Intramolecular 1,8-hydrogen-atom transfer reactions in (1→4)-O- disaccharide systems: Conformational and stereochemical requirements

Article abstract of DOI:10.1002/chem.200801414

The stereochemical and conformational factors controlling the intramolecular hydrogen-atom transfer (HAT) reaction between the two pyranose units in a (1→4)-O-disaccharide when promoted by a primary 6-O-yl radical are studied. Models with α-D-Glcp-(1→4)-β-D-Glcp, α-L-Rhamp-(1→ 4)-α-D-Galp or α-D-Manp-(1→4)-β- L-Gulp skeletons led exclusively to the abstraction of the hydrogen from H-C-5' and the formation, through a nine-membered transition state, of a 1,3,5-trioxocane ring system in a stable boat-chair conformation. Notwithstanding, derivatives of α-L-Rhamp-(1→4)-α-D-Glcp or α-D-Manp-(1→4)-α-D-Galp exclusively abstract the hydrogen from H-C-1' through a seven-membered transition state and, therefore, lead to an interglycosidic spiro ortho ester.

Full text of DOI:10.1002/chem.200801414

FULL PAPER
DOI: 10.1002/chem.200801414
Intramolecular 1,8-Hydrogen-Atom Transfer Reactions in (1!4)-O-
Disaccharide Systems: Conformational and Stereochemical Requirements
Cosme G. Francisco,[a] Antonio J. Herrera,[a] Alan R. Kennedy,[b] Angeles Martꢀn,*[a]
Daniel Meliꢁn,[c] Inꢂs Pꢂrez-Martꢀn,[a] Luis M. Quintanal,[a] and Ernesto Suꢁrez*[a]
Abstract: The stereochemical and con-
formational factors controlling the in-
tramolecular hydrogen-atom transfer
(HAT) reaction between the two pyra-
nose units in a (1!4)-O-disaccharide
when promoted by a primary 6-O-yl
radical are studied. Models with a-d-
Glcp-(1!4)-b-d-Glcp, a-l-Rhamp-(1!
4)-a-d-Galp or a-d-Manp-(1!4)-b-l-
Gulp skeletons led exclusively to the
trioxocane ring system in a stable
ꢀ
abstraction of the hydrogen from H C-
boat–chair conformation. Notwith-
standing, derivatives of a-l-Rhamp-
(1!4)-a-d-Glcp or a-d-Manp-(1!4)-
a-d-Galp exclusively abstract the hy-
5’ and the formation, through a nine-
membered transition state, of a 1,3,5-
ꢀ
drogen from H C-1’ through a seven-
Keywords:
carbohydrates
·
membered transition state and, there-
fore, lead to an interglycosidic spiro
ortho ester.
disaccharides
·
esters radical
·
reactions · trioxocane
Introduction
result of the more favourable entropy of activation of the
six-membered transition state.[4] Although examples of 1,6-
hydrogen-atom transfer (through a seven-membered transi-
tion state) from reactive carbon atoms to alkoxy radicals
have also been described,[5] only those cases in which the hy-
drogen atom to be abstracted is bonded to an oxygen-substi-
tuted carbon atom could be considered of synthetic inter-
est.[6]
Only a few cases of intramolecular HAT reactions that
proceed via eight- or higher-membered transition states
have been reported, limiting their applications to well-suited
skeletons such as steroids, in which adverse entropic effects
are avoided.[7] With these considerations in mind, we envi-
sioned that an intramolecular HAT reaction through a
higher than seven-membered transition state might be possi-
ble if we were able to obtain models with some minimum
conditions: a restricted conformational mobility to reduce
the entropic barrier, a low-energy transition state and final-
ly, a suitable distance (aprox. 3 ꢀ) between the alkoxyl radi-
cal and the hydrogen atom to be abstracted.[8] These requi-
sites can be found in (1!4)-O-disaccharide systems, such as
peracetylated b-maltose and methyl b-maltoside, in accord
with previously reported X-ray crystallographic[9] and molec-
ular mechanics[10] analysis, respectively. This b-maltose unit
has a preferred conformation centred around the exo-
anomeric effect and a syn geometry of the glycosidic bond
Radical reactions in the carbohydrate field have gained con-
siderable importance in the last decades, with a wide range
of organic synthetic applications.[1] Intramolecular hydrogen-
atom transfer (HAT) is one of the most interesting process-
es because it allows the functionalisation with high regiose-
lectivity of remote positions; however, this reaction has
been comparatively less investigated in sugars.[2] Effective
1,n-hydrogen-atom transfer has been observed from Csp3-H
to alkyl and aryl C radicals with n=4–7,[3] but 1,5-hydrogen-
atom transfer is by far the most common intramolecular
HAT reaction when promoted by an alkoxyl radical, as a
[a] Prof. Dr. C. G. Francisco, Dr. A. J. Herrera, Dr. A. Martꢁn,
Dr. I. Pꢂrez-Martꢁn, L. M. Quintanal, Prof. Dr. E. Suꢃrez
Instituto de Productos Naturales y Agrobiologꢁa del C.S.I.C.
Carretera de la Esperanza 3
38206 La Laguna, Tenerife (Spain)
Fax : (+34)922-260-135
E-mail: esuarez@ipna.csic.es
[b] Dr. A. R. Kennedy
Deparment of Pure and Applied Chemistry
University of Strathclyde
295 Cathedral Street, Glasgow G1 1XL, Scotland (UK)
[c] Dr. D. Meliꢃn
Departamento de Quꢁmica Orgꢃnica
Universidad de La Laguna, Tenerife (Spain)
ꢀ
ꢀ
(F=ꢀ34.2, Y=ꢀ28.38) and a C-6 O···H C-5’ distance of
2.5 ꢀ.[11] A study of the transition state of the C-6 O···H C-
ꢀ
ꢀ
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem200801414.
5’ HAT reaction gave a similar situation around the glycosi-
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10369

dic torsion angles (F=ꢀ32.7, Y=ꢀ37.38) and a distance of
[12]
ꢀ
3.14 ꢀ between the alkoxyl radical and H C-5’.
Based on these data, we decided to investigate the intra-
molecular 1,8-hydrogen-atom transfer reaction between the
two pyranose units in suitably substituted (1!4)-O-disac-
charides. As depicted in Scheme 1, under oxidative condi-
Scheme 2. HAT under oxidative conditions in b-maltose. a) DIB
(1.7 equiv), iodine (0.7 equiv), CH2Cl2, hn, RT, 1.5 h, 56%; b) DIB
(1.5 equiv), iodine (0.7 equiv), CH2Cl2, hn, RT, 1.5 h, 62%; c) CDCl3, RT,
60 h, 100%. DIB=(diacetoxyiodo)benzene.
acidic conditions with concomitant ring contraction to
afford the desired 1,3,5-trioxocane derivative 5 in quantita-
tive yield.
Scheme 1. Mechanism of intramolecular 1,8-hydrogen-atom transfer.
To achieve additional insight into the HAT reaction mech-
anism, the alkoxyl radical was also generated under reduc-
tive conditions by reaction of a N-hydroxyphthalimide deriv-
ative with the nBu3SnH/AIBN or nBu3SnD/AIBN systems
in benzene solutions.[18] For this purpose, we prepared the 6-
O-phthalimido derivative 6 by treatment of alcohol 1 with
N-hydroxyphthalimide under Mitsunobu conditions[19]
(Scheme 3). The reaction of permethylated phthalimide 6
tions, the electrophilic 6-O-yl radical (a) generated from the
corresponding alcohol would abstract a hydrogen atom at
C-5’ through a nine-membered transition state to produce a
nucleophilic carbon radical (b) that can be subsequently oxi-
dised to an oxonium ion (c). This intermediate could be in-
tramolecularly trapped by the alcohol to give a 1,3,5-trioxo-
cane cyclised derivative. We have described the preliminary
results in two short communications[13] and we now report
here the full details of this reaction and its extension to
other disaccharide models.
Results and Discussion
Firstly, to examine the viability of the process, we prepared
the known b-maltose derivatives 1[14] and 2[15] (Scheme 2).
The C-6 alkoxyl radicals were generated by oxidation of the
primary alcohol with (diacetoxyiodo)benzene (DIB) in the
presence of iodine, under visible light irradiation. The result
of the HAT reaction for 1 showed a direct C-5’ functionali-
sation through a nine-membered transition state to give the
1,3,5-trioxocane derivative 3 in 56% yield, which adopts a
restricted, highly stable boat–chair conformation.[16] When
the reaction was performed with the alcohol 2, a rare
1,3,5,7-tetraoxecane ring system 4 was obtained in good
yield. Compound 4 is a reasonably stable crystalline solid
the structure of which was deduced by extensive NMR spec-
troscopic analysis, including bidimensional experiments, and
determined unambiguously by X-ray crystallography.[17]
Moreover, this orthoacetate is hydrolysed under very mild
Scheme 3. HAT under reductive conditions in b-maltose. a) DEAD
(4 equiv), N-hydroxyphthalimide (4 equiv), PPh3 (4 equiv), THF, 08C,
30 min, 82%; b) nBu3SnH or nBu3SnD (9 equiv), AIBN (0.16 equiv),
PhH, reflux, 1 h, 86–78%. DEAD=diethyl azodicarboxylate, AIBN=
azobisisobutyronitrile, NPht=phthalimide.
with nBu3SnH/AIBN afforded a separable mixture of two
compounds: a new disaccharide 7 formed by hydrogen ab-
straction at C-5’ and radical quenching with inversion of
configuration and the starting maltose derivative 1, which
could arise by abstraction and retention of configuration at
C-5’, by simple reduction of the 6-O-yl radical prior to the
abstraction or by a combination of these two mechanisms.
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1,8-Hydrogen-Atom Transfer Reactions in (1!4)-O-Disaccharide Systems
FULL PAPER
Table 1. Conformations of the 1,3,5-trioxocane ring.[a]
It is important to note that by using this protocol one of
the d-glucose moieties in the maltose derivative 1 has been
transformed into a rare b-l-idopyranosyl unit in which the
4
1
pyranose ring has been changed from a C1 to a C4 confor-
mation leaving the C-2’, C-3’ and C-4’ substituents in axial
positions, as can be deduced from the coupling constants of
1
the ring hydrogen atoms in the H NMR spectrum.[20] Since
the a-l-iduronic-(1!4)-a-d-Glcp unit is present as a repeti-
tive fragment in the heparin, this methodology may be of in-
terest for the synthesis of heparinoids.[21]
To clarify the HAT mechanism, the reduction of the
phthalimide 6 was also accomplished with nBu3SnD, afford-
ing compound 8 with complete deuteration at C-5’ and com-
pound 9, which showed 57% of deuterium labelling, the re-
duction of the 6-O-yl radical consequently being responsible
for the unlabelled molecules. These results have also al-
lowed us to conclude that the abstraction at C-5’ takes place
with a 60% yield.
Arrangement C-5’ C-1’ C-4 C-5 Conformation DE
[kcalmolꢀ1
]
A[b]
B
C
D
E
F
S
S
S
R
S
R
S
R
S
R
S
boat–chair
boat–chair
boat–chair
boat–chair
boat–boat
boat–boat
crown ether
crown ether
0
Encouraged by these initial results, which may provide
access to a synthetically useful methodology towards remote
functionalisation of the C-5’ carbon atom or towards the in-
version of configuration at this centre, we decided to investi-
gate whether this protocol is exclusive to b-maltose or, on
the contrary, can be extended to other disaccharides. With
this in mind, we studied the configurational and conforma-
tional requirements of the intramolecular 1,8-HAT and we,
therefore, examined the conformation of the 1,3,5-trioxo-
cane ring for all 16 possible disaccharide diastereoisomers of
the four chiral centres involved in the cyclisation step (C-5’,
C-1’, C-4 and C-5). An analysis using molecular mechanics
calculations revealed that only four structural arrangements
(A–D) could easily accommodate 1,3,5-trioxocane rings in
stable boat–chair conformations with similar minimised en-
ergies (DEꢁ1.5 kcalmolꢀ1) as shown in Table 1. Among
them can be identified two pairs of diastereoisomers, A–B
and C–D, with very similar energies (DDEꢁ0.4 kcalmolꢀ1).
In these pairs, the C-5’, C-1’, C-4 and C-5 atoms are in an
enantiomeric relationship.
R
R
S
R
S
R
R
S
R
S
R
R
S
0.3
1.1
1.5
3.3
3.9
6.3
10.6
S
R
R
S
G
H
S
R
S
R
[a] For simplification, substituents at C-2, C-3, C-2’ and C-4’ in the carbo-
hydrate skeleton were not considered in the calculation. [b] b-Maltose ar-
rangement.
we decided to extend the protocol to other disaccharides en-
compassed in other arrangements to confirm our hypothesis.
With this aim, we synthesized a variety of disaccharide
models: a-l-Rhamp-(1!4)-a-d-Galp 10, a-d-Manp-(1!4)-
b-l-Idop 11 and a-d-Manp-(1!4)-b-l-Gulp 12 which, after
a HAT reaction, could provide structural arrangements C
and D, both slightly more energetic than b-maltose. Addi-
The next lowest energies correspond to a structural ar-
rangement in which the 1,3,5-trioxocane rings adopt theoret-
ically less-stable boat–boat (E and F) and crown ether (G
and H) conformations, which are approximately 3 and
6.5 kcalmolꢀ1, respectively, more energetic than arrange-
ment A. In these cases, the formation of the 1,3,5-trioxocane
ring would be energetically disfavoured, such that the HAT
reaction could alternatively take place at C-1’ through a
seven-membered transition state giving a spiro ortho ester,
an interesting structural motif present in several antibiotics
of the orthosomycin[22] and erythromicin[23] families, the syn-
theses of which have attracted the attention of many re-
search groups.[24] The remainder of the eight isomers not de-
picted in Table 1 display energy values too high for the 1,8-
HAT reaction to take place, and in fact the syn relative dis-
position between substituents at C-5’ and C-1’ would only
allow abstraction at C-1’.
Because the less-energetic structural arrangement A has
been investigated previously with the b-maltose derivatives,
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A. Martꢁn, E. Suꢃrez et. al.
tionally, we have also prepared disaccharides a-l-Rhamp-
(1!4)-a-d-Glcp 13 and a-d-Manp-(1!4)-a-d-Galp 14 in
which the 1,8-hydrogen-atom transfer would lead to the en-
ergetically disfavoured arrangements E and G, respectively.
