotamers
around the C5–C7 bond in carbapyranosides: gauche–gauche (gg), gauche–trans (gt),
and trans–gauche (tg) (bottom line).
As shown in Scheme 1, this carboxylic acid reacted under stan-
dard iodolactonization conditions to give the corresponding trans-
iodolactone. After elimination of iodine with DBU and treatment
with sodium methoxide in methanol, the methyl 5-hydroxy-3-
cyclohexene-1-carboxylate 1 was obtained in 96% yield. These
methanolysis conditions improved on those previously pub-
lished,13a using NaHCO3 in MeOH and obtaining compound 1 in
81% yield.
2.2. Characterization and spectroscopic analysis
Compounds 2–6, and 10–12 were characterized on the basis of
their one- (1H and 13C) and two-dimensional (COSY, HSQC, and T-
ROESY) NMR spectra. The configuration of the stereogenic carbons
C1, C2, and C3 of compounds 4a–e, 5, and 6 was assigned in each
case on the basis of the H–H coupling constants. The substituents
on C1 were found to be in axial disposition and those on C2 and
C3 equatorial, and the ring adopts a 6C3 chair conformation, as
shown in Figure 2, equivalent to the 4C1 chair conformation of gly-
cosides. This is in agreement with the conclusions of a conforma-
tional study carried out with six methyl carbapyranosides,17
based on NMR comparison of the chemical shifts and coupling
constants of these compounds with the corresponding glycosides.
The 1H NMR chemical shifts in CDCl3 and CD3CN of the prochiral
protons at C7 of compounds 4a–c, 4e and 5 were in close proximity
(Fig. 3). Only the tert-butyl derivative 4d showed isochronic signals
The alkylation of the allylic alcohol with sodium hydride and
methyl iodide in DMF provided the methyl ether derivative 2a
(92%).14 A number of different trials were carried out to prepare
t
iPr, Cy, and Bu analogs, varying conditions (AgClO4, AgBF4, AgF,
AgNO3, Ag2O, AgO2CCF3 and AgOTf) and solvents (CH2Cl2, CH3CN,
toluene, and cyclohexane). The best conditions for the introduction
of the alkyl group were: the use of Ag2O, alkyl iodides, and cyclo-
hexane as solvent. Except acetonitrile, the rest of the solvents were
i
t
also effective. The yield for the Pr and Bu derivatives 2b and 2d
OAc
OH
7
5
CO2H
CO2Me
CO2Me
1
1
a, b
c, d, or e
f
g
5
5
1
3
78−98%AcO
OR
96%
81−96%
86−96%
3
3
OH
OR
OR
OAc
4a−e
1
2a−e
3a−e
R = Me, iPr, Cy, tBu, and TBS
OAc
OAc
OAc
OAc
7
6
6
AcO
5
5
5
O
O
O
4
1
1
1
1
3
AcO
OR
AcO
OAc AcO
SEt AcO
SEt
OAc
OAc
OAc
OAc
5 (R = H)
7
8
9
6 (R = Ac)
OAc
OH
OH
7
5
1
1
h
i
1
3
5
5
3
3
60−77%
60−65%
AcO
OR
OR
OR
O
OAc
3a (R = Me)
3d (R = tBu)
10a (R = Me)
10d (R = tBu)
11a (R= Me)
12 (R = Ac)
Scheme 1. Reagents and conditions: (a) I2, KI, NaHCO3, H2O; (b) (1) DBU, toluene, reflux; (2) MeONa (cat.), MeOH; (c) MeI, NaH, DMF; (d) iPrI, CyI or tBuBr, Ag2O, cyclohexane;
(e) TBSCl, imidazole, DMAP, CH2Cl2; (f) LiAlH4, 0 °C; (g) (1) OsO4 (cat.), NMO, acetone–water (6:1); (2) Py–Ac2O; (h) m-CPBA, CH2Cl2; (i) Ac2O, H2SO4 (cat.).

C. Mayato et al. / Carbohydrate Research 352 (2012) 101–108
103
The 3JH5,H7 coupling constants, in CDCl3 and DMSO-d6, for com-
pounds 4a–e, 5, and 6 are shown in Table 1. Analysis of the data
revealed that both couplings remained almost constant throughout
the series, about 6.0 Hz in CDCl3. When the NMR experiments were
recorded at different temperatures (Figs. 3 and 4) the values were
the same. According to the Karplus equation,18 which describes the
correlation between the 3J-coupling constants and dihedral torsion
angles in NMR, the local geometry around the C5–C7 bond and
populations of the gg, gt, and tg rotamers remained unaltered by
changing the pseudo-aglycon. Therefore, it can be concluded that
the rotational populations of the hydroxymethyl group for these
carbapyranosides are independent of the pseudo-aglycon (Fig. 5).
In addition, this conclusion confirms the absence of non-bonded
interactions between the pseudo-aglycon and the hydroxymethyl
group, and that the conformational variations observed for O-,2
S-,3 and C-b-glycopyranosides4 after changing the structural nature
of the aglycon are due to other factors, probably stereoelectronic
effects.
300 K
H3
H7
H7'
273 K
253 K
238 K
223 K
H7
4.0
H7'
H3
3.9
3.8
3.7
3.6
3.5
ppm
Linear correlations between the gg and gt rotational populations
around the C5–C6 bond with the corresponding Taft’s steric param-
eters (ES)19 have been recently detected for S-glucopyranosides,3
Figure 3. Fragment of the 1H NMR spectrum of compound 4a at different
temperatures in CDCl3 (400 MHz).
C-glycopyranosides,4 and alkyl
b-
a
- and b-
D-glucopyranosyl-(1?6)-
D
-glucopyranosides20 by means of NMR and CD. Thus, it was
300 K
observed that as Taft’s steric parameter increased for the alkyl
group attached to the anomeric or pseudo-anomeric atom, the
3JH5,H6R increased; that is the population of the gt rotamer increased
at the expense of the gg rotamer. The ES values are composite terms,
derived from both potential energy steric effects (steric strains) and
entropy effects (steric hindrances to motions). According to Taft,19
introduction of a straight-chain alkyl group in place of the standard
hydrogen substituent raises the activation energy due to steric hin-
drance. Therefore, the bulkier alkyl groups freeze out the rotation
around the O1–C1 bond and therefore the more stable exo-syn rot-
amer increases its population (Fig. 6). This rotamer, also called the
exo-anomeric rotamer, fulfills the geometric requirements for the
exo-anomeric effect.
H7,7'
H3
273 K
253 K
238 K
To gain further knowledge of such rotational behavior the cou-
3
3
H7'
pling constants, JH5,H6 and JH5,H7 for glycosides and carbasugars,
respectively, were represented against Taft’s steric parameters
(ES)19 (Fig. 7). The representation revealed that for all glycosides
223 K
H7
H3
3
there is a linear correlation of the JH5,H6R coupling constant with
3
Taft’s steric parameters, but for carbapyranosides the JH5,H7 cou-
ppm
3.5
4.0
3.9
3.8
3.7
3.6
pling constants remain invariable, independently of the ES value
of the substituent. Since these constants depend on the rotamer
populations,18 there can be no relationship at all between the
structure of the pseudo-aglycon (ES) and the hydroxymethyl rot-
amer populations for our carbapyranoside models, in contrast to
glycopyranosides.
