Synthesis and reactions of 1,4-anhydrogalactopyranose and 1,4-anhydroarabinose - Steric and electronic limitations

Article abstract of DOI:10.1002/hlca.200590224

Scope and limitations of 1,4-anhydro sugars as precursors of glycofuranosyl building blocks are described. The experiments revealed that the choice of the substituents is very important for an efficient preparation as well as a successful ring-opening rea

Full text of DOI:10.1002/hlca.200590224

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Synthesis and Reactions of 1,4-Anhydrogalactopyranose and
1
,4-Anhydroarabinose – Steric and Electronic Limitations
by Toshiki Nokami, Daniel B. Werz, and Peter H. Seeberger*
Laboratory for Organic Chemistry, Swiss Federal Institute of Technology (ETH) Zürich, HCI F315,
CH-8093 Zürich
(
fax: (+41)16331235; e-mail: seeberger@org.chem.ethz.ch)
Scope and limitations of 1,4-anhydro sugars as precursors of glycofuranosyl building blocks are described.
The experiments revealed that the choice of the substituents is very important for an efficient preparation as
well as a successful ring-opening reaction of 1,4-anhydro sugars. DFT Calculations suggest that selective proto-
nation of 1,4-anhydro sugars is the key to the selective ring opening in order to afford only furanosides.
Introduction. – Various types of anhydro sugars have been investigated as monomer
units to create synthetic polysaccharides, as building blocks for oligosaccharide synthe-
sis, and as precursors en route to building blocks [1]. 1,2-Anhydro sugars are the basis of
oligosaccharide synthesis by the glycal assembly approach [2]. Moreover, 1,2-anhydro
sugars are useful not only as building blocks for oligosaccharide synthesis, but also as
precursors of common oligosaccharide building blocks including thioglycosides, pent-
4-enyl glycosides, and glycosyl phosphates [3].
Due to their high reactivity 1,2-anhydro sugars are usually generated in situ and
used without isolation (Fig. 1). By contrast, 1,4-anhydro sugars and 1,6-anhydro sugars
are stable enough to be isolated. Thus, the ring-opening reactions of these anhydro sug-
ars have been extensively investigated. In the case of 1,6-anhydro sugars, the 1,6-ether
bond is cleaved selectively, and pyranosides are obtained by hydrolysis, acetolysis, and
alcoholysis. 1,4-Anhydro sugars, on the other hand, are known to give furanosides by
acid-mediated reaction with nucleophiles and under ring-opening conditions polymer-
ization [4].
Fig. 1. Representative structures of anhydro sugars
We set out to explore whether 1,4-anhydro sugars are useful precursors of glycofur-
anoside building blocks for oligofuranoside synthesis. Oligofuranosides are of particu-
lar interest as they constitute a major part of mycolyl-arabinogalactan (AG), a compo-
©
2005 Verlag Helvetica Chimica Acta AG, Zürich

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HELVETICA CHIMICA ACTA – Vol. 88 (2005)
nent of the mycobacterial cell wall [5]. Here, we discuss substituent effects on the for-
mation and ring opening of 1,4-anhydro galactoses and 1,4-anhydro arabinoses.
Results and Discussion. – To investigate the suitability of 1,4-anhydro sugars as
building blocks for oligosaccharide synthesis, we prepared 1,4-anhydrogalactopyrano-
ses 2a–2c from galactopyranosides 1a–1c (Scheme 1) [6]. The FeCl -catalyzed reaction
3
to form 1,4-anhydrogalactose was accelerated significantly by microwave irradiation,
although the yields did not improve over conventional heating. The starting galactopy-
ranoside was consumed within 30 min by microwave irradiation, while the same reac-
tion takes several days with conventional heating. Anhydro sugars bearing a benzoyl
(
Bz) group instead of a benzyl (Bn) group were synthesized to test whether neighboring
group participation of the 2-O-Bz group allows for control of the configuration at the
anomeric position. Unfortunately, the electron-withdrawing nature of the Bz group
suppressed the formation of 1,4-anhydro sugars 2b dramatically. The nucleophilicity
of the OH group at C(4) is decreased as well as the capability of MeO to act as a leaving
group. Bulky protecting groups such as the (t-Bu)Me Si (TBS) group also resulted in a
2
significant reduction of the yield as observed for anhydro sugar 2c.