All the required precursor disaccharides 10–14 were effi-
ciently synthesized by the classical Lewis acid mediated gly-
cosylation of suitably protected d-galactopyranose, l-idopyr-
anose, d-mannopyranose and d-glucopyranose derivatives as
glycosyl acceptors with 2,3,4-tri-O-acetyl-a-l-rhamnopyra-
nosyl[25] and 2,3,4,6-tetra-O-acetyl-a-d-mannopyranosyl[26]
trichloroacetimidates as glycosyl donors, as described in the
Supporting Information.[27]
Moreover, to study the HAT reaction under reductive
conditions and acquire additional insight into its mechanism,
the phthalimido derivatives 15–19 were also prepared from
the corresponding alcohol and N-hydroxyphthalimide under
Mitsunobu conditions in accordance with a previously de-
scribed protocol.[19]
Firstly, we carried out the HAT reaction with the disac-
charide a-l-Rhamp-(1!4)-a-d-Galp 10 under oxidative
conditions by treatment with the DIB/iodine system, as
shown in Scheme 4. The reaction proceeded in good overall
yield, affording the trioxocane 20 as the main product
(88%) together with a small amount of methyl ketone 21 in
which the S configuration at C-1’ was assigned by the NOE
interaction observed between H-1’ and H-4. Since com-
pound 21 is presumably formed by partial acid-catalysed re-
arrangement of 20 under the reaction conditions, we can
conclude that the reaction occurs with complete regioselec-
tivity by abstraction of the hydrogen atom at C-5’ in nearly
quantitative yield.
Next, the HAT reaction was carried out under reductive
conditions with the phthalimide 15 by treatment with
nBu3SnH/AIBN. In this case, three compounds were ob-
tained: disaccharide 22 formed by hydrogen-atom abstrac-
tion at C-5’ and radical quenching by the stannane with in-
version of configuration, the precursor alcohol 3 that could
arise by abstraction at C-5’ or by reduction of the 6-O-yl
radical and finally the olefin 23 formed by reductive elimi-
nation of the acetate group at C-4’.
Similar to the reduction of 6, in the inverted alcohol 22,
the initial a-l-rhamnopyranosyl moiety has been trans-
formed into a 6-deoxy-b-d-gulopyranosyl derivative, the py-
1
4
ACHTUGNTRNENrUGN anose ring changing from a C4 to a C1 conformation, as
deduced from NMR spectroscopic data.
Repetition of the reduction of phthalimide 15 by using
nBu3SnD as reagent on this occasion showed, after careful
analysis of the isotopic distribution, total substitution of
deuterium at C-5’ in compound 24, whereas 70% of deuteri-
um labelling was found in the alcohol 25, and, therefore, the
reduction of the 6-O-yl radical is responsible for the unla-
belled molecules. Furthermore, the formation of unlabelled
olefin 23 sustains the mechanism of free-radical reductive b-
elimination proposed above. These results have also allowed
us to establish that the abstraction at C-5’ occurs with an in-
version/retention ratio of approximately 3.7:1.[28]
Next, we investigated the HAT reactions in arrangement
D to determine the influence of the l-configuration in the
pyranose ring from which the abstraction is made. The ini-
tial studies were performed by starting from the disacchar-
ide 11; however, analysis of the coupling constants of the
ring hydrogen atoms in this substrate reveals that the l-ido-
4
pyranose moiety seems to be closer to a C1 conformation
(Figure 1), so the 1,8 abstraction should be disfavoured
versus a 1,6-HAT reaction.
Figure 1. Chair conformations for the l-idose moiety in 11.
Treatment of compound 11 with the DIB/iodine system
under visible light irradiation surprisingly afforded as the
sole product the methylene derivative 26 in 62% yield
(Scheme 5). This reaction has been described previously for
carbohydrates as an efficient and selective methodology to
remove methoxy protecting groups,[29] although as far as we
know this is the first case in which an eight-membered tran-
sition state is involved.
Scheme 4. HAT study of arrangement C. a) DIB (1.7 equiv), iodine
(1 equiv), CH2Cl2, reflux, 1.5 h, 20 (88%), 21 (10%); b) DEAD
(2.5 equiv), N-hydroxyphthalimide (2.5 equiv), PPh3 (2.5 equiv), THF,
08C, 1.5 h, 84%, c) nBu3SnH (1 equiv), AIBN (0.1 equiv), PhH, reflux,
1.5 h, 22 (52%), 10 (22%), 23 (5%); d) nBu3SnD (2 equiv), AIBN
(0.2 equiv), PhH, reflux, 2 h, 24 (45%), 25 (18%, D/H, 7:3), 23 (15%).
As expected, when the HAT reaction of the phthalimide
16 was carried out under reductive conditions with
nBu3SnH/AIBN, only the alcohol precursor 11 was obtained
in 55% yield. To confirm the possible mechanism, the re-
duction of this phthalimide 16 was also carried out with
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1,8-Hydrogen-Atom Transfer Reactions in (1!4)-O-Disaccharide Systems
FULL PAPER
Scheme 5. HAT study of arrangement D. a) DIB (1.5 equiv), iodine
Scheme 6. HAT study of arrangement D. a) DIB (1.7 equiv), iodine
(1 equiv), CH2Cl2, hn, RT, 1.5 h; then Ac2O, Py, 3 h, 28 (42%), 29 (25%),
30 (23%); b) DEAD (2.5 equiv), N-hydroxyphthalimide (2.5 equiv), PPh3
(2.5 equiv), THF, 08C!RT, 3 h, 49%; c) nBu3SnH (1.5 equiv), AIBN
(0.2 equiv), PhH, reflux, 1 h, 31 (80%), 12 (13%); d) nBu3SnD
(1.5 equiv), AIBN (0.2 equiv), PhH, reflux, 1 h, 32 (83%), 33 (14%, D/H
55:45).
(0.6 equiv), CH2Cl2, hn, RT, 2 h, 62%; b) DEAD (2.5 equiv), N-hydroxy-
phthalimide (2.5 equiv), PPh3 (2.5 equiv), THF, 08C, 3 h, 61%,
c) nBu3SnH (1.5 equiv), AIBN (0.2 equiv), PhH, reflux, 1 h, 55%;
d) nBu3SnD (3 equiv), AIBN (0.2 equiv), PhH, reflux, 2 h, 54%, D/H,
7:3.
nBu3SnD producing the substrate 27 with 70% of deuterium
labelling in the methoxy group at C-1 and, therefore, the re-
duction of the O-radical is responsible for the 30% of unla-
belled molecules.
1
4
indicates a conformational change from C4 to C1 of the l-
gulose ring during the process.
On the other hand, the reduction of phthalimide 17 by
treatment with nBu3SnH/AIBN led preferentially to the in-
verted alcohol 32 together with a small amount of the pre-
cursor 12. Repetition of the experiment with nBu3SnD/
AIBN gave compounds 32 (83%) and 33 (14%), in which
the deuterium is only incorporated at C-5’, with no deuteri-
um detected at other positions within NMR limits; thus
under reductive conditions only 1,8-HAT is taking place.
The difference in behaviour observed between the oxida-
tive and reductive conditions could be due to the fact that
the alkoxyl radical is being generated under two different
processes, especially in terms of temperature. This fact to-
gether with the different rates of the HAT reactions and the
inversion of the pyranose ring may explain the results ob-
tained.
Once the HAT process had been studied in the arrange-
ments with a boat–chair conformation, we next turned our
attention to the energetically disfavoured arrangements that
could adopt boat–boat or crown ether conformations.
For arrangement E (boat–boat), the disaccharide a-l-
Rhamp-(1!4)-a-d-Glcp 13 was the substrate of choice
(Scheme 7). When alcohol 13 was reacted with DIB and
iodine under the standard conditions, the spiro ortho ester
34 was obtained in a 79% yield with complete regio- and
stereoselectivity; therefore, the abstraction occurred exclu-
sively at C-1’ and no compounds resulting from abstraction
at C-5’ could be detected in the crude reaction mixture. The
configuration at the spiro centre was tentatively assigned as
The formation of compounds 26 and 27 seems to indicate
4
the greater stability of the C1 chair conformation; no prod-
ucts originating from the other conformation were detected
within the limits of the NMR spectroscopy.
In an effort to avoid this, we prepared the alcohol 12,
which possesses an l-gulose unit and a more voluminous
group at the anomeric carbon atom. In this case, the values
of the coupling constants of the l-gulose unit (J1,2 =7.8,
J
2,3 =J3,4 =3.4, J4,5 =1.5 Hz) are consistent with the required
1C4 conformation. The results obtained for the HAT reaction
of this disaccharide 12 are illustrated in Scheme 6. When the
reaction was carried out under oxidative conditions, three
compounds were isolated after acetylation: the trioxocane
derivative 28 (42%) as a main product together with the
acetate 29 and the isopropylidene derivative 30. The acetate
group at C-5’ of 29 could be easily distinguished by 2D
HSQC and HMBC experiments, whereas the coupling con-
1
stants deduced from the H NMR spectra showed that the
1
d-mannopyranose ring had been inverted to a C4 chair con-
formation. The stereochemistry at C-5’ was tentatively as-
signed as R on the basis of the absence of the NOE interac-
tions between H-1’ and H2-6’.
The results suggest that the abstraction at C-5’ (com-
pounds 28 and 29), through a nine-membered transition
state, competes favourably with the abstraction of the hy-
drogen atom of the isopropyl group (compound 30) through
ꢀ
an eight-membered TS in a ratio of C-5’/C iPr 75:25, which
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A. Martꢁn, E. Suꢃrez et. al.
Scheme 8. HAT study of arrangement G. a) DIB (1.7 equiv), iodine
(1 equiv), CH2Cl2, hn, RT, 1 h, 95%; b) DEAD (2.5 equiv), N-hydroxy-
phthalimide (2.5 equiv), PPh3 (2.5 equiv), THF, 08C, 3 h, 96%, c) nBu3SnH
(2.4 equiv), AIBN (0.4 equiv), PhH, reflux, 2.5 h, 42 (52%); then Ac2O,
Py, 43 (19%), 44 (6%); d) nBu3SnD (2 equiv), AIBN (0.4 equiv), PhH,
reflux, 2.5 h, 45 (57%); then Ac2O, Py, 43 (12%), 46 (2%).
Scheme 7. HAT study of arrangement E. a) DIB (2.5 equiv), iodine
(1 equiv), CH2Cl2, hn, RT, 2.5 h, 79%; b) DEAD (2.5 equiv), N-hydroxy-
phthalimide (2.5 equiv), PPh3 (2.5 equiv), THF, 08C, 1 h, 94%,
c) nBu3SnH (2 equiv), AIBN (0.2 equiv), PhH, reflux, 2 h, 35 (48%), 36
(4%), 37 (9%), 13 (8%); d) nBu3SnD (2 equiv), AIBN (0.2 equiv), PhH,
reflux, 3 h, 38 (28%), 39 (36%), 40 (7%), 13 (7%).
R on the basis of the NOE interaction observed between
the hydrogen at C-3’ and the methoxy group at C-3.[30]
at C-4 or C-6, the stereochemistry at the spiro centre has
been tentatively assigned as S.
However, when the HAT reaction was conducted under
reductive conditions with nBu3SnH, the situation was clearly
different. The expected compound 37, formed by abstraction
at C-1’ and radical reduction by the stannane with inversion
of configuration, was obtained in poor yield.[31] Instead, the
ester 35 was the main reaction product, originated also by
abstraction at C-1’, but in which the radical was stabilised by
Furthermore, in the HAT reaction under reductive condi-
tions by using the phthalimide 19 and nBu3SnH as the re-
agent, the predictable compound 44, generated by abstrac-
tion at C-1’ and radical reduction by the stannane with in-
version of configuration, was obtained in only 6% yield.
The ester 42 was the main reaction product, formed by ab-
straction at C-1ꢅ and subsequent b-fragmentation of the C-
ꢀ
ꢀ
b-fragmentation of the C-5’ O bond prior to the stannane
5’ O bond followed by radical-stannane quenching.
quenching. Besides this, a small amount of transesterified
ester 36 was also obtained as a consequence of migration of
the ester group from the secondary (C-4’) to primary posi-
tions (C-6’).[32]
In addition, the reduction with nBu3SnD allowed us to
confirm the proposed structures. From the analysis of the
isotopic distribution in the isolated products, we concluded
that a complete deuteration had taken place in compounds
45 and 46, whereas product 43 remains unlabelled, which in-
dicates that the abstraction at C-1ꢅ took place with total in-
version, as occurred with the disaccharide 13.
The experiment was also carried out with nBu3SnD. NMR
spectroscopic analysis of the isotopic distribution in com-
pounds 38 and 39 showed a complete substitution by deute-
rium at C-5’. Moreover, the total deuteration of 40 and the
isolation of a small amount of the undeuterated alcohol pre-
cursor 37 indicated that the abstraction at C-1’ proceeded
with total inversion of configuration.
Conclusions
Finally, we decided to study the HAT process for the di-
saccharide a-d-Manp-(1!4)-a-d-Galp 14, encompassed in
The results described herein confirm that the modelling pro-
posed is consistent in predicting the regioselectivity of the
hydrogen-atom transfer reactions in (1!4)-O-disaccharide
systems. If a 1,3,5-trioxocane ring is formed in a stable boat–
chair conformation, the abstraction would occur preferen-
tially at C-5’, whereas if this process is energetically disfav-
oured, close to boat–boat or crown ether conformations, the
abstraction should occur mainly at C-1’. Nevertheless, as we
could see for the disaccharides derived from a-d-Manp-(1!