Figure 4. Fragment of the 1H NMR spectrum of compound 4d at different
temperatures in CDCl3 (400 MHz).
Table 1
3JH5,H7 Coupling constants for compounds 4–6, and 11 and 12 in CDCl3 and DMSO-d6
at 300 K and 500 MHz
The lack of a substituent at C6, or at the equivalent position C4
in the glycosides (Fig. 2), is a drawback in the interpretation of the
data, since the invariable rotamer populations exhibited by our
carbasugars could be erroneously assigned to this absence. How-
ever, 4-deoxysugars such as 7 (3JH5,H6 = 1.3 and 5.6 Hz)16 and 8
Compound
R
CDCl3
DMSO-d6
3JH5,H7
JH5,H7
3JH5,H7
3
3
0
0
JH5,H7
4a
4b
4c
4d
4e
5
6
11a
12
Me
iPr
Cy
tBu
TBS
H
Ac
Me
Ac
6.0
6.0
6.0
6.0
5.8
5.9
5.6
5.7
6.0
6.1
5.9
5.9
6.0
6.1
6.0
6.1
6.4
6.0
6.1
6.1
6.0
6.3
6.0
6.2
5.8
6.1
6.3
6.4
6.1
6.1
6.0
6.0
6.4
6.6
6.4
6.3
3
(3JH5,H6 = 4.3 and 6.0 Hz)21 showed different JH5,H6 coupling con-
stants for the two prochiral hydrogens, indicating that the absence
of the substituent at C6 in the carbasugars is not the origin of the
immobility of their coupling constants. Obviously, the substituent
at C4 (glycosides) is the strongest influence on the rotamer popu-
lation of the hydroxymethyl group. Thus, the thio-glucopyranoside
9,3 the equatorially substituted derivative at C4 in 8, showed differ-
ent coupling constants (3JH5,H6 = 2.2 and 4.9 Hz) as a consequence
of the non-bonded interaction between this substituent and the
hydroxymethyl group. Therefore, the above results indicate that
the gg, gt and tg populations of the hydroxymethyl group in our
carbapyranosides are independent of the structural nature of the
R group.
for these protons (Fig. 4). However, changing the solvent to DMSO
caused the prochiral protons to display higher chemical shift dif-
ferences. Experiments recorded in the temperature range of 300–
223 K showed a greater separation for the chemical shift of H7
and H70 as the temperature decreased (Figs. 3 and 4).

104
C. Mayato et al. / Carbohydrate Research 352 (2012) 101–108
gg
HR
HS
6
gt
O
7
ω
(gg, gt, tg)
HS
tg
HR
HR
H
S ω
5
5
O
O
X
O
X
X
R
R
R
R
1
3
H
H
H
H
Carbapyranosides
glc, gal or man
R
dependent on
)
)
ω
ω
)
R)
independent on
Figure 5. Molecular structure of glycopyranosides in their three main rotamers around the C5–C6 bond (left) and carbapyranosides (right).
the rotamer population, and therefore is in agreement with our
above data interpretation.
O5
R
C2
O
5
The rotational dependence of the hydroxymethyl group in O-,
and S-glycosides on the structural nature of the aglycon has been
explained by the different values of the exo-anomeric effect
(Fig. 8),2,3 whereas the rotational dependence observed in C-glyco-
sides on the aglycon was explained by the exo-deoxoanomeric ef-
fect.4 This assignment is based on the linear relationship
between the increased gt and decreased gg population of the
hydroxymethyl group and (i) the pKa of the alcohol bonded to
the anomeric carbon or (ii) Taft’s steric parameters (ES) of the agly-
con, and (iii) that no other effect accounts for these rotational
changes. It is also clear from this study that non-bonded interac-
tions between the pseudo-aglycon and the hydroxymethyl group
must be excluded. Furthermore, the parallelism between this
dependence and the well-known relationship between the pKa of
the substituent at the anomeric carbon and the lengths of the endo-
(O5–C1) and exo-cyclic (C1–O1) bonds6 support the stereoelec-
tronic origin of the former.
O
O
2
1
R
H
H1
exo-syn conformation
Figure 6. exo-syn Rotamer around the O1–C1 bond.
10
8
6
4
2
0
J
A relationship has been observed between the bond lengths
around the ring oxygen and anomeric carbon and the spatial dispo-
sition of the hydroxymethyl group in the X-ray structural analysis
H
Me iPr Cy
-2.0
tBu TBS
-3.0
-
-4.0
of the 2,3,4,6-tetra-O-acetyl-b-D
-glucopyranosyl chloride,23 where
0.5 0.0
1.0
both gg and gt rotamers occur simultaneously in the crystal. The
structure of the gt rotamer displayed an unusually long C5–O5 dis-
tance and that of the gg only short distances for the C1–Ol and the
C1–O5 bonds, confirming the relationship between the ring atomic
distances and the orientation of the 6-substituent. In addition, re-
cent crystallographic studies of tetrafluorinated methyl galactoside
anomers7 revealed that the values for the C1–O1 and C1–O5 bond
lengths and the O5–C1–O1–CH3 dihedral angles are in line with
what could be expected from the anomeric and exo-anomeric
effects.
Taft‘s steric parameter, ES
Figure 7. Plot of JH5,H7 coupling constant of carbopyranoses 4a–e and 5, black line;
and JH5,H6R of: O-glycopyranoses,2 red line; S-glycopyranoses,3 green line; and C-
glycopyranoses,4 blue line; versus the corresponding ES value for the aliphatic
substituent (CDCl3).
ω
ω
ω
H
O
O
X
O
R
R
R
H
All these results point to the stereoelectronic nX—rꢀCO (X = O or
nX
σ*CO
σCH σ*CO
C-glycosides
R dependent
S) in glycosides, or rCH—
rꢀCO in C-glycosides, being involved in
O-, S-glycosides
carbapyranosides
R independent
ω
the rotational behavior of the hydroxymethyl group. Carbapyrano-
sides, lacking the necessary endocyclic oxygen for the stereoelec-
tronic effect, cannot display this rotational dependence. As
expected, no relationship between the pseudo-aglycon and the
hydroxymethyl group was observed confirming the role of the
endocyclic oxygen (Fig. 8).
ω
Figure 8. Molecular orbitals involved in the exo-anomeric effect for O- and S-
glycosides (left), and in the exo-deoxoanomeric effect for C-glycosides (middle).
Absence of the rꢀCO orbital necessary for involvement in a stereoelectronic effect for
carbapyranosides (right).
3. Conclusions
It is known that the C3 substituent in 4,6-O-benzylidene man-
nopyranosyl triflates is important in the b-mannopyranosylation
reaction,22 and also that the reactivity of glycoside hydrolysis de-
pends on the hydroxymethyl rotamer population.1 So, to test if ste-
ric effects due to the axial configuration at C1 in our
carbapyranoside models (C3 position in glycosides) are transmit-
ted around the ring through a series of buttressing interactions,
modifying the hydroxymethyl rotamer behavior, compounds 11a
and 12 having an equatorial configuration at C1 were synthetized
A set of carbapyranoside derivatives were synthesized by
means of Yu’s protocol,13 and some chemical improvements were
made. The model set was then characterized and their conforma-
tional properties analyzed by 1H NMR in different solvents and
3
temperatures. Their JH5,H7 coupling constants, either in CDCl3 or
DMSO, were independent of the structure of the pseudo-aglycon.
