Synthesis of new 2-phosphono-α-d-glycoside derivatives by stereoselective oxa-Michael addition to a d-galacto derived enone

Article abstract of DOI:10.1016/j.carres.2008.03.009

The synthesis of new 2-phosphono-α-d-glycoside derivatives by stereoselective oxa-Michael addition to an enone derived from d-galactal and containing a phosphonate group is described. Retro-Michael reactions were prevented by tandem acetylation to trap the unstable enolic intermediates. The stereochemistry of the addition products was established by NOESY experiments and explained with molecular mechanics (MM) and density functional theory (DFT) calculations.

Full text of DOI:10.1016/j.carres.2008.03.009

Available online at www.sciencedirect.com
Carbohydrate Research 343 (2008) 1133–1141
Synthesis of new 2-phosphono-a-D-glycoside derivatives by
stereoselective oxa-Michael addition to a D-galacto derived enone
a,b
Francesca Leonelli,a,b, Marinella Capuzzi, Enrico Bodo,a Pietro Passacantillia,b
*
and Giovanni Piancatellia,b,
*
a
`
Dipartimento di Chimica, Universita ‘La Sapienza’, P.le Aldo Moro 5, 00185 Rome, Italy
`
Istituto di Chimica Biomolecolare del CNR-Sezione di Roma, Universita ‘La Sapienza’, P.le Aldo Moro 5, 00185 Rome, Italy
b
Received 22 January 2008; received in revised form 28 February 2008; accepted 6 March 2008
Available online 13 March 2008
Abstract—The synthesis of new 2-phosphono-a-D-glycoside derivatives by stereoselective oxa-Michael addition to an enone derived
from D-galactal and containing a phosphonate group is described. Retro-Michael reactions were prevented by tandem acetylation to
trap the unstable enolic intermediates. The stereochemistry of the addition products was established by NOESY experiments and
explained with molecular mechanics (MM) and density functional theory (DFT) calculations.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Oxa-Michael Addition; 3-Oxo-2-phosphono-a-glycosides; Alcohols; O-Glycosylation
1. Introduction
for the studies of metabolic regulation, enhancement,
and inhibition.4 It is, in fact, a stable analogue of the
naturally occurring phosphate, as the C–P bond is inert-
ed to the enzymes involved in phosphate cleavage. At
present, the interest of the chemists and biologists is
mainly concerned with glycosyl phosphonates, which
are the analogues of glycosyl phosphates involved in
the biosynthesis of oligo- and polysaccharides and
glycoconjugates.5
Although there are a number of naturally occurring
sugar 2-phosphates,6 principally in Gram-negative bac-
teria lipopolysaccharides, to the best of our knowledge,
the literature concerning 2-phosphono sugar analogues
is rather scarce,7 and nothing is known about their bio-
logical activity. In this respect, we believe that the develo-
pment of new methodologies for the stereoselective
preparation of 2-phosphono sugars might be an appeal-
ing target.
For a long time, carbohydrates have excited the interest
of researchers.1 Being among the most abundant natural
products, they are implicated in many cellular processes
such as cell–cell recognition, cellular adhesion, and
transport. They also play a fundamental role in vital
processes, being present, for example, in nucleic acids
or as a component of bacterial cellular walls.2 The
importance, complexity, and variety of natural carbo-
hydrates make their synthesis a challenging and worthy
task.
In Nature, carbohydrates are found mainly in the
form of O-glycosyl derivatives, and, therefore, organic
chemistry has witnessed a noticeable increase in research
addressed to the development of new stereocontrolled
O-glycosylation methods.3
Furthermore, among unnatural carbohydrates those
containing a phosphonate group appear very interest-
ing. The phosphonate group is a useful and versatile tool
Recently, we have reported on the stereocontrolled
preparation from 2-(diethoxyphosphoryl)hex-1-en-3-
ulose (1)8 of 3-oxo-2-phosphono-a-C-glycosides through
a Michael-type addition of organocopper reagents and
have shown that the phosphonate group has a remark-
able activating effect on the Michael addition. Hereafter,
*
Corresponding authors. E-mail addresses: francesca.leonelli@
uniroma1.it; giovanni.piancatelli@uniroma1.it
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.03.009

1134
F. Leonelli et al. / Carbohydrate Research 343 (2008) 1133–1141
we wish to describe the extension of these studies to the
addition of a series of alcohols to 1. To the best of our
knowledge, the literature concerning the O-glycosy-
lation via Michael addition of O-nucleophiles to hex-1-
en-3-uloses derived from carbohydrates is scarce9 and
mainly limited to the addition of MeOH.
OBn
O
O
OBn
OEt
BnONa
workup
1
1
BnOH/THF
-78 °C
BnO
P
OEt
O
Ac2O
Py
-20 °C
OBn
O
OEt
2
OBn
3
BnO
P
O
OBn
OEt
OEt
O
O
1
BnO
P
OEt
O
AcO
2 α/β 100/0
2. Results and discussion
Scheme 1. Michael addition of BnONa to 2-(diethoxyphosphoryl)-
hex-1-en-3-ulose 1.
We started this work with the addition at ꢀ78 °C of
BnONa in BnOH–THF to the Michael acceptor 1. Nev-
ertheless, though the reaction according to TLC moni-
toring appeared to proceed, after the workup only the
starting material was recovered. After several attempts
in which the workup conditions were varied, an ensuing
retro-Michael reaction was considered responsible for
the results obtained. Thus, quenching the reaction with
Ac2O and pyridine, we were able to obtain the enol ace-
tate 2 as the only product, confirming the above hypo-
thesis (see Scheme 1 and Table 1, entry 1).
Prompted by these findings, the addition to 1 was per-
formed with various alcohols leading to the results pre-
sented in Table 1. The yields ranged from moderate to
good with an excellent a:b ratio except in the case of
propargyl alcohol (entries 8 and 9) in which an a:b ratio
of 90:10 was recorded. No change in the diastereoiso-
meric ratio was observed by varying the reaction time.
(Table 1, entries 8 and 9).
Good results were obtained with both primary and
secondary alcohols. It is worth noting that yields were
shown to depend on reaction temperature. With the
exception of the addition of BnOH (Table 1, entries 1
and 2), the best results were obtained at ꢀ30 °C. On
the other hand, the reaction does not proceed at lower
temperature (Table 1, entries 3 and 5), while at 0 °C a
rapid decomposition of the starting material occurs.
To evaluate the activating effect of the phosphonate
group, the reactivity of enones 1 and 8 was compared.
BnOH was used as the nucleophile, and the reaction
was carried out under the same conditions for both
enones: in the case of 1 a total conversion of the starting
material was observed, whereas for 8, which lacked the
C-2 phosphonate group, only a 30% conversion was
recorded.