G
rearrangement G (crown ether), the results of which are
shown in Scheme 8. Similar to the previous substrate, the
HAT reaction under oxidative conditions led to the spiro
ortho ester 41 in nearly quantitative yield; the process oc-
curred with total regio- and stereoselectivity, abstracting
only the hydrogen atom at C-1’. Based on the absence of
NOE interactions between the H-2’ and the hydrogen atoms
10374
www.chemeurj.org
ꢄ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10369 – 10381

1,8-Hydrogen-Atom Transfer Reactions in (1!4)-O-Disaccharide Systems
FULL PAPER
1H), 3.98 (dd, J=11.5, 4.0 Hz, 1H), 4.09 (dd, J=10.8, 10.8 Hz, 1H), 4.16
(d, J=7.7 Hz, 1H), 4.32 (dd, J=9.6, 9.6 Hz, 1H), 5.27 ppm (d, J=3.3 Hz,
1H); 13C NMR (125.7 MHz, CDCl3): d=57.0 (CH3), 58.0 (CH3), 59.3
(CH3), 60.5 (CH3), 60.9 (CH3), 61.1 (CH3), 61.5 (CH3), 64.5 (CH2), 69.7
(CH), 71.4 (CH2), 79.1 (2ꢆCH), 80.5 (CH), 81.3 (CH), 83.7 (CH), 83.8
(CH), 97.1 (CH), 101.2 (C), 104.4 ppm (CH); IR (film): n˜ =2935, 2840,
1082 cmꢀ1; MS (70 eV, EI): m/z (%): 438 (1) [M]+, 393 (9), 365 (79), 350
(45), 277 (32), 233 (95); HRMS (EI): m/z: calcd for C19H34O11: 438.2101
[M]+; found: 438.2088; elemental analysis calcd (%) for C19H34O11
(438.47): C 52.05, H 7.82; found: C 52.13, H 8.19.
4)-b-l-Idop and a-d-Manp-(1!4)-b-l-Gulp (arrangement
D), the abstraction step can be influenced not only by the
stereochemistry of the trioxocane ring carbon atoms (C-5’,
C-1’, C-4 and C-5), but also by the nature and relative dispo-
sition of other substituents of the sugar molecule, especially
those which control the pyranose ring conformation.
This methodology, which has been extended to various
disaccharide models, is a useful protocol for the remote
functionalisation of the C-5’ carbon atom or for the inver-
sion of configuration at this centre without modifying the re-
mainder of the sugar, and is, therefore, of special interest in
the synthesis of chiral synthons and other carbohydrate de-
rivatives.
Orthoacetate 4: Following the general procedure for oxidative HAT and
by using in this case DIB (1.5 mmol) and iodine (0.7 mmol) in dry
CH2Cl2 (43 mL), precursor 2 gave after chromatotron chromatography
(hexanes/EtOAc 6:4) compound 4 (62%) as a crystalline solid. M.p.
195.5–196.5, 210.3–211.58C (n-pentane/EtOAc); [a]D =ꢀ3.0 (c=0.220 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=1.56 (s, 3H), 2.01 (s, 6H), 2.02
(s, 6H), 2.07 (s, 3H), 3.47 (s, 3H), 3.56 (brd, J=9.7 Hz, 1H), 3.74 (d, J=
9.0 Hz, 1H), 4.02 (brdd, J=11.7, 2.5 Hz, 1H), 4.10 (brdd, J=9.2, 3.1 Hz,
1H), 4.18 (d, J=9.1 Hz, 1H), 4.18 (m, 1H), 4.38 (d, J=8.1 Hz, 1H), 4.81
(dd, J=8.6, 8.6 Hz, 1H), 4.89 (dd, J=10.4, 5.3 Hz, 1H), 5.07 (d, J=
10.2 Hz, 1H), 5.21 (dd, J=9.4, 9.4 Hz, 1H), 5.43 (d, J=5.1 Hz, 1H),
Experimental Section
General methods: Melting points were determined with a hot-stage appa-
ratus. Optical rotations were measured at the sodium line at ambient
temperature in CHCl3 solutions. IR spectra were recorded in film unless
otherwise stated. NMR spectra were determined at 500 MHz for 1H and
125.7 MHz for 13C in CDCl3 unless otherwise stated, in the presence of
TMS as the internal standard. Mass spectra were determined at 70 eV
unless otherwise stated. Merck silica gel 60 PF (0.063–0.2 mm) was used
for column chromatography. Circular layers of 1 mm of Merck silica gel
60 PF254 were used on a Chromatotron for centrifugally assisted chroma-
tography. Commercially available reagents and solvents were analytical
grade or were purified by standard procedures prior to use. All reactions
involving air- or moisture-sensitive materials were carried out under a ni-
trogen atmosphere. The spray reagents for TLC analysis were conducted
with 0.5% vanillin in H2SO4/EtOH 4:1 and further heating until develop-
ment of colour.
1
5.74 ppm (dd, J=10.2, 10.2 Hz, 1H); H NMR (500 MHz, C6D6): d=1.47
(s, 3H), 1.61 (s, 3H), 1.64 (s, 3H), 1.73 (s, 3H), 1.88 (s, 3H), 1.91 (s, 3H),
3.15 (s, 3H), 3.20 (d, J=10.6 Hz, 1H), 3.60 (d, J=9.2 Hz, 1H), 3.79 (dd,
J=12.8, 2.8 Hz, 1H), 3.95 (m, 2H), 3.96 (d, J=8.5 Hz, 1H), 4.13 (d, J=
7.8 Hz, 1H), 4.93 (dd, J=10.6, 5.0 Hz, 1H), 5.06 (dd, J=9.2, 9.2 Hz, 1H),
5.09 (d, J=9.9 Hz, 1H), 5.33 (d, J=5.0 Hz, 1H), 5.36 (dd, J=9.2, 9.2 Hz,
1H), 6.14 ppm (dd, J=10.2, 10.2 Hz, 1H); 13C NMR (125.7 MHz,
CDCl3): d=20.3 (CH3), 20.4 (CH3), 20.5 (CH3), 20.6 (CH3), 21.0 (CH3),
22.5 (CH3), 56.7 (CH3), 64.2 (CH2), 66.9 (CH), 68.0 (CH), 70.3 (CH), 72.4
(CH2), 72.6 (CH), 73 (br, CH), 74.7 (CH), 75.2 (CH), 96.0 (CH), 101.3
(CH), 103.1 (C), 124.8 (C), 169.4 (C), 169.6 (C), 169.8 (C), 170.3 (C),
170.5 ppm (C); 13C NMR (125.7 MHz, C6D6): d=19.9 (CH3), 20.1 (CH3),
20.2 (CH3), 20.4 (CH3), 20.9 (CH3), 23.0 (CH3), 56.0 (CH3), 65.0 (CH2),
67.5 (CH), 68.5 (CH), 70.8 (CH), 72.5 (CH2), 72.8 (CH), 74 (br, CH),
75.5 (CH), 75.8 (CH), 96.8 (CH), 101.4 (CH), 103.5 (C), 125.4 (C), 169.0
(C), 169.1 (C), 169.4 (C), 170.3 ppm (2ꢆC); IR (film): n˜ =1754 cmꢀ1; MS
(FAB): m/z (%): 629 (27) [M+Na]+, 607 (100), 575 (68); HRMS (FAB):
m/z: calcd for C25H34O17Na: 629.1694 [M+Na]+; found: 629.1667; ele-
mental analysis calcd (%) for C25H34O17 (606.53): C 49.51, H 5.65; found:
C 49.52, H 5.81.
General procedure for the oxidative HAT: A solution of the correspond-
ing alcohol (1 mmol) in dry CH2Cl2 (40 mL) containing DIB (1.7 mmol)
and iodine (1 mmol) under nitrogen was irradiated with two 80 W tung-
sten-filament lamps at room temperature, monitoring by TLC (1–4 h).
The reaction mixture was then poured into 10% aqueous Na2S2O3 and
extracted with CH2Cl2, dried over Na2SO4 and concentrated. Chromatog-
raphy of the residue (hexanes/EtOAc) gave the respective cyclised com-
pounds.
Methyl 5,6-anhydro-(2,3,4,6-tetra-O-acetyl-a-d-xylo-hexos-5-ulopyrano-
syl)-(1!4)-2,3-di-O-methyl-b-d-galactopyranoside (5): A solution of or-
thoacetate 4 (15 mg, 0.025 mmol) in CDCl3 (0.5 mL) was kept at room
temperature for 60 h. Concentration under reduced pressure afforded the
title compound 5 (15 mg, 0.025 mmol, quant.) as a syrup. [a]D =ꢀ14.5
(c=0.220 in CHCl3); 1H NMR (500 MHz, CDCl3): d=2.00 (s, 6H), 2.01
(s, 3H), 2.02 (s, 3H), 2.06 (s, 3H), 2.10 (s, 3H), 3.43 (d, J=9.1 Hz, 1H),
3.47 (s, 3H), 3.85 (d, J=11.7 Hz, 1H), 3.87 (d, J=11.7 Hz, 1H), 4.08 (d,
J=11.2 Hz, 1H), 4.14 (d, J=11.7 Hz, 1H), 4.29 (dd, J=9.6, 9.6 Hz, 1H),
4.43 (d, J=7.6 Hz, 1H), 4.78 (dd, J=8.6, 8.6 Hz, 1H), 4.91 (dd, J=10.7,
5.1 Hz, 1H), 5.13 (d, J=9.7 Hz, 1H), 5.22 (dd, J=9.6, 9.6 Hz, 1H), 5.61
(d, J=4.5 Hz, 1H), 5.76 ppm (dd, J=10.2, 10.2 Hz, 1H); 13C NMR
(125.7 MHz, CDCl3): d=20.4 (CH3), 20.5 (CH3), 20.6 (2 ꢆ CH3), 20.7
(CH3), 21.0 (CH3), 57.2 (CH3), 60.5 (CH2), 65.6 (CH), 65.6 (CH2), 68.7
(CH), 69.6 (CH), 70.2 (CH), 72.4 (CH), 74.4 (CH), 75.5 (CH), 95.1 (CH),
96.5 (C), 101.7 (CH), 169.6 (2ꢆC), 169.7 (C), 170.3 (C), 170.4 (C),
170.5 ppm (C); IR (film): n˜ =1748 cmꢀ1; MS (70 eV, EI): m/z (%): 591
(<1) [MꢀCH3]+, 546 (<1), 533 (11), 505 (5), 491 (9); HRMS (EI): m/z:
calcd for C24H31O17: 591.1561 [MꢀCH3]+; found: 591.1507; elemental
analysis calcd (%) for C25H34O17 (606.53): C 49.51, H 5.65; found: C
49.58, H 5.37.
General procedure for the reductive HAT: A solution of the correspond-
ing phthalimide (1 mmol) in dry benzene (75 mL) containing nBu3SnH/
nBu3SnD and AIBN was heated at reflux for 1–3 h. After cooling to
room temperature, the reaction mixture was concentrated under reduced
pressure. The residue was dissolved in CH3CN, washed with n-hexane
and the combined more-polar extracts were concentrated under reduced
pressure. The residue was purified by chromatotron chromatography
(hexanes/EtOAc) to afford the respective reduced compounds.
Methyl 5,6-anhydro-(2,3,4,6-tetra-O-methyl-a-d-xylo-hexos-5-ulopyrano-
syl)-(1!4)-2,3-di-O-methyl-b-d-galactopyranoside (3): Following the gen-
eral procedure for oxidative HAT and by using in this case dry CH2Cl2
(50 mL), the alcohol 1 afforded after column chromatography (hexanes/
EtOAc 4:6) the title compound 3 (56%) as a syrup. [a]D =+45.5 (c=
1
0.83 in CHCl3); H NMR (500 MHz, CDCl3): d=2.93 (dd, J=9.1, 7.8 Hz,
1H), 3.25 (dd, J=9.1, 9.1 Hz, 1H), 3.26 (dd, J=9.3, 3.8 Hz, 1H), 3.32
(ddd, J=9.7, 9.7, 4.0 Hz, 1H), 3.40 (s, 3H), 3.41 (d, J=8.8 Hz, 1H), 3.47
(d, J=9.7 Hz, 1H), 3.488 (s, 3H), 3.490 (d, J=7.9 Hz, 1H), 3.493 (s, 3H),
3.55 (s, 3H), 3.55 (dd, J=9.3, 9.3 Hz, 1H), 3.59 (s, 3H), 3.62 (s, 3H), 3.65
(s, 3H), 3.78 (dd, J=9.6, 9.6 Hz, 1H), 3.83 (dd, J=11.9, 4.3 Hz, 1H), 3.91
(dd, J=11.5, 10.0 Hz, 1H), 4.15 (d, J=7.8 Hz, 1H), 5.20 ppm (d, J=
3.4 Hz, 1H); 1H NMR (500 MHz, C6D6): d=3.25 (s, 3H), 3.25 (dd, J=
8.4, 8.4 Hz, 1H), 3.31 (dd, J=9.5, 3.5 Hz, 1H), 3.33 (s, 3H), 3.34 (s, 3H),
3.36 (ddd, J=9.7, 9.7, 4.1 Hz, 1H), 3.39 (dd, J=9.2, 9.2 Hz, 1H), 3.42 (d,
J=10.1 Hz, 1H), 3.62 (d, J=10.2 Hz, 1H), 3.66 (s, 3H), 3.72 (s, 3H), 3.76
(s, 3H), 3.77 (dd, J=9.4, 9.4 Hz, 1H), 3.78 (s, 3H), 3.84 (d, J=9.6 Hz,
Reductive HAT of methyl 2,3,4,6-tetra-O-methyl-a-d-glucopyranosyl-
(1!4)-2,3-di-O-methyl-6-O-phthalimido-b-d-glucopyranoside (6)
Method A (nBu3SnH): Following the general procedure and by using
nBu3SnH (9 mmol) and AIBN (0.16 mmol) in dry benzene (16 mL), pre-
cursor 6 gave after chromatography (EtOAc) methyl 2,3,4,6-tetra-O-
Chem. Eur. J. 2008, 14, 10369 – 10381
ꢄ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10375

A. Martꢁn, E. Suꢃrez et. al.
methyl-b-l-idopyranosyl-(1!4)-2,3-di-O-methyl-b-d-glucopyranoside (7)
(43%) as a colourless oil and the precursor alcohol 1 (43%).
(brd, J=3.2 Hz, 1H), 4.85 (d, J=1.6 Hz, 1H), 4.95 (d, J=3.7 Hz, 1H),
5.36 (d, J=10.6 Hz, 1H), 5.58 (dd, J=3.2, 1.6 Hz, 1H), 5.63 ppm (dd, J=
10.6, 3.2 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=20.6 (2ꢆCH3), 20.8
(CH3), 21.9 (CH3), 55.4 (CH3), 58.1 (CH3), 59.1 (CH3), 63.6 (CH2), 66.3
(CH), 66.7 (CH), 69.6 (CH), 70.7 (CH), 73.8 (CH), 77.1 (CH), 78.4 (CH),
98.0 (CH), 98.1 (CH), 100.4 (C), 169.6 (C), 169.8 (C), 170.5 ppm (C); IR
(film): n˜ =2933, 2838, 1755, 1372, 1224, 1049 cmꢀ1; MS (FAB): m/z (%):
515 (8) [M+Na]+, 493 (8) [M+H]+, 491 (7), 461 (40), 154 (100); HRMS
(FAB): m/z: calcd for C21H32O13Na: 515.1741 [M+Na]+; found: 515.1755;
elemental analysis calcd (%) for C21H32O13 (492.47): C 51.22, H 6.55;
found: C 51.44, H 6.33.
