C-Glycosylidene derivatives (exo-glycals): Their synthesis by reaction of protected sugar lactones with tributylphosphonium ylids, conformational analysis and stereoselective reduction

Article abstract of DOI:10.1016/j.tet.2003.09.081

Stabilised tributylphosphonium ylids Bu₃PCH = CH(EWG), where EWG is CO₂Me, CO₂^tBu or CN, react with protected sugar lactones under mild conditions to give high yields of glycosylidene derivatives (4 and 5) with good Z/E selectivity. X-Ray crystallography shows that in the solid state the tetra-O-benzyl protected (Z)-glucosylideneacetonitrile (Z)-4c adopts a conformation intermediate between a boat and a twist-boat, whereas the isomeric galactose derivative (Z)-5c exists as a distorted chair. NMR data suggest that in solution chair-like conformations are again more favoured for galactosylidene derivatives than for their glucosylidene analogues. Solution phase NMR studies and molecular modelling show that the (E)-double bond geometry disfavours the chair-like geometry of the ring, even in the galactose series; this is consistent with the avoidance of allylic 1,3-strain. Reduction of the glycosylidene double bond to give stereoselective formation of β-C-glycoside derivatives may be achieved by using Et₃SiH-CF₃CO₂H or Et ₃SiH-BF₃·Et₂O.

Full text of DOI:10.1016/j.tet.2003.09.081

Tetrahedron 59 (2003) 9349–9360
C-Glycosylidene derivatives (exo-glycals): their synthesis by
reaction of protected sugar lactones with tributylphosphonium
ylids, conformational analysis and stereoselective reduction
a
Miguel Gascon-Lopez, Majid Motevalli, George Paloumbis, Peter Bladon
a
a
b
´
´
and Peter B. Wyatta
,
*
aDepartment of Chemistry, Queen Mary, University of London, Mile End Road, E1 4NS, London, UK
bInterprobe Chemical Services, Gallowhill House, Lenzie, Scotland G66 4HX, UK
Received 14 July 2003; revised 3 September 2003; accepted 25 September 2003
Abstract—Stabilised tributylphosphonium ylids Bu3PCHvCH(EWG), where EWG is CO2Me, COt2Bu or CN, react with protected sugar
lactones under mild conditions to give high yields of glycosylidene derivatives (4 and 5) with good Z/E selectivity. X-Ray crystallography
shows that in the solid state the tetra-O-benzyl protected (Z)-glucosylideneacetonitrile (Z)-4c adopts a conformation intermediate between a
boat and a twist-boat, whereas the isomeric galactose derivative (Z)-5c exists as a distorted chair. NMR data suggest that in solution chair-like
conformations are again more favoured for galactosylidene derivatives than for their glucosylidene analogues. Solution phase NMR studies
and molecular modelling show that the (E)-double bond geometry disfavours the chair-like geometry of the ring, even in the galactose series;
this is consistent with the avoidance of allylic 1,3-strain. Reduction of the glycosylidene double bond to give stereoselective formation of
b-C-glycoside derivatives may be achieved by using Et3SiH–CF3CO2H or Et3SiH–BF3·Et2O.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
common approach to C-glycosides is by attack of a carbon
nucleophile at the anomeric position of a sugar derivative.
For example, protected sugars such as 2,3,4,6-tetra-O-
benzylglucopyranose can undergo a one pot Wittig-
conjugate addition sequence on treatment with tributyl-
phosphine, methyl bromoacetate and zinc metal, leading to
stereoselective formation of b-C-glycosides.3 Kishi has
shown that addition of lithium enolates to protected sugar
lactones, followed by deoxygenation of the resultant lactols
using triethylsilane–boron trifluoride can give glyco-
pyranosylacetic acid derivatives with high selectivity for
the b-anomer.4 Dehydration of these same lactols also
provides a route to exo-glycals.5 The groups of Chapleur6
and Xie7 have prepared glycosylidenes directly from
protected sugar lactones by means of non-classical Wittig
reactions8 with stabilised triphenylphosphorane ylids;
stereoselective reduction of the resultant exocyclic
double bond, e.g. by catalytic hydrogenation, may give a
predominance of either the a- or b-anomeric C-glycoside
depending on the particular substrate and reaction
conditions.7
A growing awareness of the importance of carbohydrate
residues as recognition elements in biology has been
coupled with impressive progress in the development of
methodology for the synthesis of natural oligosaccharides
and glycopeptides. However, such substances are generally
less straightforward to prepare than simple peptides and the
presence of relatively labile O- or N-glycosidic linkages can
be a source of particular difficulty. Consequently several
research groups have investigated the attachment of amino
acid functionality through robust C-glycosidic linkages,
thus allowing the use of established methods in peptide
synthesis to construct unnatural compounds which display
multiple carbohydrate residues.1
There are many possible ways to create the key C-glycosidic
bond, including the use of transition metals and free
radicals. Elegant work by Taylor et al. has shown the
¨
versatility of the Ramberg–Backlund rearrangement in
preparing carbohydrate analogues with an exocyclic
carbon–carbon double bond,2 which are usually referred
to as glycosylidenes or exo-glycals. Arguably the most
Recently there has been renewed interest in the use of
stabilised ylids derived from trialkylphosphines rather
than the traditional triarylphosphines. Thus, Tsunoda et al.
found that cyanomethylenetrimethylphosphorane reacted
with simple lactones under particularly mild
conditions;9 Harcken and Martin reported that the reagent
Keywords: C-glycosylidene derivatives; tributylphosphonium ylids;
galactosylidene derivatives.
*
Corresponding author. Tel.: þ44-20-7882-3267; fax: þ44-20-7882-7794;
e-mail: p.b.wyatt@qmul.ac.uk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.081

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M. Gascon-Lopez et al. / Tetrahedron 59 (2003) 9349–9360
9350
MeO2CCHvPBu3 gave enhanced yields and E/Z
selectivities in Wittig reactions with a-hydroxyaldehydes
and with sugar lactols,10 whereas Stoodley and co-workers
favoured the use of alkoxycarbonylmethylenetributyl-
phosphoranes for Wittig reactions with 3-(glucopyrano-
syloxy)propenal derivatives that may be regarded as being
vinylogous esters.11
Our Wittig reactions showed excellent stereoselectivity, but
in most cases we were able to isolate small amounts of
minor stereoisomeric products following straightforward
flash chromatography. In each case we considered our
predominant product to have the (Z)-configuration at the
newly created double bond and the minor stereoisomer,
where present, to be of the (E)-configuration. Thus in the 1H
NMR spectra of the glucose derivatives 4a-c the vinylic
protons typically appeared at ca. 0.5 ppm higher field in the
major isomer, as expected for the (Z)-geometry.6a However,
the corresponding chemical shift differences were only of
the order of 0.1 ppm for the isomers of the galactose
derivative 5a and vanished altogether in the case of 5c.
Further evidence for the double bond geometry included the
observation of a nuclear Overhauser effect between the
vinylic and allylic protons of the ester (Z)-4b, but not (E)-
4b, and X-ray crystal structures of the major nitrile
stereoisomers (Z)-4c and (Z)-5c.
We now wish to report that the Wittig reactions of stabilised
tributylphosphorane ylids with sugar lactones occur under
mild conditions and give high yields of glycosylidenes with
excellent stereoselectivity. We have investigated the pre-
ferred conformations of these glycosylidene products both
in the crystalline state and in solution. We also describe
the stereoselective reduction of these products to form
C-glycosides and compare ‘ionic hydrogenation’ pro-
cedures using triethylsilane in combination with either
trifluoroacetic acid or boron trifluoride. This leads to
usefully protected C-glycoside building blocks, suitable
for the preparation of neoglycoconjugates.
In addition we found that pairs of geometrical isomers
underwent reduction of the CvC double bond to form the
same C-glycosides (Scheme 2). For example, reduction of
the geometrically isomeric C-galactosylidenes (Z)-5a and
(E)-5a generated a common b-C-galactoside b-7a. This
shows that the major and minor stereoisomers differ only in
double bond geometry and it excludes the possibility that
one of these products could arise by base-induced
epimerisation, as happened in the reaction of a mannose-
derived lactone with Ph3PvCHCO2Et.5 However, we did
obtain NMR evidence for the formation of ca. 1% of a third
glycosylidene product in the reaction of glucose-derived
lactone 1 with the ylid 3a; this product could not be isolated
but might have arisen by a small amount of epimerisation
into the mannose series.
2. Results and discussion
2.1. Wittig reactions
The known12 2,3,4,6-tetra-O-benzyl protected lactones 1
and 2, derived from glucose and galactose, respectively,
were found to react smoothly with stabilised tributyl-
phosphorane ylids to provide good yields of glycosylidene
derivatives as summarised in Scheme 1 and Table 1. These
reactions occurred under somewhat milder conditions than
had previously been employed for analogous reactions of
triphenylphosphorane ylids. For example the lactone 1 has
been reported to be recovered unchanged after heating in a
steel bomb with MeO2CCHvPPh3 in toluene at 1408C;6a
a
The strong preference for forming a,b-unsaturated esters of
(Z)-configuration is consistent with the avoidance of
repulsion between the ester group and the adjacent
subsequent report of a successful Wittig reaction between 1
and EtO2CCHvPPh3 involved 15 h reflux in toluene.7a
Scheme 1. Wittig reactions of sugar lactones with tributylphosphonium ylids.
Table 1. Wittig reactions of tributylphosphoranes with protected sugar lactones
Lactone
Phosphorane
Conditions
Yield of (Z)-glycosylidene 4 or 5 (%)
Yield of (E)-glycosylidene 4 or 5
1
1
1
2
2
2
3a
3b
3c
3a
3b
3c
Toluene, 808C, 17 h
Toluene, 808C, 12 h
CH2Cl2, 408C, 20 h
Toluene, 808C, 24 h
Toluene, 808C, 12 h
CH2Cl2, 408C, 20 h
92
92
75
76
75
68
4%
3%
10%a,b
4%
Not isolated
10%c
a
1H NMR shows Z/E ratio 6.5:1 in crude product.
Reaction of 1 with Ph3PvCHCN (4 equiv., toluene, 16 h reflux) gave a 6:1 ratio of (Z)-4c and (E)-4c and after chromatography these two compounds were
isolated in 83 and 3% yields, respectively.
1H NMR shows Z/E ratio 4.7:1 in crude product.
b
c