OBn
O
BnO
O
8
To test the general applicability of the above proce-
dure, the addition of the more sterically hindered D-glu-
cal-derived10 nucleophile 9a was performed on enone 1.
Also in this case the reaction showed complete stereo-
selectivity with the formation of 10 in a 99:1 a:b ratio
(Scheme 2).
The diastereoisomeric ratio of the oxa-Michael addi-
tion turned out to be unaffected by the reaction time
as shown by the results in Table 1 for the addition of
BnOH and propargyl alcohol (entries 1, 2 and 8, 9,
respectively). Moreover, as stated before, the reaction
was completely reversible after workup, and the addi-
tion products could not be isolated unless acetylation
of the enol intermediate was performed. These results
show that the oxa-Michael additions described above
are equilibrium processes. To confirm this conclusion,
an additional experiment was performed: enone 1 was
allowed to react at ꢀ30 °C with BnOH for 5 h in
order to ensure that all the starting material was con-
sumed (Table 1, entry 2). After this time, MeOH was
added, and the reaction was allowed to continue for
an additional 5 h at ꢀ30 °C. As usual, the addition
product was acetylated for 12 h at ꢀ20 °C with Ac2O
and pyridine. The 1H NMR spectrum of the crude reac-
tion mixture showed the presence of a 4:6 mixture of 2
and 3, confirming thermodynamic control during the
Michael addition. As a consequence, the observed a:b
stereoselectivity in the Michael addition (Table 1) is
simply due to the relative stability of the two anomers
TLC (SiO2, 2:8 hexanes–EtOAc) showed the disappearance of the
starting material together with the appearance of a product with a
higher Rf.

F. Leonelli et al. / Carbohydrate Research 343 (2008) 1133–1141
1135
Table 1. Stereoselective addition of various alcohols to 2-(diethoxyphosphoryl)hex-1-en-3-ulose 1
OBn
O
OR
OEt
1) RONa
1
2) Ac2O, Py
-20 °C
BnO
P
OEt
AcO
O
2-7
Entry
1
R
Solvent
Time (h)
T (°C)
ꢀ78
Product
a:ba
Yield (%)
Bn
(3 equiv)
Bn
(5 equiv)
Me
(4 equiv)
Me
(4 equiv)
Et
(5 equiv)
Et
(5 equiv)
n-Pentyl
(5 equiv)
Propargyl
(5 equiv)
Propargyl
(5 equiv)
2-Pr
BnOH–THF
1:1
BnOH–THF
1:0.6
1b
7c
2
100:0
55
(70)d
70
2
3
5b
ꢀ65
ꢀ78
ꢀ30
ꢀ78
ꢀ30
ꢀ20
ꢀ30
ꢀ30
ꢀ20
2
100:0
—
12c
5b
(70)d
—
MeOH
—
3
7c
4
MeOH
8b
98:2
—
60
12c
8b
(98)d
—
5
EtOH
—
4
12c
8b
6
EtOH
98:2
98:2
90:10
90:10
100:0
60
12c
9b
(70)d
80
7
n-Pentanol
Propargyl alcohol
Propargyl alcohol
2-PrOH
5
12c
9b
(85)d
50
8
6
12c
24b
12c
9b
(75)d
50
9
6
(75)d
50
10
7
(5 equiv)
12c
(65)d
a Diastereoisomeric ratios were determined by HPLC analysis of the crude reaction mixtures.
b Reaction time of the conjugate addition.
c Reaction time of the acetylation.
d Yields were calculated on the basis of enone consumption.
derived from the alcohol addition. Theoretical calcula-
tions have been, therefore, carried out on the a and b
anomers of 11–17 to evaluate such energetic differences.
O
O
HO
BnO
NaO
BnO
1:1 THF DMF
NaH, 0 °C
OBn
OBn
OBn
9
1
9a
O
OR
OEt
9a
a)
(5 equiv)
BnO
BnO
O
P
BnO
1:1 THF DMF
O
OEt
-20 °C, 9 h
HO
O
O
b) Ac2O, Py
-20 °C, 15 h
11 R = Me
12 R = Et
OBn
BnO
AcO
O
13 R = n-pentyl
P
50% (66%)a
EtO
14 R = propargyl
15 R = i-Pr
OEt
16 R = Bn
10
α:β 99:1
aYield calculated on enone consumption
Scheme 2. Michael addition to enone 1 of compound 9.10
17
R = 3,4-di-O-benzyl-D-glucal
Although these calculations could be performed in
principle on both the enolic and the ketonic forms, we
decided to analyze only the former. In analogy with
what we found for the Michael-type addition of organo-
copper reagents on the galacto-derived enone 1,8 in this
case the addition products are, in fact, also likely to
adopt the more stable enolic form.
Given the relatively high number of atoms in these
compounds and the excessively large number of local
energy minima corresponding to the many conformers,
we started our analysis by minimizing a large number
of structures generated by sampling the configurational
space through a set of classical molecular mechanics
(MM) trajectories at different temperatures. In this
way, we have determined a global minima geometry
for the a and b anomers of each compound. These
geometries were then further optimized by calculations

1136
F. Leonelli et al. / Carbohydrate Research 343 (2008) 1133–1141
Table 2. Energy differences (DE = Eb ꢀ Ea) between the b and the a anomers of compounds 11–17 obtained by both MM and DFT calculations in
kcal/mol; b% is the percentage of beta anomer population calculated by the DG0 at the indicated temperature
Entry
Compound
DE (MM)
DE (DFT)
DE + ZPE(DFT)
DG0 (b%)
T (°C)
1
2
3
4
5
6
7
11
12
13
14
15
16
17
1.77
1.62
2.26
1.61
1.78
1.74
1.20
1.62a
3.05
3.26
1.75
3.10
1.29
5.30
1.55b
2.69
2.95
1.64
2.83
1.43
—
1.35 (5.6)
2.09 (1.2)
3.68 (<1)
0.06 (46.6)
1.70 (3.2)
2.4 (<1)
—
ꢀ30
ꢀ30
ꢀ20
ꢀ30
ꢀ20
ꢀ78
ꢀ20
a Calculation with counterpoise correction gives DE (DFT + BSSE) = 1.98.
b Calculation in MeOH with PCM model yields DE (DFT) = 1.90 and DE + ZPE(DFT) = 1.85.
using density functional theory (DFT) methods, fol-
lowed by a vibrational normal mode analysis and a stan-
dard thermochemistry calculation at the experimental
temperature. The results from MM and DFT calcula-
tions are shown in Table 2 where we have reported the
energy differences after minimization for both methods,
the energy difference corrected by the ZPE after the nor-
mal mode analysis, the value of the DG0 calculated at the
given temperature, and the percentage of beta popula-
tion at the same temperature. The calculations show
clearly that the a anomer is always the most stable in
each compound. The results are in qualitative agreement
with the experimental data, although they are not able
to predict exactly the beta anomer population. It is
interesting to note, however, that the calculations clearly
detect a smaller energy difference in the case of com-
pound 14 where the experiments have also recorded a
larger beta population.
