Regioselective Galactofuranosylation for the Synthesis of Disaccharide Patterns Found in Pathogenic Microorganisms

Article abstract of DOI:10.1021/acs.joc.7b00565

Koenigs-Knorr glycosylation of acceptors with more than one free hydroxyl group by 2,3,5,6-tetrabenzoyl galactofuranosyl bromide was performed using diphenylborinic acid 2-aminoethyl ester (DPBA) as inducer of regioselectivity. High regioselectivity for the glycosylation on the equatorial hydroxyl group of the acceptor was obtained thanks to the transient formation of a borinate adduct of the corresponding 1,2-cis diol. Nevertheless formation of orthoester byproducts hampered the efficiency of the method. Interestingly electron-withdrawing groups on O-6 or on C-1 of the acceptor displaced the reaction in favor of the desired galactofuranosyl containing disaccharide. The best yield was obtained for the furanosylation of p-nitrophenyl 6-O-acetyl mannopyranoside. Precursors of other disaccharides, found in the glycocalix of some pathogens, were synthesized according to the same protocol with yields ranging from 45 to 86%. This is a good alternative for the synthesis of biologically relevant glycoconjugates.

Full text of DOI:10.1021/acs.joc.7b00565

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Article
Regioselective galactofuranosylation for the synthesis of
disaccharide patterns found in pathogenic microorganisms
Laurent Legentil, Yari CABEZAS, Olivier Tasseau, Charles Tellier, Franck Daligault, and Vincent FERRIERES
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00565 • Publication Date (Web): 20 Jun 2017
Downloaded from http://pubs.acs.org on June 21, 2017
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Regioselective galactofuranosylation for the synthesis of disaccharide patterns found in
pathogenic microorganisms
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Laurent Legentil,* a Yari Cabezas,a Olivier Tasseau,a Charles Tellier,b Franck Daligaultb and
Vincent Ferrières* a
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(a) Ecole Nationale Supérieure de Chimie de Rennes, CNRS, UMR 6226, 11 Allée de
Beaulieu, CS 50837, 35708 Rennes Cedex 7, France
(b) Université de Nantes, UMR CNRS 6286, 2 Rue de la Houssinière, 44322 Nantes Cedex 3,
France
laurent.legentil@ensc-rennes.fr or vincent.ferrieres@ensc-rennes.fr
Abstract: KoenigsꢀKnorr glycosylation of acceptors with more than one free hydroxyl group
by 2,3,5,6ꢀtetrabenzoyl galactofuranosyl bromide was performed using diphenylborinic acid
2ꢀaminoethyl ester (DPBA) as inducer of regioselectivity. High regioselectivity for the
glycosylation on the equatorial hydroxyl group of the acceptor was obtained thanks to the
transient formation of a borinate adduct of the corresponding 1,2ꢀcis diol. Nevertheless
formation of orthoester byꢀproducts hampered the efficiency of the method. Interestingly
electronꢀwithdrawing groups on Oꢀ6 or on Cꢀ1 of the acceptor displaced the reaction in favour
of the desired galactofuranosyl containing disaccharide. The best yield was obtained for the
furanosylation of pꢀnitrophenyl 6ꢀOꢀacetyl mannopyranoside. Precursors of other
disaccharides, found in the glycocalix of some pathogens, were synthesized according to the
same protocol with yields ranging from 45 to 86%. This is a good alternative for the synthesis
of biologically relevant glycoconjugates.
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Introduction
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The significant discoveries on the organization of the cell, either from prokaryote or
eukaryote origin, have pointed out the key role of the glycocalix, the complex layer of heteroꢀ
and oligosaccharides that surrounds the cell wall.1ꢀ4 Even if most cells use common sugars to
build this glycocalix, they manage to differentiate from each other thanks to the infinite
possibilities of sequence and the nature of the linkages involved. Intriguingly some
microorganisms incorporate carbohydrates in their furanose form rather than in their pyranose
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one in order to further differentiate themselves from other organisms.5,6 In particular
galactofuranose ( ꢀGalf) containing glycoconjugates are found in large amount in pathogenic
Dꢀ
D
microorganisms like Mycobacteria or Leishmania but are absent in the mammalian kingdom.7
Owing to the key role played by such motifs in the virulence or survival of the parasite or
bacteria, numerous groups have developed evolved synthetic pathways to access to such Galfꢀ
containing oligosaccharides.8ꢀ13 Alternatively galactofuranosylꢀtransferases isolated from
mycobacteria or furanosylhydrolases involved in the degradation of biomass have been used
to obtain either oligomers of Galf14,15 or heterodisaccharides.16,17 These last strategies involve
a minimum of protecting group manipulation as biocatalysts are able to selectively transfer a
furanosyl entity on a specific position of an acceptor.
Attempt to mimic such selectivity remains the grail for glycochemists. Already, regioselective
glycosylation of naked acceptors could be performed thanks to transient selective activation
of one hydroxyl group against the others using for example dibutyltin(IV) oxide18,19 or aryl
borinic acid20,21 as inducers of regioselectivity. More recently, Taylor and coworkers
developed new diarylborinic acid derivatives for the regioselective acylation,22 alkylation23 or
tosylation24 of the secondary alcohol of various alkyl glycosides. They postulated that
diarylborinic acid could form tetracoordinate adducts with 1,3ꢀdiols and 1,2ꢀcis diols thus
increasing the nucleophilicity of either the primary hydroxyl group or the least hindered
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equatorial one. The methodology was recently extended to the glycosylation of thiophenyl
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mannopyranoside using
D
ꢀarabinofuranosyl methanesulfonate as a donor.25 It is the first
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example of the synthesis of furanosyl containing disaccharides obtained by this methodology
and works remain to be done to apply such process to the synthesis of hexofuranosylꢀ
containing conjugates.