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M. Gascon-Lopez et al. / Tetrahedron 59 (2003) 9349–9360
9351
Scheme 2. Reduction of exo-glycals.
benzyloxy substituent during the Wittig reaction.7 The
cyano group is so small that the preparation of glycosyl-
idene nitriles is a particularly demanding test of the
attainable levels of stereoselectivity. Ref. 6b reports a Z/E
ratio of 1:2.8 for the reaction of 1 with NCCHvPPh3
(toluene, 16 h reflux); however, these authors do not present
detailed evidence for the assignment of geometry and upon
repetition of their experiment in our laboratory we observed
a 6:1 Z/E ratio by NMR integration and comparison with the
crystallographically characterised (Z)-4c. We found that a
change to the tributylphosphorane allowed the reaction to be
performed at a lower temperature (CH2Cl2, 20 h, reflux)
whilst still providing an excellent yield. However, the
stereoselectivity (6.5:1 Z/E ratio) was similar to that which
we had observed in our experiment with NCCHvPPh3.
2.2.1. Crystallography. The X-ray crystal structure of the
glucosylidene nitrile (Z)-4c (Fig. 1) shows that the CvC
unit and the atoms directly attached to it are completely
coplanar. Experimental and calculated torsion angles for
this and related compounds are detailed in Table 2. In the
solid state the tetrahydropyran ring adopts a conformation
which is intermediate between a boat and a twist-boat, as
assessed by analysis of the endocyclic torsion angles using
13
´
the method of Berces et al. To a first approximation this
conformation can be designated as S2. The bond between
O
the ring oxygen and the adjacent tetrahedral carbon atom
approaches coplanarity with the unsaturated grouping
[C(4)–C(3)–O(3)–C(7) torsion angle¼213.58], thus
allowing the possibility for a substantial n–pp interaction
involving a lone pair in a p-orbital of an sp2-hybridised
oxygen atom. The benzyloxymethyl substituent (C-8) has a
pseudoequatorial orientation relative to the heterocyclic
ring whilst two of the benzyloxy substituents (at C-4 and
C-5) assume pseudoaxial positions and consequently have
an antiperiplanar relationship [O(4)–C(4)–C(5)–O(5)
torsion angle¼178.68]. Such an arrangement at first sight
seems remarkable for a glucose derivative and is in stark
contrast to the representations found for similar compounds
2.2. Conformational studies of glycosylidene derivatives
In order to prepare for future work on the diastereo-
selectivity of addition reactions to the glycosylidenes, the
conformations of these compounds were examined by
crystallographic, NMR and molecular modelling
techniques.
Figure 1. X-Ray crystal structure of (Z)-4c.

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M. Gascon-Lopez et al. / Tetrahedron 59 (2003) 9349–9360
9352
Table 2. Experimental and calculated values of selected torsion angles (degrees) for the glycosylidene nitriles; calculated (gas phase) enthalpies of formation
X-Ray Calc
(Z)-4c
(Z)-5c
(Z)-4c
(Z)-5c
(E)-4c
(E)-5c
C(4)–C(3)–O(3)–C(7)
C(3)–O(3)–C(7)–C(6)
O(3)–C(7)–C(6)–C(5)
C(7)–C(6)–C(5)–C(4)
C(6)–C(5)–C(4)–C(3)
C(5)–C(4)–C(3)–O(3)
C(5)–C(4)–C(3)–C(2)
C(7)–O(3)–C(3)–C(2)
H(4)–C(4)–C(5)–H(5)
H(5)–C(5)–C(6)–H(6)
H(6)–C(6)–C(7)–H(7)
213.5
þ54.8
236.0
217.6
þ56.5
242.8
þ136.3
þ167.3
261.6
þ99.4
2156.7
242.6
þ53.5
262.4
þ61.6
249.3
þ40.4
2146.4
þ143.9
2171.8
þ63.0
263.5
213.9
þ55.6
237.8
216.4
þ54.6
241.7
þ134.4
þ169.9
258.7
þ94.9
2159.3
242.5
þ53.8
264.1
þ63.6
251.4
þ40.9
2146.2
þ149.4
2165.9
þ66.2
269.3
214.3
þ56.4
238.7
216.2
þ55.2
242.1
þ135.2
þ168.4
258.2
þ95.5
2159.0
26.6
þ38.3
265.6
þ61.0
232.4
þ3.9
2179.2
þ176.1
2149.2
þ62.6
271.5
DHf (calc) (kJ mol21
)
2188.2
2177.8
2193.8
2173.3
in recent publications, where the substituents are shown as
pseudoequatorial.2,5,7a However, the situation is analogous
to that in 2-substituted methylenecyclohexene derivatives,14
where adoption of an axial orientation by the substituent at
C-2 can reduce 1,3-allylic strain, i.e. the steric repulsions
with an atom or group directly attached to the CvC bond;
the minimisation of such strain has already been used to
account for the selective formation of the Z-geometrical
isomer when exo-glycals are formed by dehydration.5
Finally, it should be noted that H(6) and H(7) of the
tetrahydropyran ring are antiperiplanar to one another
[H(6)–C(6)–C(7)–H(7) torsion angle¼2156.78].
the CN function.7b The view of the ethyl ester (Z)-5d
provided in Ref. 7b again shows a chair-like arrangement,
but as the atomic co-ordinates of this structure are not
available from the Cambridge Crystallographic Data Centre
a quantitative analysis of this structure is not possible here.
2.2.2. NMR studies. The solution phase conformations of
known glycosylidenes were examined using NMR data
available from our own work or reported in the literature.2,5
In particular the three-bond coupling constants between the
protons of the heterocyclic rings were sought. Unfortunately
the presence of overlapping signals prevents a complete
analysis of every spectrum but the most complete data are
given in Table 3 (glucosylidenes) and Table 4 (galacto-
sylidenes). In some cases the use of C6D6 as NMR solvent,
rather than CDCl3, was necessary in order to assist the
analysis: this led to substantial movements in chemical shift,
thus helping to resolve overlapping peaks. However, the
available data indicate similar coupling constants in the two
solvents, thus suggesting that similar conformations are
adopted in these two solvents. Since the numbering of atoms
in the ring depends on the nature of the R1 and R2 groups, as
well as the preferences of the original authors, these results
have been presented using the Greek letters H(a)–H(d) to
denote the four key hydrogen atoms as shown in Figure 3.
In contrast to the above results, the crystal structure of the
galactosylidene nitrile (Z)-5c (Fig. 2 and Table 2) presents a
4C1 chair-like arrangement.15 Planarity around the CvC
unit is preserved but it does not extend to the bond between
C(7) and the ring oxygen atom [C(7)–O(3)–C(3)–C(4)
torsion angle¼242.68]. The benzyloxy groups at C(4) and
C(5) occupy pseudoequatorial positions, so that H(4) and
H(5) are antiperiplanar to one another [H(4)–C(4)–C(5)–
H(5) torsion angle¼2171.88]. Previously Molina et al. have
used X-ray crystallography to determine the double bond
geometry in the galactosylidene derivative (Z)-5d, an
analogue of (Z)-5c which has a CO2Et group in place of
Figure 2. X-Ray crystal structure of (Z)-5c.

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M. Gascon-Lopez et al. / Tetrahedron 59 (2003) 9349–9360
9353
3
Table 3. JHH values (Hz) for ring protons of glucosylidene derivatives 4
three (E)-configured Wittig products (E)-4a-c, all of which
have Jab#2 Hz and where the double bond geometry would
impose excessive 1,3-allylic repulsion on such a confor-
mation. In cases where the CvC bond is fully substituted,
chair-like arrangements should be similarly disfavoured:
this assertion is supported by the values of Jab¼2.2 Hz,
reported in the literature for both the isopropylidene
derivative 4h and the cyclohexylidene derivative 4i.2
Compound
R1
R2
Jab
Jbg
Jgd
9.7
Sourcea
(Z)-4a
(Z)-4a
(E)-4a
(Z)-4b
(E)-4b
(E)-4b
(Z)-4c
(Z)-4c
(E)-4c
(Z)-4d
4e
CO2Me
CO2Me
H
H
H
3.2
3.6c
1.8
4.1
1.7
1.6c
ND
5.0c
2.0
ND
7.2
5.3
4.6
2.2
2.2
NDb
5.7c
3.9
10.2c
10.2
10.0
10.4
10.3c
9.1
CO2Me
H
COt2Bu
H
H
CN
CN
H
CO2Et
H
Br
ND
4.1
COt2Bu
COt2Bu
H
H
CN
H
H
H
H
Me
4.2c
ND
6.3c
3.7
9.9c
10
The NMR data for the galactosylidene derivatives 5
(Table 4) show large values of Jab and relatively small
Jbg and Jgd, consistent with chair-like conformations for the
(Z)-geometrical isomers and for the methylene derivative
5e. Lower values of Jab are observed for (E)-5a and (E)-5c,
again suggesting that the E-geometry destabilises the chair
conformation.
ND
ND
ND
ND
5.3
9.6
ND
9.7
9.7
9.9
Ref. 5
Ref. 5
Ref. 2
Ref. 2
Ref. 2
Ref. 2
(Z)-4f
(Z)-4g
4h
Ph
Me
4i
–[CH2]5–
5.6
9.9
a
Where no source is given data are from the present work.
Another notable trend in the 1H NMR data is the observation
b
c
ND indicates that the coupling constant could not be determined as the
relevant protons gave rise to overlapping multiplets.
Value obtained from spectrum in C6D6: all other data not so indicated
refer to spectra in CDCl3.
4
of J couplings between the allylic and olefinic protons of
between 1.0 and 1.8 Hz only in the cases of the Z-configured
galactosylidene derivatives (Z)-5a, (Z)-5b, (Z)-5c, (Z)-5d,
(Z)-5j and of the methylene C-galactoside 5e. For the
E-geometrical isomers and for the glucose derivatives the
analogous four-bond allylic couplings could not be detected.
Again this suggests that the Z-galactosylidenes and
Z-glucosylidenes adopt two distinct types of ring confor-
mation. A Karplus-like variation of allylic coupling
constants with conformation has previously been observed:
the cisoid allylic coupling is close to zero (as is seen for the
glucose derivatives) when the allylic C–H and the CvC
double bond are synperiplanar to one another.16 Examin-
ation of the crystal structures of the nitriles (Z)-4c and (Z)-5c
from the two series reveals that such a relationship is indeed
present for the glucose derivative, but not for the galactose
derivative [the respective H(4)–C(4)–C(3)vC(2) torsion
angles are 15.7 and 94.58].
3
Table 4. JHH values for ring protons of galactosylidene derivatives 5
Compound
R1
R2
Jab
Jbg
Jgd
Source
(Z)-5a
(E)-5a
(Z)-5b
(Z)-5c
(E)-5c
(Z)-5d
5e
CO2Me
H
H
CO2Me
H
H
CN
H
9.4
3.4
9.2
9.8a
5.2
9.3
9.0
8.1
2.6
3.4
2.6
2.5a
3.2
2.8
2.7
2.7
1.5
4.6
1.4
1.2a
3.2
1.0
2.3
2.5
COt2Bu
CN
H
CO2Et
H
Et
Ref. 5
Ref. 5
Ref. 5
H
H
(Z)-5j
a
Indicates value obtained from spectrum in C6D6: all data not so indicated
refer to spectra in CDCl3.
2.2.3. Molecular modelling calculations. The glycosyl-
idene nitriles (E)- and (Z)- 4c and 5c were subjected to
further conformational analysis using MOPAC-6 semi-
empirical calculations (Table 2). The crystal structures of
(Z)-4c and (Z)-5c were used as starting points. It is to be
expected that differences might be observed between these
structures and the (gas phase) results of structure optimiz-
ation using MOPAC-6. Nevertheless, when the crystal-
lographically determined conformations were subjected to
energy minimisation the conformational changes which
occurred were relatively minor, suggesting that crystal
packing effects are not important in establishing a
preference for the observed conformations.
Figure 3. Designation of ring protons for use with Tables 3 and 4.
For the glucosylidene derivatives 4, the available values of
Jgd are generally large (9.1–10.4 Hz) and it appears
probable that all of these compounds adopt solution phase
conformations in which H(g) and H(d) are antiperiplanar to
one another. Taken in isolation these data are consistent not
only with twist conformations of the type seen in the crystal
The structures (E)-4c and (E)-5c for which crystallographic
data were not available were modelled by first reversing the
cis–trans isomerism of the available structures. The
program INTERCHEM (Interprobe Chemical Services,
Lenzie) was used for this purpose. Before submission of
the structures to MOPAC for optimization, simple
molecular mechanics optimizations were performed. This
step served to remove possible bad contacts, which might
not have been acceptable to MOPAC. In the case of the
glucosylidene derivative (E)-4c the calculated minimum
energy conformation had similar ring torsion angles to those
4
structure of (Z)-4c, but also with a C1 chair arrangement.
1C4 Inverted chairs, with equatorial hydrogen atoms, can be
ruled by the large values of Jgd.
The values of Jab span a range from 1.6 to 7.2 Hz and thus it
seems that in solution these diverse compounds cannot be
described by a single type of conformation and may very
well exist as equilibrium mixtures of conformers with
4
similar energies. A C1 conformation is most likely when
Jab is large, as in the case of the methylene derivative 4e;
conversely this type of arrangement can be excluded for the
O
of (Z)-4c so that it could again be described as a S2 form.