Figure 1. Optimized structures (ab initio calculations) of the two
possible anomeric compounds derived from the Michael addition of
BnOH on compound 1.
Fig. 1), the more stable a anomer has an axial configu-
ration of the glycoside, while the b has an equatorial
one. This result is consistent with the prediction based
on the anomeric effect12 according to which, for a stereo-
electronic effect, the tendency of heteroatomic substitu-
ents bonded at C-1 is to prefer the axial orientation
instead of the less hindered equatorial orientation that
would be expected from steric considerations.
The counterpoise correction11 has been applied to
compound 11 to assess the size of basis set superposition
errors (BSSEs) and to further check the quality of our
calculations. BSSE effects, though present, do not signifi-
cantly alter our results.
Although it would be interesting to further explore the
nature of the anomeric effect in such compounds, it
turns out that these specific molecules are not the ideal
candidates for a more thorough analysis of their elec-
tronic structure due to their sizes and the prohibitive
calculation times that such an analysis would require,
especially with the use of more appropriate basis sets.
The optimized structures of all the compounds (11–17)
exhibit an intramolecular hydrogen bonding in which
the donor is the enolic hydrogen at C-3 and the acceptor
is the oxygen of the phosphonate group (O@P) at C-2.
The a anomeric configurations of compounds 2–7
were further elucidated by NOESY experiments. The
NOESY spectra of compounds 2, 4–7 showed, for exam-
ple, a correlation between the H-1 and the OCH2 of the
benzyl group on C-4, and that of compound 3 showed a
correlation between the OCH3 and the H-5. The dis-
tances between atoms obtained from the integration of
the signals in the NOESY spectra are in excellent agree-
ment with those obtained by theoretical calculations.
In conclusion, the Michael addition of O-nucleophiles
to the D-galacto derived enone 1 allowed us to prepare
To investigate the possible role of solvent effects in the
calculations, we have optimized the structures for com-
pound 11 using a continuum solvent model (PCM) and
including zero point energy corrections (ZPE). How-
ever, the qualitative behavior turned out to be substan-
tially the same, and the energy differences are even
larger. The structure of the solvated molecules turned
out to be similar to the ones obtained in vacuum since
these were used as the starting geometries in the PCM
calculations. We think that an optimization including
explicit solvent molecules both during the MM and dur-
ing the DFT stages might produce results that are in bet-
ter quantitative agreement with the experiments.
Unfortunately, the number of atoms in the compounds
examined here, and the relative complexity of their sol-
vent partners, did not allow us to implement such a
strategy.
From the analysis of the ab initio optimized structures
of the two possible anomeric compounds derived from
the alcohol addition to enone 1 (see, for example,

F. Leonelli et al. / Carbohydrate Research 343 (2008) 1133–1141
1137
the new glycoside derivatives 2–5 and 7 with an excellent
a:b ratio. The preparation of propargyl glycoside 6, even
with a slightly minor a:b anomeric ratio, represents a
very important result given the recent application of this
class of compounds as novel and stable glycoside
donors.3e The general applicability of the reaction was
tested by performing the addition of primary and sec-
ondary alcohols and of the more sterically hindered
9a, resulting in the preparation of the novel disaccharide
derivative 10. The phosphonate group performed, there-
fore, not only as a good electron-withdrawing group for
the oxa-Michael addition, but also as an interesting sub-
stituent either for its potential biological activity and/or
for the possibility of further functionalizations like,
for example, a tandem Horner–Wadsworth–Emmons
olefination reaction.
100-5 column (Macherey–Nagel), at a flow of 0.8 mL/
min; tR in min.
3.2. Synthesis of compounds 2–7 and 10
3.2.1. Benzyl 3-O-acetyl-4,6-di-O-benzyl-2-deoxy-2-
diethoxyphosphoryl-a-D-threo-hex-2-enopyranoside (2).
To a stirred solution of 1 (35 mg, 0.076 mmol) in anhyd
THF (0.6 mL),
a
0.5 M BnONa–BnOHà solution
(0.23 mmol, 0.46 mL) was added at ꢀ78 °C,§ and the
stirring was continued for 1 h under an inert atmosphere
of Ar. Pyridine (1 mL) and Ac2O (0.5 mL) were then
added, and the reaction mixture was stirred for 7 h at
ꢀ20 °C. After this time, the reaction mixture was diluted
with Et2O (5 mL), washed in a separatory funnel with
cold satd NaHCO3 (3 ꢁ 5 mL), H2O (until neutral),
and brine. The organic extract was then dried (Na2SO4)
and concentrated under reduced pressure. The crude
product was purified by column chromatography
(SiO2, 7:3 n-hexane–EtOAc) to give the unreacted enone
1 (7 mg, 0.016 mmol) and 2 (26 mg, 0.042 mmol, 55%)
3. Experimental
3.1. General experimental methods
20
as a viscous oil. Data for 2. ½aꢂD ꢀ47.5 (c 3.4, CHCl3).
1H NMR (200 MHz) and 13C NMR (50.3 MHz) spectra
were recorded on a Varian Gemini 200 spectrometer
with CDCl3 as the solvent and as the internal standard.
Chemical shifts are reported in d units (ppm) and cou-
pling constants (J) are in Hertz. 2D 1H,1H-NOESY
experiments were performed on a Bruker AC 300 P
spectrometer operating at 300.13 MHz and equipped
with a Bruker multinuclear probe head. NOESY exper-
iments were performed in the TPPI phase-sensitive
mode with a spectral sweep width of 2.4 kHz in both
dimensions, 1024 data points in f2 and 512 increments
in f1, and a recycle delay of 2 s; a mixing time of
700 ms was used; zero filling in f1 to 1024 real data
points and 90° phase-shifted square-sine bell window
functions in both dimensions were applied before
Fourier transformation. IR spectra were obtained with
a Shimadzu-470 scanning infrared spectrophotometer,
with absorptions reported in cmꢀ1. HRESIMS spectra
were recorded with Micromass Q-TOF Micro Mass
Spectrometer (Waters) in the electrospray-ionization
mode. Optical rotations were measured using the
sodium D line on a DIP 370 Jasco digital polarimeter.