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After having proposed to work with unprotected thioimidates as donors,26 we now report on
the use of diphenylborinic acid 2ꢀaminoethyl ester (DPBA) to induce regioselectivity for
galactofuranosylation of various glycosidic acceptors:
D
ꢀmannopyranosides (
ꢀGalp), ꢀgalactopyranoside ꢀGalpNAc),
ꢀRhap) and DꢀGalf. The target compounds are disaccharidic parts of
DꢀManp), Dꢀ
galactopyranoside
(D
Nꢀacetylꢀ
D
(
D
Lꢀ
rhamnopyranoside (
L
biomolecules anchored to the cell wall of pathogenic microorganisms (Figure 1).5,6
Representative examples include βꢀ(1→3) and (1→6)ꢀ ꢀManp linkage found in Aspergillus,
Trypanosoma or Leishmania sp.; βꢀ(1→3)ꢀ ꢀGalp or βꢀ(1→3)ꢀ ꢀGalpNAc linkage identified
D
D
D
in Bacteroides, Fibrobacter or Agelas sp. for the first one or Bacteroides and Shigella for the
ꢀRhap bond presented by Mycobacterium.6,27 Wide ligation diversity
second one; βꢀ(1→4)ꢀ
L
was also established between two DꢀGalf entities: βꢀ(1→5) and βꢀ(1→6) found in particular in
Mycobacterium tuberculosis, Cryphonectria parasitica and Aspergillus.28
Some of these disaccharides linked the Galf nonꢀreducing end to the most nucleophilic
equatorial oxygen of the sugar at the reducing end. This oxygen is in addition in a 1,2ꢀcis
configuration with one of the proximal hydroxyl group. Such glycosidic bonds could therefore
be selectively obtained thanks to glycosylation in presence of diarylborinic inducer. First the
conditions of glycosylation were optimized with mannopyranosidic acceptor using
peracylated galactofuranosyl bromide as donor. Different groups were introduced on the
acceptor either on the primary hydroxyl group or at the anomeric position in order to
investigate the influence of the inductive effect on the glycosylation. An attempt of
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rationalization of the results was performed thanks to ab initio calculation. Finally the
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methodology was extended to the other relevant acceptors.
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FIGURE 1. Natural occurrence of galactofuranose in some glycocalix of selected
organisms.
Results and discussion
Our aim is to develop a regioꢀ and stereoselective glycosylation to obtain Galfꢀcontaining
disaccharides. The conditions developed by Taylor29 were first applied on a model reaction
between various Galf donors and Manp acceptors (Figure 2). Different activating groups were
introduced from peracylated derivatives of galactofuranose, namely the bromide,30 the
thiophenyl31 or the trichloroacetimidate32 according to available protocols to give 1a, 1b and
1c respectively. As for the acceptors, we decided to evaluate the influence of the protecting
group on both positions Cꢀ1 and Oꢀ6. The primary position has to be masked anyway in order
to avoid glycosylation at this position. Starting from commercially available pꢀnitrophenyl
mannopyranoside (pNP Manp) 2a, the electronꢀdonating group tertꢀbutyldimethylsilyl was
first introduced on position Oꢀ6 by action of the corresponding silylating agent TBSCl in
presence of imidazole and DMAP with a moderate 40% yield. The electronꢀwithdrawing
group acetyl on the other hand was added using vinyl acetate in THF in presence of the
supported lipase from Candida antartica (CALꢀB). This last strategy was also applied to the
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octyl and thiotolyl αꢀManp 3a and 3b to obtain the corresponding 6ꢀOAc mannoside 4a and
4b with 89% and 69% yields respectively.
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FIGURE 2. Building blocks used in the regioselective glycosylation.
With the donors 1 and acceptors 2 in hand, different attempts of glycosylation were
implemented (Table 1). Following the findings of Taylor and coworkers, a catalytic amount of
diphenylborinic acid 2ꢀaminoethyl ester (DPBA) was used first (Entries 1, 3 to 7). The
reactions proceeded in acetonitrile in presence of molecular sieves 4Å in order to limit the
hydrolysis of the donors 1. These donors were used also in excess in the case where the
hydrolysis is too high. With TBS Manp 2b as acceptor and bromide 1a as donor, the reaction
proceeded quickly in presence of both silver oxide and the borinic acid to give the target
disaccharide 5b in 36% yield (Entry 1). It was unambiguously characterized thanks to 1H and
13C NMR spectroscopy. The isolated disaccharide presented an anomeric proton at 5.55 ppm
associated with a carbon at 103.8 ppm. Coupling constant JH1,H2 was almost zero, a typical
value for an anomeric proton of a furanoside in 1,2ꢀtrans configuration. The regioisomery of
the disaccharide was further confirmed by 2DꢀNMR HMBC experiments. A long range
correlation between CGalfꢀ1 and HManpꢀ3 indicated a (1→3)ꢀglycosidic bond. The other product
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of the reaction, and the major one, was identified as the orthoester 6b. It showed a
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1
characteristic signal in H NMR at 6.47 ppm associated with a carbon at 105.3 ppm. The
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related coupling constant JH1,H2 reached 4.4 Hz thus indicating a 1,2ꢀcis configuration. In
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addition C NMR showed a carbon at 123.3 ppm assigned to the quaternary carbon of the
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orthoester function.
For comparative purpose, we tested the absence of DPBA (Entry 2) or of TBS on the primary
hydroxyl group of the acceptor (Entry 3). Both conditions led to a complex mixture of
products. As expected when no borinic acid was added the glycosylation occurred on different
positions of the acceptor and the disaccharide 5b was isolated in only 10% yield. Also no
protecting group on Oꢀ6 resulted in the concomitant glycosylation of both positions 3 and 6,
the two positions that were activated by the inducers of regioselectivity.29 In these conditions
only trisaccharide 3,6ꢀdiꢀOꢀ(βꢀDꢀGalf)ꢀDꢀManp could be isolated.
Then we tried to isomerize the orthoester 6b into 5a by heating the reaction media or by the
addition of a Lewis acid but only the degradation of the orthoester occurred. Alternatively
another halogenophile, the silver triflate was used as promoter as it is known to avoid
orthoester formation. However in these acidic conditions, the TBS group has been cleaved
and again the trisaccharide 3,6ꢀdiꢀOꢀ(βꢀDꢀGalf)ꢀDꢀManp was obtained. Therefore the silyl
group was swapped by an acetyl one. After reaction between 1a and 2c (Entry 4), the major
product remained the orthoester 6c and 5c was obtained only in 19% yield. As the acetyl
group is tolerant to acidic condition, silver triflate was this time used successfully as promoter
(Entry 5). It allowed to access to 5c with a better yield and no orthoester was isolated.