Therefore, in contrast to O-, S- and C-b-glycosides,2–4 the rotational
populations of the hydroxymethyl group in carbapyranosides seem
not to depend on the structure of their pseudo-aglycon. The
absence of the endocyclic oxygen, and consequently of the
3
and their JH5,H7 coupling constants analyzed. As can be observed
3
in Table 1, their JH5,H7 values are very similar to those of com-
pounds 4–6 indicating that the configuration at C1 does not alter

C. Mayato et al. / Carbohydrate Research 352 (2012) 101–108
105
stereoelectronic exo-and endo-anomeric effects, has a crucial role
4.6. Methyl ( )-(1R,5R)-5-hydroxy-3-cyclohexene-1-carboxylate
in such rotational behavior.
1
( )-3-Cyclohexene carboxylic acid (500 mg, 3.96 mmol) was
dissolved in a solution of NaHCO3 (1.00 g in 10 mL, 3 equiv) in
water. Then a solution of I2 (1.06 g, 1.05 equiv) and KI (3.94 g,
6 equiv) in 10 mL of water was added and the flask protected from
light. After 24 h, it was extracted with CH2Cl2, washed successively
with Na2S2O3 and NaHCO3 water solutions, dried over anhydrous
Na2SO4, and the solvent was evaporated. The crude was re-dis-
solved in 24 mL of dry toluene under nitrogen atmosphere, and
1.8 mL (1.5 equiv) of DBU was added. The reaction was heated at
reflux for 6 h. Then it was filtered on Celite and concentrated.
The crude was re-dissolved in 5 mL of dry MeOH and NaOMe
added. After 30 min, this was neutralized with Amberlite IR-120,
filtered, concentrated, and purified by column chromatography
on silica gel (n-hexane/EtOAc 5:5) to yield compound 1 (1.20 g,
96%). Spectroscopic data of this compound were identical to those
reported in Ref. 13c.
4. Experimental
4.1. General
1H NMR spectra were recorded at 500 MHz, and 13C NMR at
100 MHz, VTU 300.0 K. Chemical shifts are reported in parts per
million. The residual solvent peak (CDCl3) was used as an internal
reference, 7.26 for protons and 77.0 ppm for the central peak of
carbon. 1H NMR experiments at different temperatures were re-
corded in a 400 MHz instrument. For analytical thin-layer chroma-
tography, silica gel ready-foils were used, developed with 254 nm
UV light and/or spraying AcOH/H2O/H2SO4 (80:16:4) and heating
at 150 °C. Flash column chromatography was performed using sil-
ica gel (60 Å). All reagents were obtained from commercial sources
and used without further purification. Solvents were dried and dis-
tilled before use. All reactions were performed under a dry nitro-
gen atmosphere.
4.7. Methyl ( )-(1R,5R)-5-methoxy-3-cyclohexene-1-
carboxylate 2a
4.2. General procedure for the reduction of methyl esters
To a solution of the methyl ester in dry THF (2 mL/mmol) at 0 °C,
2 equiv of LiAlH4 (1.0 M in Et2O) were added. After 2 h, 1 equiv of
NaOH (4% in water) was added; the ice bath retired and the
reaction stirred for 1.5 h. Then, the mixture was diluted with water
and extracted twice with CH2Cl2. The organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The product was purified by column chromatography.
100 mg (0.64 mmol) of the alcohol 1 was dissolved in 1.3 mL of
dry DMF (2 mL/mmol). Then 400 lL (10 equiv) of iodomethane and
32 mg (2 equiv) of sodium hydride were added, and the reaction
was stirred for 1 h. Next, it was diluted with CH2Cl2, neutralized
with a saturated aqueous solution of NH4Cl, and washed with
water. The aqueous fraction was re-extracted with EtOAc. The
combined organic layers were dried over anhydrous Na2SO4, fil-
tered, concentrated, and purified by column chromatography on
silica gel (n-hexane/EtOAc 8:2) to yield compound 2a (100 mg,
92%). Spectroscopic data of this compound were identical to those
reported in Ref. 14.
4.3. General procedure for the dihydroxylation and acetylation
To a solution of the starting material in 2 mL/mmol of the ace-
tone–H2O mixture (6:1), 1.1 equiv of NMOꢁH2O and OsO4 as cata-
lyst were added and the reaction stirred overnight. The reaction
was quenched with a few drops of saturated Na2S2O3 solution
and left stirred for 15 min. Then, the reaction was concentrated
and the crude dissolved in 10 mL/mmol of Py–Ac2O (1:1). When
it was completed, the solvent was removed under reduced pres-
sure and the residue re-dissolved in EtOAc, washed with water
and brine, dried over anhydrous Na2SO4, filtered, and the solvent
evaporated in vacuum. The product was purified by column
chromatography.
4.8. Methyl ( )-(1R,5R)-5-iso-propoxy-3-cyclohexene-1-
carboxylate 2b
Alcohol 1 (215 mg, 1.38 mmol) was dissolved in 2.7 mL of dry
cyclohexane (2 mL/mmol), and 645 mg (2 equiv) of silver oxide
and 430 lL (3 equiv) of iso-propyl iodide were added. The reaction
was stirred during 24 h. Then, it was diluted with CH2Cl2, filtered
on Celite, concentrated, and purified by column chromatography
on silica gel (n-hexane/EtOAc 8.5:1.5) to yield the compound 2b
(215 mg, 81%): TLC Rf = 0.5 (n-hexane/EtOAc 7:3); 1H NMR (CDCl3):
d 5.68 (m, H-3), 5.61 (m, H-4), 4.01 (m, H-5), 3.67 (quint, J = 6.1 Hz),
3.62 (s, 3H), 2.57 (m, H-1), 2.25 (m, H-6), 2.19 (m, H-2 and H-20),
1.54 (ddd, J = 9.5, 9.5 and 12.4 Hz, H-60), 1.09 (d, J = 6.1 Hz, 3H),
1.08 (d, J = 6.1 Hz, 3H); 13C NMR (CDCl3): d 175.0 (s), 129.7 (d, C-
4), 127.0 (d, C-3), 71.3 (d, C-5), 69.2 (d), 51.6 (q), 38.3 (d, C-1),
32.1 (t, C-6), 27.4 (t, C-2), 22.9 (q), 22.4 (q); Anal. Calcd for
4.4. General procedure for the epoxidation
To a stirred solution of the alkene in CH2Cl2 (10 mL/mmol) m-
CPBA 60% (2 equiv) was added and the reaction mixture was stir-
red overnight. The solids were filtrated and the filtrate was washed
with saturated NaHCO3 and water. The combined organic layers
were dried over Na2SO4, filtered, concentrated, and purified by col-
umn chromatography on silica gel, previously neutralized by add-
ing 1% triethylamine to the eluting system.
C
11H18O3: C, 66.64; H, 9.15. Found: C, 66.66; H, 9.32.