Compound 21: [a]D =+54.2 (c=0.310 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=2.04 (s, 3H), 2.07 (s, 3H), 2.17 (s, 3H), 2.22 (s, 3H), 3.41 (s,
3H), 3.43 (s, 3H), 3.52 (s, 3H), 3.54 (m, 1H), 3.59 (dd, J=10.0, 3.1 Hz,
1H), 3.62 (dd, J=10.0, 3.1 Hz, 1H), 3.81 (dd, J=12.5, 1.7 Hz, 1H), 4.10
(dd, J=3.1, 1.1 Hz, 1H), 4.12 (dd, J=12.5, 1.5 Hz, 1H), 4.73 (d, J=
4.2 Hz, 1H), 4.91 (d, J=3.1 Hz, 1H), 5.26 (dd, J=7.5, 4.2 Hz, 1H), 5.43
(d, J=1.9 Hz, 1H), 5.90 ppm (dd, J=7.5, 1.9 Hz, 1H); 13C NMR
(125.7 MHz, CDCl3): d=20.5 (CH3), 20.6 (CH3), 20.7 (CH3), 26.5 (CH3),
55.6 (CH3), 57.0 (CH3), 59.0 (CH3), 62.3 (CH), 68.0 (CH), 69.0 (CH2),
69.8 (CH), 73.0 (CH), 76.3 (CH), 76.7 (CH), 77.0 (CH), 98.4 (CH), 99.0
(CH), 169.3 (C), 169.7 (C), 170.1 (C), 201.7 ppm (C); IR (film): n˜ =2923,
2836, 1748, 1372, 1218, 1049 cmꢀ1; MS (70 eV, EI): m/z (%): 492 (1) [M]+,
449 (>1), 363 (7), 233 (12), 75 (100); HRMS (EI): m/z: calcd for
C21H32O13: 492.1843 [M]+; found: 492.1859; elemental analysis calcd (%)
for C21H32O13: C 51.22, H 6.55; found: C 51.14, H 6.78.
Compound 8: [a]D =+33.0 (c=0.61 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=3.02 (dd, J=9.0, 7.9 Hz, 1H), 3.08 (brs, 1H), 3.20 (brd, J=
9.9 Hz, 1H), 3.25 (dd, J=9.2, 9.2 Hz, 1H), 3.35 (s, 3H), 3.41 (s, 3H), 3.42
(brs, 1H), 3.43 (s, 3H), 3.46 (dd, J=10.1, 3.4 Hz, 1H), 3.49 (s, 3H), 3.55
(s, 3H), 3.56 (s, 3H), 3.63 (s, 3H), 3.68 (dd, J=12.7, 1.9 Hz, 1H), 3.72
(dd, J=9.6, 9.6 Hz, 1H), 3.73 (dd, J=2.5, 2.5 Hz, 1H), 3.82 (dd, J=9.5,
9.5 Hz, 1H), 3.96 (ddd, J=8.6, 3.0, 2.0 Hz, 1H), 4.14 (d, J=7.7 Hz, 1H),
4.18 (dd, J=12.7, 1.9 Hz, 1H), 4.90 ppm (s, 1H); 1H NMR (500 MHz,
C6D6): d=2.94 (brs, 1H), 3.00 (s, 3H), 3.09 (s, 3H), 3.09 (m, 1H), 3.12 (s,
3H), 3.14 (dd, J=9.5, 8.5 Hz, 1H), 3.28 (s, 3H), 3.29 (dd, J=10.2, 8.3 Hz,
1H), 3.39 (dd, J=9.5, 4.8 Hz, 1H), 3.41 (brs, 1H), 3.43 (s, 3H), 3.51 (s,
3H), 3.56 (brs, 1H), 3.57 (s, 3H), 3.70 (dd, J=9.5, 7.6 Hz, 1H), 4.01 (dd,
J=9.5, 9.5 Hz, 1H), 3.92–3.97 (m, 2H), 4.10 (d, J=7.6 Hz, 1H), 4.31 (br
d, 1H), 5.18 ppm (s, 1H); 13C NMR (125.7 MHz, CDCl3): d=56.6 (CH3),
57.8 (CH3), 58.5 (CH3), 58.9 (CH3), 60.18 (CH2), 60.23 (CH3), 60.4 (CH3),
61.1 (CH3), 71.9 (CH2), 73.8 (CH), 74.6 (CH), 74.9 (CH), 75.2 (CH), 76.4
(CH), 77.1 (CH), 83.9 (CH), 86.2 (CH), 102.0 (CH), 104.2 ppm (CH);
13C NMR (50.3 MHz, C6D6): d=56.0 (CH3), 57.09 (CH3), 57.14 (CH3),
58.4 (CH3), 59.7 (CH3), 59.9 (CH3), 60.6 (CH3), 61.6 (CH2), 71.7 (CH2),
73.8 (CH), 75.1 (CH), 75.3 (CH), 75.7 (CH), 76.78 (CH), 76.84 (CH),
84.2 (CH), 86.5 (CH), 101.3 (CH), 104.7 ppm (CH); IR (film): n˜ =
3494 cmꢀ1; MS (70 eV, EI): m/z (%): 408 (<1) [MꢀCH3OH]+, 377 (<1),
308 (4), 275 (9), 265 (45); HRMS (EI): m/z: calcd for C18H32O10
:
408.1995 [MꢀCH3OH]+; found: 408.1977; elemental analysis calcd (%)
for C19H36O11 (440.68): C 51.81, H 8.24; found: C 52.07, H 7.85.
Reductive HAT of methyl 2,3,4-tri-O-acetyl-a-l-rhamnopyranosyl-(1!
4)-2,3-di-O-methyl-6-O-phthalimido-a-d-galactopyranoside (15)
Method B (nBu3SnD): Following the general procedure and by using
nBu3SnH (9 mmol) and AIBN (0.16 mmol) in dry benzene (16 mL), pre-
cursor 6 gave after chromatography (EtOAc) methyl 2,3,4,6-tetra-O-
methyl-b-l-(5-2H1)idopyranosyl-(1!4)-2,3-di-O-methyl-b-d-glucopyrano-
Method A (nBu3SnH): Following the general procedure and by using
nBu3SnH (1 mmol) and AIBN (0.1 mmol), the phthalimide 15 afforded
after chromatography (hexanes/EtOAc, 50:50!30:70) methyl 2,3,4-tri-O-
acetyl-6-deoxy-b-d-gulopyranosyl-(1!4)-2,3-di-O-methyl-a-d-galactopyr-
anoside (22) (52%) as a crystalline solid, the precursor alcohol 10
(22%), described in the Supporting Information, and methyl 2,3-di-O-
acetyl-4,6-dideoxy-b-d-erythro-hex-4-enopyranosyl-(1!4)-2,3-di-O-
methyl-a-d-galactopyranoside (23) (5%) as a colourless oil.
side
(8)
(37%)
and
methyl
2,3,4,6-tetra-O-methyl-a-d-
[5-2H1]glucopyranosyl-(1!4)-2,3-di-O-methyl-b-d-glucopyranoside
(9)
(41%, H/2H ratio, 43:57).
1
Compound 8: 1H NMR (500 MHz, C6D6): d=2.95 (brd, J=2.1 Hz, 1H),
3.00 (s, 3H), 3.10 (s, 3H), 3.11 (s, 3H), 3.11 (m, 1H), 3.14 (dd, J=9.0,
7.8 Hz, 1H), 3.28 (s, 3H), 3.30 (dd, J=9.2, 9.2 Hz, 1H), 3.39 (d, J=
9.6 Hz, 1H), 3.41 (brd, J=3.2 Hz, 1H), 3.43 (s, 3H), 3.51 (s, 3H), 3.56
(brd, J=2.6 Hz, 1H), 3.57 (s, 3H), 3.69 (d, J=9.6 Hz, 1H), 3.98 (m, 1H),
4.01 (dd, J=9.5, 9.5 Hz, 1H), 4.10 (d, J=7.7 Hz, 1H), 4.32 (brd, J=
11.8 Hz, 1H), 5.19 ppm (d, J=1.3 Hz, 1H); 13C NMR (125.7 MHz, C6D6):
d=56.27 (CH3), 57.38 (CH3), 57.40 (CH3), 58.7 (CH3), 60.0 (CH3), 60.2
(CH3), 60.8 (CH3), 61.8 (CH2), 71.9 (CH2), 75.3 (CH), 75.6 (CH), 76.0
(CH), 77.0 (CH), 77.1 (CH), 84.5 (CH), 86.8 (CH), 101.6 (CH),
105.0 ppm (CH); MS (FAB): m/z (%): 464 (100) [M+Na]+, 442 (10), 307
(25), 289 (13); HRMS (FAB): m/z: calcd for C19H352H1NaO11: 464.2218
[M+Na]+; found: 464.2211.
Compound 9: 13C NMR (50.3 MHz, C6D6): d=56.3 (CH3), 59.0 (2ꢆCH3),
59.9 (CH3), 60.2 (CH3), 60.3 (CH3), 60.6 (CH3), 61.8 (CH2), 72.0 (CH),
72.240 (CH2), 72.298 (CH2), 74.3 (CH), 75.5 (CH), 80.47 (CH), 80.53
(CH), 82.7 (CH), 84.1 (CH), 84.9 (CH), 86.9 (CH), 97.8 (CH), 104.6 ppm
(CH); MS (FAB): m/z (%): 464/463 (29/21) [M+Na]+, 410/409 (7/6);
HRMS (FAB): m/z: calcd for C19H352H1NaO11/C19H36NaO11: 464.2218/
463.2155 [M+Na]+; found: 464.2229/463.2162.
Compound 22: M.p. 153.2–154.98C (acetone/n-hexane); [a]D =+60.0
1
(c=0.530 in CHCl3); H NMR (500 MHz, CDCl3): d=1.19 (d, J=6.4 Hz,
3H), 2.03 (s, 3H), 2.13 (s, 3H), 2.17 (s, 3H), 3.23 (m, 1H), 3.39 (s, 3H),
3.47 (dd, J=10.1, 3.5 Hz, 1H), 3.48 (s, 3H), 3.49 (s, 3H), 3.57 (dd, J=
10.1, 3.0 Hz, 1H), 3.63 (m, 1H), 3.77–3.83 (m, 2H), 4.15 (dddd, J=6.5,
6.5, 6.5, 1.3 Hz, 1H), 4.19 (brd, J=3.1 Hz, 1H), 4.81 (d, J=3.5 Hz, 1H),
4.83 (dd, J=3.7, 1.4 Hz, 1H), 4.94 (d, J=8.3 Hz, 1H), 5.04 (dd, J=8.3,
3.5 Hz, 1H), 5.34 ppm (dd, J=3.6, 3.6 Hz, 1H); 13C NMR (100.6 MHz,
CDCl3): d=15.715 (CH3), 20.6 (CH3), 20.7 (CH3), 20.8 (CH3), 55.4
(CH3), 58.4 (CH3), 59.1 (CH3), 60.2 (CH2), 67.9 (CH), 68.4 (CH), 68.8
(CH), 69.0 (CH), 70.100 (CH), 73.3 (CH), 78.0 (CH), 79.2 (CH), 97.9
(CH), 99.8 (CH), 168.9 (C), 169.5 (C), 169.8 ppm (C); IR (film): n˜ =3506,
2940, 2840, 1748, 1372, 1222, 1045 cmꢀ1; MS (FAB): m/z (%): 518 (6)
[M+Na+H]+, 517 (21) [M+Na]+, 391 (32), 273 (63), 73 (100); HRMS
(FAB): m/z: calcd for C21H35O13Na: 518.1975 [M+Na+H]+; found:
518.1984; elemental analysis calcd (%) for C21H34O13 (494.49): C 51.01, H
6.93; found: C 51.15, H 6.89.
Compound 23: [a]D =ꢀ33.8 (c=0.290 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=1.83 (s, 3H), 2.05 (s, 3H), 2.10 (s, 3H), 2.21 (dd, J=9.8,
7.5 Hz, 1H), 3.41 (s, 3H), 3.50 (s, 3H), 3.51 (s, 3H), 3.57–3.58 (m, 2H),
3.60–3.75 (m, 2H), 3.82 (ddd, J=6.6, 6.6, 1.3 Hz, 1H), 4.24 (dd, J=1.1,
1.1 Hz, 1H), 4.66 (brd, J=3.7 Hz, 1H), 4.85 (d, J=1.6 Hz, 1H), 5.25 (dd,
J=5.0, 5.0 Hz, 2ꢅ-H), 5.30 (d, J=5.3 Hz, 1H), 5.51 ppm (ddd, J=5.3, 3.7,
1.6 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=19.5 (CH3), 20.8 (CH3),
20.9 (CH3), 55.4 (CH3), 58.7 (CH3), 59.1 (CH3), 61.4 (CH2), 64.1 (CH),
66.0 (CH), 69.6 (CH), 73.4 (CH), 78.0 (CH), 79.6 (CH), 95.1 (CH), 97.9
(CH), 98.4 (CH), 151.1 (C), 169.9 (C), 170.2 ppm (C); IR (film): n˜ =3468,
2935, 2834, 1747, 1682, 1372, 1247, 1049 cmꢀ1; MS (70 eV, EI): m/z (%):
435 (<1) [M+H]+, 402 (<1), 374 (1), 212 (11), 88 (100); HRMS (EI):
m/z: calcd for C19H31O11: 435.1866 [M+H]+; found: 435.1877; elemental
analysis calcd (%) for C19H30O11 (434.43): C 52.53, H 6.96; found: C
52.23, H 6.90.
Oxidative HAT of methyl 2,3,4-tri-O-acetyl-a-l-rhamnopyranosyl-(1!4)-
2,3-di-O-methyl-a-d-galactopyranoside (10): Following the general proce-
dure, in this case without irradiation and heating at reflux, the alcohol 10
gave after chromatotron chromatography (hexanes/EtOAc 25:75) methyl
5,6-anhydro-(2,3,4-tri-O-acetyl-6-deoxy-a-l-lyxo-hexos-5-ulopyranosyl)-
(1!4)-2,3-di-O-methyl-a-d-galactopyranoside (20) (88%) as
a white
crystalline solid and methyl (1’S)-4,6-O-(2,3,4-tri-O-acetyl-6-deoxy-a-l-
lyxo-hexos-5-ulosylidene)-2,3-di-O-methyl-a-d-galactopyranoside
(21)
(10%) as a colourless oil.