However other regioisomers, the pNP βꢀDꢀGalfꢀ(1→2)ꢀDꢀManp and pNP βꢀDꢀGalfꢀ(1→4)ꢀDꢀ
Manp were formed as well. It confirms that acidic conditions are detrimental to the formation
of the borinate complex.24 Finally, when other Galf donors 1b and 1c were used (Entries 6 and
7), the yield did not improve and the regioselectivity was poorer as previously reported.29
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TABLE 1. Optimization of the conditions for the regioselective galactofuranosylation of
4
5
6
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8
9
p
NP Man
p
derivatives.
OH
O
O
N
RO
HO
O
BPh2
OpNP
BzO
O
BzO
H2
O
BzO
O
X
RO
HO
(DPBA)
H
O
O
BzO
BzO
+
+
BzO
BzO
HO
OR
O
+ regioisomers
BzO
OBz
MS 4A
HO
O
O
HO
OBz
7
O
Ph
6a R=H
OpNP
BzO
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1a X = Br
1b X = SPh
1c X = OC(NH)CCl3
2a R = H
2b R = TBS
2c R = Ac
5a R=H
5b R=TBS
5c R= Ac
6b R=TBS
6c R= Ac
OpNP
Entry Donor Acceptor Promoter DPBA Solvent Time
Ratio
5:6:7
5
(2 eq.)
(1 eq.)
(1 eq.)
(eq.)
(h)
(Yield %)
1
2
Ag2O
Ag2O
0.1
ꢀ
CH3CN
CH3CN
2
5b (36)
5b (10)
5:6:0
1a
1a
2b
2b
28
Mixture
Trisacꢀ
3
Ag2O
0.1
CH3CN
2
1a
2a
ꢀ
charidea
4
5
Ag2O
0.1
0.1
CH3CN
CH3CN
19
19
5c (19)
5c (33)
1:2.4:0
13:0:2b
1a
1a
2c
2c
AgOTf
NIS,
AgOTf
6
0.1
CH3CN
19
ꢀ
ꢀ
1b
2c
7
8
TMSOTf
Ag2O
0.1
1
CH3CN
CH3CN
CH2Cl2
THF
19
6
5c (25)
5b (46)
5b (40)
5b (25)
5c (85)
5c (80)
8:0:2c
7:3:0
1:0:0
1:1:0
1:0:0
1:0:trc
1c
1a
1a
1a
1a
1a
2c
2b
2b
2b
2c
2c
9
Ag2O
1
8
10
11
12
Ag2O
1
8
Ag2O
1
CH3CN
CH3CN
2
AgOTf
1
19
a
b
c
Mainly pNP 3,6ꢀdiꢀOꢀ(βꢀ
D
ꢀGalf)ꢀ
D
ꢀManp. Mainly pNP βꢀ
D
ꢀGalfꢀ(1→2)ꢀDꢀManp and pNP βꢀDꢀGalfꢀ(1→4)ꢀDꢀManp. Mainly pNP βꢀDꢀ
Galfꢀ(1→4)ꢀ ꢀManp
D
Interestingly, when a stoichiometric amount of DPBA was used, the yield greatly improved
and no or trace amount of orthoester was formed (Entries 8 to 12). In addition the use of
alternative solvents like THF or dichloromethane decreased either the yields or the selectivity
(Entries 9 and 10). Also, the glycosylation of 6ꢀOꢀTBS Manp 2b proceeded with lower yields
than with 6ꢀOꢀAc Manp 2c, and a higher amount of orthoester 6b was isolated (Entries 8 vs.
11). As for the promoter, the acidic AgOTf can be used but trace amount of regioisomers
(mainly βꢀ(1
→
4)ꢀ) contaminated again the disaccharide 5c (Entry 12). The best result was
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obtained using the bromide 1a as donor, activated by one molar ratio of silver oxide, the 6ꢀOꢀ
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acetyl acceptor 2c, DPBA (one equivalent), in acetonitrile. Under these conditions, the pNP
ꢀGalfꢀ(1 3)ꢀ ꢀManp compound 5c was obtained in a quite worthy yield of 85% with no
contamination by the orthoester (Entry 11).
βꢀ
D
→
αꢀD
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Following this optimization, the methodology was then applied to 6ꢀOꢀacetylated mannosidic
acceptors 4a and 4b (Table 2) that differ on the nature of the substituent attached to the
anomeric position. On one hand, the presence of the electronꢀdonating group octyl at the
anomeric position seemed to favour greatly the formation of the orthoester 9a (Entry 1).
Solely the use of silver trifluoromethanesulfonate instead of silver oxide allowed isolating the
target compound 8a with 57% yield (Entry 2). Once again, contamination by other
regioisomers hampered the use of such acidic promoter. On the other hand, a completely
different outcome arose with a thiotolyl group on Cꢀ1 of the mannose as the donor 1a easily
glycosylated the position 3 of the mannoside 4b. Formation of the orthoester 9b was low and
no other regioisomers were isolated (Entry 3 and 4). It confirms the great influence of the
electronꢀdensity of the substituent on both position Oꢀ6 and Cꢀ1.
TABLE 2. Extension to octyl and thiotolyl mannoside.
Entry Acceptor Promoter Time Disaccharide Ratio
(h)
(Yield %)
8:9:10
1
2
3
4
Ag2O
AgOTf
Ag2O
2
5
2
6
8a (40)
8a (57)
8b (96)
8b (69)
45:55:0
4:0:1a
95:5:0
1:0:0
4a
4a
4b
4b
AgOTf
a Mainly octyl βꢀ
DꢀGalfꢀ(1→4)ꢀDꢀManp.
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To explain these results, we decided to compare the difference of reactivity of the tested
acceptors 2b, 2c, 4a and 4b in complex with diphenylborinic acid using DFT calculation in
the gasꢀphase (B3LYP/6ꢀ31+G*) (Table 3 and Supporting Information).
TABLE 3. Calculated Mulliken charges and Fukui indexes of diphenylborinate adduct
of 2b, 2c, 4a and 4b (B3LYP/6ꢀ31+G*).