4.9. Methyl ( )-(1R,5R)-5-cyclohexyloxy-3-cyclohexene-1-
carboxylate 2c
4.5. General procedure for the epoxide opening
100 mg (0.64 mmol) of the alcohol 1 were dissolved in 1.3 mL of
dry cyclohexane (2 mL/mmol), and 750 mg (5 equiv) of silver oxide
and 840 lL (10 equiv) of cyclohexyl iodide were added. The reac-
Epoxides were treated with a catalytic amount of sulfuric acid
in acetic anhydride (2.5 mL/mmol). The reaction mixture was stir-
red for 3 h at room temperature, then was cooled to 0 °C and water
(25 mL/mmol) was added followed by stirring for 1 h. The aqueous
layer was extracted with ethyl ether, and the combined organic ex-
tracts washed with NaHCO3 and water. The organic phase was
dried over Na2SO4 and concentrated to give a crude product which
was purified by chromatography on silica gel.
tion was stirred for 5 days. Then, it was diluted on CH2Cl2, filtered
on celite, concentrated, and purified by column chromatography
on silica gel (n-hexane/EtOAc 8.5:1.5) to yield compound 3c
(25 mg) and recovered 47 mg of the starting material 1: TLC
Rf = 0.7 (n-hexane/EtOAc 7:3); 1H NMR (CDCl3): d 5.72 (m, H-3),
5.67 (m, H-4), 4.10 (m, H-5), 3.68 (s, 3H), 3.38 (m, 1H), 2.61 (m,

106
C. Mayato et al. / Carbohydrate Research 352 (2012) 101–108
H-1), 2.31 (m, H-6), 2.25 (m, H-2 and H-20), 1.85 (m, 2H), 1.63 (m,
2H), 1.59 (ddd, J = 9.5, 9.5 and 12.4 Hz, H-60), 1.51 (m, 1H), 1.30–
1.20 (m, 5H); 13C NMR (CDCl3): d 175.1 (s), 130.0 (d, C-4), 127.0
(d, C-3), 75.5 (d), 71.3 (d, C-5), 51.7 (q), 38.5 (d, C-1), 33.3 (t),
32.8 (t), 32.3 (t, C-6), 27.5 (t, C-2), 25.7 (t), 24.3 (t), 24.2 (t); Anal.
Calcd for C14H22O3: C, 70.56; H, 9.30. Found: C, 70.61; H, 9.45.
4.14. ( )-(1R,5R)-5-Cyclohexyloxy-3-cyclohexen-1-yl-methanol
3c
Following the general procedure for the reduction of methyl es-
ters, 160 mg of compound 2c yielded 129 mg (91%) of 3c, after col-
umn chromatography (n-hexane/EtOAc 4:6): TLC Rf = 0.5 (n-
hexane/EtOAc 1:1); 1H NMR (CDCl3): d 5.78 (m, H-3), 5.71 (m, H-
4), 4.06 (m, H-5), 3.55 (m, 2H), 3.40 (m, 1H), 2.13–2.03 (m, H-2
and H-6), 1.97–1.72 (m, 7H), 1.52 (m, 1H), 1.39 (ddd, J = 9.5, 9.5
and 12.4 Hz, H-60), 1.28–1.17 (m, 5H); 13C NMR (CDCl3): d 129.3
(d, C-4), 128.3 (d, C-3), 70.8 (d, C-5), 75.3 (d), 66.9 (t), 34.7 (d, C-
1), 33.1 (t), 32.9 (t), 32.5 (t, C-6), 28.1 (t, C-2), 25.6 (t), 24.2 (t),
24.2 (t); Anal. Calcd for C13H22O2: C, 74.24; H, 10.54. Found: C,
74.24; H, 10.65.
4.10. Methyl ( )-(1R,5R)-5-tert-butoxy-3-cyclohexene-1-
carboxylate 2d
Alcohol 1 (118 mg, 0.76 mmol) was dissolved in 1.5 mL of dry
cyclohexane (2 mL/mmol). Next 354 mg (2 equiv) of silver oxide
and 260 lL (3 equiv) of tert-butyl bromide were added, and the
reaction was stirred for 12 h. Then, it was diluted on CH2Cl2, fil-
tered on Celite, concentrated, and purified by column chromatog-
raphy on silica gel (n-hexane/EtOAc 8.5:1.5) to yield compound
2d (147 mg, 91%): TLC Rf = 0.7 (n-hexane/EtOAc 7:3); 1H NMR
(CDCl3): d 5.71 (m, H-3), 5.57 (m, H-4), 4.16 (m, H-5), 3.69 (s,
3H), 2.66 (m, H-1), 2.24–2.17 (m, H-2, H-20 and H-6), 1.63 (ddd,
J = 9.5, 9.5 and 12.7 Hz, H-60), 1.21 (s, 9H); 13C NMR (CDCl3): d
175.1 (s), 131.7 (d, C-4), 126.7 (d, C-3), 73.9 (s), 66.5 (d, C-5),
51.7 (q), 39.0 (d, C-1), 34.1 (t, C-6), 28.3 (q ꢂ 3), 27.3 (t, C-2); Anal.
Calcd for C12H20O3: C, 67.89; H, 9.50. Found: C, 67.90; H, 9.58.
4.15. ( )-(1R,5R)-5-tert-Butoxy-3-cyclohexen-1-yl-methanol 3d
Following the general procedure for the reduction of methyl
esters, 120 mg of compound 2d yielded 100 mg (96%) of 3d,
after column chromatography (n-hexane/EtOAc 4:6): TLC Rf = 0.5
(n-hexane/EtOAc 1:1); 1H NMR (CDCl3): d 5.74 (m, H-3), 5.61
(m, H-4), 4.10 (m, H-5), 3.54 (m, 2H), 2.09 (m, H-2), 1.95–1.90
(m, H-1, H-6 and OH), 1.76 (m, H-20), 1.42 (ddd, J = 8.4, 8.4 and
10.8 Hz, H-60), 1.22 (s, 9H); 13C NMR (CDCl3): d 130.9 (d, C-4),
127.9 (d, C-3), 73.9 (s), 67.0 (t), 65.6 (d, C-5), 34.8 (d, C-1), 34.1
(t, C-6), 28.3 (q ꢂ 3), 27.7 (t, C-2); Anal. Calcd for C11H20O2: C,
71.70; H, 10.94. Found: C, 71.71; H, 11.10.
4.11. Methyl ( )-(1R,5R)-5-tert-butyl-dimethyl-silyloxy-3-
cyclohexene-1-carboxylate 2e
4.16. ( )-(1R,5R)-5-tert-Butyl-dimethyl-silyloxy-3-cyclohexen-
1-yl-methanol 3e
110 mg (0.70 mmol) of alcohol 1 were dissolved in 3.5 mL of dry
CH2Cl2 (5 mL/mmol). Then 194 mg (4 equiv) of imidazole and
217 mg (2 equiv) of tert-butyl dimethyl silyl chloride were added,
and the reaction stirred during 1 h. Next, it was diluted with
CH2Cl2, washed with NaHCO3 water solution, dried over anhydrous
Na2SO4, concentrated, and purified by column chromatography on
silica gel (n-hexane/EtOAc 9.5:0.5) to yield the compound 2e
(182 mg, 96%). Spectroscopic data of this compound were identical
to those reported in Ref. 24.