Scheme 1. Synthesis of 1,4-Anhydrogalactoses 2a–2c
1
,4-Anhydro-D-arabinopyranose 4 was prepared according to the method devel-
oped for 1,4-anhydro-
D
-galactopyranose 2, starting from arabinofuranoside 3a and ara-
binopyranoside 3b (Scheme 2). In both cases, the monomers were obtained in poor
yield (16 and 10%, resp.), while a series of oligoarabinosides was obtained as major
products. The oligoarabinosides were less than five-units-long as determined by
mass-spectrometric analysis. All attempts to identify conditions that would suppress
the undesired formation of oligoarabinosides failed. The Lewis acid FeCl favors not
3
only the formation of anhydro sugars, but also initiates the ring opening of the bicyclic
system to create oligomeric structures.
Reaction of 1,4-anhydrogalactopyranose 2a with alcohols in the presence of tri-
fluoromethanesulfonic acid (TfOH) or camphorsulfonic acid (CSA) was examined
(Table). Various alcohols afforded the corresponding galactofuranose products that
are useful as building blocks for oligosaccharide synthesis. When the reaction was per-
formed in the presence of MeOH, methyl galactofuranoside 5a was obtained as a 1:2
mixture of a- and b-isomers (Entry 1). Reaction with allylic alcohol and subsequent
allylation gave allyl galactofuranoside 5b with better stereoselectivity (Entry 2). Galac-
tofuranoside 5b is useful for the synthesis of galactofuranosyl galactofuranose units as

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Scheme 2. Synthesis of 1,4-Anhydroarabinose
reported by Ogawa and co-workers [7]. Pentenyl galactofuranoside 5c was prepared,
when pent-4-en-1-ol was employed (Entry 3). Octan-1-ol gave octyl galactofuranoside
5
d in the presence of CSA (Entry 4). CSA proved to be superior in this reaction to
TfOH that afforded a highly complex mixture. When octyl 2,3,5-tri-O-benzyl-b- -gal-
actofuranoside was used as an acceptor, (1 ! 6)-linked galactofuranosyl disaccharide
e was obtained as a difficult-to-separate mixture of a- and b-isomers in the presence
D
5
of CSA instead of TfOH (Entry 5). Disaccharide 5e is one of the repeating units in the
Mycobacterium tuberculosis galactan [8]. These results suggest that TfOH is a strong-
enough acid to degrade the octyl galactofuranoside.
Next, we introduced a benzoate group at the 2-O position in order to control the
configuration at the anomeric position. Unfortunately, the reaction of 1,4-anhydro-
2,3-di-O-benzoylgalactofuranose 2b did not afford any furanoside, and starting mate-
rial was recovered without degradation (Scheme 3). This result indicates that the elec-
tron-withdrawing nature of benzoate protecting groups decreases the electron density
of the 4-O-atom significantly. Thus, selective protonation of the 4-O atom did not occur.
Scheme 3. The Ring Opening of 1,4-Anhydrogalactose Bearing Benzoyl Groups
1
,4-Anhydroarabinose 4 gave only arabinofuranoside in good yield when MeOH
was used as a nucleophile in the presence of TfOH (Scheme 4) [9]. Although the
high reactivity of 1,4-anhydroarabinose 4 makes its preparation very difficult as men-
tioned before, 1,4-anhydroarabinose is a potentially promising precursor for arabino-
furanoside building blocks.
Our experiments revealed only furanose products in the acid-initiated ring-opening
reactions of our 1,4-anhydro sugars. In principal, two different reaction pathways can
be envisioned (Fig. 2,A and B). To achieve a better understanding of this system,

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Table. The Ring Opening of 1,4-Anhydrogalactose with Alcoholic Nucleophiles
Entry
Nucleophile
MeOH
Product
Yield
%]
Selectivity
a/b
[
1
5a
5b
74
32 :68
2
3
78
20 :80
5c
5d
5e
81
44
59
45 :55
47:53
26 :74
4a
)
)
8
C H17OH
5a
a) CSA (3 equiv.)
model calculations on a simple unsubstituted bicyclic compound were performed. For
this purpose, we selected 2,7-dioxabicyclo[2.2.1]heptane as the core structure of 1,4-
anhydro sugars [10]. Geometry optimization was carried out using density functional
theory (DFT; B3LYP/6-311G(d)) [11][12] and the Gaussian03 program package [13].