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Entry Mannoside
acceptor
Mulliken
charge at Oꢀ3
fk at Oꢀ3
1
2
3
4
ꢀ0.35
ꢀ0.31
ꢀ0.32
ꢀ0.33
0.180
0.115
0.135
0.115
2b
2c
4a
4b
Surprisingly, the estimation of the Mulliken charges on the most reactive equatorial oxygen
Oꢀ3 did not vary much between the different mannosides. Only the Fukui index fk, a measure
of the strength of the nucleophile,33 decreased significantly with the presence of electronꢀ
withdrawing groups either on Oꢀ6 or on Cꢀ1. Interestingly, those molecules 2c and 4b also
formed no or trace amount of orthoesters. On the contrary, electronꢀdonating groups like the
TBS (2b) or the alkyl (4a) one reinforced the nucleophilicity on Oꢀ3. Those acceptors
generated after glycosylation the largest amount of orthoester. Orthoesters are known to form
in various amounts during KoenigsꢀKnorr glycosylation.34 According to Taylor et al‘s work
on pyranosyl bromide,29 the formation of such orthoester is not favoured because the reaction
pathway follows a pure SN2 mechanism. Here, the presence of the bromide in a 1,2ꢀtrans
configuration and the assistance of the benzoyl group on Oꢀ2 favour the transient
acyloxonium specie and not the oxonium intermediate (Figure 3). The formation of such
intermediate is in addition predominant in the furanose series.35 The attack of the nucleophile
could then occur either at the quaternary carbon or at the anomeric one via an SN2
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mechanism. Strong nucleophiles like 4a or 2b reacted first at the quaternary carbon and then
at the anomeric position leading to a mixture of orthoester and disaccharide. The resulting
orthoesters were stable enough to be isolated by silica gel chromatography.36 On the contrary,
if less nucleophilic acceptors 2c and 4b were used, the attack occured only at the anomeric
center to give the corresponding disaccharides 5c and 8b. For the moment we are not able to
decide if such selectivity is under kinetic or thermodynamic control. Nevertheless these
results could be compared with the armed/disarmed effect linked with the nature of the
substituent on the donor. Such activating/deactivating effects are however rarely reported
when dealing with the acceptor and thus pave the way to a new understanding of the acceptor
reactivity.
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FIGURE 3. Mechanism of the formation of the orthoester and the disaccharide
according to the nucleophilicity of the acceptor.
The same trend of reactivity was observed when the furanosylation assisted by DPBA was
extended to the acceptors pNP galactopyranoside 12, Nꢀacetylꢀgalactosamine 14,
Lꢀ
rhamnoside 15 and galactofuranoside 16 (Table 4). The building blocks 12 and 14 were
obtained through biocatalysed acetylation as before (Figure 4)21,37,38 while 15 and 16 came
from commercial sources.
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FIGURE 4. Acceptors used to obtain Gal
microorganisms.
fꢀcontaining disaccharides found in various
On one hand 12 that bears electronꢀwithdrawing groups on Oꢀ6 and Cꢀ1 and shows a low
Fukui index at Oꢀ3, gave the corresponding disaccharide 17 with excellent yield and without
formation of the orthoester (Entry 1). On the other hand the 6ꢀdeoxyꢀhexose 15 is rather
nucleophilic and during the regioselective furanosylation catalysed by silver oxide, more than
30% of orthoester was formed (Entry 4). Alternative silver triflate protocol allowed to
increase the yield for disaccharide 19 to 59% but the regioselectivity was decreased and 20%
of the regiosiomer pNP βꢀGalfꢀ(1→4)ꢀLꢀRhap was obtained as well (Entry 5). Surprisingly,
pNP Nꢀacetylꢀgalactosamine 14 whose calculated Fukui index was very low, gave the
corresponding disaccharide 18 with poor yield (Entry 2). The amount of the corresponding
orthoester was also low. The low nucleophilicity of Oꢀ3, due to the presence of the acetamide
group on Cꢀ2 could explain the poor yield for the glycosylation.39 However 55% yield could
be reached with silver triflate as promoter with the downside formation of regioisomers (Entry
3).
The last acceptor tested in the regioselective glycosylation was the pNP Galf 16. In presence
of the DPBA, we were expecting to form the diphenylborinate adduct between the Oꢀ6 and
the Oꢀ5 and thus exacerbating the nucleophilicity of the primary hydroxyl group. Indeed the
reaction between the bromide furanosyl 1a and pNP Galf 16 in presence of the borinic acid
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and silver oxide led quickly to the total conversion of the acceptor (Entry 6). The minor
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6
product of the reaction was then identified as the targeted pNP βꢀGalfꢀ(1→6)ꢀGalf 20 thanks
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to 2DꢀNMR experiments. The major one was the orthoester derivative isolated in 56% yield.
This was expected as primary hydroxyl groups are much more reactive than secondary
hydroxyl groups thus leading to high Fukui index and therefore to a high ratio of orthoester. It
is worth to mention nevertheless that no other regioisomer was isolated which means that
DPBA indeed formed a complex with Oꢀ6 and Oꢀ5 of the Galf moiety. Finally to prevent from
the formation of the orthoester, silver triflate was used and allowed to obtain 20 with 45%
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yield in mixture with the regioisomer pNP βꢀGalfꢀ(1→5)ꢀGalf (Entry 7).
TABLE 4. Extension to relevant acceptors to obtain Galfꢀcontaining disaccharides.
Product
(Yield %)
Byꢀproduct
(%)
Entry Acceptor
fk
Promoter
1
0.121a
Ag2O
Ag2O
17 (86)
None
12
2
18 (10)
Orthoester (37)
0.101a
0.134a
0.157b
14
βꢀGalfꢀ(1→4)ꢀ
3
AgOTf
Ag2O
18 (55c)
19 (45)
19 (59c)
20 (12)
20 (45c)
GalpNHAc (20)
4
Orthoester (33)
15
βꢀGalfꢀ(1→4)ꢀ
LꢀRhap (20)
5
AgOTf
Ag2O
6
Orthoester (56)
16
βꢀGalfꢀ(1
→5)ꢀ
7
AgOTf
Galf (10)
a Fukui index at Oꢀ3. b Fukui index at Oꢀ6. c As an inseparable mixture. Yield and ratio determined by 1H NMR.