Following the general procedure for the reduction of methyl
esters, 74.4 mg of compound 2e yielded 60.9 mg (91%) of 3e,
after column chromatography (n-hexane/EtOAc 5:5): TLC Rf = 0.5
(n-hexane/EtOAc 1:1); 1H NMR (CDCl3): d 5.71 (m, H-3), 5.59
(m, H-4), 4.28 (m, H-5), 3.51 (m, H-7 and H-70), 2.42 (s, OH), 2.07
(m, H-2), 1.96 (m, H-6), 1.87 (m, H-1), 1.76 (m, H-20), 1.37 (m, H-60),
0.88 (s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3): d 131.1 (d, C-4), 127.8
(d, C-3), 67.2 (t, C-7), 67.0 (d, C-5), 35.0 (t, C-6), 34.7 (d, C-1), 27.8
(t, C-2), 25.9 (q ꢂ 3), 18.2 (s), ꢃ4.6 (q ꢂ 2); Anal. Calcd for
4.12. ( )-(1R,5R)-5-Methoxy-3-cyclohexen-1-yl-methanol 3a
C13H26O2Si: C, 64.41; H, 10.81. Found: C, 64.44; H, 10.80.
Following the general procedure for the reduction of methyl es-
ters, 88.0 mg of compound 2a yielded 64.1 mg (87%) of 3a, after
column chromatography (n-hexane/EtOAc 4:6): TLC Rf = 0.5 (n-
hexane/EtOAc 3:7); 1H NMR (CDCl3): d 5.77 (m, H-3 and H-4),
3.88 (m, H-5), 3.56 (m, 2H), 3.38 (s, 3H), 2.14–2.10 (m, H-2 and
H-6), 1.90 (m, H-1), 1.84–1.75 (m, H-20 and OH), 1.31 (ddd,
J = 9.5, 9.5 and 12.4 Hz, H-60); 13C NMR (CDCl3): d 128.8 (d, C-4),
128.1 (d, C-3), 75.2 (d, C-5), 67.2 (t), 55.7 (q), 34.8 (d, C-1), 31.1
(t, C-6), 28.2 (t, C-2); Anal. Calcd for C8H14O2: C, 67.57; H, 9.92.
Found: C, 67.59; H, 10.07.
4.17. ( )-(1R,2S,3R,5S)-2-Acetoxy-5-acetoxymethyl-3-methoxy-
cyclohexyl acetate 4a
Following the general procedure for dihydroxylation and acety-
lation, 154 mg of compound 3a yielded 316 mg (96%) of 4a, after
column chromatography (n-hexane/EtOAc 6:4): TLC Rf = 0.4 (n-
hexane/EtOAc 1:1); 1H NMR (CDCl3): d 5.41 (ddd, J = 2.4, 3.1 and
3.7 Hz, H-1), 4.77 (dd, J = 3.1 and 9.8 Hz, H-2), 3.98 (dd, J = 6.0
and 11.0 Hz, H-7), 3.93 (dd, J = 6.1 and 11.0 Hz, H-70), 3.56 (ddd,
J = 4.7, 9.8 and 11.1 Hz, H-3), 3.40 (s, 3H), 2.23–2.10 (m, H-4eq
and H-5), 2.10 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 1.88 (ddd, J = 3.7,
6.4 and 14.5 Hz, H-6eq), 1.40 (ddd, J = 2.4, 12.5 and 14.5 Hz, H-
4.13. ( )-(1R,5R)-5-iso-Propoxy-3-cyclohexen-1-yl-methanol 3b
6
ax), 1.15 (ddd, J = 11.5, 11.5 and 11.5 Hz, H-4ax); 13C NMR (CDCl3):
Following the general procedure for the reduction of methyl
esters, 100 mg of compound 2b yielded 74 mg (86%) of 3b,
after column chromatography (n-hexane/EtOAc 4:6): TLC Rf = 0.5
(n-hexane/EtOAc 4:6); 1H NMR (CDCl3): d 5.77 (m, H-3), 5.70 (m,
H-4), 4.02 (m, H-5), 3.77 (quint, J = 6.1 Hz, 1H), 3.55 (m, 2H),
2.13–2.03 (m, H-2 and H-6), 1.93–1.75 (m, H-1, H-20 and OH), 1.39
(ddd, J = 9.5, 9.5 and 12.4 Hz, H-60), 1.17 (d, J = 6.1 Hz, 3H), 1.15
(d, J = 6.1 Hz, 3H); 13C NMR (CDCl3): d 129.1 (d, C-4), 128.4 (d, C-
3), 71.0 (d, C-5), 69.2 (d), 67.0 (t), 34.5 (d, C-1), 32.4 (t, C-6), 28.1
(t, C-2), 22.8 (q), 22.7 (q); Anal. Calcd for C10H18O2: C, 70.55; H,
10.66. Found: C, 70.55; H, 10.68.
d 170.9 (s), 170.3 (s), 170.0 (s), 76.1 (d, C-3), 75.0 (d, C-2), 69.3 (d,
C-1), 67.6 (t, C-7), 57.4 (q), 32.4 (d, C-4), 31.5 (d, C-6), 30.0 (d, C-5),
21.0 (q), 20.9 (q), 20.8 (q); Anal. Calcd for C14H22O7: C, 55.62; H,
7.33. Found: C, 55.65; H, 7.53.
4.18. ( )-(1R,2S,3R,5S)-2-Acetoxy-5-acetoxymethyl-3-iso-
propoxy-cyclohexyl acetate 4b
Following the general procedure for dihydroxylation and acety-
lation, 74.0 mg of compound 3b yielded 127 mg (88%) of 4b, after

C. Mayato et al. / Carbohydrate Research 352 (2012) 101–108
107
column chromatography (n-hexane/EtOAc 6:4): TLC Rf = 0.6 (n-
hexane/EtOAc 1:1); 1H NMR (CDCl3): d 5.40 (ddd, J = 2.4, 3.1 and
3.7 Hz, H-1), 4.73 (dd, J = 3.1 and 9.7 Hz, H-2), 3.97 (dd, J = 6.0
and 10.9 Hz, H-7), 3.92 (dd, J = 5.9 and 10.9 Hz, H-70), 3.70 (quint,
J = 6.1 Hz, 1H), 3.66 (ddd, J = 4.7, 9.7 and 11.1 Hz, H-3), 2.15–2.05
(m, H-4eq and H-5), 2.10 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H), 1.88
(ddd, J = 3.7, 6.5 and 14.4 Hz, H-6eq), 1.39 (ddd, J = 2.4, 12.4 and
14.4 Hz, H-6ax), 1.21 (ddd, J = 11.5, 11.5 and 11.5 Hz, H-4ax), 1.14
(d, J = 6.1 Hz), 1.10 (d, J = 6.1 Hz); 13C NMR (CDCl3): d 171.0 (s),
170.2 (s), 170.0 (s), 75.3 (d, C-2), 72.8 (d, C-3), 71.7 (d), 69.6 (d,
C-1), 67.6 (t, C-7), 34.5 (d, C-4), 31.5 (d, C-6), 30.2 (d, C-5), 23.0
(q), 22.5 (q), 21.0 (q), 20.8 (q), 20.8 (q); Anal. Calcd for C16H26O7:
C, 58.17; H, 7.93. Found: C, 58.20; H, 8.15.