Frequency calculations ensured the stationarity of the optimized structures
(
NImag=0). A natural bond orbital (NBO) analysis elucidated the relative contribu-
tions of s and p orbitals of the different lone pairs. No significant differences in s and
p character were encountered. However, the NBO analysis revealed a significant over-
lap of one O-atom lone pair (n ) with a low-lying s*(CÀO) orbital that are collinear
O
with each other (see Fig. 2, bottom). As a result, the energy of this lone pair as well
as its basicity decreases. By the same token, the bond length a increases. For the lone
pairs of the other O-atom, no such favorable arrangement of n and s*(CÀO) exists.
O

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Scheme 4. The Ring Opening of 1,4-Anhydroarabinose
Fig. 2. Two possibilities, A and B,for the ring opening of
,4-Anhydro sugars
1
Therefore, the pathway B, the protonation of the lower O-atom (5-O) and the ring
opening to afford the five-membered ring is favored.
Other studies involving model compounds with OR substituents were also in line
with this view. To corroborate the results of the NBO considerations, four different pro-
tonated isomers of the parent compound were elucidated. An immediate ring opening
subsequent to the attack of the proton was set to be forbidden. Fig. 3 shows the differ-
ent protonated isomers and their Hartree-Fock (HF) energies, as well as their relative
energies that are easily understood by the different basicity as discussed before. The
protonation of 5-O-atom is the most favorable to afford the furanose as ring-opened
product. Taking these significant energetic differences into a Boltzmann distribution
at 300 K and assuming similar reactivity (similar activation barriers), only ca. 10% of
the starting material should be converted to the pyranose. The substitution pattern
does not influence this result significantly as selected model studies have shown. This
simple theoretical view may explain why only furanoses were encountered as ring-
opened products of 1,4-anhydro sugars.
Conclusions. – Here, we have shown the scope and limitations of 1,4-anhydro sugars
as glycofuranosyl building blocks. Our experiments revealed that the choice of the sub-
stituents is very important for efficient synthesis as well as a successful ring opening of

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HELVETICA CHIMICA ACTA – Vol. 88 (2005)
Fig. 3. Different possibilities for the protonation of 1,4-anhydro sugars and their HF energies [hartree] and
relative energies [kcal/mol]
1,4-anhydro sugars. The use of microwaves as an alternative energy source decreased
the reaction times for the FeCl -catalyzed formation of the 1,4-anhydrogalactose sugars
3
significantly. In general, the use of electron-withdrawing and sterically demanding pro-
tecting groups such as (t-Bu)Me Si resulted in a significant decrease in yield. In con-
2
trast, Bn-substituted 1,4-anhydroarabinose proved to be extremely reactive in the
ring-opening reaction. Little stereoselectivity was obtained in all cases. DFT Calcula-
tions suggest that different basicities of the corresponding O-atom lone pairs play a
major role in selective protonation of 1,4-anhydro sugars. This behavior was assumed
to be the key to the selective ring opening affording only furanoside structures.
We are grateful to ETH-Zürich, the Alexander von Humboldt Foundation (Feodor Lynen Research Fellow-
ship to D. B. W.), and to the Deutsche Forschungsgemeinschaft (Emmy Noether Fellowship to D. B. W.) for gen-
erous support of this research. We would like to thank CEM Corporation for support of our microwave chemis-
try program.
Experimental Part
General. All chemicals used were reagent-grade and used as supplied except where noted. CH
chased from JT Baker and purified by a Cycle-Tainer Solvent Delivery System. Pyridine and MeCN were
refluxed over CaH and distilled prior to use. Anal. TLC was performed on E. Merck silica-gel 60 F254 plates
0.25 mm). Compounds were visualized by dipping the plates in a cerium sulfate ammonium molybdate soln.,
2 2
Cl was pur-
2
(
followed by heating. Liquid chromatography (LC) was performed using forced flow of the indicated solvent
1
on Sigma H-type silica (10–40 mm). H-NMR Spectra were obtained on Varian VXR-300 (300 MHz) and Varian
Mercuryplus-400 (400 MHz) spectrometers, and are reported in ppm (d) relative to CHCl
3
(7.26 ppm). Coupling
constants (J) are reported in Hertz. C-NMR Spectra were obtained on Varian VXR-300 (75 MHz) and Varian
Mercuryplus-400 (100 MHz) spectrometers, and are reported in d relative to CDCl (77.0 ppm) as an internal
1
3
3
reference. Microwave irradiations were performed by means of a monopod reactor (Discover from CEM Cor-
poration) with focused microwaves.