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M. Gascon-Lopez et al. / Tetrahedron 59 (2003) 9349–9360
9354
Table 5. Reductions of glycosylidene methyl esters 4a and 5a
Glycosylidene
methyl ester
Conditions
% Yield
b-C-glycoside
Other
isolated products
(Z)-4a
(Z)-4a
(Z)-4a
(Z)-5a
(Z)-5a
(E)-5a
Et3SiH (2.5 equiv.), CF3CO2H (2.5 equiv.), CH2Cl2, 2 h, room temperature
Et3SiH (24 equiv.), CF3CO2H (100 equiv.), 2 h, CH2Cl2, room temperature
Et3SiH (32 equiv.), BF3·Et2O (7.8 equiv.), CH2Cl2, 23 h, room temperature
Et3SiH (24 equiv.), CF3CO2H (100 equiv.), CH2Cl2, 2 h, room temperature
Et3SiH (32 equiv.), BF3·Et2O (7.8 equiv.), CH2Cl2, 23 h, room temperature
Et3SiH (31 equiv.), BF3·Et2O (7.1 equiv.), CH2Cl2, 14 h, room temperature
–
9a (25%)
11 (3%)
50
80
41
72
50
b-12a (15%)
Scheme 3. Proposed mechanism for formation of 11.
On the other hand, the minimum energy conformation of the
galactosylidene derivative (E)-5c was calculated to be a 4E
envelope arrangement. Thus these calculations support the
experimental observations that the chair form is more
favoured for galactose than for glucose but that it is
destabilised by the presence of a substituent on the CvC
bond trans to the ring oxygen atom.
formed. Additionally a number of by-products were
produced, including the alcohol 9a arising from formal
hydration of the CvC bond and an isochroman 11 which
can be generated by an intramolecular Friedel–Crafts
alkylation involving the oxonium intermediate 10
(Scheme 3). The isolated sample of isochroman 11 was a
single stereoisomer by 600 MHz 1H NMR, but the
configuration at C-4 of the heterocyclic ring could not be
established. From the reduction of (Z)-5a a minor b-C-
glycosidic product b-12a was isolated (Fig. 4), wherein the
reduction of the CvC bond had been accompanied by the
cleavage of one of the four O-benzyl groups, leaving an
exposed hydroxyl group: NMR studies showed J1,2¼9 Hz
and indicated that the OH proton coupled to one or other of
the overlapping signals due to H-2 and H-4 of the pyranose
system. a-C-Glycosides were not observed, consistent with
axial delivery of hydride to oxonium intermediates as
originally proposed by Kishi in discussing the deoxygena-
tion of sugar lactols.4 Greatly improved yields of b-C-
glycosides could be obtained by reducing the glycosyl-
idenes using triethylsilane in combination with boron
2.3. Reductions of glycosylidene derivatives
The hydrogenation of glycosylidene derivatives has pre-
viously been investigated by Xie and co-workers.7a These
authors found that the glucosylidene derivative (Z)-4d,
which bears a CO2Et substituent on the CvC bond, could
be reduced by the combination of nickel chloride and
sodium borohydride (‘nickel boride’) in methanol to give
predominantly the a-C-glucoside without cleavage of the
O-benzyl protecting groups; the galactosylidene analogue
(Z)-5d underwent reduction under these conditions to give
mainly the b-C-galactoside. On the other hand, catalytic
hydrogenation of either (Z)-4d or (Z)-5d (15 h, room
temperature, Pd–C) was reported to remove all the benzyl
groups and give exclusively the b-C-glycosides.7
We first attempted reductions of the glycosylidene methyl
esters using the triethylsilane–trifluoroacetic acid system in
dichloromethane (Scheme 2; Table 5). This gave modest
yields of b-C-glycosides. The b-configuration of the
galactose derivative 7a was evident from the 1H NMR
coupling J1,2¼9.3 Hz in the pyranose ring; in the case of the
glucose derivative 6a overlapping peaks were present and so
hydrogenolysis of the benzyl groups and protection as the
known peracetyl derivative b-8a (J1,2¼9.9 Hz) was per-
Figure 4. By-product of Et3SiH–CF3CO2H reduction of (Z)-5a.

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M. Gascon-Lopez et al. / Tetrahedron 59 (2003) 9349–9360
9355
trifluoride etherate and again complete stereoselectivity was
observed (Table 5). Both the isomeric products (E)-5a and
(Z)-5a, produced in the Wittig reaction of the galactose-
derived lactone 2 with Bu3PvCHCO2Me, underwent
reduction by BF3·Et2O–Et3SiH to give the same b-C-
galactoside b-7a: this shows that the pair of products
formed in the Wittig reaction are geometrical isomers.
volume with estimated standard deviations: a:
˚
17.723(8) A; b: 7.534(4) A; c: 111.689(7) A; a: 908; b:
˚
˚
3
˚
107.30(6)8; g: 908; volume: 1490(1) A ; temperature
160(2) K; space group P21, no. of molecules in unit cell
˚
(Z): 2; wavelength of radiation l: 0.71073 A; linear
absorption coefficient (m): 0.083 mm21; number of reflec-
tions measured: 3004; number of independent reflections:
2829 [Rint¼0.0147]; final R indices [I.2s(I)]: R1¼0.0528,
wR2¼0.1083.
3. Conclusions
Crystallographic data (excluding structure factors) for the
structures 4c and 5c in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 215129 and 215130,
respectively. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: þ44-1223-336033 or
e-mail: deposit @ccdc.cam.ac.uk].
We have found that stabilised ylids 3 derived from
tributylphosphine undergo clean and efficient couplings
with carbohydrate-derived lactones 1 and 2 under mild
conditions, yielding the (Z)-glycosylidenes 4 and 5 as the
major products. Although some of these products, notably
(Z)-5c, may exist in chair-like conformations both in the
crystal and in solution, many of the glycosylidene
derivatives adopt alternative arrangements, such as the
twisted boat seen in the crystal structure of (Z)-4c. 1,3-
Allylic repulsion is important in determining these confor-
mational preferences, particularly when the exocyclic
double bond carries a substituent trans- to the oxygen
atom of the pyranose ring. We have investigated the
reduction of the exocyclic double bond and have found that
the combination of triethylsilane and boron trifluoride
etherate gives excellent selectivity in favour of the
b-configured esters and is compatible with the presence of
benzyl ether and methyl ester protecting groups. The use of
these products as intermediates in the synthesis of
neoglycoconjugates is currently being investigated in our
laboratories.
4.3. Materials and general experimental procedures
‘Petrol’ or ‘petroleum spirit’ refers to the fraction of bp 40–
608C. Toluene was distilled from sodium benzophenone
ketyl before use. Flash chromatography was performed on
BDH silica gel (33–70 mm). Protected sugar lactones 1 and
2 were prepared by DMSO-Ac2O oxidation of the
corresponding hemiacetals.12 All new compounds were
homogeneous as assessed by TLC and high field NMR.
Melting points were determined using a Reichert hot stage
microscope. Specific rotations were determined on an
Optical Activity Ltd AA-1000 polarimeter with a path
length of 0.5 or 2 dm. IR spectra of films and KBr discs were
recorded using a Shimadzu FTIR 8300 and ATR spectra
were recorded using a Perkin–Elmer 1720 instrument.
X-Ray diffraction data were collected on a CAD4
diffractometer using v–2u scans. NMR spectra were
recorded on Jeol EX270 and Bruker AM250, AMX400 or
AMX600 spectrometers. FAB mass spectra were recorded
on a ZAB-SE4F machine at the School of Pharmacy,
University of London; other mass spectra were provided by
the EPSRC National Service in Swansea using a Finnigan
MAT 900.
4. Experimental
4.1. X-Ray diffraction data of 3,7-anhydro-4,5,6,8-tetra-
O-benzyl-2-deoxy-D-gluco-oct-2-enononitrile (Z)-4c
Crystals of (Z)-4c were obtained by slow evaporation of a
solution of (Z)-4c in a mixture of diethyl ether and
petroleum spirit.
4.3.1. (E)- and (Z)-3,7-Anhydro-4,5,6,8-tetra-O-benzyl-2-
deoxy-D-gluco-oct-2-enonic acid, methyl ester 4a. A
Chemical formula: C36H35NO5; formula weight 561.65;
crystal system: monoclinic; unit cell dimensions and
˚
volume with estimated standard deviations: a: 9.902(7) A;
solution
of
(methoxycarbonylmethylene)tri-n-butyl-
˚
b: 10.524(9) A; c: 14.585(12) A; a: 908; b: 90.63(7)8; g:
˚
phosphorane 3a (3.22 g, 11.7 mmol) in dry toluene (5 mL)
was added to a solution of 2,3,4,6-tetra-O-benzyl-D-
glucono-1,5-lactone 1 (3.16 g, 5.87 mmol) in dry toluene
(5 mL) at 808C under N2. The reaction mixture was stirred
for 17 h and concentrated under reduced pressure. The
yellow residue was subjected to flash chromatography using
petroleum spirit/EtOAc (5:1).
3
˚
908; volume: 1520(2) A ; temperature 295(2) K; space
group P21, no. of molecules in unit cell (Z): 2; wavelength
˚
of radiation l: 0.71073 A; linear absorption coefficient (m):
0.081 mm21; number of reflections measured: 3103;
number of independent reflections: 2841 [Rint¼0.0127];
final R indices [I.2s(I)]: R1¼0.0489, wR2¼0.1132.
Less polar product: (E)-3,7-anhydro-4,5,6,8-tetra-O-benzyl-
2-deoxy-D-gluco-oct-2-enonic acid, methyl ester (E)-4a
(146 mg, 4%), an oil, [a]3D2¼þ27.9 (c 0.50, CHCl3); nmax
(film)/cm21 1705 (CvO) and 1645 (CvC); dH (600 MHz,
CDCl3) 3.68 (1H, dd, J¼11.2, 4.8 Hz, H-8a), 3.68 (3H, s,
CO2Me), 3.70 (1H, dd, J¼10.1, 3.9 Hz, H-6), 3.76 (1H, dd,
J¼11.2, 1.8 Hz, H-8b), 3.94 (1H, dd, J¼3.9, 1.8 Hz, H-5),
4.40 (1H, d, J¼11.6 Hz, 1/2£OCH2Ph), 4.42 (1H, d,
J¼11.4 Hz, 1/2£OCH2Ph), 4.53 (1H, d, J¼11.4 Hz,
4.2. X-Ray diffraction data of 3,7-anhydro-4,5,6,8-tetra-
O-benzyl-2-deoxy-D-galacto-oct-2-enononitrile (Z)-5c
Crystals of (Z)-5c were obtained by slow evaporation of a
solution of (Z)-5c in a mixture of diethyl ether and
petroleum spirit.
Chemical formula: C36H35NO5; formula weight 561.65;
crystal system: monoclinic; unit cell dimensions and