Compound 20: M.p. 216.5–217.48C (acetone/n-hexane); [a]D =+98.1
(c=0.270 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.37 (s, 3H), 1.95
(s, 3H), 2.08 (s, 3H), 2.15 (s, 3H), 3.39 (s, 3H), 3.43 (s, 3H), 3.48 (dd, J=
10.1, 3.2 Hz, 1H), 3.52 (s, 3H), 3.54 (m, 1H), 3.67 (dd, J=10.1, 3.7 Hz,
1H), 3.91 (dd, J=13.2, 2.1 Hz, 1H), 4.08 (dd, J=13.2, 1.6 Hz, 1H), 4.17
10376
www.chemeurj.org
ꢄ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10369 – 10381

1,8-Hydrogen-Atom Transfer Reactions in (1!4)-O-Disaccharide Systems
FULL PAPER
Method B (nBu3SnD): Following the general procedure and by using
nBu3SnD (2 mmol) and AIBN (0.2 mmol), the phthalimide 15 gave after
column chromatography (hexanes/EtOAc 50:50!30:70) methyl 2,3,4-tri-
O-acetyl-6-deoxy-b-d-(5-2H1)gulopyranosyl-(1!4)-2,3-di-O-methyl-a-d-
OMe-2H]idopyranoside (27) (54%, 1H/2H ratio, 3:7) as a colourless oil:
1H NMR (400 MHz, CDCl3): d=1.99 (s, 3H), 2.04 (s, 3H), 2.09 (s, 3H),
2.15 (s, 3H), 3.26 (dd, J=7.1, 3.2 Hz, 1H), 3.52 (s, 3H), 3.539 (brs, 2H),
3.544 (s, 3H), 3.56 (s, 3H), 3.74 (dd, J=7.1, 7.1 Hz, 1H), 3.79 (dd, J=6.9,
4.8 Hz, 1H), 3.84 (m, 1H), 3.96 (m, 1H), 4.01 (ddd, J=6.6, 4.8, 4.8 Hz,
1H), 4.04 (ddd, J=9.3, 5.8, 2.4 Hz, 1H), 4.09 (dd, J=12.2, 2.4 Hz, 1H),
4.24 (dd, J=12.2, 5.8 Hz, 1H), 4.74 (d, J=2.9 Hz, 1H), 5.09 (d, J=
1.3 Hz, 1H), 5.24 (dd, J=9.5, 9.5 Hz, 1H), 5.27 (dd, J=3.2, 1.8 Hz, 1H),
5.29 ppm (dd, J=9.5, 3.4 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=
20.6 (CH3), 20.7 (2ꢆCH3), 20.8 (CH3), 56.867 (CH2, t, JCD =22.6 Hz),
57.145 (CH3), 59.5 (CH3), 60.1 (CH3), 62.3 (CH2), 62.7 (CH2), 66.4 (CH),
68.7 (CH), 69.3 (CH), 69.7 (CH), 75.0 (CH), 75.3 (CH), 77.6 (CH), 79.9
(CH), 98.2 (CH), 99.7 (CH), 169.6 (C), 169.8 (C), 169.9 (C), 170.6 ppm
(C); MS (70 eV, EI): m/z (%): 494 (<1) [M+HCO]+, 493 (<1), 478
(<1), 477 (<1), 331 (72), 88 (100); HRMS (EI): m/z: calcd for
C21H322HO13/C21H33O13: 494.1984/493.1921 [M+HCO]+; found: 494.1992/
493.1920.
galactopyranoside
(24)
(45%),
methyl
2,3,4-tri-O-acetyl-a-l-
[5-2H1]rhamnopyranosyl-(1!4)-2,3-di-O-methyl-a-d-galactopyranoside
(25) (18%, 1H/2H ratio, 3:7), both as colourless oils, and the olefin 23
(15%).
Compound 24: 1H NMR (500 MHz, CDCl3): d=1.18 (s, 3H), 2.02 (s,
3H), 2.12 (s, 3H), 2.16 (s, 3H), 3.24 (m, 1H), 3.38 (s, 3H), 3.46 (dd, J=
10.1, 3.5 Hz, 1H), 3.47 (s, 3H), 3.48 (s, 3H), 3.56 (dd, J=10.1, 3.0 Hz,
1H), 3.63 (m, 1H), 3.76–3.82 (m, 2H), 4.19 (dd, J=3.0, 0 Hz, 1H), 4.80
(d, J=3.5 Hz, 1H), 4.81 (d, J=3.7 Hz, 1H), 4.94 (d, J=8.3 Hz, 1H), 5.03
(dd, J=8.3, 3.5 Hz, 1H), 5.33 ppm (dd, J=3.6, 3.6 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3): d=15.576 (CH3), 20.6 (CH3), 20.7 (CH3), 20.7
(CH3), 55.4 (CH3), 58.4 (CH3), 59.0 (CH3), 60.2 (CH2), 67.9 (CH), 68.4
(CH), 69.0 (CH), 70.036 (CH), 73.3 (CH), 78.0 (CH), 79.2 (CH), 97.9
(CH), 99.8 (CH), 168.8 (C), 169.5 (C), 169.8 ppm (C); MS (FAB): m/z
(%): 519 (2) [M+Na+H]+, 518 (7), 355 (10), 274 (27), 73 (100); HRMS
(FAB): m/z: calcd for C21H342HO13Na: 519.2038 [M+Na+H]+; found:
519.2014.
Oxidative HAT of isopropyl 2,3,4,6-tetra-O-methyl-a-d-mannopyranosyl-
(1!4)-2,3-di-O-methyl-b-l-gulopyranoside (12): Following the general
procedure and by using in this case dry CH2Cl2 (47 mL), the alcohol 12
gave after acetylation of the reaction crude and chromatotron chroma-
tography of the residue (hexanes/EtOAc 4:6) isopropyl (5’R)-5’,6-anhy-
dro-2’,3’,4’,6’-tetra-O-methyl-a-d-lyxo-hexos-5’-ulopyranosyl-(1!4)-2,3-
di-O-methyl-b-l-gulopyranoside (28) (42%) as a colourless oil and an in-
separable mixture of isopropyl (5’R)-5’-O-acetyl-2’,3’,4’,6’-tetra-O-methyl-
a-d-lyxo-hexos-5’-ulopyranosyl-(1!4)-6-O-acethyl-2,3-di-O-methyl-b-l-
gulopyranoside (29) (25%) and 2,3,4,6-tetra-O-methyl-a-d-mannopyra-
nosyl-(1!4)-1,6-O-isopropylidene-2,3-di-O-methyl-b-l-gulopyranose (30)
(23%).
Compound 28: [a]D =+75.5 (c=0.102 in CHCl3); 1H NMR (400 MHz,
C6D6): d=1.11 (d, J=6.1 Hz, 3H), 1.22 (d, J=6.1 Hz, 3H), 3.14 (s, 3H),
3.22 (s, 3H), 3.31 (s, 3H), 3.33 (s, 3H), 3.38 (d, J=10.3 Hz, 1H), 3.48 (s,
3H), 3.49 (m, 1H), 3.54 (dd, J=3.4, 3.4 Hz, 1H), 3.57 (dd, J=8.2, 3.2 Hz,
1H), 3.62 (s, 3H), 3.64 (d, J=10.3 Hz, 1H), 3.70 (dd, J=2.6, 1.6 Hz, 1H),
3.78 (dd, J=3.7, 1.1 Hz, 1H), 3.86 (dd, J=13.2, 1.9 Hz, 1H), 3.91 (dd, J=
13.0, 2.4 Hz, 1H), 3.98 (sep, J=6.1 Hz, 1H), 4.28 (d, J=10.3 Hz, 1H),
4.32 (dd, J=10.3, 2.6 Hz, 1H), 4.98 (d, J=7.9 Hz, 1H), 4.99 ppm (d, J=
1.9 Hz, 1H); 13C NMR (100.6 MHz, C6D6): d=22.1 (CH3), 23.9 (CH3),
57.7 (CH3), 59.1 (CH3), 59.4 (CH3), 59.5 (CH3), 59.7 (CH3), 60.9 (CH3),
64.5 (CH2), 70.6 (CH), 71.4 (CH), 72.8 (CH2), 74.7 (CH), 77.5 (CH), 77.8
(CH), 78.5 (CH), 79.0 (CH), 80.3 (CH), 98.6 (CH), 100.4 (CH),
102.5 ppm (C); IR (film): n˜ =2926, 1457, 1376, 1114, 1030 cmꢀ1; MS
(70 eV, EI): m/z (%): 466 (5) [M]+, 421 (4), 393 (28), 261 (100); HRMS
(EI): m/z calcd for C21H38O11: 466.2414 [M]+; found: 466.2397; elemental
analysis calcd (%) for C21H38O11 (466.52): C 54.07, H 8.21; found: C
54.14, H 8.31.
Compound 29: 1H NMR (500 MHz, C6D6): d=1.10 (d, J=6.0 Hz, 3H),
1.23 (d, J=6.3 Hz, 3H), 1.77 (s, 3H), 1.82 (s, 3H), 3.09 (s, 3H), 3.22 (s,
3H), 3.23 (s, 3H), 3.276 (s, 3H), 3.279 (s, 3H), 3.49 (dd, J=8.3, 2.8 Hz,
1H), 3.51 (s, 3H), 3.62–3.64 (m, 1H), 3.64 (dd, J=8.3, 3.1 Hz, 1H), 3.83
(dd, J=3.4, 3.4 Hz, 1H), 3.93 (d, J=3.1 Hz, 1H), 4.10 (d, J=10.3 Hz,
1H), 4.12 (dd, J=3.7, 1.7 Hz, 1H), 4.19 (d, J=10.3 Hz, 1H), 4.34 (ddd,
J=7.1, 4.6, 1.1 Hz, 1H), 4.57 (m, 1H), 4.65 (dd, J=11.7, 7.4 Hz, 1H),
4.78 (dd, J=11.7, 4.6 Hz, 1H), 5.05 (d, J=8.0 Hz, 1H), 5.33 ppm (d, J=
8.3 Hz, 1H).
Compound 30: 1H NMR (500 MHz, C6D6): d=1.29 (s, 3H), 1.55 (s, 3H),
3.14 (s, 3H), 3.19 (s, 3H), 3.22 (s, 3H), 3.23 (s, 3H), 3.27 (s, 3H), 3.41
(dd, J=10.3, 1.7 Hz, 1H), 3.44 (s, 3H), 3.47 (dd, J=3.7, 2.0 Hz, 1H), 3.53
(dd, J=10.3, 4.3 Hz, 1H), 3.62 (m, 1H), 3.68 (dd, J=3.1, 2.0 Hz, 1H),
3.74 (dd, J=9.7, 9.7 Hz, 1H), 3.78 (ddd, J=9.7, 5.1, 1.7 Hz, 1H), 3.95
(dd, J=6.3, 6.3 Hz, 1H), 3.99 (dd, J=12.8, 7.7 Hz, 1H), 4.04 (dd, J=9.4,
3.4 Hz, 1H), 4.14 (dd, J=12.5, 8.0 Hz, 1H), 4.52–4.60 (m, 1H), 5.26 (d,
J=2.0 Hz, 1H), 5.32 ppm (d, J=2.0 Hz, 1H); 13C NMR (125.7 MHz,
C6D6; mixture of 29 and 30): d=20.5 (CH3), 21.7 (CH3), 22.3 (CH3), 23.5
(CH3), 23.9 (CH3), 27.6 (CH3), 57.0 (CH3), 57.2 (CH3), 58.5 (CH3), 58.9
(2ꢆCH3), 59.0 (2ꢆCH3), 59.1 (2ꢆCH3), 59.2 (CH3), 59.4 (CH3), 60.3
(CH3), 60.9 (CH2), 64.8 (CH2), 71.2 (CH), 71.4 (CH), 71.5 (CH2), 71.6
(CH), 72.1 (CH2), 73.6 (CH), 75.1 (CH), 75.6 (CH), 76.8 (CH), 77.0
1
Compound 25: H NMR (500 MHz, CDCl3): d=1.22 (s, 3H), 1.23 (d, J=
6.6 Hz, 3H), 1.99 (s, 3H), 2.05 (s, 3H), 2.14 (s, 3H), 3.42 (s, 3H), 3.47 (s,
3H), 3.54 (s, 3H), 3.56 (dd, J=10.1, 2.9 Hz, 1H), 3.64 (dd, J=10.1,
3.5 Hz, 1H), 3.66 (m, 1H), 3.80–3.86 (m, 2H), 3.98 (dddd, J=10.0, 6.3,
6.3, 6.3 Hz, 1H), 4.12 (d, J=2.7, 0 Hz, 1H), 4.88 (d, J=3.5 Hz, 1H), 5.05
(d, J=2.1 Hz, 1H), 5.071 (d, J=10.0 Hz, 1H), 5.073 (dd, J=9.8, 9.8 Hz,
1H), 5.31 (dd, J=10.0, 3.3 Hz, 1H), 5.47 ppm (dd, J=3.3, 2.1 Hz, 1H);
13C NMR (100.6 MHz, CDCl3): d=17.350 (CH3), 17.489 (CH3), 20.7
(CH3), 20.8 (CH3), 20.9 (CH3), 55.4 (CH3), 58.8 (CH3), 59.3 (CH3), 62.0
(CH2), 67.5 (CH), 69.0 (CH), 69.8 (CH), 69.9 (CH), 70.869 (CH), 70.932
(CH), 75.1 (CH), 78.0 (CH), 79.8 (CH), 98.1 (CH), 99.7 (CH), 169.8 (C),
170.0 (C), 170.0 ppm (C); MS (FAB): m/z (%): 519 (7) [M+Na+H]+,
518 (26), 517 (5), 274 (46), 273 (27), 73 (100); HRMS (FAB): m/z: calcd
for C21H342HO13Na/C21H35O13Na: 519.2038/518.1975 [M+Na+H]+; found:
519.2042/518.1970.