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General Procedure for the Preparation of 1,4-Anhydro Sugars by Microwave Chemistry. Galactopyranoside
i.e., (1a–1c) (0.1–0.4 mmol) and FeCl (10–30%) were dissolved in MeCN (5 ml). Microwave heating was per-
3
formed in a sealed tube for 30 min at 908. The maximum power of microwave was set to 150 W, and the power
was controlled during the heating to keep 908. After microwave irradiation and cooling, the mixture was filtered
over a short silica gel pad and concentrated. The crude product was purified by flash silica-gel column chroma-
tography (FC) with mixtures of AcOEt and hexane as eluent.
General Procedure for Ring Opening of 1,4-Anhydro Sugars: Pentenyl 2,3,6-Tri-O-benzyl-
side (5c). 1,4-Anhydrogalactose 2a (135 mg, 0.31 mmol) and pent-4-en-1-ol (134 mg, 1.6 mmol) were dissolved
in CH Cl (3 ml) and cooled to 08. After 10 min, TfOH (30 ml, 51 mg, 0.34 mmol) was added, then the soln. was
allowed to warm slowly to r.t. The completion of the reaction was checked by TLC, then the mixture was neu-
tralized with Et N and concentrated in vacuo. The residue was purified by FC (silica gel; AcOEt/hexane 2 :5) to
D-galactofurano-
2
2
3
yield 5c (130 mg, 81%) as a colorless syrup.
Methyl 2,3-Di-O-benzoyl-6-O-benzyl-a-
D-galactopyranoside (1b). The selective ring-opening reaction of
4
2
,6-O-benzylidene acetal was performed according to the method mentioned above. The ring opening of methyl
,3-di-O-benzoyl-4,6-O-benzylidene-a- -galactopyranose (1.0 g, 2.0 mmol) afforded 0.73 g (72%) of 1b. TLC
0.35. [a] =+109.0 (c=2.4, CHCl
): 8.01–7.97 (m, 4 H); 7.52–7.47 (m, 2 H); 7.38–7.32 (m, 9 H); 5.74–5.66 (m, 2 H);
D
1
(
AcOEt/hexane 2 :5): R
f
D
3 3
). IR (CHCl ) 3008, 1721, 1452, 1281, 1107. H-
NMR (300 MHz, CDCl
3
5
3
1
.22 (d, J=2.7, 1 H); 4.64 (d, J=12.0, 1 H); 4.59 (d, J=11.7, 1 H); 4.45 (s, 1 H); 4.15 (t, J=4.5, 1 H); 3.88–
.79 (m, 2 H); 3.43 (s, 3 H); 3.17–3.13 (s, 1 H). C-NMR (75 MHz, CDCl ): 166.3; 166.1; 137.7; 133.5; 133.4;
3
1
3
30.1; 129.7; 129.7; 128.8; 128.6; 128.6; 128.1; 128.0; 97.9; 74.1; 71.3; 70.3; 69.5; 69.3; 68.5, 55.8. HR-MALDI-
+
þ
MS: 515.1684 ([M+Na] , C28
H
28NaO , calc. 515.1682).
8
1
,4-Anhydro-2,3-di-O-benzoyl-6-O-benzyl-b-
D
-galactopyranose (2b). Compound 1b (200 mg, 0.40 mmol)
0.65. [a] =+159.0 (c=1.8, CHCl ). IR (CHCl
): 8.10–8.05 (m, 4 H); 7.64–7.56 (m, 2 H); 7.49–7.43 (m, 4
H); 7.36–7.28 (m, 5 H); 5.95 (d, J=2.4, 1 H); 5.17 (d, J=1.5, 1 H); 5.12 (m, 1 H); 4.82 (d, J=1.5, 1 H); 4.58
d, J=12.0, 1 H); 4.54 (d, J=12.0, 1 H); 4.09 (dd, J=7.2, 6.0, 1 H); 3.48 (dd, J=9.6, 5.7, 1 H); 3.42 (dd,
afforded 23 mg (12%) of 2b. TLC (AcOEt/hexane 2 :5): R
032, 1722, 1271, 1113. H-NMR (300 MHz, CDCl
3
f
D
3
3
)
1
3
(
1
3
J=9.6, 7.2, 1 H). C-NMR (75 MHz, CDCl
28.3; 127.7; 127.7; 98.4; 81.6; 81.3; 77.2; 74.4; 73.6; 69.6. HR-MALDI-MS: 483.1420 ([M+Na] , C27
calc. 483.1420).