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Conclusion
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As a conclusion, the high potential of diphenylborinic acid 2ꢀaminoethyl ester as inducer of
regioselective galactofuranosylation of various acceptors was confirmed. In this study we
have validated the extension of Taylor’s methodology from hexopyranosyl bromide to a 1,2ꢀ
trans hexofuranosyl bromide unable to react in a pure SN2 glycosylation pathway. When
using silver oxide as promoter, only one regioisomer was formed as expected. High amount of
orthoester however was formed when the Oꢀ6 or Cꢀ1 position of the acceptor possessed an
electronꢀdonating group. Silver triflate could be used instead but such an acidic catalyst
destabilized the borinate adduct and the resulting regioselectivity dropped. The role of the
substituents on the acceptor was partly explained thanks to ab initio calculation of the Fukui
index of all borinate complexes. Electronꢀdonating groups at primary and anomeric positions
significantly increased the Fukui indexes and borinate adducts with high Fukui index on the
equatorial oxygen generated the greater amount of orthoester. This is a confirmation that the
electronꢀdensity of the substituent at the anomeric position of the acceptor can modulate the
glycosylation reaction. Finally, despite these limitations, we managed to obtain quickly and
efficiently galactofuranosyl containing disaccharides found in the glycocalix of pathogenic
microorganisms. The minimum protecting group manipulation and the simplicity of the
method represent an attractive alternative to biocatalysed process that still suffer from too
strong specificity and low conversion yields.
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Experimental Section
General Experimental Details
All reactions were carried out in ovenꢀdried glassware. All reagents were purchased from
commercial sources and were used without further purification unless noted. Dried
acetonitrile, dichloromethane and THF were purchased sealed on molecular sieves. Unless
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otherwise stated, all reactions were monitored by TLC on Silica Gel 60 F254. TLC spots were
detected under 254 nm UVꢀlight or by staining with cerium ammonium molybdate solution.
Column chromatography was performed on Silica Gel (25 or 50 µm). Optical rotations were
measured at 20 °C on a PerkinꢀElmer 341 polarimeter. NMR spectra were recorded at 400
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13
MHz for 1H and 100 MHz for C. Chemical shifts are given in δ units (ppm) and referenced
to either CDCl3 or CD3OD. Coupling constants J were calculated in Hertz (Hz). Proton and
carbon NMR peaks were unambiguously assigned by COSY (double quantum filtered with
gradient pulse for selection), HSQC (gradient echoꢀanti echo selection and shape pulse) and
HMBC (echoꢀanti echo gradient selection, magnitude mode) correlation experiments. For
each isolated oligosaccharide, the reducing end (bearing pNP or alkyl chain) was quoted as
“a”, and the letter increased toward the nonꢀreducing end (for example the sugar after was
quoted as “b”). High Resolution Masses were ) were recorded in positive mode using direct
Electrospray ionization on a Waters QꢀTof 2 spectrometer.
4ꢀNitrophenyl 6ꢀ
OꢀtertꢀbutyldimethylsilylꢀαꢀDꢀmannopyranoside (2b): To a solution of 4ꢀ
Nitrophenyl αꢀ ꢀmannopyranoside 2a (1.5 g, 4.98 mmol) in DMF (30 mL) were added
D
imidazole (1.02 g, 14.94 mmol), a catalytic amount of DMAP (30 mg, 0.25 mmol) followed
by TBSCl (901 mg, 5.98 mmol). The reaction mixture was stirred at room temperature until
no evolution was observed through TLC monitoring (8 h). The reaction mixture was diluted
into CH2Cl2 (100 mL) and washed with water (100 mL). The organic layer was washed twice
with a saturated aq NH4Cl solution, water and brine. The resulting organic layer was dried
with MgSO4, filtered and concentrated under reduced pressure. The remaining silane was
removed by submitting the crude material to vacuum during several hours. The 6ꢀOꢀprotected
mannopyranoside 2b was obtained as a white solid (829 mg, 40%) and could be used without
further purification. 20 + 115 (c 1, MeOH). 1H NMR (CD3OD): δH 8.20 (2H, d, J = 9.3 Hz,
ʞ
ʟ
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HAr), 7.28 (2H, d, J = 9.3 Hz, HAr), 5.64 (1H, d, J1,2 = 1.8 Hz, Hꢀ1), 4.04 (1H, dd, J2,3 = 3.4
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Hz, Hꢀ2), 3.92 (1H, dd, J6,5 = 2 Hz, J6,6’ = 11.2 Hz, Hꢀ6), 3.87 (1H, dd, J3,4 = 9.3 Hz, Hꢀ3),
3.74 (1H, dd, J6’,5 = 6.8 Hz, Hꢀ6’), 3.65 (1H, app. t, J4,5 = 9.5 Hz, Hꢀ4), 3.50 (1H, ddd, Hꢀ5),
13
0.8 (9H, s, C(CH3)3), 0.02 (3H, s, OSi(CH3)2), 0.00 (3H, s, OSi(CH3)2). C NMR (CD3OD):
9
δC 162.7 (CAr), 143.8 (CAr), 126.7 (CAr), 118.0 (CAr), 100.0 (Cꢀ1), 76.6 (Cꢀ5), 72.4 (Cꢀ3), 71.5
(Cꢀ2), 68.4 (Cꢀ4), 64.3 (Cꢀ6), 26.3 [SiC(CH3)3], 19.1 [SiC(CH3)3], ꢀ5.15 [OSi(CH3)2], ꢀ5.17
[OSi(CH3)2]. HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C18H29NO8SiNa 438.1560; Found
438.1560.
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General procedure for the regioselective acetylation of pyranosides: A solution (0.1 M) of
4ꢀnitrophenyl glycopyranoside in THF was heated to 45 °C until complete dissolution. Then
vinyl acetate (3 equiv.) and Novozym®435 were added (Lipase acrylic resin Candida
antartica from Novozymes) in a w/w ratio 1:1.2 [glycoside : immobilized enzyme]. The
reaction mixture was stirred at 45 °C until complete conversion of starting material (≈ 7 h).
The enzyme was filtered off and rinsed with MeOH. The resulting filtrate was then
concentrated under reduced pressure and purified by column chromatography on silica gel
(DCM/MeOH ratio 95:5).