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M. Gascon-Lopez et al. / Tetrahedron 59 (2003) 9349–9360
9356
1/2£OCH2Ph), 4.54 (1H, d, J¼12.2 Hz, 1/2£OCH2Ph),
4.60 (1H, d, J¼12.2 Hz, 1/2£OCH2Ph), 4.62 (1H, ddd,
J¼10.3, 4.7, 1.8 Hz, H-7), 4.61 (1H, d, J¼11.7 Hz,
1/2£OCH2Ph), 4.67 (1H, d, J¼11.9 Hz, 1/2£OCH2Ph),
4.69 (1H, d, J¼11.9 Hz, 1/2£OCH2Ph), 5.67 (1H, s, 2-H),
5.93 (1H, d, J¼1.8 Hz, H-4), 7.14–7.16 (2H, m, Ph), and
7.24–7.36 (18H, m, Ph); dC (151.0 MHz, CDCl3) 51.0,
68.7, 69.4, 70.8, 71.0, 72.3, 73.3, 74.9, 77.7, 80.5, 100.3,
127.5, 127.6, 127.79, 127.82, 127.87, 128.25, 128.36, 137.3,
137.7, 137.9, 138.0, 165.9 and 167.9; m/z (FAB) MþþH
595.2708 [C37H39O7 requires 595.2696].
J¼11.3, 1.8 Hz, H-8a), 3.97 (1H, dd, J¼4.1, 1.7 Hz, H-5),
4.43 (1H, d, J¼11.3 Hz, 1/2£OCH2Ph), 4.47 (1H, d,
J¼11.5 Hz, 1/2£OCH2Ph), 4.55 (1H, d, J¼12.2 Hz,
1/2£OCH2Ph), 4.58 (1H, d, J¼11.5 Hz, 1/2£OCH2Ph),
4.60–4.63 (1H, m, H-7), 4.62 (1H, d, J¼12.1 Hz,
1/2£OCH2Ph), 4.64 (1H, d, J¼11.8 Hz, 1/2£OCH2Ph),
4.70 (1H, d, J¼11.3 Hz, 1/2£OCH2Ph), 4.71 (1H, d,
J¼11.7 Hz, 1/2£OCH2Ph), 5.63 (1H, s, H-2, irradiation of
this signal gave no significant nOe at H-4), 5.96 (1H, d,
J¼1.7 Hz, H-4), 7.17–7.38 (20H, m, 4£Ph); dH (250 MHz,
t
C6D6) 1.46 (9H, s, Bu), 3.70 (2H, d, J¼2.9 Hz, H-8aþH-
8b), 4.06 (1H, dd, J¼10.3, 4.2 Hz, H-6), 3.97 (1H, dd,
J¼4.2, 1.6 Hz, H-5), 4.31–4.86 (8H, m, 4£OCH2Ph), 4.92
(1H, dt, J¼10.3, 2.9 Hz, H-7), 6.04 (1H, s, H-2), 6.43 (1H,
br s, H-4) and 7.09–7.44 (20H, m, 4£Ph); dC (62.9 MHz,
CDCl3) 28.3 (CH3), 68.9, 69.5, 70.7, 71.1, 72.4, 73.4, 74.8,
77.9, 79.6, 80.9, 102.8 (CvCH), 127.5, 127.6, 127.8, 128.3,
128.4, 137.5 (C-ipso), 137.9 (C-ipso), 138.2 (C-ipso), 138.2
(C-ipso), 164.3 (CvCH) and 166.8 (CvO); m/z (FAB)
MþþNa 659.2985 [C40H44O7Na requires 659.2985].
More polar product: (Z)-3,7-anhydro-4,5,6,8-tetra-O-
benzyl-2-deoxy-D-gluco-oct-2-enonic acid, methyl ester
(Z)-4a (3.23 g, 92%), obtained as a waxy syrup;
[a]2D5¼þ47.0 (c 2.85, CHCl3); nmax (film)/cm21 1720
(CvO), 1701, and 1651; dH (400 MHz, CDCl3) 3.70 (3H,
s, CO2Me), 3.82 (1H, dd, J¼11.5, 3.8 Hz, H-8a), 3.82–3.84
(1H, m, H-5 or H-6), 3.84 (1H, d, J¼3.2 Hz, H-4), 3.85–
3.89 (1H, m, H-6 or H-5), 3.89 (1H, dd, J¼11.5, 2.1 Hz,
H-8b), 4.34 (1H, ddd, J¼9.7, 3.5, 2.0 Hz, H-7), 4.50 (1H, d,
J¼12.0 Hz, 1/2£OCH2Ph), 4.53 (1H, d, J¼11.5 Hz,
1/2£OCH2Ph), 4.53 (1H, d, J¼12.8 Hz, 1/2£OCH2Ph),
4.61 (1H, d, J¼11.7 Hz, 1/2£OCH2Ph), 4.64 (1H, d,
J¼12.4 Hz, 1/2£OCH2Ph), 4.65 (1H, d, J¼11.1 Hz,
1/2£OCH2Ph), 4.71 (1H, d, J¼11.8 Hz, 1/2£OCH2Ph),
4.76 (1H, d, J¼12.3 Hz, 1/2£OCH2Ph), 5.19 (1H, s, H-2)
and 7.11–7.39 (20H, m, 4£Ph); dH (400 MHz, C6D6) 3.56
(3H, s, CO2Me), 3.83 (1H, dd, J¼11.8, 3.6 Hz, H-8a), 3.86
(1H, d, J¼3.6 Hz, 4-H), 3.93 (1H, d, J¼11.8, 1.9 Hz, H-8b),
3.96 (1H, dd, J¼5.7, 3.6 Hz, H-5), 4.10 (1H, dd, J¼10.2,
5.7 Hz, H-6), 4.25 (1H, d, J¼11.8 Hz, 1/2£OCH2Ph), 4.37
(1H, d, J¼11.9 Hz, 1/2£OCH2Ph), 4.45 (1H, d, J¼11.9 Hz,
1/2£OCH2Ph), 4.50 (1H, d, J¼11.8 Hz, 1/2£OCH2Ph),
4.56 (1H, ddd, J¼10.1, 3.5, 1.9 Hz, H-7), 4.59 (1H, d,
J¼11.6 Hz, 1/2£OCH2Ph), 4.70 (1H, d, J¼11.6 Hz,
1/2£OCH2Ph), 4.71 (1H, d, J¼12.3 Hz, 1/2£OCH2Ph),
4.84 (1H, d, J¼12.3 Hz, 1/2£OCH2Ph), 5.44 (1H, s, H-2),
7.02–7.29 (18H, m, Ar-H) and 7.51–7.53 (2H, m, Ar-H);
dC (62.9 MHz, CDCl3) 50.9, 68.3, 71.4, 72.7, 73.4, 73.6,
77.4, 77.7, 82.7, 99.4 (CvCH), 127.4, 127.7, 127.8, 127.9,
128.3, 128.4, 128.5, 137.1 (C-ipso), 137.6 (C-ipso), 137.8
(C-ipso), 138.4 (C-ipso), 161.9 (CvCH) and 165.1 (CvO);
m/z (FAB) MþþNa 617.2540 [C37H38O7Na requires
617.2515].
More polar product: (Z)-3,7-anhydro-4,5,6,8-tetra-O-ben-
zyl-2-deoxy-D-gluco-oct-2-enonic acid, tert-butyl ester (Z)-
4b (1.20 g, 92%) as a waxy syrup; [a]2D5¼þ41.4 (c 5.4,
CHCl3); nmax (film)/cm21 1713 (CvO) and 1647 (CvC);
dH (600 MHz, CDCl3) 1.48 (9H, s, tBu), 3.81–3.82 (1H, m,
H-5 or H-6), 3.83 (1H, d, J¼8.6, 3.5 Hz, H-8a), 3.86 (1H, d,
J¼4.1 Hz, H-4), 3.86–3.88 (1 H, m, H-6 or H-5), 3.88 (1H,
dd, J¼11.1, 2.0 Hz, H-8b), 4.26 (1H, ddd, J¼10.0, 3.5,
2.0 Hz, H-7), 4.51 (1H, d, J¼11.8 Hz, 1/2£OCH2Ph), 4.54
(1H, d, J¼11.2 Hz, 1/2£OCH2Ph), 4.55 (1H, d, J¼11.6 Hz,
1/2£OCH2Ph), 4.61 (1H, d, J¼12.3 Hz, 1/2£OCH2Ph),
4.63 (1H, d, J¼11.6 Hz, 1/2£OCH2Ph), 4.67 (1H, d,
J¼11.2 Hz, 1/2£OCH2Ph), 4.72 (1H, d, J¼11.8 Hz,
1/2£OCH2Ph), 4.73 (1H, d, J¼12.3 Hz, 1/2£OCH2Ph),
5.14 (1H, s, H-2, irradiation of this signal gave 6.1% nOe at
H-4), 7.15–7.40 (20H, m, 4£Ph); dC (151.0 MHz, CDCl3)
28.3 (CH3), 68.4 (CH2), 71.6 (CH2), 73.0 (CH2), 73.6 (CH2),
76.7 (CH2), 77.2 (CH), 77.4 (CH), 78.1 (CH), 79.7 (C), 83.2
(CH), 101.9 (CvCH), 127.5, 127.7, 127.8, 127.9, 128.0,
128.3, 128.5, 128.5, 137.3 (C-ipso), 137.7 (C-ipso), 138.0 (C-
ipso), 138.4 (C-ipso), 160.7 (CvCH), and 164.2 (CvO); m/z
(FAB) MþþNa 659.2985 [C40H44O7Na requires 659.2985].
4.3.3. (Z)- and (E)-3,7-Anhydro-4,5,6,8-tetra-O-benzyl-2-
solution of
3c (0.67 g,
deoxy-D-gluco-oct-2-enononitrile 4c.
(cyanomethylene)tri-n-butylphosphorane
A
4.3.2. (E)- and (Z)-3,7-Anhydro-4,5,6,8-tetra-O-benzyl-2-
deoxy-D-gluco-oct-2-enonic acid, tert-butyl ester 4b. A
solution of (tert-butoxycarbonylmethylene)tri-n-butyl-
phosphorane 3b (1.29 g, 4.08 mmol) in dry toluene
(10 mL) was added to a solution of 2,3,4,6-tetra-O-benzyl-
D-glucono-1,5-lactone 1 (1.10 g, 2.04 mmol) in dry toluene
(10 mL) at 808C under N2. The reaction mixture was stirred
for 12 h and concentrated under reduced pressure. The
yellow residue was subjected to flash chromatography using
petroleum spirit/AcOEt (8:1) to give the following products.
2.77 mmol) in dry CH2Cl2 (3 mL) was added to a solution
of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone 1 (0.75 g,
1.39 mmol) in dry CH2Cl2 (2 mL) at 408C under N2. The
reaction mixture was stirred 20 h and concentrated under
reduced pressure. The Z/E isomer ratio of this crude product
1
was 6.5:1 as determined by H NMR. The yellow residue
(1.56 g) was subjected to flash chromatography using
petroleum spirit/Et2O (5:2) to give firstly (E)-3,7-anhydro-
2-deoxy-4,5,6,8-tetra-O-benzyl-D-gluco-oct-2-enononitrile
(E)-4c (0.081 g, 10%) as a colourless oil and from the later
fractions (Z)-3,7-anhydro-2-deoxy-4,5,6,8-tetra-O-benzyl-
D-gluco-oct-2-enononitrile (Z)-4c (0.58 g, 1.04 mmol,
75%) as a white solid.
Less polar product: (E)-3,7-anhydro-4,5,6,8-tetra-O-benzyl-
2-deoxy-D-gluco-oct-2-enonic acid, tert-butyl ester (E)-4b
(45 mg, 3%), [a]D24¼þ22.2 (c 0.95, CHCl3); nmax (film)/
cm21 1695 (CvO) and 1645 (CvC); dH (600 MHz,
t
CDCl3) 1.49 (9H, s, Bu), 3.70 (1H, dd, J¼11.3, 4.6 Hz,
Less polar product: (E)-3,7-anhydro-4,5,6,8-tetra-O-benzyl-
2-deoxy-D-gluco-oct-2-enononitrile (E)-4c; [a]2D0¼þ30.5 (c
H-8b), 3.72 (1H, dd, J¼10.4, 4.1 Hz, H-6), 3.78 (1H, dd,