Methyl
2,3,4,6-tetra-O-acetyl-a-d-mannopyranosyl-(1!4)-2,3-di-O-
methyl-1,6-O-methylene-b-l-idopyranoside (26): Following the general
procedure for the oxidative HAT and by using in this case DIB
(1.5 mmol) and iodine (0.6 mmol) in dry CH2Cl2 (35 mL), precursor 11
gave after chromatotron chromatography (hexanes/EtOAc 1:1) the title
compound 26 (62%) as a foam: [a]D =+46.1 (c=0.466 in CHCl3);
1H NMR (400 MHz, CDCl3): d=2.00 (s, 3H), 2.04 (s, 3H), 2.08 (s, 3H),
2.15 (s, 3H), 3.06 (dd, J=9.0, 2.9 Hz, 1H), 3.49 (dd, J=12.5, 3.7 Hz, 1H),
3.54 (s, 3H), 3.63 (s, 3H), 3.83 (dd, J=9.8, 7.4 Hz, 1H), 3.86 (m, 1H),
3.91 (dd, J=9.8, 9.8 Hz, 1H), 4.09 (dd, J=12.2, 2.6 Hz, 1H), 4.17–4.22
(m, 2H), 4.23 (dd, J=12.2, 5.8 Hz, 1H), 4.88 (d, J=7.2 Hz, 1H), 5.09 (d,
J=6.9 Hz, 1H), 5.19 (d, J=1.6 Hz, 1H), 5.23 (dd, J=9.8, 9.8 Hz, 1H),
5.26 (m, 1H), 5.33 (dd, J=3.2, 1.9 Hz, 1H), 5.41 ppm (d, J=3.2 Hz, 1H);
13C NMR (100.6 MHz, CDCl3): d=20.6 (CH3), 20.7 (2
ꢆ CH3), 20.8
(CH3), 59.2 (CH3), 61.3 (CH3), 62.8 (CH2), 66.4 (CH2), 67.0 (CH), 68.6
(CH), 69.2 (CH), 69.4 (CH), 76.8 (CH), 77.2 (CH), 80.0 (CH), 82.8 (CH),
91.2 (CH2), 95.5 (CH), 99.6 (CH), 169.68 (C), 169.71 (C), 169.8 (C),
170.5 ppm (C); IR (film): n˜ =2939, 1748, 1371, 1224, 1043 cmꢀ1; MS
(70 eV, EI): m/z (%): 550 (<1) [M]+, 491 (<1), 459 (<1), 331 (100), 169
(97); HRMS (EI): m/z: calcd for C23H34O15: 550.1898 [M]+; found:
550.1886; elemental analysis calcd (%) for C23H34O15 (550.51): C 50.18, H
6.23; found: C 50.28, H 6.22.
Reductive HAT of methyl 2,3,4,6-tetra-O-acetyl-a-d-mannopyranosyl-
(1!4)-2,3-di-O-methyl-6-O-phthalimido-b-l-idopyranoside (16)
Method A (nBu3SnH): Following the general procedure and by using
nBu3SnH (1.5 mmol) and AIBN (0.2 mmol), the phthalimide 16 gave
after column chromatography (hexanes/EtOAc 30:70), the alcohol 11
(55%) described in the Supporting Information.
Method B (nBu3SnD): Following the general procedure and by using
nBu3SnD (3 mmol) and AIBN (0.2 mmol), the phthalimide 16 afforded
after column chromatography (hexanes/EtOAc 30:70) methyl 2,3,4,6-
tetra-O-acetyl-a-d-mannopyranosyl-(1!4)-2,3-di-O-methyl-b-l-[1-
Chem. Eur. J. 2008, 14, 10369 – 10381
ꢄ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10377

A. Martꢁn, E. Suꢃrez et. al.
(CH), 77.1 (CH), 77.2 (CH), 77.7 (CH), 77.8 (CH), 77.9 (CH), 78.0 (CH),
79.3 (CH), 82.2 (CH), 94.5 (CH), 96.6 (CH), 99.9 (CH), 100.3 (CH),
102.1 (C), 104.6 (C), 168.6 (C), 170.0 ppm (C).
Methyl (1R)-4,6-O-(2,3,4-tri-O-acetyl-d-rhamnopyranosylidene)-2,3-di-O-
methyl-a-d-glucopyranoside (34): Following the general procedure for
the oxidative HAT and by using in this case DIB (2.5 mmol), the alcohol
13 gave after chromatotron chromatography (hexanes/EtOAc 60:40) the
title compound 34 (79%) as a crystalline solid. M.p. 194.2–195.68C (n-
hexane/EtOAc); [a]D =+40.6 (c=0.315 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=1.28 (d, J=6.3 Hz, 3H), 1.95 (s, 3H), 2.04 (s, 3H), 2.16 (s,
3H), 3.23 (dd, J=8.9, 3.7 Hz, 1H), 3.40 (s, 3H), 3.53 (s, 3H), 3.55 (dd,
J=9.3, 9.3 Hz, 1H), 3.58 (dd, J=9.3, 9.3 Hz, 1H), 3.64 (s, 3H), 3.74–3.79
(m, 2H), 3.88 (dd, J=9.9, 5.1 Hz, 1H), 3.98 (dd, J=10.4, 10.4 Hz, 1H),
4.80 (d, J=3.7 Hz, 1H), 5.09 (dd, J=9.9, 9.9 Hz, 1H), 5.27 (dd, J=10.1,
3.5 Hz, 1H), 5.37 ppm (d, J=3.5 Hz, 1H); 13C NMR (100.6 MHz,
CDCl3): d=17.5 (CH3), 20.6 (CH3), 20.76 (CH3), 20.79 (CH3), 55.3
(CH3), 59.6 (CH3), 61.2 (CH3), 61.6 (CH), 62.9 (CH2), 68.4 (CH), 69.6
(CH), 70.0 (CH), 70.6 (CH), 73.5 (CH), 79.5 (CH), 81.4 (CH), 98.6 (CH),
108.1 (C), 169.7 (C), 169.89 (C), 169.94 ppm (C); IR (film): n˜ =2916,
2839, 1754, 1373, 1222, 1092, 1044 cmꢀ1; MS (70 eV, EI): m/z (%): 492 (1)
[M]+, 461 (3), 304 (44), 262 (27), 88 (100); HRMS (EI): m/z: calcd for
C21H32O13: 492.1843 [M]+; found: 492.1827; elemental analysis calcd (%)
for C21H32O13 (492.47): C 51.22, H 6.55; found: C 51.23, H 6.39.
Reductive HAT of isopropyl 2,3,4,6-tetra-O-methyl-a-d-mannopyranosyl-
(1!4)-2,3-di-O-methyl-6-O-phthalimido-b-l-gulopyranoside (17)
Method A (nBu3SnH): Following the general procedure and by using
nBu3SnH (1.5 mmol) and AIBN (0.2 mmol), the phthalimide 17 gave
after column chromatography (hexanes/EtOAc 2:8) isopropyl 2,3,4,6-
tetra-O-methyl-b-l-gulopyranosyl-(1!4)-2,3-di-O-methyl-b-l-gulopyra-
noside (31) (80%) as a colourless oil and the precursor alcohol 12
(13%), described in the Supporting Information.
Compound 31: [a]D =+63.7 (c=0.160 in CHCl3); 1H NMR (500 MHz,
C6D6): d=1.09 (d, J=6.0 Hz, 3H), 1.19 (d, J=6.0 Hz, 3H), 3.00 (s, 3H),
3.02 (dd, J=3.9, 1.5 Hz, 1H), 3.10 (s, 3H), 3.20 (s, 3H), 3.278 (s, 3H),
3.281 (dd, J=9.6, 1.8 Hz, 1H), 3.30 (s, 3H), 3.45 (dd, J=8.1, 3.0 Hz, 1H),
3.51 (s, 3H), 3.57 (m, 1H), 3.58 (dd, J=3.3, 3.3 Hz, 1H), 3.61 (dd, J=8.0,
3.3 Hz, 1H), 3.72 (dd, J=9.6, 6.0 Hz, 1H), 3.80 (dd, J=3.3, 3.3 Hz, 1H),
3.89 (sep, J=6.3 Hz, 1H), 4.00 (ddd, J=10.8, 9.9, 5.4 Hz, 1H), 4.11 (m,
1H), 4.12 (dd, J=4.2, 1.2 Hz, 1H), 4.23 (ddd, J=9.3, 5.1, 1.2 Hz, 1H),
4.37 (ddd, J=10.8, 9.9, 6.0 Hz, 1H), 4.97 (d, J=8.1 Hz, 1H), 5.04 ppm (d,
J=8.1 Hz, 1H); 13C NMR (125.7 MHz, C6D6): d=22.2 (CH3), 24.0 (CH3),
58.1 (CH3), 58.7 (CH3), 59.1 (CH3), 59.4 (CH3), 59.6 (CH3), 59.8 (CH3),
60.3 (CH2), 71.1 (CH), 71.7 (CH2), 72.6 (CH), 72.9 (CH), 75.2 (CH), 77.3
(CH), 77.8 (CH), 78.6 (CH), 78.9 (CH), 80.0 (CH), 99.6 (CH), 101.7 ppm
(CH); IR (film): n˜ =3505 (OH), 2928, 1371, 1097, 1052 cmꢀ1; MS (70 eV,
Reductive HAT of methyl 2,3,4-Tri-O-acetyl-a-l-rhamnopyranosyl-(1!
4)-2,3-di-O-methyl-6-phthalimido-a-d-glucopyranoside (18)
Method A (nBu3SnH): Following the general procedure and by using
nBu3SnH (2 mmol) and AIBN (0.2 mmol), the phthalimide 18 gave after
column chromatography (hexanes/EtOAc 60:40!50:50) methyl 4-O-
(2,3,4-tri-O-acetyl-5,6-dideoxy-l-lyxo-hexonoyl)-2,3-di-O-methyl-a-d-glu-
copyranoside (35) (48%), methyl 6-O-(2,3,4-tri-O-acetyl-5,6-dideoxy-l-
lyxo-hexonoyl)-2,3-di-O-methyl-a-d-glucopyranoside (36) (4%), methyl
2,3,4-tri-O-acetyl-6-deoxy-b-l-mannopyranosyl-(1!4)-2,3-di-O-methyl-a-
d-glucopyranoside (37) (9%) and the precursor alcohol 13 (8%), de-
scribed in the Supporting Information, all as colourless oils.
Compound 35: [a]D =+54.8 (c=0.155 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=0.91 (t, J=7.4 Hz, 3H), 1.61 (q, J=7.4 Hz, 2H), 2.06 (s, 3H),
2.11 (s, 3H), 2.13 (s, 3H), 3.32 (dd, J=9.6, 3.6 Hz, 1H), 3.43 (s, 3H), 3.49
(s, 3H), 3.51 (s, 3H), 3.59–3.70 (m, 3H), 3.63 (dd, J=9.6, 9.6 Hz, 1H),
4.87 (d, J=3.6 Hz, 1H), 4.91 (dd, J=9.6, 9.6 Hz, 1H), 5.15 (d, J=6.5 Hz,
1H), 5.20 (ddd, J=6.4, 6.4, 4.4 Hz, 1H), 5.42 ppm (dd, J=6.5, 4.2 Hz,
1H); 13C NMR (100.6 MHz, CDCl3): d=9.435 (CH3), 20.4 (CH3), 20.6
(CH3), 20.7 (CH3), 23.6 (CH2), 55.4 (CH3), 58.9 (CH3), 60.1 (CH3), 60.8
(CH2), 69.4 (CH), 70.3 (CH), 71.0 (CH), 71.3 (CH), 72.034 (CH), 79.6
(CH), 81.5 (CH), 97.4 (CH), 167.4 (C), 169.6 (C), 170.1 (C), 170.2 ppm
(C); IR (film): n˜ =3500, 2938, 1748, 1373, 1220, 1048 cmꢀ1; MS (70 eV,
EI): m/z (%): 463 (<1) [MꢀC2H7]+, 434 (1), 403 (1), 231 (23), 101 (11),
88 (100); HRMS (EI): m/z calcd for C19H27O13: 463.1452 [MꢀC2H7]+;
found: 463.1455; elemental analysis calcd (%) for C21H34O13 (494.49): C
51.01, H 6.93; found: C 51.12, H 6.96.
Compound 36: [a]D =+40.7 (c=0.290 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=0.91 (t, J=7.2 Hz, 3H), 1.58–1.64 (m, 2H), 2.08 (s, 3H),
2.11 s, (3H), 2.13 (s, 3H), 3.00 (brs, 1H), 3.21 (dd, J=9.2, 3.4 Hz, 1H),
3.43 (s, 3H), 3.44–3.47 (m, 2H), 3.51 (s, 3H), 3.64 (s, 3H), 3.75 (ddd, J=
7.6, 3.8, 1.9 Hz, 1H), 4.20 (dd, J=11.8, 1.9 Hz, 1H), 4.54 (dd, J=11.8,
4.2 Hz, 1H), 4.82 (d, J=3.4 Hz, 1H), 5.14 (d, J=6.9 Hz, 1H), 5.23 (ddd,
J=7.6, 6.1, 3.8 Hz, 1H), 5.40 ppm (dd, J=7.2, 3.8 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3): d=9.5 (CH3), 20.4 (CH3), 20.6 (CH3), 20.8 (CH3),
23.7 (CH2), 55.3 (CH3), 58.7 (CH3), 61.3 (CH3), 64.5 (CH2), 69.0 (CH),
69.7 (CH), 69.8 (CH), 71.1 (CH), 72.0 (CH), 81.7 (CH), 82.5 (CH), 97.6
(CH), 167.6 (C), 169.6 (C), 170.1 (C), 170.5 ppm (C); IR (film): n˜ =3488,
2938, 1748, 1373, 1220, 1063 cmꢀ1; MS (70 eV, EI): m/z (%): 463 (1)
[MꢀC2H7]+, 431 (2), 403 (1), 365 (16), 231 (34), 101 (22), 88 (100);
HRMS (EI): m/z: calcd for C19H27O13: 463.1452 [MꢀC2H7]+; found:
463.1444; elemental analysis calcd (%) for C21H34O13 (494.49): C 51.01, H
6.93; found: C 51.22, H 6.83.
EI): m/z (%): 408 (1) [Mꢀ
(CH3)2CHOH]+, 261 (32), 219 (44), 187 (72),
ACHTUNGTRENNUNG
88 (100); HRMS (EI): m/z: calcd for C18H32O10
:
408.1995 [Mꢀ
(CH3)2CHOH]+; found: 408.2005; elemental analysis calcd (%) for
C21H40O11 (468.54): C 53.83, H 8.61; found: C 54.08, H 8.38.