,4-Anhydro-2,3-di-O-benzyl-6-O-[(tert-butyl)dimethylsilyl]-b-
benzyl-6-O-[(tert-butyl)dimethylsilyl]-a- -galactopyranoside (1c) (170 mg, 0.35 mmol) afforded 40 mg (25%)
of 2c. TLC (AcOEt/hexane 2 :5): R 0.80. [a] =+42.8 (c=1.2, CHCl ). IR (CHCl ) 2930, 1454, 1256, 1109,
): 7.40–7.31 (m, 10 H); 5.36 (d, J=4.2, 1 H); 4.69 (d, J=11.4, 1 H); 4.56 (d,
J=11.7, 1 H); 4.54 (d, J=11.7, 1 H); 4.49 (d, J=12.0, 1 H); 4.16–4.14 (m, 1 H); 4.09–4.02 (m, 1 H); 3.92
3
): 165.8; 165.7; 137.5; 133.4; 133.4; 129.8; 129.7; 129.0; 128.4;
+
þ
1
H
24NaO ;
7
1
D-galactopyranose (2c). Methyl 2,3-di-O-
D
f
D
3
3
1
1
007. H-NMR (300 MHz, CDCl
3
1
3
(
ddd, J=10.8, 6.0, 1.5, 1 H); 3.72 (t, J=10.8, 1 H); 0.90 (s, 9 H); 0.12 (s, 3 H); 0.09 (s, 3 H). C-NMR (75
MHz, CDCl ): 137.7; 137.5; 128.4; 128.4; 128.1; 128.0; 127.8; 127.7; 97.0; 85.5; 82.0; 81.0; 72.5; 71.3; 66.2;
3
+
+
6
3.4; 25.7; 17.9; À4.6; À4.6. HR-MALDI-MS: 479.2232 ([M+Na] , C26
,4-Anhydro-2,3-di-O-benzyl-a- -arabinopyranose (4). Methyl 2,3-di-O-benzyl-a-
12 mg, 0.32 mmol) afforded 16 mg (16%) of 4. TLC (AcOEt/hexane 2 :5): R 0.30. [a]
): 7.38–7.31 (m, 10 H); 5.53 (d,
J=2.4, 1 H); 4.71 (dd, J=4.5, 1.5, 1 H); 4.61 (d, J=11.7, 1 H); 4.53 (d, J=11.7, 1 H); 4.52 (s, 2 H); 3.86–3.84
H
36NaO
5
Si ; calc. 479.2230).
-arabinopyranose (3a;
=À65.1 (c=1.6,
1
D
D
1
f
D
1
3 3 3
CHCl ). IR (CHCl ) 2900, 1725, 1454, 1115. H-NMR (300 MHz, CDCl
1
3
(
3
m, 1 H); 3.63 (dd, J=7.2, 3.9, 1 H); 3.58 (d, J=7.2, 1 H); 3.55 (d, J=1.5, 1 H). C-NMR (75 MHz, CHCl ):
1
37.3; 128.4; 128.0; 127.9; 127.8; 127.8; 98.5; 87.4; 82.9; 80.0; 72.4; 71.0; 65.5. HR-MALDI-MS: 335.1261
+
þ
([M+Na] , C19
H
20NaO ; calc. 335.1259).
4
Methyl 2,3,6-Tri-O-benzyl-a-
afforded 15 mg (24%) of 5aa and 33 mg (50%) of 5ab (a/b 32 :68). TLC (AcOEt/hexane 2 :5): R
D
-galactofuranoside (5aa). The ring opening with MeOH (45 mg, 1.4 mmol)
0.30 (5aa),
) 2928, 1453, 1364, 1108. H-NMR (300 MHz, CHCl ):
.37–7.26 (m, 15 H); 4.72 (d, J=11.4, 1 H); 4.70 (d, J=4.2, 1 H); 4.62 (s, 2 H); 4.57 (d, J=11.4, 1 H); 4.55 (d,
f
1
0
7
.20 (5ab). [a]
D
=+22.4 (c=2.0, CHCl
3
). IR (CHCl
3
3
J=12.3, 1 H); 4.50 (d, J=12.0, 1 H); 4.34 (dd, J=7.2, 6.3, 2 H); 4.11–4.05 (m, 2 H); 3.81–3.75 (m, 1 H); 3.48
1
3
(
3
d, J=6.0, 1 H); 3.40 (s, 3 H); 2.79 (d, J=6.9, 1 H). C-NMR (75 MHz, CDCl ): 137.9; 137.8; 137.3; 128.4;
1
28.3; 128.2; 128.1; 128.0; 127.7; 127.7; 127.5; 101.8; 84.3; 81.5; 81.1; 73.3; 72.7; 72.5; 70.9; 55.9. HR-MALDI-
+
þ
MS: 487.2098 ([M+Na] ; C30
H
34NaO ; calc. 487.2097).