4ꢀNitrophenyl 6ꢀ
OꢀacetylꢀαꢀDꢀmannopyranoside (2c): Synthesized according to general
procedure from pNP αꢀ
D
ꢀmannopyranoside 2a (1.0 g, 3.32 mmol), vinyl acetate (918 ꢁL, 9.96
20
mmol) and Novozym®435 (1.2 g) to afford 2c as a pale yellow solid (1.03 g, 90%).
+
ʞ
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1
3
128 (c 1, MeOH). H NMR (CD3OD): δH 8.24 (2H, d, J = 9.3 Hz, HAr), 7.27 (2H, d, HAr),
5.63 (1H, d, J1,2 = 1.7 Hz, Hꢀ1), 4.33 (1H, dd, J6,6’ = 11.8 Hz, J6a,5 = 2 Hz, Hꢀ6), 4.19 (1H, dd,
J6’,5 = 6.4, Hꢀ6’), 4.05 (1H, dd, J2,3 = 3.4 Hz, Hꢀ2), 3,88 (1H, dd, J3,4 = 9 Hz, Hꢀ3), 3.73 (1H,
app. t, J4,5 = 9.8 Hz, Hꢀ4), 3.61 (1H, ddd, Hꢀ5), 1.94 (3H, s, CH3CO). 13C NMR (CD3OD): δC
172.7 (CO), 162.6 (CAr), 144.0 (CAr), 126.7 (CAr), 117.9 (CAr), 100 (Cꢀ1); 73.5 (Cꢀ4), 72.2 (Cꢀ
3), 71.5 (Cꢀ2), 68.3 (Cꢀ5), 64.8 (Cꢀ6), 20.7 (CH3CO). HRMS (ESI/QꢀTOF) m/z: [M+Na]+
Calcd for C14H17NO9Na 366.0801 ; Found 366.0797.
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Octyl 6ꢀ
O
ꢀacetylꢀαꢀ
Dꢀmannopyranoside (4a): Synthesized according to general procedure
4
5
6
7
from octyl αꢀ
D
ꢀmannopyranoside 3a40 (300 mg, 1 mmol), vinyl acetate (284 ꢁL, 3.31 mmol)
and Novozym®435 (400 mg) to afford 2c as a colorless oil (305 mg, 90%).
+ 43 (c 1,
20
ʞ ʟ
͸
8
9
MeOH). 1H NMR (CD3OD): δH 4.70 (1H, d, J1,2 = 1.6 Hz, Hꢀ1), 4.39 (1H, dd, J6,6’ = 11.7 Hz,
J6,5 = 2.0 Hz, Hꢀ6), 4.20 (1H, dd, J6’,5 = 6.4 Hz, Hꢀ6‘), 3.79 (1H, dd, J2,3 = 3.2 Hz, Hꢀ2), 3.73–
3.65 (3H, m, Hꢀ5, Hꢀ3, OCH2), 3.60 (1H, t, J4,5 = 9.4 Hz, Hꢀ4), 3.42 (1H, dt, 2J = 9.6 Hz, 3J =
6.3 Hz, OCH2), 2.06 (3H, s, COCH3), 1.66–1.54 (2H, m, OCH2CH2), 1.45–1.27 (10H, m,
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3
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(CH2)5CH3), 0.91 (3H, t, J = 6.8 Hz, CH2CH3). C NMR (CD3OD): δC 172.8 (CO), 101.7
(Cꢀ1), 72.6 (Cꢀ3), 72.1, 72.1 (Cꢀ2, Cꢀ5), 68.7, 68.7 (Cꢀ4, OCH2), 65.3 (Cꢀ6), 33.0, 30.6, 30.5,
30.4, 27.4, 23.7[(CH2)5CH3], 20.8 (COCH3), 14.4 (CH2CH3). HRMS (ESI/QꢀTOF) m/z:
[M+Na]+ Calcd for C16H30O7Na 357.18837 ; Found 357.1882.
Thiotolyl 6ꢀ
OꢀacetylꢀαꢀDꢀmannopyranoside (4b): Synthesized according to general
procedure from thiotolyl αꢀ
D
ꢀmannopyranoside 3b41 (780 mg, 2.7 mmol), vinyl acetate (750
20
ꢁL, 8.2 mmol) and Novozym®435 (1 g) to afford 4b as a colorless oil (624 mg, 69%).
ʞ ʟ
͸
1
3
+244 (c 1.25, MeOH). H NMR (CD3OD): δH 7.40 (2H, d, J = 8.1 Hz, HAr), 7.14 (2H, d,
HAr), 5.35 (1H, d, J1,2 = 1.5 Hz, Hꢀ1), 4.43ꢀ4.35 (1H, m, Hꢀ6), 4.29ꢀ4.20 (2H, m, Hꢀ5, Hꢀ6’),
4.07 (1H, dd, J2,3 = 2.9 Hz, Hꢀ2), 3.72ꢀ3.64 (2H, m, Hꢀ3, Hꢀ4), 2.32 (3H, s, CH3), 2.00 (3H, s,
13
COCH3). C NMR (CD3OD): δC 172.7 (CO), 139.0, 133.5, 131.7, 130.7 (CAr), 90.3 (Cꢀ1),
73.4 (Cꢀ2), 73.0, 72.9 (Cꢀ4, Cꢀ5), 69.0 (Cꢀ3), 65.0 (Cꢀ6), 21.1 (CH3), 20.8 (COCH3). HRMS
(ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C15H20O6SNa 351.08728 ; Found 351.0872.
4ꢀNitrophenyl 6ꢀ
OꢀacetylꢀβꢀDꢀgalactopyranoside (12): Synthesized according to general
procedure from pNP βꢀ
Dꢀgalactopyranoside 11 (100 mg, 0.3 mmol), vinyl acetate (100 ꢁL,
1
1mmol) and Novozym®435 (120 mg) to afford 12 as a colorless oil (56 mg, 50%). H NMR
(CD3OD+CDCl3): δH 8.20 (2H, d, 3J = 9.3 Hz, HAr), 7.19 (2H, d, HAr), 4.99 (1H, d, J1,2 = 7.7
Hz, Hꢀ1), 4.34 (1H, dd, J6,6’ = 11.5 Hz, J6,5 = 7.8 Hz, Hꢀ6), 4.25 (1H, dd, J6’,5 = 4.5 Hz, Hꢀ6‘),
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3.99–3.91 (1H, m, Hꢀ5), 3.90 (1H, dt, J4,3 = 3.5 Hz, J4,5 = 0.9 Hz, Hꢀ4), 3.85 (1H, dd, J2,3 = 9.7
4
5
6
13
Hz, Hꢀ2), 3.61 (1H, dd, Hꢀ3), 2.07 (3H, s, CH3). C NMR (CD3OD): δC 172.2 (CO), 163.4,
7
8
9
143.5, 126.3, 117.4 (CAr), 101.6 (Cꢀ1), 74.1 (Cꢀ3, Cꢀ5), 71.4 (Cꢀ2), 69.5 (Cꢀ4), 64.4 (Cꢀ6),
20.9 (CH3). HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C14H17NO9Na 366.0801 ; Found
366.0804.