Yields are given for isolated products after column chro-
matography. All reactions were performed under an
inert atmosphere of Ar in flame-dried glassware. All sol-
vents and commercially available reagents were used
without purification unless otherwise noted. All reac-
tions were monitored by thin-layer chromatography
(TLC) carried out on E. Merck F-254 silica glass plates
visualized with UV light and a heat-gun after being
sprayed with a 2 N H2SO4 solution. Column chromato-
graphy was performed with E. Merck Silica Gel 60
(230–400 mesh). HPLC analysis was carried out on a
Shimadzu LC-10AD; RID detector, 250/4 Nucleosil
1H NMR: d 7.50–7.21 (m, 15H, 3Ph), 5.53 (d, 1H, J1,P
3.73, H-1), 4.79 (A of AB, 1H, JAB 11.33, HA of
CH2Ph), 4.67 (B of AB, 1H, JBA 11.33, HB of CH2Ph),
4.67 (br s, 2H, CH2Ph), 4.63–4.50 (m, 3H, CH2Ph, H-5),
4.22–3.89 (m, 5H, H-4, 2OCH2CH3), 3.80 (A of ABX,
1H, JAB 9.73, JAX 6.71, 6-HA), 3.69 (B of ABX, 1H,
JBA 9.73, JBX 6.51, 6-HB), 2.09 (s, 3H, CO(CH3)), 1.29
(td, 3H, JCH ;CH 7.06, JCH ;P 0.57, OCH2CH3), 1.23
3
2
3
(td, 3H, JCH ;CH 7.06, JCH ;P 0.60, OCH2CH3). 13C
3
2
3
NMR: d 168.6 (C@O), 157.7 (d, JC-3,P 2.98, C-3),
138.0, 137.6, 137.5 (CquatPh), 128.3, 128.3, 128.2,
128.1, 127.9, 127.63, 127.60 (Ph), 119.3 (d, JC-2,P
176.62, C-2), 95.3 (d, JC-1,P 12.30, C-1), 73.4 (2CH2Ph),
71.0 (CH2Ph), 70.3 (d, JC-4,P 9.70, C-4), 69.6 (C-5), 68.3
(C-6), 62.2 (d, JCH ;P 4.89, 2OCH2CH3), 20.8
2
(CO(CH3)), 16.2 (d, JCH ;P 5.22, OCH2CH3), 16.1 (d,
3
JCH ;P 5.22, OCH2CH3). IR (CHCl3): 1760. HPLC:
3
(1:1 n-hexane–EtOAc): tRa 13.4 (100%). HRESIMS:
Calcd for C33H39O9P [M+Na]+: m/z 633.2229; found:
m/z 633.2231.
3.2.2. Methyl 3-O-acetyl-4,6-di-O-benzyl-2-deoxy-2-
diethoxyphosphoryl-a-D-threo-hex-2-enopyranoside (3).
To a stirred solution of 1 (30 mg, 0.065 mmol) in anhyd
MeOH (0.25 mL), a 1 M MeONa–MeOH solution
(0.26 mmol, 0.26 mL) was added at ꢀ30 °C, and the stir-
ring was continued for 8 h under an inert atmosphere of
Ar. Pyridine (3 mL) and Ac2O (1.5 mL) were then
à The 0.5 M BnONa–BnOH was prepared by adding anhyd BnOH
(2 mL) to NaH (40 mg, 1 mmol, 60% suspension in mineral oil) at
0 °C. The solution was stirred at rt for 30 min.
§ When the BnOH addition reaction was performed at ꢀ65 °C, 2 was
obtained in 70% yield.

1138
F. Leonelli et al. / Carbohydrate Research 343 (2008) 1133–1141
added, and the reaction mixture was stirred for 12 h at
ꢀ20 °C. After this time, the reaction mixture was diluted
with Et2O (5 mL), washed in a separatory funnel with
cold satd NaHCO3 (3 ꢁ 5 mL), H2O (until neutral),
and brine. The organic extract was then dried (Na2SO4)
and concentrated under reduced pressure. The crude
product was purified by column chromatography
(SiO2, 7:3 n-hexane–EtOAc) to give the unreacted
enone 1 (12 mg, 0.026 mmol) and 3 (21 mg, 0.039 mmol,
60%) as a viscous oil and as an inseparable mixture of
3H, JCH ;CH 7.06, JCH ;P 0.60, POCH2CH3), 1.29 (td,
3
2
3
3H, JCH ;CH 7.06, JCH ;P 0.60, POCH2CH3), 1.22 (t,
3
2
3
3H, JCH ;CH 7.07, OCH2CH3). 13C NMR: d 168.6 (d,
2
3
JCO,P 1.66, C@O), 157.3 (d, JC-3,P 3.15, C-3), 138.0,
137.7 (CquatPh), 128.3, 128.2, 127.8, 127.6, 127.59 (Ph),
119.7 (d, JC-2,P 176.10, C-2), 95.4 (d, JC-1,P 12.37, C-1),
73.42, 73.38 (2CH2Ph), 70.3 (d, JC-4,P 9.73, C-4), 69.3
(C-5), 68.4 (C-6), 64.6 (OCH2CH3), 62.2 (d, JCH ;P
2
4.84, 2POCH2CH3), 20.8 (CO(CH3)), 16.3 (d, JCH ;P
3
3.84, POCH2CH3), 16.1 (d, JCH ;P 3.77, POCH2CH3),
3
20
a:b anomers. Data for 3. ½aꢂD ꢀ50.5 (c 1.1, CHCl3).
15.1 (OCH2CH3). IR (CHCl3): 1761. HPLC: (1:1 n-hex-
ane–EtOAc): tRa 16.3 (98%), tRb 17.3 (2%). HRESIMS:
Calcd for C28H37O9P [M+Na]+: m/z 571.2073; found:
m/z 571.2087.
1H NMR: d 7.42–7.21 (m, 10H, 2Ph), 5.23 (d, 1H, J1,P
3.69, H-1), 4.62 (br s, 2H, CH2Ph), 4.61 (A of AB,
1H, JAB 11.87, HA of CH2Ph), 4.55 (B of AB, 1H, JBA
11.87, HB of CH2Ph), 4.54–4.39 (m, 1H, H-5), 4.24–
3.96 (m, 5H, H-4, 2OCH2CH3), 3.79 (A of ABX, 1H,
JAB 9.77, JAX 6.68, 6-HA), 3.73 (B of ABX, 1H, JBA
9.77, JBX 6.68, 6-HB), 3.46 (s, 3H, OCH3), 2.06 (s, 3H,
CO(CH3)), 1.31 (td, 3H, JCH ;CH 7.06, JCH ;P 0.63,
3.2.4. n-Pentyl 3-O-acetyl-4,6-di-O-benzyl-2-deoxy-2-
diethoxyphosphoryl-a-D-threo-hex-2-enopyranoside (5).