C-4), 31.6 (d, C-6), 30.2 (d, C-5), 25.5 (q ꢂ 3), 21.0 (q), 20.9 (q),
20.8 (q), 17.9 (s), ꢃ4.6 (q), ꢃ4.9 (q); Anal. Calcd for C19H34O7Si:
C, 56.69; H, 8.51. Found: C, 56.71; H, 8.66.
4.22. ( )-(1R,2S,3R,5S)-2-Acetoxy-5-acetoxymethyl-3-hydroxy-
cyclohexyl acetate 5
Compound 4e (110 mg, 0.27 mmol) was dissolved in 2.7 mL of
dry acetonitrile (10 mL/mmol) in a Teflon flask. Under nitrogen
atmosphere and at 0 °C 100
lL of the complex PyꢁHF (7:3) were
slowly added. Then, the ice bath was removed and the reaction
stirred overnight. It was quenched with saturated NaHCO3 solu-
tion, extracted with CH2Cl2, dried over anhydrous Na2SO4, filtered,
and the solvent evaporated. The crude was purified by column
chromatography on silica gel (n-hexane/EtOAc 1:1) to yield com-
pound 5 (65.5 mg, 84%): TLC Rf = 0.2 (n-hexane/EtOAc 1:1); 1H
NMR (CDCl3): d 5.44 (ddd, J = 2.4, 3.0 and 3.6 Hz, H-1), 4.63 (dd,
J = 3.0 and 9.8 Hz, H-2), 4.01 (ddd, J = 4.7, 9.8 and 11.5 Hz, H-3),
3.98 (dd, J = 5.9 and 11.0 Hz, H-7), 3.93 (dd, J = 6.0 and 11.0 Hz,
H-70), 2.20–2.14 (m, H-4eq, H-5 and OH), 2.08 (s, 3H), 2.06 (s,
6H), 1.90 (ddd, J = 3.6, 6.4 and 14.5 Hz, H-6eq), 1.41 (ddd, J = 2.4,
12.6 and 14.5 Hz, H-6ax), 1.24 (ddd, J = 11.5, 11.5 and 11.5 Hz, H-
4ax); 13C NMR (CDCl3): d 171.0 (s), 170.9 (s), 170.1 (s), 77.2 (d, C-
2), 69.1 (d, C-1), 67.6 (d, C-3), 67.4 (t, C-7), 35.5 (d, C-4), 31.8 (d,
C-6), 30.2 (d, C-5), 21.0 (q), 20.9 (q), 20.8 (q); Anal. Calcd for
4.19. ( )-(1R,2S,3R,5S)-2-Acetoxy-5-acetoxymethyl-3-
cyclohexyloxy-cyclohexyl acetate 4c
Following the general procedure for dihydroxylation and acety-
lation, 65.0 mg of compound 3c yielded 89.0 mg (78%) of 4c, after
column chromatography (n-hexane/EtOAc 6:4): TLC Rf = 0.6 (n-
hexane/EtOAc 1:1); 1H NMR (CDCl3): d 5.40 (ddd, J = 2.4, 3.1 and
3.7 Hz, H-1), 4.74 (dd, J = 3.1 and 9.7 Hz, H-2), 3.96 (dd, J = 6.0
and 10.9 Hz, H-7), 3.92 (dd, J = 5.9 and 10.9 Hz, H-70), 3.71 (ddd,
J = 4.7, 9.7 and 11.1 Hz, H-3), 3.35 (m, 1H), 2.10–2.00 (m, H-4eq
and H-5), 2.10 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 1.87 (ddd, J = 3.7,
6.5 and 14.4 Hz, H-6eq), 1.72 (m, 2H), 1.63 (m, 2H), 1.50 (m, 1H),
1.39 (ddd, J = 2.4, 12.4 and 14.4 Hz, H-6ax), 1.30–1.20 (m, 6H); 13C
NMR (CDCl3): d 171.0 (s), 170.3 (s), 170.1 (s), 77.7 (d), 75.2 (d, C-
2), 72.8 (d, C-3), 69.7 (d, C-1), 67.7 (t, C-7), 34.6 (d, C-4), 33.4 (t),
32.6 (t), 31.6 (d, C-6), 30.3 (d, C-5), 25.6 (t), 24.1 (t), 24.1 (t), 21.2
(q), 20.9 (q), 20.9 (q); Anal. Calcd for C19H30O7: C, 61.60; H, 8.16.
Found: C, 61.64; H, 8.34.
C13H20O7: C, 54.16; H, 6.99. Found: C, 54.15; H, 7.12.
4.23. ( )-(1R,2R,3R,5R)-5-(Acetoxymethyl)cyclohexane-1,2,3-
triyl triacetate 6
Following the general procedure for acetylation, 110 mg of
compound 5 (0.38 mmol) yielded 122 mg (97%) of 6, after column
chromatography (n-hexane/EtOAc 6:4): TLC Rf = 0.5 (n-hexane/
EtOAc 1:1); 1H NMR (CDCl3): d 5.43 (ddd, J = 3.0, 3.2 and 3.2 Hz,
H-1), 5.16 (ddd, J = 5.0, 10.4 and 11.5, Hz, H-3), 4.85 (dd, J = 3.2
and 10.3 Hz, H-2), 3.95 (dd, J = 5.6 and 11.0 Hz, H-7), 3.89 (dd,
J = 6.1 and 11.0 Hz, H-70), 2.24–2.18 (m, H-4eq, and H-5), 2.10 (s,
3H), 2.06 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H), 1.90 (ddd, J = 3.2, 6.4
and 14.8 Hz, H-6eq), 1.41 (ddd, J = 2.4, 12.7 and 14.8 Hz, H-6ax),
1.24 (ddd, J = 11.5, 11.5 and 12.6 Hz, H-4ax); 13C NMR (CDCl3): d
170.8 (s), 170.3 (s), 170.2 (s), 170.0 (s), 73.0 (d, C-2), 69.2 (d, C-
1), 68.8 (d, C-3), 67.1 (t, C-7), 32.8 (d, C-4), 31.3 (d, C-6), 29.8 (d,
C-5), 20.8 (2 ꢂ q), 20.6 (q), 20.6 (q); Anal. Calcd for C15H22O8: C,
54.54; H, 6.71. Found: C, 54.50; H, 6.82.