7
Methyl 2,3,6-Tri-O-benzyl-b-
D
-galactofuranoside (5ab). [a]
454, 1362, 1101, 1042. H-NMR (300 MHz, CHCl ): 7.36–7.26 (m, 15 H); 4.95 (s, 1 H); 4.60–4.46 (m, 6 H);
.13 (dd, J=5.7, 3.3, 2 H); 4.05 (dd, J=6.6, 2.1, 1 H); 3.98 (dd, J=2.4, 0.9, 1 H); 3.91 (td, J=6.0, 3.6, 1 H);
D
=À51.0 (c=1.9, CHCl
3 3
). IR (CHCl ) 2923,
1
1
4
3

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HELVETICA CHIMICA ACTA – Vol. 88 (2005)
1
3
3
1
4
.55 (d, J=5.7, 2 H); 3.37 (s, 3 H); 2.46 (d, J=6.3, 1 H). C-NMR (75 MHz, CDCl ): 137.9; 137.5; 137.1; 128.3;
3
28.3; 128.3; 127.8; 127.7; 127.6; 107.2; 87.2; 83.1; 81.7; 73.4; 72.3; 71.8; 71.5; 70.1; 54.9. HR-MALDI-MS:
+
þ
87.2091 ([M+Na] , C30
H
34NaO ; calc. 487.2097).
7
Prop-2-enyl 5-O-Acetyl-2,3,6-tri-O-benzyl-b-
D-galactofuranoside (5b). The ring opening with allylic alcohol
(
(
(
58 mg, 1.0 mmol) and the sequential protection at 5-O afforded 45 mg (78%) of 5ba and 5bb (a/b 20 :80). TLC
1
AcOEt/texane 2 :5): R
m, 15 H); 5.97–5.84 (m, 1 H); 5.36 (td, J=6.3, 3.6, 1 H); 5.29 (ddd, J=17.4, 3.0, 1.5, 1 H); 5.18 (ddd, J=10.8, 3.0,
.2, 1 H); 5.09 (s, 1 H); 4.58–4.44 (m, 6 H); 4.24 (dd, J=7.2, 3.6, 1 H); 4.18 (ddt, J=12.9, 5.1, 1.5, 1 H); 4.03 (dd,
J=3.0, 1.8, 1 H); 3.96 (ddt, J=12.6, 6.0, 1.5, 1 H); 3.84 (dd, J=7.2, 3.0, 1 H); 3.64 (d, J=6.0, 1 H); 2.02 (s, 3 H).
f 3
0.45 (5ba), 0.50, (5bb). Selected data for 5bb: H-NMR (300 MHz, CDCl ): 7.36–7.26
1
1
3
C-NMR (75 MHz, CDCl ): 170.4; 137.9; 137.5; 137.4; 134.1; 128.4; 128.3; 128.0; 127.9; 127.8; 127.6; 127.5;
3
+
1
C
17.3; 105.1; 88.1; 83.0; 79.4; 73.0; 72.3; 72.1; 70.4; 68.7; 68.1; 20.9. HR-MALDI-MS: 555.2365 ([M+Na] ,
þ
32
H
36NaO ; calc. 555.2359).