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M. Gascon-Lopez et al. / Tetrahedron 59 (2003) 9349–9360
9357
0.65, CHCl3); nmax (KBr)/cm21 2218 (CuN) and 1639
(CvC); dH (250 MHz, CDCl3) 3.65 (1H, dd, J¼11.3,
4.4 Hz, H-8a), 3.70 (1 H, dd, J¼10, 3 Hz, H-6), 3.74 (1 H,
dd, J¼11.3, 2.0 Hz, H-8b), 3.92 (1H, dd, J¼3.7, 2.1 Hz,
H-5), 4.37 (1H, d, J¼11.5 Hz, 1/2£OCH2Ph), 4.39 (1H, d,
J¼11.4 Hz, 1/2£OCH2Ph), 4.48–4.61 (5 H, m, benzyl-H5),
4.53–4.60 (1H, m, H-7), 4.68 (1H, d, J¼1.8 Hz, H-4), 4.73
(1H, d, J¼11.7 Hz, 1/2£OCH2Ph), 5.01 (1H, s, H-2) and
7.16–7.39 (20H, m, 4£Ph); dC (62.9 MHz, CDCl3) 68.5,
71.4, 71.8, 72.6, 72.9, 73.5, 76.0, 79.4, 80.3, 117.3 (CuN),
127.8, 127.9, 128.2, 128.4, 128.5, 128.6, 136.8 (C-ipso),
137.5 (C-ipso), 137.8 (C-ipso), 168.8 (CvCH); m/z (FAB)
MþþNa 562.2606 [C36H35NO5Na requires 562.2593].
127.74, 127.77, 128.3, 137.8 (C-ipso), 138.0 (C-ipso), 138.1
(C-ipso), 138.1 (C-ipso), 165.0 (CvCH), 167.5 (CvO); m/z
(FAB) MþþNa 617.2540 [C37H38O7Na requires 617.2515].
More polar product: (Z)-3,7-anhydro-4,5,6,8-tetra-O-
benzyl-2-deoxy-D-galacto-oct-2-enonic acid, methyl ester
(Z)-5a was a waxy syrup; [a]2D4¼þ81.6 (c 1.03, CHCl3);
nmax (KBr)/cm21 1724 (CvO) and 1653 (CvC); dH
(270 MHz, CDCl3) 3.64 (3H, s, CO2Me), 3.73 (1H, dd,
J¼9.3, 2.6 Hz, H-5), 3.78 (2H, d, J¼6.7 Hz, H-8a, H-8b),
4.01 (1H, td, J¼6.9, 1.3 Hz, H-7), 4.13 (1H, dd, J¼2.5,
1.5 Hz, H-6), 4.44 (1H, dd, J¼9.4, 1.5 Hz, H-4), 4.46 (1H, d,
J¼11.6 Hz, 1/2£OCH2Ph), 4.55 (1H, d, J¼11.6 Hz,
1/2£OCH2Ph), 4.61 (1H, d, J¼11.4 Hz, 1/2£OCH2Ph),
4.70 (1H, d, J¼11.6 Hz, 1/2£OCH2Ph), 4.70 (2H, s,
OCH2Ph), 4.78 (1H, d, J¼11.4 Hz, 1/2£OCH2Ph), 4.94
(1H, d, J¼11.6 Hz, 1/2£OCH2Ph), 5.61 (1H, d, J¼1.5 Hz,
H-2), 7.23–7.35 (20H, m); dC (67.9 MHz, CDCl3) 50.9,
68.0, 72.5, 73.5, 73.5, 74.4, 74.6, 76.3, 78.5, 81.6, 99.4
(CvCH), 127.5, 127.6, 127.7, 127.8, 127.9, 127.9, 128.2,
128.4, 137.5 (C-ipso), 137.7 (C-ipso), 137.9 (C-ipso), 138.2
(C-ipso), 165.1 (CvCH), 165.4 (CvO); m/z (FAB)
MþþNa 617.2535 [C37H38O7Na requires 617.2515].
More polar product: (Z)-3,7-anhydro-4,5,6,8-tetra-O-
benzyl-2-deoxy-D-gluco-oct-2-enononitrile (Z)-4c; mp
95–978C (from Et2O/petrol); [a]2D0¼þ74.6 (c 2.45,
CHCl3); nmax (KBr)/cm21 2218 (CuN) and 1639; dH
(250 MHz, CDCl3) 3.75–3.94 (5H, m, H-4, H-5, H-6, H-8a,
H-8b), 4.20 (1H, ddd, J¼9.1, 3.3, 2.1 Hz, H-7), 4.52–4.72
(8H, m, 4£OCH2Ph), 4.70 (1H, s, H-2) and 7.16–7.39 (20H,
m, 4£Ph); dH (400 MHz, C6D6) 3.56 (1H, dd, J¼11.5,
3.2 Hz, H-8a), 3.61 (1H, dd, J¼11.5, 2.0 Hz, H-8b), 3.63
(1H, d, J¼5.0 Hz, H-4), 3.72 (1H, dd, J¼6.3, 5.0 Hz, H-5),
3.91 (1 H, dd, J¼9.9, 6.4 Hz, H-6), 4.09 (1H, ddd, J¼10.0,
3.2, 2.0 Hz, H-7), 4.12 (1H, d, J¼11.8 Hz, 1/2£OCH2Ph),
4.24 (1H, d, J¼11.8 Hz, 1/2£OCH2Ph), 4.34–4.38 (3H,
m, H-2 and 2£benzylic H), 4.41 (1H, d, J¼11.7 Hz,
1/2£OCH2Ph), 4.46 (1H, d, J¼12.2 Hz, 1/2£OCH2Ph),
4.49 (1H, d, J¼11.5 Hz, 1/2£OCH2Ph), 4.61 (1H, d,
J¼11.5 Hz, 1/2£OCH2Ph), 7.05–7.24 (18H, m, Ar-H18)
and 7.34–7.37 (2H, m, Ar-H2); dC (62.9 MHz, CDCl3) 67.9,
72.5, 73.5, 73.6, 73.9, 76.9, 78.0, 78.7, 82.6, 115.2 (CuN),
128.3, 128.4, 128.6, 128.7, 136.6 (C-ipso), 137.5 (C-ipso),
137.5 (C-ipso), 137.9 (C-ipso), 168.5 (CvCH); m/z (FAB)
MþþNa 562.2580 [C36H35NO5Na requires 562.2593].
4.3.5. (Z)-3,7-Anhydro-4,5,6,8-tetra-O-benzyl-2-deoxy-
D-galacto-oct-2-enonic acid, tert-butyl ester (Z)-5b. A
solution of (tert-butoxycarbonylmethylene)tri-n-butyl-
phosphorane 3b (310 mg, 0.98 mmol) in dry toluene
(2 mL) was added to a solution of 2,3,4,6-tetra-O-benzyl-
D-galacto-1,5-lactone 2 (264 mg, 0.49 mmol) in dry toluene
(2 mL) at 808C under N2. The reaction mixture was stirred
for 12 h and concentrated under reduced pressure. The
yellow residue was subjected to flash chromatography using
petroleum spirit/AcOEt (6:1) to give (Z)-3,7-anhydro-
4,5,6,8-tetra-O-benzyl-2-deoxy-D-galacto-oct-2-enonic acid,
tert-butyl ester (Z)-5b (234 mg, 0.37 mmol, 75%) as a waxy
syrup; nmax (film)/cm21 1713 (st, CvO), 1650; dH (270 MHz,
CDCl3) 1.43 (9H, s, tBu), 3.69 (1H, dd, J¼9.3, 2.6 Hz, H-5),
3.73–3.83 (2H, m, H-8a, H-8b), 3.95 (1H, td, J¼7.2, 1.4 Hz,
H-7), 4.12 (1H, dd, J¼2.6, 1.4 Hz, H-6), 4.40 (1H, dd, J¼9.2,
1.4 Hz, H-4), 4.47–4.97 (8H, m, 4£OCH2Ph), 5.50 (1H, d,
J¼1.4 Hz, H-2)and7.25–7.36(20H, m, 4£Ph); dC (101 MHz,
CDCl3)28.7, 68.3, 73.0, 74.0,74.1, 74.7, 75.1, 76.9, 78.6, 80.0,
82.2, 102.3, 128.0, 128.12, 128.18, 128.23, 128.37, 128.38,
128.7, 128.8, 138.1, 138.2, 138.5, 138.9, 164.0 and 165.0; m/z
(FAB) MþþNa 659.2971 [C40H44O7Na requires 659.2985].
4.3.4. (E)- and (Z)-3,7-Anhydro-4,5,6,8-tetra-O-benzyl-2-
deoxy-D-galacto-oct-2-enonic acid, methyl ester 5a. A
solution of (methoxycarbonylmethylene)tri-n-butylphos-
phorane 3a (0.401 g, 1.46 mmol) in dry toluene (3 mL)
was added to a solution of 2,3,4,6-tetra-O-benzyl-D-galacto-
1,5-lactone 2 (0.394 g, 0.73 mmol) in dry toluene (2 mL) at
808C under N2. The reaction mixture was stirred for 24 h
and concentrated under reduced pressure. The yellow
residue was subjected to flash chromatography with
petroleum spirit/Et2O (2:1) to give first (E)-3,7-anhydro-
4,5,6,8-tetra-O-benzyl-2-deoxy-D-galacto-oct-2-enonic acid,
methyl ester (E)-(5a) (18 mg, 4%) and then (Z)-3,7-anhydro-
4,5,6,8-tetra-O-benzyl-2-D-galacto-oct-2-enonic acid, methyl
ester (Z)-5a (330 mg, 76%).
4.3.6. (Z)- and (E)-3,7-Anhydro-4,5,6,8-tetra-O-benzyl-2-
deoxy-D-galacto-oct-2-enononitrile 5c. A solution of
(cyanomethylene)tri-n-butylphosphorane 3c (269 mg,
1.11 mmol) in dry CH2Cl2 (1.5 mL) was added to a solution
of 2,3,4,6-tetra-O-benzyl-D-galacto-1,5-lactone 2 (295 mg,
0.56 mmol) in dry CH2Cl2 (1.5 mL) at 408C under N2. The
reaction mixture was stirred 20 h and concentrated under
reduced pressure. The yellow residue (659 mg), which had a
Less polar product: (E)-3,7-anhydro-4,5,6,8-tetra-O-benzyl-
2-deoxy-D-galacto-oct-2-enonic acid, methyl ester (E)-5a
was a colourless oil; [a]3D0¼221.4 (c 1.27, CHCl3); nmax
(KBr)/cm21 1711 (CvO) and 1645 (CvC); dH (600 MHz,
CDCl3) 3.68 (3H, s, CO2Me), 3.75 (1 H, dd, J¼11.0, 3.7 Hz,
H-8a), 3.82 (1 H, dd, J¼11.0, 7.5 Hz, H-8b), 3.90 (1H, t,
J¼3.4 Hz, H-5), 4.20, (1H, ‘t’, J¼4.3 Hz, H-6), 4.45–4.68
(8H, m, 4£PhCH2O), 4.55–4.60 (1H, m, H-7), 5.69 (1H, d,
J¼3.1 Hz, H-4), 5.72 (1H, s, H-2), 7.23–7.34 (20H, m,
4£Ph); dC (67.9 MHz, CDCl3) 51.1, 68.5, 70.5, 71.0, 71.6,
71.8, 72.4, 73.2, 76.1, 77.9, 105.2 (CvCH), 127.6, 127.65,
1
Z/E isomer ratio of 4.7:1 as determined by H NMR, was
subjected to flash chromatography using petroleum spirit/
Et2O (2:1) to give first (E)-3,7-anhydro-4,5,6,8-tetra-O-
benzyl-2-deoxy-D-galacto-oct-2-enononitrile
(E)-5c
(45 mg, 10%) as a colourless oil. From the later fractions
(Z)-3,7-anhydro-2-deoxy-4,5,6,8-tetra-O-benzyl-D-galacto-
oct-2-enononitrile (Z)-5c (212 mg, 68%) was obtained as a
white solid.