4.20. ( )-(1R,2S,3R,5S)-2-Acetoxy-5-acetoxymethyl-3-tert-
butoxy-cyclohexyl acetate 4d
Following the general procedure for dihydroxylation and acety-
lation, 114 mg of compound 3d yielded 210 mg (98%) of 4d, after
column chromatography (n-hexane/EtOAc 6:4): TLC Rf = 0.6 (n-
hexano/AcOEt 1:1); 1H NMR (CDCl3): d 5.41 (ddd, J = 2.5, 3.1 and
3.9 Hz, H-1), 4.67 (dd, J = 3.1 and 9.6 Hz, H-2), 3.94 (d, J = 6.0 Hz,
H-7 and H-70), 3.83 (ddd, J = 4.7, 9.6 and 11.1 Hz, H-3), 2.11 (m,
H-5), 2.10 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.96 (m, H-4eq), 1.87
(ddd, J = 3.9, 6.5 and 14.4 Hz, H-6eq), 1.40 (ddd, J = 2.5, 12.2 and
14.4 Hz, H-6ax), 1.26 (ddd, J = 11.5, 11.5 and 11.5 Hz, H-4ax), 1.17
(s, 9H); 13C NMR (CDCl3): d 171.0 (s), 170.2 (s), 170.1 (s), 74.7 (d,
C-2), 74.1 (s), 69.8 (d, C-1), 67.7 (t, C-7), 67.2 (d, C-3), 36.4 (d, C-
4), 31.5 (d, C-6), 30.5 (d, C-5), 28.6 (q ꢂ 3), 21.1 (q), 21.0 (q), 20.8
(q); Anal. Calcd for C17H28O7: C, 59.29; H, 8.19. Found: C, 59.32;
H, 8.36.
4.24. Compound 10a
Following the general procedure for epoxidation, 30 mg of com-
pound 3a (0.21 mmol) yielded 20 mg (60%) of 10a, after column
chromatography (n-hexane/EtOAc 4:6): TLC Rf = 0.4 (n-hexane/
EtOAc 3:7); 1H NMR (CDCl3): d 3.56–3.50 (m, H-5 and H-7), 3.47
(s, 3H), 3.47 (m, H-70), 3.29 (br s, H-3), 3.14 (br d, J = 3.6 Hz, H-4),
2.16 (m, H-2), 2.02 (m, H-6), 1.60 (m, H-1), 1.50 (m, H-20), 0.98
(m, H-60); 13C NMR (CDCl3): d 75.1 (q), 67.2 (t, C-7), 57.0 (d, C-5),
54.4 (d, C-4), 53.4 (d, C-3), 30.6 (t, C-6), 29.6 (d, C-1), 27.7 (t, C-
2); HRMS (EI) Calcd for C8H14O3: 158.0943. Found: 158.0947.
4.21. ( )-(1R,2S,3R,5S)-2-Acetoxy-5-acetoxymethyl-3-tert-butyl-
dimethyl-silyloxy-cyclohexyl acetate 4e
Following the general procedure for dihydroxylation and acety-
lation, 60.9 mg of compound 3e yielded 84.5 mg (84%) of 4e, after
column chromatography (n-hexane/EtOAc 6:4): TLC Rf = 0.7 (n-
hexane/EtOAc 1:1); 1H NMR (CDCl3): d 5.41 (ddd, J = 2.5, 3.1 and
3.8 Hz, H-1), 4.68 (dd, J = 3.1 and 9.4 Hz, H-2), 3.97 (ddd, J = 4.9,
9.4 and 10.9 Hz, H-3), 3.96 (dd, J = 5.8 and 10.9 Hz, H-7), 3.93
(dd, J = 6.1 and 10.9 Hz, H-70), 2.13 (m, H-5), 2.08 (s, 3H), 2.06 (s,
3H), 2.01 (s, 3H), 1.95 (m, H-4eq), 1.87 (ddd, J = 3.8, 6.4 and
14.4 Hz, H-6eq), 1.41 (ddd, J = 2.5, 12.4 and 14.4 Hz, H-6ax), 1.27
(ddd, J = 11.5, 11.5 and 11.5 Hz, H-4ax), 0.86 (s, 9H), 0.07 (s, 3H),
0.05 (s, 3H); 13C NMR (CDCl3): d 170.9 (s), 170.3 (s), 170.0 (s),
76.4 (d, C-2), 69.4 (d, C-1), 67.9 (d, C-3), 67.7 (t, C-7), 36.7 (d,
4.25. Compound 10d
Following the general procedure for epoxidation, 68 mg of com-
pound 3d (0.37 mmol) yielded 57 mg (77%) of 10d, after column
chromatography (n-hexane/EtOAc 4:6): TLC Rf = 0.4 (n-hexane/
EtOAc 1:1); 1H NMR (CDCl3): d 3.80 (dd, J = 6.2 and 8.9 Hz, H-5),
3.49 (dd, J = 5.2, 10.7 Hz, H-7), 3.41 (dd, J = 6.4 and 10.7 Hz, H-70),
3.24 (br s, H-3), 3.03 (d, J = 3.6 Hz, H-4), 2.09 (m, H-2), 1.80 (m,
H-6), 1.62 (m, H-1), 1.50 (m, H-20), 1.24 (s, 9H), 1.05 (m, H-60);

108
C. Mayato et al. / Carbohydrate Research 352 (2012) 101–108
13C NMR (CDCl3): d 74.7 (s), 67.2 (t, C-7), 65.6 (d, C-5), 56.8 (d, C-4),
53.6 (d, C-3), 32.9 (t, C-6), 29.8 (d, C-1), 28.1 (3 ꢂ q), 27.2 (t, C-2);
HRMS (EI) Calcd for C11H20O3: 200.1412. Found: 200.1417.
(c) Mayato, C.; Dorta, R. L.; Vázquez, J. T. Tetrahedron: Asymmetry 2004, 15,
2385; (d) Roën, A.; Padrón, J. I.; Vázquez, J. T. J. Org. Chem. 2003, 68, 4615.
3. Sanhueza, C. A.; Dorta, R. L.; Vázquez, J. T. Tetrahedron: Asymmetry 2008, 19, 258.
4. (a) Mayato, C.; Dorta, R. L.; Vázquez, J. T. Tetrahedron: Asymmetry 2007, 18, 931;
(b) Mayato, C.; Dorta, R. L.; Vázquez, J. T. Tetrahedron: Asymmetry 2007, 18,
2803.
4.26. ( )-(1R,2R,3S,5R)-2-Acetoxy-5-acetoxymethyl-3-methoxy-
5. The stereoelectronic exo-anomeric effect consists of the conformational
preference of glycosides for the gauche orientation (Lemieux, R. U.; Pavia, A.
A.; Martin, J. C.; Watanabe, K. A. Can. J. Chem. 1969, 47, 4427), as a consequence
of the stereoelectronic interaction between the p orbital of the interannular
oxygen and the r⁄ orbital of the pyranose C1–O5 bond. Furthermore, this effect
is responsible for the reduction and extension of C1–O1 and C1–O5 bonds,
respectively, as observed in X-ray diffraction studies (Briggs, A. J.; Glenn, R.;
Jones, P. G.; Kirby, A. J.; Ramaswamy, P. J. Am. Chem. Soc. 1984, 106, 6200).
6. (a) Kirby, A. J. The Anomeric Effect and Related Stereoelectronic Effects at Oxygen;
Springer: New York, 1983; (b) Thatcher, G. R. J. Anomeric and Associated
Stereoelectronic Effects. Scope and Controversy. In The Anomeric Effect and
Associated Stereoelectronic Effects; Thatcher, G. R. J., Ed.; ACS Symposium Series
539; Washington, DC, 1993; (c) Juaristi, E.; Cuevas, G. The Anomeric Effect. In
New Directions in Organic and Biological Chemistry; Rees, C. W. Ed.; CRC Press:
Boca Ratón, Florida, 1995; (d) Tvaroska, I.; Carver, J. P. J. Phys. Chem. 1995, 99,
6234; (e) Cramer, C.; Truhlar, D. G.; French, A. D. Carbohydr. Res. 1997, 298, 1.