7
Pent-4-enyl 2,3,6-Tri-O-benzyl-b-
.6 mmol) afforded 130 mg (81%) of 5ca and 5cb (a/b 45 :55). TLC (AcOEt/hexane 2 :5): R
D
-galactofuranoside (5c). The ring opening with pent-4-en-1-ol (134 mg,
0.45. Selected
) 2921, 1747, 1263, 1102. H-NMR (300 MHz, CDCl ):
.78 (d, J=7.2, 2 H); 7.65 (d, J=7.5, 2 H); 7.43–7.27 (m, 19 H); 5.91–5.75 (m, 1 H); 5.25 (dt, J=6.9, 4.5, 1
1
f
1
data for 5cb: [a]
D
=À20.6 (c=2.2, CHCl
3
). IR (CHCl
3
3
7
H); 5.08–4.97 (m, 3 H); 4.62–4.48 (m, 6 H); 4.42–4.39 (m, 2 H); 4.29–4.24 (m, 2 H); 4.05 (dd, J=3.6, 1.5, 1
H); 3.97 (dd, J=7.2, 3.3, 1 H); 3.78–3.67 (m, 3 H); 3.43 (dt, J=9.9, 6.6, 1 H); 2.17–2.10 (m, 2 H); 1.75–1.66
1
3
(
m, 2 H). C-NMR (75 MHz, CDCl
3
): 154.8; 143.3; 143.2; 141.1; 138.0; 137.7; 137.4; 137.3; 128.3; 128.2;
1
6
27.9; 127.8; 127.7; 127.5; 127.4; 127.0; 125.2; 119.9; 114.8; 105.9; 88.2; 83.0; 79.0; 75.1; 73.1; 72.3; 72.1; 70.0;
+
þ
8
8.7; 67.0; 46.7; 30.3; 28.8. HR-MALDI-MS: 763.3260 ([M+Na] , C47
Octyl 5-O-Acetyl-2,3,6-tri-O-benzyl-b- -galactofuranoside (5d). The ring opening with octan-1-ol (326 mg,
.5 mmol) and the protection at 5-O afforded 119 mg (44%) of 5da and 5db (a/b 47:53). TLC (AcOEt/hexane
H48NaO ; calc. 763.3247).
D
2
1
1
:5): R
f
0.30. Selected data for 5db: [a]
): 7.37–7.26 (m, 15 H); 5.36 (td, J=6.0, 3.2, 1 H); 4.58–4.45 (m, 6 H); 4.20 (dd, J=7.2, 3.2, 1
H); 3.99 (dd, J=3.2, 1.6, 1 H); 3.82 (dd, J=7.2, 3.2, 1 H); 3.69–3.63 (m, 3 H); 3.38 (dt, J=6.4, 6.4, 1 H); 2.03 (s, 3
D
=À10.7 (c=0.6, CHCl
3
). IR (neat): 2926, 1744, 1455, 1237. H-NMR
(
400 MHz, CDCl
3
1
3
H); 1.57 (br. s, 2 H); 1.28 (br. s, 10 H); 0.89 (t, J=6.8, 3 H). C-NMR (100 MHz, CHCl
3
): 170.2; 137.9; 137.5;
1
7
37.4; 128.3; 128.2; 128.2; 128.2; 127.8; 127.8; 127.6; 127.5; 127.4; 105.9; 88.3; 83.0; 79.1; 73.1; 72.4; 72.1;
0.5; 68.8; 67.8; 32.0; 29.7; 29.5; 29.4; 26.3; 22.8; 21.1; 14.2. HR-FAB-MS: 605.3477 ([M+H] , C37H47O ;
+
þ
7
calc. 605.3478).
Octyl 5-O-Acetyl-2,3,6-tri-O-benzyl-b-
5e). The ring opening of 2a with octyl 2,3,5-tri-O-benzyl-b-
sequential protection of 5-O with Ac O and pyridine afforded 63 mg (59%) of 5ea and 5eb (a/b 26 :74).
TLC (AcOEt/hexane 1:5): R 0.25. Selected data for 5eb: [a] ). IR (neat): 2926,
=À47.8 (c=1.0, CHCl
744, 1454, 1237. H-NMR (400 MHz, CHCl ): 7.35–7.21 (m, 30 H); 5.08 (s, 1 H); 5.04 (s, 1 H); 4.73 (d,
J=11.4, 1 H); 4.62–4.40 (m, 10 H); 4.29 (d, J=11.7, 1 H); 4.12 (dd, J=6.3, 3.3, 1 H); 4.08–4.02 (m, 1 H);
D
-galactofuranosyl-(1 ! 6)-2,3,5-tri-O-benzyl-b-
D-galactofuranoside
-galactofuranoside (112 mg, 0.20 mmol) and the
(
D
2
f
D
3
1
1
3
4
2
.01–3.98 (m, 3 H); 3.88 (dd, J=9.9, 3.0, 1 H); 3.78 (dt, J=7.8, 3.0, 1 H); 3.72–3.62 (m, 3 H); 3.53–3.51 (m,
H); 3.35 (dt, J=9.6, 6.9, 1 H); 2.39 (d, J=6.0, 1 H); 1.52 (br. s, 2 H); 1.26 (br. s, 10 H); 0.87 (br. t, J=6.9, 3
1
3
H). C-NMR (100 MHz, CDCl
3
): 170.2; 138.3; 137.8; 137.7; 137.6; 137.5; 137.2; 128.3; 128.24; 128.22; 128.20;
1
8
1
28.16; 128.1; 128.0; 127.9; 127.8; 127.7; 127.62; 127.55; 127.45; 127.39; 106.5; 105.8; 88.5; 88.1; 83.2; 82.9;
0.6; 79.5; 72.1; 72.0; 71.9; 70.5; 69.1; 68.8; 67.7; 31.9; 29.6; 29.5; 26.3; 22.8; 21.1; 14.2. HR-FAB-MS:
+
þ
12
037.5439 ([M+H] , C64
78
H O ; calc. 1037.5415).