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4ꢀNitrophenyl 6ꢀ
O
ꢀacetylꢀ2ꢀdeoxyꢀβꢀ
DꢀN
ꢀacetylgalactosamine (14): Synthesized according
to described procedure38 from pNP βꢀ
DꢀNꢀacetylgalactosamine 13 (280 mg, 0.8 mmol), vinyl
acetate (10 mL) Novozym®435 (350 mg) in a mixture of acetone/pyridine (29/21 mL) to
afford 14 as a white solid (161 mg, 51%). Spectroscopic data were in accordance with
previous report.
General procedure for the 2ꢀADPBꢀassisted glycosidic coupling: Bromide donor 1a30 (2
equiv.), acceptor (1 equiv.) and 2ꢀaminoethyl diphenylborinate (2ꢀDPBA, 1 equiv.) were
suspended in dry CH3CN (40 mM) with activated 4 Å molecular sieves (100 mg / mL) and
under a nitrogen atmosphere. The mixture was stirred for 30 min and Ag2O (1 equiv.) was
added. Alternatively, the mixture was protected from light and AgOTf (1 equiv.) was used.
After stirring at room temperature, when no evolution was observed through TLC monitoring,
the reaction mixture was diluted with EtOAc and filtered through a plug of Celite. In the case
of AgOTfꢀpromoted reactions, a few drops of Et3N were added to neutralize the reaction prior
to dilution and filtration. The filtrate was concentrated under reduced pressure and the
resulting crude material was purified by column chromatography on silica gel (cyclohexane/
ethyl acetate ratio 4:1).
4ꢀNitrophenyl
2,3,5,6ꢀtetraꢀ
OꢀbenzoylꢀβꢀDꢀgalactofuranosylꢀ(1→3)ꢀ6ꢀOꢀtert-
butyldimethylsilylꢀαꢀ
Dꢀmannopyranoside (5b): Synthesized according to general procedure
starting from 6ꢀOꢀTBSꢀmannopyranoside 2b (63 mg, 0.15 mmol), galactofuranosyl bromide
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1a (200 mg, 0.30 mmol), 2ꢀDPBA (34 mg, 0.15 mmol) and Ag2O (35 mg, 0.15 mmol).
Reaction reached completion after 6 h. Purification by column chromatography on silica gel
afforded 5b (70 mg, 46%) as a white solid. Further elution allowed isolating the
corresponding orthoester 6b (37 mg, 24%).
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5b:
+ 12 (c 1, CH2Cl2). H NMR (CDCl3): δH 8.19 (2H, d, J = 9.3 Hz, HAr), 8.10, 8.04,
7.99, 7.93 (8H, 4dd, J = 8.3 Hz, J = 1.2 Hz, HAr), 7.61ꢀ7.29 (12H, m, HAr), 7.15 (2H, d, HAr),
6.03ꢀ5.98 (1H, m, Hꢀ5b), 5.76 (1H, dd, J3b,4b = 5.8 Hz, J3b,2b = 2 Hz, Hꢀ3b), 5.70 (1H, d, J1a,2a
= 1.5 Hz, Hꢀ1a), 5.55 (1H, bs, Hꢀ1b), 5.49 (1H, dd, J2b,1b = 0.7 Hz, Hꢀ2b), 4.95 (1H, dd, J4b,5b
= 3.6 Hz, Hꢀ4b), 4.80 (2H, d, J6b,5b = 4.9 Hz, Hꢀ6b), 4.28 (1H, bs, Hꢀ2a), 4.14 (1H, dd, J3a,2a
=
3.3 Hz, J3a,4a = 9.3 Hz, Hꢀ3a), 4.02 (1H, app. td, J4a,5a = 9.6 Hz, J4a,OH = 2.7 Hz, Hꢀ4), 3.87
(1H, dd, J6a,6‘a = 11 Hz, J6a,5a = 4.2 Hz, Hꢀ6a), 3.81 (1H, dd, J6‘a,5a = 5.4 Hz, Hꢀ6‘a), 3.65ꢀ3.58
(1H, m, Hꢀ5a), 3.17 (1H, d, OH), 2.94 (1H, d, JOH,2a = 2.5 Hz, OH), 0.84 (9H, s, tBuꢀSi), 0.04
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[6H, s, OSi(CH3)2]. C NMR (CDCl3): δC 166.3, 166.2, 165.7, 165.6 (COPh), 160.8, 142.6
(CpNP), 133.8, 133.7, 133.4, 133.2, 130.2, 129.9, 129.8, 129.4, 129.3, 128.8, 128.5, 128.4
(CPh), 125.8, 116.5 (CpNP), 103.8 (Cꢀ1b), 97.7 (Cꢀ1a), 83.1 (Cꢀ2b), 81.2 (Cꢀ4b), 77.3 (Cꢀ3a),
76.8 (Cꢀ3b), 73.0 (Cꢀ5a), 70.1 (Cꢀ5b), 67.5 (Cꢀ2a), 66.8 (Cꢀ4a), 63.6 (Cꢀ6a), 63.3(Cꢀ6b), 25.8
[SiC(CH3)3], 18.2 [SiC(CH3)3], ꢀ5.5, ꢀ5.4 [OSi(CH3)2]. HRMS (ESI/QꢀTOF) m/z: [M+Na]+
Calcd for C52H55NO17SiNa 1016.3137 ; Found 1016.3134.