7. Linclau, B.; Golten, S.; Light, M.; Sebban, M.; Oulyadi, H. Carbohydr. Res. 2011,
346, 1129.
cyclohexyl acetate 11a
Following the general procedure for epoxide opening, 15 mg of
10a (0.09 mmol) yielded 17 mg (60%) of compound 11a, after col-
umn chromatography (n-hexane/EtOAc 6:4): TLC Rf = 0.4 (n-hex-
ane/EtOAc 1:1); 1H NMR (CDCl3): d 4.94 (dd, J = 9.7 and 9.7 Hz,
H-2), 4.82 (ddd, J = 4.8, 9.8 and 11.5 Hz, H-1), 3.98 (dd, J = 5.7 and
10.9 Hz, H-7), 3.92 (dd, J = 6.4 and 10.9 Hz, H-70), 3.34 (s, 3H),
3.23 (ddd, J = 4.7, 9.5 and 11.5 Hz, H-3), 2.14 (m, H-4eq), 2.02 (m,
H-6eq), 1.78 (m, H-5), 1.24 (m, H-4ax), 1.13 (m, H-6ax), 2.05 (s,
3H), 2.04 (s, 3H), 1.99 (s, 3H); 13C NMR (CDCl3): d 171.0 (s),
170.9 (s), 170.4 (s), 79.1 (d, C-3), 76.1 (d, C-2), 71.5 (d, C-1), 67.3
(t, C-7), 57.4 (q), 32.8 (d, C-6), 31.9 (d, C-4), 31.3 (d, C-5), 20.9
(q), 20.8 (q), 20.7 (q); HRMS (EI) Calcd for [C14H22O7+1]:
303.1444. Found: 303.1433.
8. Houk, K. N.; Eksterowicz, J. E.; Wu, Y.-D.; Fuglesang, C. D.; Mitchell, D. B. J. Am.
Chem. Soc. 1993, 115, 4170.
9. Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077.
10. Ogawa, S. In Carbohydrate Mimics, Concepts and Methods; Wiley-VCH:
Weinheim, 1998; pp 87–106.
4.27. (1R,2s,3S,5s)-5-(Acetoxymethyl)cyclohexane-1,2,3-triyl
11. The conformation of the hydroxymethyl group is described as gauche–gauche
triacetate 12
(gg,
x = ꢃ60), gauche–trans (gt, x = 60), and trans–gauche (tg, x = 180)
rotamers. The first descriptor indicates the torsional relationship between O7
and C4, and the second is that between O7 and C6.
Following the general procedure for epoxide opening, 25 mg of
10d (0.12 mmol) yielded 26 mg (65%) of compound 12, after col-
umn chromatography (n-hexane/EtOAc 6:4): TLC Rf = 0.5 (n-hex-
ane/EtOAc 1:1); 1H NMR (CDCl3): d 5.07 (dd, J = 9.8 and 9.8 Hz,
H-2), 4.87 (ddd, J = 5.0, 10.4 and 11.5 Hz, H-1 and H-3), 3.96 (d,
J = 6.0 Hz, 2H-7), 2.14–2.09 (m, H-4eq and H-6eq), 2.05 (s, 3H),
2.03 (s, 3H), 2.02 (s, 6H), 1.92 (m, H-5), 1.29–1.24 (m, H-4ax and
H6ax); 13C NMR (CDCl3): d 170.8 (s), 170.2 (s), 170.1 (2 ꢂ s), 74.5
(d, C-2), 71.5 (d, C-1 and C-3), 68.9 (t, C-7), 32.6 (d, C-4 and C-6),
31.3 (d, C-5), 20.9 (2 ꢂ q), 20.8 (q), 20.7 (q); HRMS (EI) Calcd for
[C15H22O8+1]: 331.1393. Found: 331.1394.
12. Arjona, O.; Gómez, A. M.; López, J. C.; Plumet, J. Chem Rev. 1919, 2007, 107.
13. (a) Yu, S.-H.; Chung, S.-K. Tetrahedron: Asymmetry 2004, 15, 581; (b) Yu, S.-H.;
Chung, S.-K. Tetrahedron: Asymmetry 2005, 16, 2729; (c) Marshall, J. A.; Xie, S. J.
Org. Chem. 1995, 60, 7230.
14. Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling, D. E.; Schreiber,
S. L. J. Am. Chem. Soc. 1990, 112, 5583.
15. VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1973, 1976, 23.
16. Compound
7 was prepared from the penta-O-acetyl-b-D-glucopyranose
following the procedure published by: Hirota, K.; Onogi, S.; Maki, Y. Chem.
Pharm. Bull 1991, 39, 2702.
17. Bock, K.; Fernández-Bolaños, J.; Ogawa, S. Carbohydr. Res. 1988, 174, 354.
3
18. The populations of the three rotamers can be calculated from the JH5,H6
coupling constants (glycosides) by means of a different set of equations: (a)
Haasnoot, C. A. G.; De Leeuw, F. A. A. M.; Altona, C. Tetrahedron 1980, 36, 2783;
(b) Manor, P. C.; Saenger, W.; Davies, D. B.; Jankowski, K.; Rabczenko, A.
Biochim. Biophys. Acta 1974, 340, 472; (c) Stenutz, R.; Carmichael, I.; Widmalm,
G.; Serianni, A. S. J. Org. Chem. 2002, 67, 949; (d) Thibaudeau, C.; Stenutz, R.;
Hertz, B.; Klepach, T.; Zhao, S.; Wu, Q.; Carmichael, I.; Serianni, A. J. Am. Chem.
Soc. 2004, 121, 15668.
Acknowledgments
This work was supported by the Ministerio de Ciencia e Innova-
ción (Spain) through Grant CTQ2007-67532-C02-02/BQU. C.M.
thanks the Consejería de Educación, Cultura y Deportes (Gobierno
de Canarias) for his fellowship.
19. (a) Taft, R. W., Jr. J. Am. Chem. Soc. 1952, 74, 2729; (b) Taft, R. W., Jr. J. Am. Chem.
Soc. 1952, 74, 3120; (c) Taft, R. W., Jr. J. Am. Chem. Soc. 1953, 75, 4532; (d) Taft,
R. W., Jr. J. Am. Chem. Soc. 1953, 75, 4538.
20. (a) Roën, A.; Padrón, J. I.; Mayato, C.; Vázquez, J. T. J. Org. Chem. 2008, 73, 3351;
(b) Roën, A.; Mayato, C.; Padrón, J. I.; Vázquez, J. T. J. Org. Chem. 2008, 73, 7266.
21. van Dorst, J. A. L. M.; van Heusden, C. J.; Voskamp, A. F.; Kamerling, J. P.;
Vliegenthart, J. F. G. Carbohydr. Res. 1996, 291, 63.
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