Method B (nBu3SnD): Following the general procedure and by using
nBu3SnD (1.5 mmol) and AIBN (0.2 mmol), the phthalimide 17 afforded
after column chromatography (hexanes/EtOAc 2:8) isopropyl 2,3,4,6-
tetra-O-methyl-b-l-(5’-2H)gulopyranosyl-(1!4)-2,3-di-O-methyl-b-l-gu-
lopyranoside (32) (83%) and isopropyl 2,3,4,6-tetra-O-methyl-a-d-
[5ꢅ-2H]mannopyranosyl-(1!4)-2,3-di-O-methyl-b-l-gulopyranoside (33)
1
(14%, H/2H ratio, 45:55), both as colourless oils.
Compound 32: 1H NMR (400 MHz, C6D6): d=1.09 (d, J=6.0 Hz, 3H),
1.18 (d, J=6.3 Hz, 3H), 3.00 (s, 3H), 3.01 (d, J=3.7 Hz, 1H), 3.10 (s,
3H), 3.20 (s, 3H), 3.278 (s, 3H), 3.281 (d, J=9.4 Hz, 1H), 3.30 (s, 3H),
3.45 (dd, J=8.3, 3.1 Hz, 1H), 3.51 (s, 3H), 3.57 (d, J=9.1 Hz, 1H), 3.58
(dd, J=3.4, 3.4 Hz, 1H), 3.61 (dd, J=8.0, 2.8 Hz, 1H), 3.74 (dd, J=9.4,
6.0 Hz, 1H), 3.80 (dd, J=3.4, 3.4 Hz, 1H), 3.89 (sep, J=6.1 Hz, 1H), 4.00
(ddd, J=10.8, 9.9, 5.4 Hz, 1H), 4.12 (dd, J=3.7, 1.4 Hz, 1H), 4.23 (dd,
J=9.7, 5.3, 1.4 Hz, 1H), 4.36 (ddd, J=10.6, 10.6, 5.7 Hz, 1H), 4.97 (d, J=
8.0 Hz, 1H), 5.04 ppm (d, J=8.0 Hz, 1H); 13C NMR (125.7 MHz, C6D6):
d=22.2 (CH3), 24.0 (CH3), 58.1 (CH3), 58.8 (CH3), 59.1 (CH3), 59.4
(CH3), 59.6 (CH3), 59.8 (CH3), 60.3 (CH2), 71.1 (CH), 71.606 (CH2), 72.9
(CH), 75.2 (CH), 77.3 (CH), 77.734 (CH), 78.6 (CH), 78.9 (CH), 80.0
(CH), 99.6 (CH), 101.7 ppm (CH); MS (70 eV, EI): m/z (%): 409 (4)
[Mꢀ
ACHTUNGTRENNUNG
(CH3)2CHOH]+, 306 (47), 261 (15), 188 (26), 88 (100); HRMS (EI):
m/z: calcd for C18H312HO10
:
409.2058 [Mꢀ
(CH3)2CHOH]+; found:
ACHTUNGTRENNUNG
409.2047.
Compound 33: 1H NMR (500 MHz, C6D6): d=1.07 (d, J=6.0 Hz, 3H),
1.16 (d, J=6.3 Hz, 3H), 3.06 (s, 3H), 3.17 (s, 3H), 3.23 (s, 3H), 3.26 (s,
3H), 3.29 (s, 3H), 3.37 (dd, J=7.2, 6.0 Hz, 1H), 3.40–3.44 (m, 4H), 3.50
(s, 3H), 3.50–3.54 (m, 3H), 3.56 (dd, J=7.8, 3.0 Hz, 1H), 3.60 (dd, J=
7.2, 2.9 Hz, 1H), 3.74 (dd, J=3.3, 3.3 Hz, 1H), 3.88 (sep, J=6.3 Hz, 1H),
3.97 (ddd, J=11.1, 5.7, 5.7 Hz, 1H), 4.04 (m, 1H), 4.13 (m, 1H), 4.24
(ddd, J=8.7, 5.6, 1.6 Hz, 1H), 4.26 (dd, J=3.6, 1.2 Hz, 1H), 5.03 (d, J=
7.8 Hz, 1H), 5.13 ppm (d, J=2.7 Hz, 1H); 13C NMR (125.7 MHz, C6D6):
d=22.1 (CH3), 24.0 (CH3), 57.7 (CH3), 58.8 (CH3), 59.1 (CH3), 59.3
(CH3), 59.4 (CH3), 59.5 (CH3), 60.4 (CH2), 71.2 (CH), 72.2 (CH), 72.956
(CH2), 73.017 (CH2), 73.27 (CH), 73.32 (CH), 77.7 (CH), 77.870 (CH),
77.931 (CH), 79.0 (CH), 79.7 (CH), 81.3 (CH), 97.9 (CH), 100.0 ppm
Compound 37 (contaminated with small amounts of alcohols 35 and 36):
1H NMR (500 MHz, CDCl3): d=1.28 (d, J=6.5 Hz, 3H), 1.99 (s, 3H),
2.05 (s, 3H), 2.15 (s, 3H), 3.19 (dd, J=9.5, 3.8 Hz, 1H), 3.39 (s, 3H), 3.50
(s, 3H), 3.51–3.58 (m, 2H), 3.59 (s, 3H), 3.64–3.72 (m, 3H), 3.81–3.89 (m,
1H), 4.80 (d, J=3.4 Hz, 1H), 4.98 (d, J=0.8 Hz, 1H), 5.01 (dd, J=10.3,
2.7 Hz, 1H), 5.03 (dd, J=10.3, 10.3 Hz, 1H), 5.46 ppm (dd, J=2.7,
(CH); MS (70 eV, EI): m/z (%): 409/408 (<1) [Mꢀ
(CH3)2CHOH]+, 339
ACHTUNGTRENNUNG
(8), 306 (3), 188 (28), 88 (100); HRMS (EI): m/z: calcd for C18H312HO10/
C18H32O10
408.1981.
:
409.2058/408.1995 [Mꢀ
(CH3)2CHOH]+; found: 409.2058/
ACHTUNGTRENNUNG
10378
www.chemeurj.org
ꢄ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10369 – 10381

1,8-Hydrogen-Atom Transfer Reactions in (1!4)-O-Disaccharide Systems
FULL PAPER
0.8 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=17.2 (CH3), 20.6 (CH3),
20.7 (CH3), 20.8 (CH3), 55.2 (CH3), 59.0 (CH3), 61.3 (CH3), 61.9 (CH2, C-
6), 69.0 (CH), 69.9 (CH), 70.4 (CH), 70.602 (CH), 70.9 (CH), 75.9 (CH),
82.3 (CH), 82.7 (CH), 97.6 (CH), 98.8 (CH), 169.8 (C), 170.0 (C),
170.1 ppm (C).
(15), 88 (100); HRMS (EI): m/z: calcd for C22H31O14: 519.1714
[MꢀCH3O]+; found: 519.1738; elemental analysis calcd (%) for
C23H34O15 (550.51): C 50.18, H 6.23; found: C 50.05, H 6.09.
Reductive HAT of methyl 2,3,4,6-tetra-O-acetyl-a-d-mannopyranosyl-
(1!4)-2,3-di-O-methyl-6-O-phthalimido-a-d-galactopyranoside (19)
Method B (nBu3SnD): Following the general procedure and by using
nBu3SnD (2 mmol) and AIBN (0.2 mmol), the phthalimide 18 afforded
after column chromatography (hexanes/EtOAc 60:40!50:50) methyl 4-
O-(2,3,4-tri-O-acetyl-5,6-dideoxy-l-(5-2H1)lyxo-hexonoyl)-2,3-di-O-
methyl-a-d-glucopyranoside (38) (28%), methyl 6-O-(2,3,4-tri-O-acetyl-
5,6-dideoxy-l-(5-2H1)lyxo-hexonoyl)-2,3-di-O-methyl-a-d-glucopyrano-
Method A (nBu3SnH): Following the general procedure and by using
nBu3SnH (2.4 mmol) and AIBN (0.4 mmol), the phthalimide 19 gave
after column chromatography (hexanes/EtOAc 30:70) methyl 4-O-
(2,3,4,6-tetra-O-acetyl-5-deoxy-d-lyxo-hexonoyl)-2,3-di-O-methyl-a-d-
galactopyranoside (42) (52%), and a mixture of two compounds that
under standard acetylation and further chromatotron chromatography
(hexanes/EtOAc 40:60) yielded methyl 2,3,4,6-tetra-O-acetyl-a-d-manno-
pyranosyl-(1!4)-6-O-acetyl-2,3-di-O-methyl-a-d-galactopyranoside (43)
(19%) and methyl 2,3,4,6-tetra-O-acetyl-b-d-mannopyranosyl-(1!4)-6-
O-acetyl-2,3-di-O-methyl-a-d-galactopyranoside (44) (6%), both as col-
ourless oils.
side
(39)
(36%),
methyl
2,3,4-tri-O-acetyl-6-deoxy-b-l-
(1-2H1)mannopyranosyl-(1!4)-2,3-di-O-methyl-a-d-glucopyranoside (40)
(7%), and the precursor alcohol 13 (7%), all as colourless oils.
Compound 38: 1H NMR (500 MHz, CDCl3): d=0.90 (d, J=7.6 Hz, 3H),
1.59 (m, 1H), 2.07 (s, 3H), 2.12 (s, 3H), 2.14 (s, 3H), 2.41 (brs, 1H), 3.32
(dd, J=9.5, 3.4 Hz, 1H), 3.44 (s, 3H), 3.50 (s, 3H), 3.51 (s, 3H), 3.59–3.69
(m, 3H), 3.64 (dd, J=9.5, 9.5 Hz, 1H), 4.88 (d, J=3.4 Hz, 1H), 4.91 (dd,
J=9.5, 9.5 Hz, 1H), 5.16 (d, J=6.5 Hz, 1H), 5.20 (dd, J=8.4, 4.2 Hz,
1H), 5.42 ppm (dd, J=6.5, 4.2 Hz, 1H); 13C NMR (100.6 MHz, CDCl3):
Compound 42: [a]D =+54.8 (c=0.023 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=1.85–1.96 (m, 2H), 2.04 (s, 3H), 2.08 (s, 3H), 2.14 (s, 6H),
2.42 (dd, J=6.5, 6.5 Hz, 1H), 3.36 (s, 3H), 3.43 (s, 3H), 3.48 (dd, J=10.0,
3.7 Hz, 1H), 3.51 (s, 3H), 3.64 (dd, J=10.0, 3.4 Hz, 1H), 3.63–3.70 (m,
2H), 3.95 (ddd, J=7.0, 7.0, 0 Hz, 1H), 4.07 (ddd, J=11.4, 6.0, 6.0 Hz,
1H), 4.10 (ddd, J=11.4, 7.4, 5.7 Hz, 1H), 4.90 (d, J=3.7 Hz, 1H), 5.15
(d, J=6.8 Hz, 1H), 5.46 (dd, J=6.8, 3.7 Hz, 1H), 5.49 (ddd, J=10.3, 4.0,
4.0 Hz, 1H), 5.53 ppm (dd, J=3.4, 0 Hz, 1H); 13C NMR (125.7 MHz,
CDCl3): d=20.4 (CH3), 20.70 (CH3), 20.75 (CH3), 20.8 (CH3), 30.0
(CH2), 55.5 (CH3), 57.6 (CH3), 59.1 (CH3), 60.190 (CH2), 60.4 (CH2), 68.1
(CH), 68.5 (CH), 69.218 (CH), 70.2 (CH), 71.3 (CH), 77.4 (2ꢆCH), 98.0
(CH), 167.8 (C), 169.7 (C), 170.0 (2 ꢆ C), 170.8 ppm (C); IR (film): n˜ =
3499, 2924, 1746, 1372, 1218 cmꢀ1; MS (70 eV, EI): m/z (%): 535 (34)
[MꢀOH]+, 521 (26), 331 (22), 289 (34), 88 (100); HRMS (EI): m/z: calcd
for C23H35O14: 535.2027 [MꢀOH]+; found: 535.2031; elemental analysis
calcd (%) for C23H36O15 (552.52): C 50.00, H 6.57; found: C 50.00, H 6.83.
Compound 43: [a]D =+81.6 (c=0.024 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=2.01 (s, 3H), 2.04 (s, 3H), 2.06 (s, 3H), 2.11 (s, 3H), 2.16 (s,
3H), 3.42 (s, 3H), 3.48 (s, 3H), 3.52 (s, 3H), 3.54 (dd, J=10.1, 2.8 Hz,
1H), 3.62 (dd, J=10.4, 3.5 Hz, 1H), 3.89 (ddd, J=6.9, 6.9, 0 Hz, 1H),
4.06 (dd, J=12.3, 2.2 Hz, 1H), 4.08 (dd, J=11.0, 7.6 Hz, 1H), 4.11 (dd,
J=2.8, 0 Hz, 1H), 4.33 (dd, J=11.3, 6.6 Hz, 1H), 4.36 (dd, J=12.6,
3.5 Hz, 1H), 4.51 (ddd, J=9.8, 3.1, 3.1 Hz, 1H), 4.917 (d, J=1.6 Hz, 1H),
4.919 (d, J=3.5 Hz, 1H), 5.18 (dd, J=3.1, 1.9 Hz, 1H), 5.34–5.40 ppm
(m, 2H); 13C NMR (125.7 MHz, CDCl3): d=20.72 (2ꢆCH3), 20.75 (CH3),
20.8 (CH3), 20.9 (CH3), 55.4 (CH3), 58.3 (CH3), 58.4 (CH3), 61.8 (CH2),
62.1 (CH2), 65.8 (CH), 67.4 (CH), 68.7 (CH), 68.8 (CH), 70.1 (CH), 74.9
(CH), 77.0 (CH), 78.5 (CH), 97.6 (CH), 98.8 (CH), 169.7 (C), 169.9 (C),
170.2 (C), 170.3 (C), 170.8 ppm (C); IR (film): n˜ =2930, 2845, 1748,
1229 cmꢀ1; MS (70 eV, EI): m/z (%): 594 (<1) [M]+, 503 (<1), 492 (<1),
d=9.360 (CH3), 20.4 (CH3), 20.6 (CH3), 20.8 (CH3), 23.4 (CH, t, JCD
=
19.0 Hz), 55.4 (CH3), 58.9 (CH3), 60.2 (CH3), 60.9 (CH2), 69.4 (CH), 70.3
(CH), 71.0 (CH), 71.4 (CH), 72.044 (CH), 79.7 (CH), 81.6 (CH), 97.5
(CH), 167.5 (C), 169.6 (C), 170.1 (C), 170.3 ppm (C); MS (70 eV, EI):
m/z (%): 464 (<1) [MꢀC2H5D]+, 435 (2), 404 (1), 232 (25), 101 (17), 88
(100); HRMS (EI): m/z: calcd for C19H28O13: 464.1530 [MꢀC2H5D]+;
found: 464.1544.