To a stirred solution of 1 (56 mg, 0.122 mmol) in
anhyd n-pentanol (0.2 mL), a 1 M CH3(CH2)4ONa–
CH3(CH2)4OH solution (0.610 mmol, 0.61 mL) was
added at ꢀ20 °C, and the stirring was continued for
9 h under an inert atmosphere of Ar. Pyridine (4 mL)
and Ac2O (2 mL) were then added, and the reaction
mixture was stirred for 12 h at ꢀ20 °C. After this time,
the reaction mixture was diluted with Et2O (5 mL),
washed in a separatory funnel with cold satd NaHCO3
(3 ꢁ 5 mL), H2O (until neutral), and brine. The organic
extract was then dried (Na2SO4) and concentrated under
reduced pressure. The crude product was purified by col-
umn chromatography (SiO2, 7:3 n-hexane–EtOAc) to
give the unreacted enone 1 (5 mg, 0.010 mmol) and 5
(56 mg, 0.095 mmol, 80%) as a viscous oil and as an
3
2
3
OCH2CH3), 1.29 (td, 3H, JCH ;CH 7.06, JCH ;P 0.63,
3
2
3
OCH2CH3). 13C NMR: d 168.6 (C@O), 157.5 (d, JC-3,P
3.05, C-3), 137.9, 137.6 (CquatPh), 128.4, 128.2, 127.9,
127.8, 127.7, 127.6 (Ph), 119.5 (d, JC-2,P 177.00, C-2),
96.5 (d, JC-1,P 12.21, C-1), 73.4 (2CH2Ph), 70.1 (d,
JC-4,P 9.92, C-4), 69.4 (C-5), 68.4 (C-6), 62.3 (d, JCH ;P
2
3.81, 2 OCH2CH3), 56.2 (OCH3), 20.8 (CO(CH3)),
16.3 (d, JCH ;P 3.05, OCH2CH3), 16.1 (d, JCH ;P 3.43,
3
3
OCH2CH3). IR (CHCl3): 1761. HPLC: (1:1 n-hexane–
EtOAc): tRa 21.5 (98%), tRb 22.8 (2%). HRESIMS:
Calcd for C27H35O9P [M+K]+: m/z 573.1656; found:
m/z 573.1680.
3.2.3. Ethyl 3-O-acetyl-4,6-di-O-benzyl-2-deoxy-2-dieth-
oxyphosphoryl-a-D-threo-hex-2-enopyranoside (4). To a
stirred solution of 1 (36 mg, 0.078 mmol) in anhyd
20
inseparable mixture of a,b anomers. Data for 5. ½aꢂD
1
ꢀ65.9 (c 3.1, CHCl3). H NMR: d 7.39–7.21 (m, 10H,
EtOH (0.3 mL),
a
1 M EtONa–EtOH solution
2Ph), 5.33 (d, 1H, J1,P 3.38, H-1), 4.62 (br s, 2H,
CH2Ph), 4.59 (A of AB, 1H, JAB 11.86, HA of CH2Ph),
4.53 (B of AB, 1H, JBA 11.86, HB of CH2Ph), 4.51 (td,
1H, J5,6 6.5, J5,4 2.6, H-5), 4.22–3.92 (m, 5H, H-4,
2POCH2CH3), 3.85–3.65 (m, 3H, 6-H, HA of OCH2-
(CH2)3CH3), 3.61–3.46 (m, 1H, HB of OCH2(CH2)3-
CH3), 2.07 (s, 3H, CO(CH3)), 1.68–1.48 (m, 2H,
OCH2CH2(CH2)2CH3), 1.39–1.20 (m, 4H, O(CH2)2-
(CH2)2CH3), 1.31 (td, 3H, JCH ;CH 7.05, JCH ;P 0.58,
(0.39 mmol, 0.39 mL) was added at ꢀ30 °C, and the stir-
ring was continued for 8 h under an inert atmosphere of
Ar. Pyridine (3 mL) and Ac2O (1.5 mL) were then
added, and the reaction mixture was stirred for 12 h at
ꢀ20 °C. After this time, the reaction mixture was diluted
with Et2O (5 mL), washed in a separatory funnel with
cold satd NaHCO3 (3 ꢁ 5 mL), H2O (until neutral),
and brine. The organic extract was then dried (Na2SO4)
and concentrated under reduced pressure. The crude
product was purified by column chromatography
(SiO2, 6:4 n-hexane–EtOAc) to give the unreacted enone
1 (5 mg, 0.010 mmol) and 4 (26 mg, 0.047 mmol, 60%) as
a viscous oil and as an inseparable mixture of a,b ano-
3
2
3
POCH2CH3), 1.28 (td, 3H, JCH ;CH 7.07, JCH ;P 0.55,
3
2
3
POCH2CH3), 0.88 (pt, 3H, O(CH2)4CH3). 13C NMR:
d 168.6 (d, JCO,P 1.50, C@O), 157.3 (d, JC-3,P 3.12,
C-3), 138.0, 137.7 (CquatPh), 128.3, 128.2, 127.8, 127.6,
127.5 (Ph), 119.7 (d, JC-2,P 175.93, C-2), 95.4 (d, JC-1,P
12.37, C-1), 73.4, 73.3 (2CH2Ph), 70.1 (d, JC-4,P 9.70,
C-4), 69.3 (C-5), 69.2, (OCH2(CH2)3CH3), 68.4 (C-6),
20
mers. Data for 4. ½aꢂD ꢀ51.5 (c 1.3, CHCl3). 1H
NMR: d 7.39–7.21 (m, 10H, 2Ph), 5.35 (d, 1H, J1,P
3.97, H-1), 4.62 (br s, 2H, CH2Ph), 4.60 (A of AB,
1H, JAB 11.86, HA of CH2Ph), 4.55 (B of AB, 1H, JBA
11.86, HB of CH2Ph), 4.59–4.41 (m, 1H, H-5), 4.21–
3.93 (m, 5H, H-4, 2POCH2CH3), 3.91–3.53 (m, 4H,
CH2-6, OCH2CH3), 2.06 (s, 3H, CO(CH3)), 1.31 (td,
62.1 (d, JCH ;P 4.67, 2POCH2CH3), 29.3, 28.2, 22.3
2
(OCH2(CH2)3CH3), 20.8 (CO(CH3)), 16.3 (d, JCH ;P
3
4.08, POCH2CH3), 16.1 (d, JCH ;P 4.03, POCH2CH3),
3
13.9 (OCH2CH3). IR (CHCl3): 1759. HPLC: (1:1 n-hex-
ane–EtOAc): tRa 11.1 (98%), tRb 11.7 (2%). HRESIMS:

F. Leonelli et al. / Carbohydrate Research 343 (2008) 1133–1141
1139
Calcd for C31H43O9P [M+Na]+: m/z 613.2542; found:
m/z 613.2570.
the unreacted enone 1 (12 mg, 0.026 mmol) and 7
(31 mg, 0.055 mmol, 50%) as a viscous oil and as an
20
inseparable mixture of a,b anomers. Data for 7. ½aꢂD
1
3.2.5. Propargyl 3-O-acetyl-4,6-di-O-benzyl-2-deoxy-
2-diethoxyphosphoryl-a-D-threo-hex-2-enopyranoside 6.