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M. Gascon-Lopez et al. / Tetrahedron 59 (2003) 9349–9360
9358
Less polar product: (E)-3,7-anhydro-4,5,6,8-tetra-O-benzyl-
2-deoxy-D-galacto-oct-2-enononitrile (E)-5c; [a]2D1¼þ13.4
(c 0.81, CHCl3); nmax (KBr)/cm21 2216 (CuN), 1632
(CvC); dH (270 MHz, CDCl3) 3.65 (1H, dd, J¼10.0,
5.2 Hz, H-8a), 3.70 (1 H, dd, J¼10.0, 6.4 Hz, H-8b), 3.86
(1H, dd, J¼5.2, 3.2 Hz, H-5), 4.11 (1H, t, J¼3.2 Hz, H-6),
4.32 (1H, td, J¼5.8, 3.2 Hz, H-7), 4.45–4.83 (9H, m,
4£OCH2Ph and H-4), 5.02 (1H, s, H-2) and 7.17–7.36
(20H, m, 4£Ph); dC (62.9 MHz, CDCl3) 68.2, 71.8, 72.3,
72.9, 73.4, 73.5, 74.6, 78.5, 78.6, 82.2, 116.9 (CuN), 127.7,
127.8, 127.9, 128.0, 128.2, 128.4, 128.4, 128.5, 137.0
(C-ipso), 137.3 (C-ipso), 137.6 (C-ipso), 137.7 (C-ipso) and
169.9 (CvCH); m/z (FAB) MþþNa 562.2604
[C36H35NO5Na requires 562.2593].
4.91 (2H, s, OCH2Ph), 5.29 (1H, s, OH), 7.17–7.42 (20H,
m, 4£Ph); dC (62.9 MHz, CDCl3) 40.3 (CH2), 52.0 (CH3),
68.5, 71.5, 73.2, 74.9, 75.2, 75.6, 77.2, 78.5, 81.8, 83.2,
97.0, 127.5 (CH), 127.6 (CH), 127.7 (CH), 127.8 (CH),
127.8 (CH), 128.0 (CH), 128.1 (CH), 128.3 (CH), 128.47
(CH), 128.52 (CH), 128.5 (CH), 137.8 (C-ipso), 138.3
(C-ipso), 138.6 (C-ipso), and 172.8 (CvO); m/z (FAB)
MþþNa 635.2649 [C37H40O8Na requires 635.2621]; some
of starting material (Z)-4a (3 mg, 4%) was recovered and
several other products were formed but could not be
isolated.
4.3.8. Methyl (2,3,4,6-tetra-O-benzyl-b-D-glucopyrano-
syl)acetate (b-6a) by reduction of (Z)-4a using a large
excess of Et3SiH–CF3CO2H. Trifluoroacetic acid
(21.5 mL, 0.28 mol) was added to a solution of triethyl-
silane (10.7 mL, 67.3 mmol) and (Z)-3,7-anhydro-4,5,6,8-
tetra-O-benzyl-2-deoxy-D-gluco-oct-2-enonic acid, methyl
ester (Z)-4a (1.67 g, 2.8 mmol) in dry CH2Cl2 (30 mL) at
188C. The reaction mixture was stirred for 2 h and
concentrated under reduced pressure. CHCl3 (3£3 mL)
was added to the residue and evaporated to eliminate traces
of volatile reagents and by-products. The crude material was
subjected to flash chromatography using a gradient from
petroleum spirit/Et2O (5:2) to CH2Cl2/Et2O (10:1) to give
the following products.
More polar product: (Z)-3,7-anhydro-4,5,6,8-tetra-O-
benzyl-2-deoxy-D-galacto-oct-2-enononitrile (Z)-5c; mp
100–1028C; [a]2D1¼þ88.7 (c 1.04, CHCl3); (found: C,
76.6; H, 6.5; N, 2.5. C36H35NO5 requires C, 77.0; 6.3; N,
2.5%); nmax (KBr)/cm21 2220 (CuN) and 1633 (CvC); dH
(400 MHz, C6D6) 3.31 (1H, dd, J¼9.8, 2.5 Hz, H-5), 3.58–
3.63 (2H, m, H-7, H-8a), 3.74 (1H, dd, J¼10.4, 9.9 Hz,
H-8b), 3.84 (1H, dd, J¼2.5, 1.2 Hz, H-6), 4.18 (1H, d,
J¼11.7 Hz, 1/2£OCH2Ph), 4.20 (1H, d, J¼11.3 Hz,
1/2£OCH2Ph), 4.25 (1H, d, J¼11.9 Hz, 1/2£OCH2Ph),
4.30 (1H, d, J¼11.8 Hz, 1/2£OCH2Ph), 4.32 (1H, d,
J¼11.7 Hz, 1/2£OCH2Ph), 4.37 (1H, dd, J¼9.8, 1.8 Hz,
H-4), 4.47 (1H, d, J¼11.4 Hz, 1/2£OCH2Ph), 4.49 (1H, d,
J¼11.1 Hz, 1/2£OCH2Ph), 4.81 (1H, d, J¼11.1 Hz,
1/2£OCH2Ph), 4.93 (1H, d, J¼1.8 Hz, H-2) and 7.06–
7.27 (20H, m, 4£Ph); dH (270 MHz, CDCl3) 3.67–3.76 (3H,
m), 4.00 (1H, dd, J¼6.9, 6.4 Hz), 4.14 (1H, s, 2-H), 4.46
(1H, d, J¼11.7 Hz, 1/2£OCH2Ph), 4.54 (1H, d, J¼11.7 Hz,
1/2£OCH2Ph), 4.61 (1H, d, J¼11.1 Hz, 1/2£OCH2Ph),
4.68 (1H, d, J¼11.4 Hz, 1/2£OCH2Ph), 4.71 (2H, s,
OCH2Ph), 4.71–4.79 (1H, m), 4.85 (1H, d, J¼11.1 Hz,
1/2£OCH2Ph), 4.93 (1H, d, J¼11.4 Hz, 1/2£OCH2Ph),
5.02 (1H, d, J¼1.5 Hz, H-2) and 7.22–7.33 (20H, m, 4£Ph);
m/z (FAB) MþþNa 562.2610 [C36H35NO5Na requires
562.2593].
Less polar product: methyl (2,3,4,6-tetra-O-benzyl-b-D-
glucopyranosyl)acetate (b-6a) (0.84 g, 50%) as a white
solid; mp 65–678C (lit.,17 65–668C), [a]2D3¼25.2 (c 0.92,
CHCl3) (lit.,17 [a]D20¼23.5; c 1, CHCl3); nmax (film)/cm21
1745 (CvO); dH (270 MHz, CDCl3) 2.48 (1H, dd, J¼15.3,
8.2 Hz, 1/2£CH2CO2), 2.74 (1H, dd, J¼15.3, 4.0 Hz,
1/2£CH2CO2), 3.37 (1H, t, J¼9.2 Hz, H-3), 3.47 (1H,
ddd, J¼9.5, 3.1, 2.9 Hz, H-5), 3.60 (1H, s, CO2Me), 3.62–
3.79 (5H, m, H-1, H-2, H-4, H-6a, H-6b), 4.50–4.92 (8H, m,
4£OCH2Ph), 7.14–7.36 (20H, m, 4£Ph); dC (62.9 MHz,
CDCl3) 37.4 (CH2), 51.6 (CH3), 68.6, 73.3, 74.96, 75.01,
75.5, 75.8, 78.4, 79.1, 81.2, 87.1, 127.5 (CH), 127.67 (CH),
127.71 (CH), 127.7 (CH), 127.8 (CH), 127.9 (CH), 128.2
(CH), 128.37 (CH), 128.40 (CH), 128.4 (CH), 137.9
(C-ipso), 138.06 (C-ipso), 138.13 (C-ipso), 138.4 (C-ipso)
and 171.4 (CvO).
4.3.7. Attempted reduction of (Z)-3,7-anhydro-4,5,6,8-
tetra-O-benzyl-2-deoxy-D-gluco-oct-2-enonic acid,
methyl ester (Z)-4a using a modest excess of Et3SiH–
CF3CO2H. Trifluoroacetic acid (151 mg, 0.32 mmol) was
added to a solution of triethylsilane (37 mg, 0.32 mmol) and
(Z)-3,7-anhydro-4,5,6,8-tetra-O-benzyl-2-deoxy-D-gluco-
oct-2-enonic acid methyl ester (Z)-4a (79 mg, 0.13 mmol)
in dry CH2Cl2 (5 mL) at 188C. The reaction mixture was
stirred for 2 h and concentrated under reduced pressure.
CHCl3 (3£3 mL) was repeatedly added to the residue and
evaporated in order to eliminate traces of volatile reagents
and by-products. The crude product was subjected to flash
chromatography using a gradient from petroleum spirit/
AcOEt (5:1) to CH2Cl2 and then Et2O to give methyl
(2,3,4,6-tetra-O-benzyl-1-hydroxy-D-glucopyranosyl)-
acetate 9a (20 mg, 25%) as an oil; nmax (film)/cm21 3433
(O–H), 1720 (CvO); dH (270 MHz, CDCl3) 2.30 (1H, d,
J¼15.5 Hz, 1/2£CH2CO2), 2.74 (1H, d, J¼15.5 Hz,
1/2£CH2CO2), 3.32 (1H, dd, J¼9.5, 1.4 Hz), 3.59–3.76
(4H, m), 3.66 (1H, s, CO2Me), 4.00 (1H, ddd, J¼10.1, 3.6,
1.9 Hz, H-7), 4.13 (1H, dd, J¼9.3, 8.7 Hz), 4.48, 4.58, 4.62,
4.65, 4.84, 4.97 (6H, 6£d, J¼10.9–12.3 Hz, 3£OCH2Ph),
More polar product: 3-[1,2,4-tris(benzyloxy)-3-hydroxy-
butyl]isochroman-4-acetic acid, methyl ester 11 (55 mg,
3%) as a white solid; mp 65–668C, [a]2D4¼þ 28.4 (c 1.3,
CHCl3); nmax (film)/cm21 3518 (O–H), 1717 (CvO); dH
(600 MHz, CDCl3) 2.00 (1H, d, J¼3.0 Hz, OH), 2.53 (1H,
dd, J¼15.6, 7.8 Hz, 1/2£CH2CO2), 2.77 (1H, dd, J¼15.6,
3.6 Hz, 1/2£CH2CO2), 3.29 (1H, ddd, J¼9.6, 9.3, 3.0 Hz,
H-30), 3.42–3.45 (2H, m, H-20, H-3), 3.61 (1H, dd, J¼9.0,
8.4 Hz, H-10), 3.63–3.66 (1H, m, H-4), 3.67 (3H, s, OCH3),
3.67–3.70 (2H, m, H-4a0 , H-4b0 ), 4.02 (1H, d, J¼15.6 Hz,
1/2£OCH2Ph), 4.06 (1H, d, J¼15.6 Hz, 1/2£OCH2Ph),
4.51 (1H, d, J¼12.6 Hz, 1/2£OCH2Ph), 4.56 (1H, d,
J¼10.8 Hz, 1/2£OCH2Ph), 4.60 (1H, d, J¼12.6 Hz,
1/2£OCH2Ph), 4.60 (1H, d, J¼12.6 Hz, 1/2£OCH2Ph),
4.73 (1H, d, J¼10.8 Hz, 1/2£OCH2Ph), 4.75 (1H, d,
J¼12.0 Hz, 1/2£OCH2Ph), 4.92 (1H, d, J¼12.0 Hz,
1/2£OCH2Ph), 7.06–7.07 (2H, m, Ph), 7.13–7.18 (5H, m,
Ph), 7.22–7.27 (7H, m, Ph), 7.30–7.33 (5H, m, Ph) and 7.40
(1H, dd, J¼7.2, 1.2 Hz, Ph); dC (62.9 MHz, CDCl3) 37.7