Compound 39: 1H NMR (500 MHz, CDCl3): d=0.89 (d, J=7.3 Hz, 3H),
1.59 (dddd, J=8.0, 8.0, 8.0, 8.0 Hz, 1H), 2.07 (s, 3H), 2.10 (s, 3H), 2.12
(s, 3H), 3.04 (br s, 1H), 3.20 (dd, J=9.5, 3.4 Hz, 1H), 3.42 (s, 3H), 3.43–
3.46 (m, 2H), 3.50 (s, 3H), 3.63 (s, 3H), 3.74 (ddd, J=7.5, 3.9, 2.0 Hz,
1H), 4.19 (dd, J=12.0, 2.0 Hz, 1H), 4.53 (dd, J=12.0, 4.2 Hz, 1H), 4.81
(d, J=3.5 Hz, 1H), 5.13 (d, J=7.1 Hz, 1H), 5.21 (dd, J=8.2, 3.7 Hz, 1H),
5.39 ppm (dd, J=7.2, 3.7 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=9.3
(CH3), 20.4 (CH3), 20.6 (CH3), 20.8 (CH3), 23.3 (CH, t, JCD =20.0 Hz),
55.3 (CH3), 58.6 (CH3), 61.3 (CH3), 64.5 (CH2), 69.0 (CH), 69.7 (CH),
69.8 (CH), 71.1 (CH), 71.9 (CH), 81.7 (CH), 82.5 (CH), 97.6 (CH), 167.6
(C), 169.6 (C), 170.1 (C), 170.5 ppm (C); MS (70 eV, EI): m/z (%): 464
(<1) [MꢀC2H5D]+, 432 (1), 403 (1), 366 (10), 232 (17), 101 (35), 88
(100); HRMS (EI): m/z: calcd for C19H28O13: 464.1530 [MꢀC2H5D]+;
found: 464.1510.
Compound 40 (contaminated with small amounts of alcohols 38 and 39):
1H NMR (500 MHz, CDCl3): d=1.28 (d, J=6.1 Hz, 3H), 1.99 (s, 3H),
2.05 (s, 3H), 2.16 (s, 3H), 3.19 (dd, J=9.5, 3.4 Hz, 1H), 3.40 (s, 3H), 3.50
(s, 3H), 3.51–3.58 (m, 2H), 3.59 (s, 3H), 3.64–3.72 (m, 3H), 3.80–3.89 (m,
1H), 4.80 (d, J=3.4 Hz, 1H), 5.01 (dd, J=10.3, 3.0 Hz, 1H), 5.03 (dd, J=
10.3, 10.3 Hz, 1H), 5.46 ppm (dd, J=2.7 Hz, 1H); 13C NMR (100.6 MHz,
CDCl3): d=17.2 (CH3), 20.6 (CH3), 20.7 (CH3), 20.8 (CH3), 55.2 (CH3),
58.9 (CH3), 61.3 (CH3), 62.0 (CH2), 68.9 (CH), 69.9 (CH), 70.4 (CH),
70.570 (CH), 70.9 (CH), 75.9 (CH), 82.3 (CH), 82.7 (CH), 97.7 (CH),
169.8 (C), 170.0 (C), 170.1 ppm (C).
331 (46), 169 (36), 88 (100); HRMS (EI): m/z: calcd for C25H38O16
:
594.2160 [M]+; found: 594.2156; elemental analysis calcd (%) for
C25H38O16 (594.56): C 50.50, H 6.44; found: C 50.49, H 6.41.
Compound 44: [a]D =+0.071 (c=0.206 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=2.00 (s, 3H), 2.04 (s, 3H), 2.06 (s, 3H), 2.09 (s, 3H), 2.18 (s,
3H), 3.38 (s, 3H), 3.50 (s, 3H), 3.51 (s, 3H), 3.54–3.58 (m, 2H), 3.61
(ddd, J=10.1, 5.4, 2.8 Hz, 1H), 3.89 (ddd, J=7.8, 3.8, 0.9 Hz, 1H), 4.14
(dd, J=12.0, 7.9 Hz, 1H), 4.18 (dd, J=12.0, 5.4 Hz, 1H), 4.20 (m, 1H),
4.23 (dd, J=11.7, 4.1 Hz, 1H), 4.24 (dd, J=12.0, 3.5 Hz, 1H), 4.83 (d, J=
2.8 Hz, 1H), 4.99 (d, J=0.9 Hz, 1H), 5.06 (dd, J=10.1, 3.5 Hz, 1H), 5.22
(dd, J=10.1, 10.1 Hz, 1H), 5.53 ppm (dd, J=3.5, 0.9 Hz, 1H); 13C NMR
(125.7 MHz, CDCl3): d=20.6 (CH3), 20.7 (2ꢆCH3), 20.77 (CH3), 20.80
(CH3), 55.2 (CH3), 58.9 (CH3), 59.1 (CH3), 62.6 (CH2), 64.2 (CH2), 66.5
(CH), 68.0 (CH), 68.742 (CH), 71.0 (CH), 72.0 (CH), 72.3 (CH), 77.8
(CH), 79.9 (CH), 97.7 (CH), 97.9 (CH), 169.6 (C), 170.0 (C), 170.4 (C),
170.6 (C), 170.7 ppm (C); IR (film): n˜ =2928, 2842, 1746, 1370,
1227 cmꢀ1; MS (70 eV, EI): m/z (%): 594 (<1) [M]+, 563 (<1), 531 (<1),
492 (2), 417 (2), 328 (88), 88 (100); HRMS (EI): m/z: calcd for
C25H38O16: 594.2160 [M]+; found: 594.2176; elemental analysis calcd (%)
for C25H38O16 (594.56): C 50.50, H 6.44; found: C 50.46, H 6.31.
Methyl (1S)-4,6-O-(2,3,4,6-tetra-O-acetyl-d-mannopyranosylidene)-2,3-
di-O-methyl-a-d-galactopyranoside (41): Following the general procedure
for the oxidative HAT, the alcohol 14 gave after chromatotron chroma-
tography (hexanes/EtOAc 45:55) the title compound 41 (95%) as a crys-
talline solid. M.p. 183–1848C (n-hexane/EtOAc); [a]D =+81.1 (c=0.460
in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.95 (s, 3H), 2.04 (s, 3H),
2.07 (s, 3H), 2.15 (s, 3H), 3.40 (s, 3H), 3.48 (s, 3H), 3.54 (s, 3H), 3.59
(dd, J=10.0, 3.4 Hz, 1H), 3.61 (m, 1H), 3.68 (dd, J=10.1, 3.4 Hz, 1H),
3.82 (ddd, J=10.1, 5.6, 2.6 Hz, 1H), 3.86 (dd, J=12.2, 1.6 Hz, 1H), 4.15
(dd, J=12.2, 2.6 Hz, 1H), 4.26–4.30 (m, 3H), 4.90 (d, J=3.4 Hz, 1H),
5.27 (dd, J=10.0, 10.0 Hz, 1H), 5.39 (dd, J=10.1, 3.4 Hz, 1H), 5.46 ppm
(d, J=3.4 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=20.6 (CH3), 20.7
(2 ꢆ CH3), 20.8 (CH3), 55.5 (CH3), 58.1 (CH3), 59.2 (CH3), 61.6 (CH),
62.6 (CH2), 63.2 (CH2), 65.7 (CH), 66.0 (CH), 69.5 (CH), 70.0 (CH), 70.3
(CH), 76.7 (CH), 76.9 (CH), 98.4 (CH), 108.3 (C), 169.7 (C), 169.7 (2ꢆ
C), 170.5 ppm (C); IR (film): n˜ =2935, 2834, 1747, 1372, 1223, 1046 cmꢀ1
;
Method B (nBu3SnD): Following the general procedure and by using
nBu3SnD (2.4 mmol) and AIBN (0.4 mmol), the phthalimide 19 gave
MS (70 eV, EI): m/z (%): 519 (2) [MꢀCH3O]+, 477 (11), 389 (13), 304
Chem. Eur. J. 2008, 14, 10369 – 10381
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10379

A. Martꢁn, E. Suꢃrez et. al.
after chromatotron chromatography (hexanes/EtOAc 30:70) methyl 4-O-
(2,3,4,6-tetra-O-acetyl-5-deoxy-d-(5-2H)lyxo-hexonoyl)-2,3-di-O-methyl-
a-d-galactopyranoside (45) (57%) and a mixture of two compounds that
under standard acetylation and further chromatotron chromatography
(hexanes/EtOAc 30:70) yielded methyl 2,3,4,6-tetra-O-acetyl-a-d-manno-
pyranosyl-(1!4)-6-O-acetyl-2,3-di-O-methyl-a-d-galactopyranoside (43)
(12%) and methyl 2,3,4,6-tetra-O-acetyl-b-d-(1-2H)mannopyranosyl-(1!
4)-6-O-acetyl-2,3-di-O-methyl-a-d-galactopyranoside (46) (2%), both as
colourless oils.
Compound 45: 1H NMR (500 MHz, CDCl3): d=1.85–1.95 (m, 1H), 2.04
(s, 3H), 2.08 (s, 3H), 2.14 (s, 6H), 2.45 (dd, J=6.6, 6.6 Hz, 1H), 3.36 (s,
3H), 3.43 (s, 3H), 3.48 (dd, J=10.0, 3.7 Hz, 1H), 3.50 (s, 3H), 3.63 (dd,
J=10.0, 3.4 Hz, 1H), 3.64–3.70 (m, 2H), 3.95 (ddd, J=6.9, 6.9 Hz, 1H),
4.07 (dd, J=11.4, 6.0 Hz, 1H), 4.10 (dd, J=11.1, 6.0 Hz, 1H), 4.90 (d, J=
3.7 Hz, 1H), 5.15 (d, J=6.8 Hz, 1H), 5.46 (dd, J=6.6, 3.7 Hz, 1H), 5.48
(dd, J=6.0, 4.0 Hz, 1H), 5.53 ppm (dd, J=2.8, 0 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3): d=20.4 (CH3), 20.67 (CH3), 20.72 (CH3), 20.8
(CH3), 29.6 (CHD, t, JCD =21.2 Hz), 55.4 (CH3), 57.6 (CH3), 59.1 (CH3),
60.092 (CH2), 60.3 (CH2), 68.0 (CH), 68.4 (CH), 69.143 (CH), 70.1 (CH),
71.3 (CH), 77.32 (CH), 77.36 (CH), 97.9 (CH), 167.7 (C), 169.7 (C),
169.97 (C), 170.00 (C), 170.8 ppm (C); MS (70 eV, EI): m/z (%): 536 (10)
[MꢀOH]+, 522 (11), 322 (19), 290 (41), 88 (100); HRMS (EI): m/z: calcd
for C23H342HO14: 536.2090 [MꢀOH]+; found: 536.2109.
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ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Compound 46 (contaminated with small amounts of 43): 1H NMR
(400 MHz, CDCl3): d=2.00 (s, 3H), 2.04 (s, 3H), 2.06 (s, 3H), 2.09 (s,
3H), 2.18 (s, 3H), 3.38 (s, 3H), 3.50 (s, 3H), 3.51 (s, 3H), 3.54–3.58 (m,
2H), 3.61 (m, 1H), 3.90 (m, 1H), 4.12–4.25 (m, 5H), 4.83 (d, J=2.6 Hz,
1H), 5.05 (dd, J=10.0, 3.4 Hz, 1H), 5.21 (dd, J=10.1, 10.1 Hz, 1H),
5.53 ppm (d, J=3.4 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=20.6
(CH3), 20.7 (2ꢆCH3), 20.76 (CH3), 20.79 (CH3), 55.2 (CH3), 58.9 (CH3),
59.1 (CH3), 62.6 (CH2), 64.2 (CH2), 66.5 (CH), 68.0 (CH), 68.666 (CH),
71.0 (CH), 71.9 (CH), 72.2 (CH), 77.8 (CH), 79.8 (CH), 97.8 (CH), 169.7
(C), 170.1 (C), 170.4 (C), 170.68 (C), 170.71 ppm (C).
1’ O C-4; YH =C-1’ O C-4 H-4), see: J. Jimꢂnez-Barbero, J. F.
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Acknowledgements
This work was supported by Research programs CTQ2004-06381/BQU,
CTQ2004-02367/BQU and CTQ2007-67492/BQU of the Ministerio de
Educaciꢇn y Ciencia (Spain), and cofinanced by the Fondo Europeo de
Desarrollo Regional (FEDER). A.J.H., I.P.-M. and L.M.Q. thank the
Program I3P-CSIC for fellowships.
[17] CCDC-174444 (4) contains the supplementary crystallographic data
(excluding structure factors) for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. Crystal data and
structural refinements (compound 4): C25H34O17; Mt =606.52; mono-
clinic; space group P21; a=6.5670 (2), b=14.4480 (6), c=15.6960
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(6) ꢀ; b=101.754 (3)8; V=1458.01 (9) ꢀ3; Z=2; 1calcd
1.382 mgcmꢀ3
(MoKa)=0.71073 ꢀ; (000)=640; T=150 (2) K;
=
;
m
N
FACHTUNGTRENNUNG
colourless crystal; 0.80ꢆ0.20ꢆ0.15 mm; collected reflections 5103;
the structure was solved by the direct method, all hydrogen atoms
were refined anisotropically by using full-matrix least-squares based
F2 to give R1 =0.0618, wR2 =0.1023 for 5103 independently ob-
served reflections (jFo j>2s(jFoj)) and 385 parameters.
N
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10380
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Chem. Eur. J. 2008, 14, 10369 – 10381

1,8-Hydrogen-Atom Transfer Reactions in (1!4)-O-Disaccharide Systems
FULL PAPER
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Received: July 11, 2008
Published online: October 1, 2008
Chem. Eur. J. 2008, 14, 10369 – 10381
ꢄ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10381