To a stirred solution of 1 (50 mg, 0.11 mmol) in anhyd
propargyl alcohol (0.3 mL), a 1 M HC„CCH2ONa–
HC„CCH2OH solution (0.55 mmol, 0.55 mL) was
added at ꢀ30 °C, and the stirring was continued for
9 h under an inert atmosphere of Ar. Pyridine (4 mL)
and Ac2O (2 mL) were then added, and the reaction
mixture was stirred for 12 h at ꢀ20 °C. After this time,
the reaction mixture was diluted with Et2O (5 mL),
washed in a separatory funnel with cold satd NaHCO3
(3 ꢁ 5 mL), H2O (until neutral), and brine. The organic
extract was then dried (Na2SO4) and concentrated under
reduced pressure. The crude product was purified by col-
umn chromatography (SiO2, 7:3 n-hexane–EtOAc) to
give the unreacted enone 1 (17 mg, 0.037 mmol) and 6
(31 mg, 0.055 mmol, 50%) as a viscous oil and as an
ꢀ60.4 (c 2.3, CHCl3). H NMR: d 7.36–7.23 (m, 10H,
2Ph), 5.44 (d, 1H, J1,P 3.71, H-1), 4.62 (br s, 2H,
CH2Ph), 4.49–4.60 (m, 3H, CH2Ph, H-5), 3.91–4.23
(m, 6H, 2OCH2CH3, H-4, CH(CH3)2), 3.79 (A of
ABX, 1H, JAB 9.71, JAX 6.96, 6-HA), 3.71 (B of ABX,
1H, JBA 9.71, JBX 6.39, 6-HB), 2.06 (s, 3H, CO(CH3)),
1.31 (t, 3H, JCH ;CH 6.96, OCH2CH3), 1.28 (t, 3H,
3
2
JCH ;CH 6.96, OCH2CH3), 1.21 (d, 3H,
J 3.98,
3
2
CH(CH3)2), 1.20 (d, 3H, J 3.90, CH(CH3)2). 13C
NMR: d 168.7 (C@O), 157.3 (d, JC-3,P 3.08, C-3),
138.0, 137.8 (CquatPh), 128.3, 128.2, 127.8, 127.6, 127.5
(Ph), 119.9 (d, JC-2,P 175.74, C-2), 94.1 (d, JC-1,P 12.30,
C-1), 73.4, 73.3, 71.5, 70.3 (d, JC-4,P 9.63, C-4), 69.1,
68.4, 62.2 (d, JCH ;P 4.91, OCH2CH3), 62.2 (d, JCH ;P
2
2
4.96, OCH2CH3), 23.5, 21.7, 20.8, 16.2 (d, JCH ;P 4.51,
3
OCH2CH3), 16.1 (d, JCH ;P 4.55, OCH2CH3). IR
3
(CHCl3): 1764. HPLC: (1:1 n-hexane–EtOAc): tRa 14.6
(100%). HRESIMS: Calcd for C29H39O9P [M+Na]+:
m/z 585.2229; found: m/z 585.2236.
20
inseparable mixture of a,b anomers. Data of 6. ½aꢂD
1
ꢀ27.9 (c 1.3, CHCl3). H NMR: d 7.44–7.22 (m, 10H,
2Ph), 5.52 (d, 1H, J1,P 3.69, H-1), 4.63 (br s, 2H,
CH2Ph), 4.57 (br s, 2H, CH2Ph), 4.55–4.44 (m, 1H,
H-5), 4.35–4.27 (m, 2H, OCH2C„CH), 4.20–4.00 (m,
5H, H-4, 2OCH2CH3), 3.84–3.66 (m, 2H, CH2-6), 2.37
(t, 1H, OCH2C„CH), 2.07 (s, 3H, CO(CH3)), 1.32
(td, 3H, JCH ;CH 7.06, JCH ;P 0.53, OCH2CH3), 1.30
3.2.7. 3-O-Acetyl-4,6-di-O-benzyl-2-deoxy-2-diethoxy-
phosphoryl-a-D-threo-hex-2-enopyranosyl-(1?6)-1,5-an-
hydro-3,4-di-O-benzyl-D-arabino-hex-1-enitol (10). To
a stirred solution of 1 (50 mg, 0.11 mmol) in anhyd
THF (0.15 mL) and DMF (0.15 mL), a 1 M solution
of 9a (0.6 mmol, 0.6 mL) in 1:1 THF–DMF was added
at ꢀ20 °C, and the stirring was continued for 9 h under
an inert atmosphere of Ar. Pyridine (4 mL) and Ac2O
(2 mL) were then added, and the reaction mixture was
stirred for 15 h at ꢀ20 °C. After this time, the reaction
mixture was diluted with Et2O (5 mL), washed in a
separatory funnel with cold satd NaHCO3 (3 ꢁ 5 mL),
H2O (until neutral), and brine. The organic extract
was then dried (Na2SO4) and concentrated under re-
duced pressure. The crude product was purified by col-
umn chromatography (SiO2, 7:3 n-hexane–EtOAc) to
give the unreacted enone 1 (12 mg, 0.026 mmol) and
10 (47 mg, 0.055 mmol, 50%) as a viscous oil and as
an inseparable mixture of a,b anomers. Data for 10.
3
2
3
(td, 3H, JCH ;CH 7.06, JCH ;P 0.54, OCH2CH3). 13C
3
2
3
NMR: d 168.6 (C@O), 158.1 (d, JC-3,P 2.86, C-3),
137.9, 137.6 (CquatPh), 128.4, 128.2, 127.9, 127.71,
127.69 (Ph), 119.1 (d, JC-2,P 177.67, C-2), 94.3 (d,
JC-1,P 11.83, C-1), 79.0 (C„CH), 74.6, 73.5 (CH2Ph),
70.2 (d, JC-4,P 9.66, C-4), 69.8 (C„CH), 69.7 (C-5),
68.1 (C-6), 62.6 (d, JCH ;P 5.13, OCH2CH3), 62.4 (d,
2
JCH ;P 5.20, OCH2CH3), 55.4 (OCH2C„CH), 20.8
2
(CO(CH3)), 16.3 (d, JCH ;P 6.46, 2OCH2CH3). IR
3
(CHCl3): 1761. HPLC: (1:1 n-hexane–EtOAc): tRa 16.9
(90%), tRb 17.9 (10%). HRESIMS: Calcd for
C29H35O9P [M+Na]+: m/z 581.1916; found: m/z
581.1901.