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M. Gascon-Lopez et al. / Tetrahedron 59 (2003) 9349–9360
9359
(CH2), 38.4 (CH2), 51.7 (CH3), 68.8 (CH2), 73.0 (CH2), 73.5
(CH2), 73.8 (CH), 74.7 (CH2), 76.0 (CH), 78.3 (CH), 79.3
(CH), 86.7 (CH), 126.2 (CH), 126.8 (CH), 127.6 (CH),
127.78 (CH), 127.84 (CH), 128.2 (CH), 128.4 (CH), 128.5
(CH), 128.7 (CH), 129.0 (CH), 130.7 (CH), 136.9 (C-ipso),
138.1 (C-ipso), 138.2 (C-ipso), 138.7 (C-ipso), 140.4
(C-ipso) and 171.8 (CvO); m/z (FAB) MþþNa 619.2692
[C37H40O7Na requires 619.2672].
(CH), 128.4 (CH), 128.5 (CH), 138.0 (C-ipso), 138.2 (C-
ipso), 138.3 (C-ipso), 138.8 (C-ipso) and 171.6 (CvO); m/z
(FAB) MþþNa 619.2690 [C37H40O7Na requires 619.2672].
The more polar product was considered to be substantially
one regioisomer of methyl (tri-O-benzyl-b-D-galactopyra-
nosyl)acetate b-12a (38 mg, 15%), which was obtained as a
colourless, viscous oil, [a]3D2¼þ30.4 (c 1.03, CHCl3); nmax
(film)/cm21 3450 (br, O–H) and 1738 (CvO); dH
(250 MHz, C6D6) 2.09 (1H, br, OH), 2.64 (1H, dd,
J¼15.7, 8.6 Hz, CHCO2Me), 2.99 (1H, dd, J¼15.7,
2.5 Hz, CHCO2Me), 3.19 (1H, dd, J¼8.8, 2.8 Hz, H-3),
3.39 (3H, s, CO2Me), 3.59–3.68 (2H, m, H-6a and H-6b),
3.78–3.84 (1H, m, H-5), 3.87–3.96 (2H, m, H-2 and H-4,
appearance changes on irradiation of OH or H-3), 4.02 (1H,
td, J¼ca. 9, 3 Hz, 1-H, collapses on irradiation of either
CHCO2Me proton), 4.16–4.42 (4H, m, 2£OCH2Ph), 4.59
(1H, d, J¼11.3 Hz, 1/2£OCH2Ph), 4.90 (1H, d, J¼11.3 Hz,
1/2£OCH2Ph), 7.10–7.41 (15H, m, 3£Ph); dC (101 MHz,
CDCl3) 37.7, 51.7, 68.5, 70.2, 71.7, 72.7, 73.5, 74.5, 76.5,
77.3, 83.9, 127.6, 127.77, 127.82, 127.9, 128.1, 128.3,
128.4, 128.7, 137.7, 137.9, 138.5 and 172.0; m/z (ES)
524.2650 [MþNHþ4 requires 524.2643].
4.3.9. Methyl (2,3,4,6-tetra-O-benzyl-b-D-glucopyrano-
syl)acetate (b-6a) by reduction of (Z)-4a using Et3SiH–
BF3·Et2O. BF3·Et2O (1.69 mL, 13.43 mmol) was added to a
solution of triethylsilane (8.84 mL, 55.40 mmol) and (Z)-
3,7-anhydro-4,5,6,8-tetra-O-benzyl-2-deoxy-D-gluco-oct-2-
enonic acid, methyl ester (Z)-4a (1.025 g, 1.72 mmol) in dry
CH2Cl2 (5 mL) at 08C under a nitrogen atmosphere. The
reaction mixture was stirred for 23 h at room temperature
and quenched with a saturated solution of NaHCO3
(10 mL). After the addition of H2O (50 mL), the reaction
mixture was extracted with CH2Cl2 (3£50 mL). The
combined organic layers were dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure
to give a colourless oil; this was recrystallised using ether
and petroleum spirit to give b-6a as white crystals (808 mg,
80%), identical by 1H NMR with material from the previous
experiment.
4.3.11. Reduction of (E)-3,7-anhydro-4,5,6,8-tetra-O-
benzyl-2-deoxy-D-galacto-oct-2-enonic acid, methyl
ester (E)-5a using Et3SiH–BF3·Et2O: formation of
b-7a. Boron trifluoride diethyl ether complex (20 mL,
0.16 mmol) was added to a mixture of triethylsilane
(0.11 mL, 0.66 mmol) and (E)-5a (12 mg, 0.021 mmol) in
dry CH2Cl2 (0.5 mL) under N2 at 08C. The reaction mixture
was stirred overnight at room temperature and quenched
with a saturated solution of NaHCO3 (5 mL). After the
addition of H2O (10 mL), the reaction mixture was extracted
with EtOAc (3£10 mL). The combined organic layers were
dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure to give a yellow waxy product,
which was subjected to flash chromatography using
petroleum spirit/Et2O (1:1) to give b-7a (6 mg, 50%)
identical by 1H and 13C NMR to b-7a prepared in the
preceding experiment.
4.3.10. Methyl (2,3,4,6-tetra-O-benzyl-b-D-galactopyra-
nosyl)acetate (b-7a) and methyl (tri-O-benzyl-b-D-galac-
topyranosyl)acetate (b-12a) by reduction with (Z)-5a
with excess Et3SiH–CF3CO2H. Trifluoroacetic acid
(4.10 mL, 53.55 mmol) was added to a solution of (Z)-3,7-
anhydro-3,7-anhydro-4,5,6,8-tetra-O-benzyl-2-deoxy-D-
galacto-oct-2-enonic acid, methyl ester (Z)-5a (319 mg,
0.54 mmol) and triethylsilane (1.494 g, 12.85 mmol) in dry
CH2Cl2 (6 mL) at 188C under nitrogen. The reaction
mixture was stirred for 2 h and concentrated under reduced
pressure. The waxy residue (317 mg) was subjected to flash
chromatography using gradients from CH2Cl2 to petroleum
spirit/Et2O (1:1) to CH2Cl2/Et2O (20:1) to give the
following products.
Less polar product: methyl (2,3,4,6-tetra-O-benzyl-b-D-
galactopyranosyl)acetate b-7a (132 mg, 41%) as a colour-
less oil; [a]2D3¼þ1.3 (c 0.93, CHCl3) lit.3 [a]2D0¼þ8.6 (c 1.3,
CHCl3); nmax (film)/cm21 1740 (CvO); dH (400 MHz,
CDCl3) 2.49 (1H, dd, J¼15.3, 7.9 Hz, 1/2£CH2CO2), 2.76
(1H, dd, J¼15.3, 3.4 Hz, 1/2£CH2CO2), 3.53–3.60 (6H, m,
H-5, H-6a, H-6b, CO2Me), 3.63 (1H, dd, J¼9.3, 2.6 Hz,
H-3), 3.72 (1H, dd, J¼9.3, 9.3 Hz, H-2), 3.76 (1H, td,
J¼9.3, 3.7 Hz, H-1, homonuclear decoupling confirms
coupling to CH2CO2), 4.00 (1H, d, J¼2.5 Hz, H-4), 4.40
(1H, d, J¼11.8 Hz, 1/2£OCH2Ph), 4.45 (1H, d, J¼11.8 Hz,
1/2£OCH2Ph), 4.60 (1H, d, J¼11.6 Hz, 1/2£OCH2Ph),
4.61 (1H, d, J¼11.1 Hz, 1/2£OCH2Ph), 4.65 (1H, d,
J¼11.7 Hz, 1/2£OCH2Ph), 4.74 (1H, d, J¼11.7 Hz,
1/2£OCH2Ph), 4.92 (1H, d, J¼11.6 Hz, 1/2£OCH2Ph),
4.97 (1H, d, J¼11.1 Hz, 1/2£OCH2Ph) and 7.22–7.35
(20H, m, 4£Ph); dC (100.6 MHz, CDCl3) 37.8 (CH2), 51.6
(CH3), 68.7 (CH2), 72.2 (CH2), 73.5 (CH2), 73.9 (CH), 74.6
(CH2), 75.2 (CH2), 76.4 (CH), 77.2 (CH), 78.2 (CH), 84.8
(CH), 127.6 (CH), 127.6 (CH), 127.7 (CH), 127.7 (CH),
127.9 (CH), 128.0 (CH), 128.1 (CH), 128.2 (CH), 128.4
4.3.12. Methyl (2,3,4,6-tetra-O-benzyl-b-D-galactopyra-
nosyl)acetate (b-7a) by reduction of (Z)-5a using
Et3SiH–BF3·Et2O. BF3·Et2O (0.345 mL, 2.72 mmol) was
added to a mixture of Et3SiH (1.8 mL, 11.2 mmol) and (Z)-
3,7-anhydro-4,5,6,8-tetra-O-benzyl-2-deoxy-D-galacto-oct-
2-enonic acid, methyl ester (Z)-5a (206.7 mg, 0.348 mmol)
in dry CH2Cl2 (1 mL) at 08C under a nitrogen atmosphere.
The reaction mixture was stirred for 23 h at room
temperature, then diluted with CH2Cl2 (10 mL) and added
to a stirred, saturated, ice-cold aqueous solution of NaHCO3
(30 mL). The mixture was extracted with CH2Cl2
(3£10 mL) and the combined organic extracts were dried
(MgSO4), evaporated and subjected to flash chromato-
graphy (2:1 petrol/Et2O) to give b-7a (149 mg, 72%),
1
identical by H NMR to the samples prepared in the two
preceding experiments.
4.3.13. Methyl (2,3,4,6-tetra-O-acetyl-b-D-glucopyrano-
syl)ethanoate (b-8a). A solution of methyl (2,3,4,6-tetra-O-
benzyl-b-D-glucopyranosyl)acetate
0.168 mmol) in MeOH/THF (2 mL/0.3 mL) was stirred
(b-6a)
(100 mg,