Computational Details. The geometries of the model compounds were fully optimized with GAUSSIAN03
13] at the density functional level of theory (B3LYP) [11] by use of the split-valence 6-311G(d) basis set [12] for
[
C, H, and O. Frequency calculations were carried out to characterize the nature of the stationary points. The
electronic structures were analyzed by Natural Bond Orbital (NBO) analysis.
REFERENCES
ˇ
[
1] M. Cern y´ , ‘Advances in Carbohydrate Chemistry and Biochemistry’, Academic Press, New York, 2003, 58,
121–198.
[
[
2] S. J. Danishefsky, M. T. Bilodeau, Angew. Chem.,Int. Ed. 1996, 35, 1380.
3] a) P. H. Seeberger, M. Eckhardt, C. E. Gutteridge, S. J. Danishefsky, J. Am. Chem. Soc. 1997, 119, 10064; b)
C. M. Timmers, N. C. R. van Straten, G. A. van der Marel, J. H. van Boom, J. Carbohydr. Chem. 1998, 17,
471; c) O. J. Plante, E. R. Palmacci, R. B. Andrade, P. H. Seeberger, J. Am. Chem. Soc. 2001, 123, 9545.

H
ELVETICA
CHIMICA
ACTA – Vol. 88 (2005)
2831
[
[
4] a) V. Jaouen, A. Jegou, A. Veyrieres, Synlett 1996, 1218; b) V. Jaouen, A. Jegou, L. Lemee, A. Veyrieres,
Tetrahedron 1999, 55, 9245; c) J. Kovensky, P. Sina y¨ , Eur. J. Org. Chem. 2000, 3523; d) A. Caravano, D.
Mengin-Lecreulx, J.-M. Brondello, S. P. Vincent, P. Sina y¨ , Chem.–Eur. J. 2003, 9, 5888; e) T. Yoshida, K.
Hattori, Y. Choi, M. Arai, H. Funaoka, T. Uryu, J. Polym. Sci.,Part A: Polym. Chem. 1998, 36, 841, and
refs. cit. therein.
5] T. L. Lowary in ‘Glycoscience III’, Eds. B. Fraser-Reid, K. Tatsuta, J. Thiem, Springer, Berlin, 2001,
p. 2005–2080.
[
[
[
6] P.-M. Aberg, B. Ernst, Acta Chem. Scand. 1994, 48, 228.
7] F. Sugawara, H. Nakayama, T. Ogawa, Agric. Biol. Chem. 1986, 50, 1557.
8] a) A. K. Pathak, V. Pathak, L. Seitz, J. A. Maddry, S. S. Gurcha, G. S. Besra, W. J. Suling, R. C. Reynolds,
Bioorg. Med. Chem. 2001, 9, 3129; b) M. K. Gurjar, L. K. Reddy, S. Hotha, J. Org. Chem. 2001, 66, 4657; c)
L. Gandolfi-Donadio, C. Gallo-Rodriguez, R. M. de Lederkremer, J. Org. Chem. 2003, 68, 6928.
9] J. Desire, J. Prandi, Carbohydr. Res. 1999, 317, 110.
[
[
[
10] H. K. Hall Jr., F. DeBlauwe, J. Am. Chem. Soc. 1975, 97, 655.
11] a) C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785; b) B. Miehlich, A. Savin, H. Stoll, H. Preuss,
Chem. Phys. Lett. 1989, 157, 200; c) A. D. Becke, J. Chem. Phys. 1993, 98, 5648.
[
[
12] R. Krishnan, J. S. Binkley, R. Seeger, J. A. Pople, J. Chem. Phys. 1980, 72, 650.
13] Gaussian 03, Revision B.03, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, J. A. Montgomery Jr., T. Vreven, N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi,
V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M.
Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M.
Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts,
R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Moro-
kuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A.
G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.
L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W.
Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez and J. A. Pople, Gaussian, Inc., Wallingford CT, 2004.
Received July 22,2005