20
1
3.2.6. 20-Propyl 3-O-acetyl-4,6-di-O-benzyl-2-deoxy-2-
diethoxyphosphoryl-a-D-threo-hex-2-enopyranoside (7).
To a stirred solution of 1 (50 mg, 0.11 mmol), a 0.3 M
2-PrONa–2-PrOH solution (0.55 mmol, 1.65 mL) was
added at ꢀ20 °C, and the stirring was continued for
9 h under an inert atmosphere of Ar. Pyridine (4 mL)
and Ac2O (2 mL) were then added, and the reaction
mixture was stirred for 12 h at ꢀ20 °C. After this time,
the reaction mixture was diluted with Et2O (5 mL),
washed in a separatory funnel with cold satd NaHCO3
(3 ꢁ 5 mL), H2O (until neutral), and brine. The organic
extract was then dried (Na2SO4) and concentrated under
reduced pressure. The crude product was purified by
column chromatography (7:3 n-hexane–EtOAc) to give
½aꢂD ꢀ31.8 (c 1.9, CHCl3). H NMR: d 7.47–7.16 (m,
20H, 4Ph), 6.32 (dd, 1H, J1 ;2 6.20, J1 ;3 1.05, H-10),
0
0
0
0
0
0
5.41 (d, 1H, J1,P 3.72, H-1), 4.84 (dd, 1H, J2 ;1 6.20,
J2 ;3 3.05, H-20), 4.83 (A of AB, 1H, JAB 11.65, HA of
CH2Ph), 4.70 (B of AB, 1H, JBA 11.65, HB of CH2Ph),
4.62–4.34 (m, 7H, 3CH2Ph, H-5), 4.23–3.56 (m, 12H,
2OCH2CH3, H-4, CH2-6, H-30, H-40, H-50, CH2-60),
2.06 (s, 3H, CO(CH3)), 1.29 (t, 3H, JCH ;CH 7.05,
0
0
3
2
OCH2CH3), 1.27 (td, 3H, JCH ;CH 7.06, OCH2CH3).
3
2
13C NMR: d 168.5 (C@O), 157.7 (d, JC-3,P 3.05, C-3),
144.4 (C-10), 138.4, 138.3, 137.9, 137.7 (CquatPh),
128.3, 128.2, 127.9, 127.7, 127.6, 127.5 (Ph), 119.3 (d,
JC-2,P 176.52, C-2), 99.7 (C-20), 95.6 (d, JC-1,P 12.04,
C-1), 76.4 (C-30), 75.1 (C-40), 74.5 (C-50), 73.5, 73.4,

1140
F. Leonelli et al. / Carbohydrate Research 343 (2008) 1133–1141
73.3, 70.3 (4CH2Ph), 70.2 (d, JC-4,P 9.68, C-4), 69.4 (C-5),
ported in Table 2. In the second step, we have calculated
the vibrational frequencies of the optimized structures in
MeOH and we have been able to correct the PCM ener-
gies for the ZPE energies.
68.1 (C-6), 67.4 (C-60), 62.3 (d, JCH ;P 4.77, 2OCH2CH3),
2
20.8 (CO(CH3)), 16.3 (d, JCH ;P 3.70, OCH2CH3), 16.2 (d,
3
JCH ;P 3.70, OCH2CH3). IR (CHCl3): 1762. HPLC: (1:1
3
n-hexane–EtOAc): tRa 12.6 (99%), tRb 13.7 (1%). HRE-
SIMS: Calcd for C46H53O12P [M+Na]+: m/z 851.3172;
found: m/z 851.3214.
The 6-31G(d,p) basis may lead to appreciable basis set
superposition errors (BSSEs). The counterpoise correc-
tion,11 while not rigorous, can be used to produce cor-
rected energies. We have therefore repeated our
calculations on compound 11 using the counterpoise
correction implemented in GAUSSIAN 03 to further check
the quality of our calculations procedure. We have di-
vided the molecule into two fragments by setting one
of them to ꢀOCH3. The result is reported in Table 2
as DE(DFT + BSSE).
3.3. Theoretical calculations
For each compound, we ran a set of classical MM
trajectories to sample the configurational space. The tra-
jectories were calculated in vacuum using a Verlet algo-
rithm and the MM3 force field as implemented by the
Tinker suite of codes.13 In general, a first trajectory of
9 ꢁ 105 steps of 0.1–0.2 fs was generated using a temper-
ature of 2000 K. Snapshots of this trajectory were saved,
each 1 ꢁ 103 fs, and optimized using a truncated New-
ton minimization method. By selecting the lowest energy
structures, we obtained a small set of candidates for cre-
ating a second set of trajectories at a lower temperature
(1000 K). We repeated this cycle once more also for
500 K, and at this point, we were able to easily identify
a global minimum structure. The MM energy differences
between the b and the a isomers are reported as ‘MM’ in
Table 2.
Acknowledgments
Financial support from the University of Rome ‘La
Sapienza’ and CASPUR Supercomputing Center is
gratefully acknowledged. We also thank Dr. Giovanna
Mancini of CNR ‘Istituto delle Metodologie Chimiche-
Sezione Meccanismi di Reazione’ for the NOESY spec-
tra and very helpful discussions.
Supplementary data
For each compound, the a and the b MM global min-
ima determined by means of the above procedure were
further optimized using density functional theory
(DFT) methods: the calculations have been carried out
with the GAUSSIAN 03 suite of codes,14 using a DFT
method based on the B3LYP functional. Given the size
of the molecules involved in the calculations, we have
been forced to use the relatively small 6-31G(d,p) basis
set. A larger one would have been certainly desirable,
but would have made the calculation times prohibitive.
For all the molecules, we have started by minimizing
the structures obtained from MM calculations with the
relatively small 6-31G basis set. The resulting structure
was then optimized again with a 6-31G(d,p) basis. The
energy differences between the optimized structures of
the b and the a anomers are those reported as DE(DFT)
in Table 2. For each structure, we have also performed a
normal mode analysis and a thermochemistry calcula-
tion at a given temperature in order to have a good esti-
mate of the free-energy difference. The only exception is
represented by compound 17 where we were not able to
perform the 6-31G(d,p) basis set optimization and the
normal mode analysis because of the large number of
atoms involved. In this case, the DFT energy shown in
Table 2 refers to the 6-31G results.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.carres.