´ ´
M. Gascon-Lopez et al. / Tetrahedron 59 (2003) 9349–9360
9360
W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002, 102,
491–514.
under hydrogen at atmospheric pressure over 20% Pd(OH)2
on charcoal (25 mg) for 20 h. The reaction mixture was
filtered through Celitew and concentrated under reduced
pressure to a waxy residue, which was dissolved in a
mixture of pyridine (1 mL) and acetic anhydride (0.5 mL).
The reaction mixture was stirred overnight at room
temperature under N2 and concentrated under reduced
pressure to give a white residue, which was subjected to
flash chromatography using petroleum spirit/AcOEt (3:2) to
give methyl (2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-
ethanoate (b-8a) (59 mg, 0.25 mmol, 87%) as a white
solid; mp 110–1128C (lit.18 1088C); nmax (film)/cm21 1742
(st CvO), 1729 (st, CvO); dH (600 MHz, CDCl3) 2.00
(3H, s, OAc), 2.02 (3H, s, OAc), 2.03 (3H, s, OAc), 2.11
(3H, s, OAc), 2.49 (1H, dd, J¼16.0, 4.4 Hz, 1/2£CH2CO2),
2.58 (1H, dd, J¼16.0, 7.7 Hz, 1/2£CH2CO2), 3.67–3.73
(1H, m, H-5), 3.70 (3H, s, CO2Me), 3.96 (1H, ddd, J¼9.9,
7.7, 4.4 Hz, H-1), 4.06 (1H, dd J¼12.4, 2.2 Hz, H-6a), 4.25
(1H, dd, J¼12.4, 4.7 Hz, H-6b), 4.93 (1H, dd, J¼9.9, 9.4 Hz,
H-2), 5.07 (1H, dd, J¼9.6, 9.6 Hz, H-4), and 5.20 (1H, dd,
J¼9.4, 9.4 Hz, H-3); dC (62.9 MHz, CDCl3) 20.6, 37.0,
51.9, 62.0, 68.4, 71.4, 74.1, 74.4, 75.7, 169.4, 169.6, 170.2,
170.4, and 170.6; m/z (FAB) MþþH 405.1408.
[C37H40O7Na requires 405.1397].
2. Griffin, F. K.; Paterson, D. E.; Murphy, P. V.; Taylor, R. J. K.
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ˆ
9. Tsunoda, T.; Takagi, H.; Takaba, D.; Kaku, H.; Ito, S.
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Acknowledgements
12. Overkleeft, H. S.; van Wiltenburg, J.; Pandit, U. K.
Tetrahedron 1994, 50, 4215–4224.
´
13. (a) Berces, A.; Whitfield, D. M.; Nukada, T. Tetrahedron
We are grateful to Queen Mary, University of London for a
studentship to MGL and to the University of London Central
Research Fund for an equipment grant. We thank Drs
Harold Toms and Peter Haycock for the ULIRS 600 MHz
NMR service at Queen Mary, Mr Greg Coumbarides for
other NMR spectra at Queen Mary, Mr Mike Cocksedge for
the ULIRS mass spectrometry service at the School of
Pharmacy and Mrs B. Stein at the EPSRC National Mass
Spectrometry Service Centre, Swansea. We appreciate the
contributions of Drs Christine Bladon and Jason Eames
through their helpful suggestions and discussions.
2001, 57, 477–491. (b) http://www.nrc.ca/ibs/6ring.html. The
conformation of a six-membered ring can be expressed in
spherical polar co-ordinates such that d indicates the amount
of puckering; u¼0 or 1808 corresponds to a chair; u¼908,
f¼60n (where n¼0, 1, 2…) corresponds to a boat and u¼908,
f¼60(nþ0.5) corresponds to a twist-boat. (Z)-4c gives
d¼0.92; f¼768 u¼888.
14. Johnson, F. Chem. Rev. 1968, 68, 375–413.
15. (Z)-5c gives d¼0.88; f¼98 u¼1688 when analysed by the
methods of Ref. 13.
16. Sternhell, S. Quart. Rev. 1969, 23, 236–270.
17. Allevi, P.; Ciuffreda, P.; Colombo, D.; Monti, D.; Speranza,
G.; Manitto, P. J. Chem. Soc., Perkin Trans. 1 1989,
1281–1283.
References
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