2008.03.009.
References
1. Nicolaou, K. C.; Mitchell, J. H. Angew. Chem., Int. Ed.
2001, 40, 1576–1624.
2. For example, see: (a) Dube, D. H.; Bertozzi, C. R. Nat.
Rev. Drug Disc. 2005, 4, 477–488; (b) Sears, P.; Wong,
C.-H. Science 2001, 291, 2344–2350; (c) Dwek, R. A.;
Butters, T. D.; Platt, F. M.; Zitzmann, N. Nat. Rev. Drug
Disc. 2002, 1, 65–75; (d) Dwek, R. A. Chem. Rev. 1996, 96,
683–720.
3. Inter alia: (a) Kanie, O.; Ohtsuka, I.; Ako, T.; Daikoku,
S.; Kanie, Y.; Kato, R. Angew. Chem., Int. Ed. 2006, 45,
3851–3854; (b) Deng, S.; Gangadharmath, U.; Chang,
C.-W.T. J. Org. Chem. 2006, 71, 5179–5185; (c) Di
Bussolo, V.; Romano, M. R.; Favero, L.; Pineschi, M.;
Crotti, P. J. Org. Chem. 2006, 71, 1696–1699; (d)
Wilkinson, B. L.; Bornaghi, L. F.; Poulsen, S.-A.; Hous-
ton, T. A. Tetrahedron 2006, 62, 8115–8125; (e) Hotha, S.;
Kashyap, S. J. Am. Chem. Soc. 2006, 128, 9620–9621; (f)
Pellissier, H. Tetrahedron 2005, 61, 2947–2993.
4. Engel, R. Chem. Rev. 1977, 77, 349–367.
5. (a) Pachamuthu, K.; Figueroa-Perez, I.; Ali, I. A. I.;
Schmidt, R. R. Eur. J. Org. Chem. 2004, 3959–3961; (b)
Orsini, F.; Caselli, A. Tetrahedron Lett. 2002, 43, 7259–
7261 and references cited therein; (c) Dondoni, A.; Marra,
A.; Pasti, C. Tetrahedron: Asymmetry 2000, 11, 305–317
and references cited therein; (d) Junker, H. D.; Fessner,
W. D. Tetrahedron Lett. 1998, 39, 269–272 and references
cited therein.
To account for the solvent effects, we have performed
an additional calculation on compound 11. As a first
step, we have optimized the structures obtained in vac-
uum using the PCM model15 with the specific MeOH
solvent. We have obtained a new DE(DFT), which is re-

F. Leonelli et al. / Carbohydrate Research 343 (2008) 1133–1141
1141
6. Inter alia: (a) Paramonov, N.; Rangarajan, M.; Hashim,
A.; Gallagher, A.; Aduse-Opoku, J.; Slaney, J. M.;
Hounsell, E.; Curtis, M. A. Mol. Microbiol. 2005, 58,
847–863; (b) Leone, S.; Izzo, V.; Silipo, A.; Sturiale, L.;
Garozzo, D.; Lanzetta, R.; Parrilli, M.; Molinaro, A.; Di
Donato, A. Eur. J. Biochem. 2004, 271, 2691–2704; (c)
Silipo, A.; Leone, S.; Molinaro, A.; Lanzetta, R.; Parrilli,
M. Carbohydr. Res. 2004, 339, 2241–2248; (d) Bystrova,
O. V.; Lindner, B.; Moll, H.; Kocharova, N. A.; Knirel, Y.
A.; Za¨hringer, U.; Pier, G. B. Carbohydr. Res. 2003, 338,
1895–1905; (e) Lahmann, M.; Garegg, P. J.; Konradsson,
P.; Oscarson, S. Can. J. Chem. 2002, 80, 1105–1111; (f)
Pekari, K.; Schmidt, R. R. J. Org. Chem. 2003, 68, 1295–
1308; (g) Vinogradov, E.; Korenevsky, A.; Beveridge, T. J.
Carbohydr. Res. 2002, 337, 1285–1289; (h) Sadovskaya, I.;
Brisson, J. R.; Thibault, P.; Richards, J. C.; Lam, J. S.;
Altman, E. Eur. J. Biochem. 2000, 267, 1640–1650.
7. (a) Jessop, C. M.; Parson, A. F.; Routledge, A.; Irvine, D.
J. Tetrahedron Lett. 2004, 45, 5095–5098; (b) Kumamoto,
K.; Yoshida, H.; Ogata, T.; Inokawa, S. Bull. Chem. Soc.
Jpn. 1969, 42, 3245–3248; (c) Paulsen, H.; Greve, W.
Chem. Ber. 1973, 106, 2114–2123.
8. Leonelli, F.; Capuzzi, M.; Calcagno, V.; Passacantilli, P.;
Piancatelli, G. Eur. J. Org. Chem. 2005, 2671–2676.
9. (a) Mann, B.; Pitts, D.; Koviach, J. J. Carbohydr. Chem.
2005, 24, 161–168; (b) Michael, K.; Kessler, H. Tetra-
hedron Lett. 1996, 37, 3453–3456 and references cited
therein; (c) Sakakibara, T.; Nakagawa, T. Carbohydr. Res.
1989, 191, 231–241; (d) Lichtenthaler, F. W.; Nishiyama,
S.; Weimer, T. Liebigs Ann. Chem. 1989, 12, 1163–1170.
10. Alonso, R. A.; Vite, G. D.; McDevitt, R. E.; Fraser-Reid,
B. J. Org. Chem. 1992, 57, 573–584.
12. For example, see: (a) Juaristi, E.; Cuevas, G. Tetrahedron
1992, 48, 5019–5087; (b) Kirby, A. J. The Anomeric and
Related Stereoelectronic Effects at Oxygen; Springer:
Berlin, 1983; (c) Deslongchamps, P. Stereoelectronic
Effects in Organic Chemistry; Wiley: New York, 1983.
13. (a) Ren, P.; Ponder, J. W. J. Phys. Chem. B 2003, 107,
5933–5947; (b) Ren, P.; Ponder, J. W. J. Comput. Chem.
2002, 23, 1497–1506.
14. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.,
Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.;
Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.;
Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz,
J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challa-
combe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong,
M. W.; Gonzalez, C.; Pople, J. A. GAUSSIAN 03, Revision
C.02; Gaussian: Wallingford CT, 2004.
15. (a) Cossi, M.; Scalmani, G.; Rega, N.; Barone, V. J. Chem.
Phys. 2002, 117, 43–54; (b) Cammi, R.; Mennucci, B.;
Tomasi, J. J. Phys. Chem. A 2000, 104, 5631–5637.
11. Boys, S. F.; Bernardi, F. Mol. Phys. 1970, 19, 553–566.