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6b:
+ 65 (c 1, CH2Cl2). H NMR (CDCl3): δH 8.16 (2H, d, J = 9.3 Hz, HAr), 7.97, 7.93,
7.86, 7.76 (8H, 4dd, J = 8.5 Hz, J = 1.3 Hz, HAr), 7.61ꢀ7.30 (12H, m, HAr), 7.06 (2H, d, J =
9.3 Hz, HAr), 6.47 (1H, d, J1b,2b = 4.4 Hz, Hꢀ1b), 5.56 (1H, dd, J3b,4b = 3.5 Hz, J3b,2b = 0.9 Hz,
Hꢀ3b), 5.47 (1H, d, J2a,1a = 1.8 Hz, Hꢀ1a), 5.37ꢀ5.32 (1H, m, Hꢀ5b), 5.30 (1H, dd, Hꢀ2b), 4.69
(1H, dd, J4b,5b = 8.0 Hz, Hꢀ4b), 4.56 (1H, dd, J6b,6‘b = 12.5 Hz, J6b,5b = 3.9 Hz, Hꢀ6b), 4.38 (1H,
dd, J6‘b,5b = 4.9 Hz, Hꢀ6‘b), 4.08 (1H, dd, J3a,2a = 3,3 Hz, J3a,4a = 9.4 Hz, Hꢀ3a), 3.93 (1H,
app.td, J4a,5a = 9.5 Hz, J4a,OH = 2 Hz, Hꢀ4a), 3.78 (2H, d, J6a,5a = 4.3 Hz, Hꢀ6a), 3.64 (1H, br s,
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Hꢀ2a), 3.58ꢀ3.53 (1H, m, Hꢀ5a), 3.04 (1H, d, OH), 2.37(1H, d, JOH,2a = 2.8 Hz, OH), 0.83 (9H,
s, tBuꢀSi), 0.02 [6H, s, OSi(CH3)2]. 13C NMR (CDCl3): δC 165.6, 165.3, 165.2 (COPh), 160.8,
142.6 (CpNP), 136.1, 133.7, 133.4, 133.2, 133.1, 130.0, 129.9, 129.8, 129.6, 129.5, 129.4,
128.6, 128.5, 128.3, 128.2, 125.8 (CPh), 125.7 (CpNP), 123.3 (PhCO3), 116.3 (CpNP), 105.3 (Cꢀ
1b), 97.4 (Cꢀ1a), 85.7 (Cꢀ2b), 83.9 (Cꢀ4b), 76.8 (Cꢀ3b), 73.7 (Cꢀ3a), 72.7 (Cꢀ5a), 71.2 (Cꢀ5b),
69.0 (Cꢀ2a), 67.3 (Cꢀ4a), 64.0 (Cꢀ6a), 62.8 (Cꢀ6b), 25.8 [SiC(CH3)3], 18.3 [SiC(CH3)3], ꢀ5.5, ꢀ
5.6 [OSi(CH3)2]. HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C52H55NO17SiNa 1016.3137 ;
Found 1016.3130.
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4ꢀNitrophenyl
2,3,5,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactofuranosylꢀ(1→3)ꢀ6ꢀOꢀacetylꢀαꢀDꢀ
mannopyranoside (5c): Synthesized according to general procedure starting from 6ꢀOꢀAcꢀ
mannopyranoside 2c (52 mg, 0.15 mmol), galactofuranosyl bromide 1a (200 mg, 0.30 mmol),
2ꢀDPBA (34 mg, 0.15 mmol) and Ag2O (35 mg, 0.15 mmol). Reaction reached completion
after 2 h. Purification by column chromatography on silica gel afforded 5c (119 mg, 85%) as
a white solid. 20 + 37.5 (c 0.8, CH2Cl2). 1H NMR (CDCl3): δH 8.20 (2H, d, J = 9.3 Hz, HAr),
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8.11, 8.02, 7.99, 7.93 (8H, 4 dd, J = 1.3 Hz, J = 8.4 Hz, HAr), 7.60ꢀ7.32 (12H, m, HAr), 7.14
(2H, d, HAr), 5.99ꢀ5.94 (1H, m, Hꢀ5b), 5.77 (1H, dd, J3b,2b = 2.2 Hz, J3b,4b = 6.0 Hz, Hꢀ3b),
5.71 (1H, d, J1a,2a = 1.5 Hz, Hꢀ1a), 5.54 (1H, br s, Hꢀ1b), 5.49 (1H, dd, J2b,1b = 0.7 Hz, Hꢀ2b),
4.95 (1H, dd, J4b,5b = 3.7 Hz, Hꢀ4b), 4.83 (1H, dd, J6b,6‘b = 11.9 Hz, J6b,5b = 4.8 Hz, Hꢀ6b), 4.78
(1H, dd, J6‘b,5b = 6.1 Hz, Hꢀ6‘b), 4.39 (1H, dd, J6a,5a = 5.2 Hz, J6a,6‘a = 12.2 Hz, Hꢀ6a), 4.31
(1H, br s, Hꢀ2a), 4.27 (1H, dd, J6‘a,5a = 2.2 Hz, Hꢀ6‘a), 4.13 (1H, dd, J3a,2a = 3.3 Hz, J3a,4a = 9.3
Hz, Hꢀ3), 3.96 (1H, app. td, J4a,OH = 3.4 Hz, J4a,5a = 9.7Hz, Hꢀ4a), 3.74 (1H, ddd, Hꢀ5a), 3.24
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(1H, d, OH), 3.08 (1H, d, J2a,OH = 1.9 Hz, OH), 2.04 (3H, s, CH3CO). C NMR (CDCl3): δC
171.3 (COCH3), 166.3, 165.6 (COPh), 160.6, 142.8, 133.8, 133.7, 133.5, 133.3, 130.0, 129.9,
129.8, 129.4, 129.3, 128.7, 128.6, 128.5, 128.4, 125.7, 116.4 (CAr), 103.9 (Cꢀ1b), 97.8 (Cꢀ1a),
83.3 (Cꢀ2b), 81.0 (Cꢀ4b), 77.0 (Cꢀ3a),76.7 (Cꢀ3b), 71.7 (Cꢀ5a), 70.0 (Cꢀ5b), 67.6 (Cꢀ2a), 65.3
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(Cꢀ4a), 63.1, 63.0 (Cꢀ6a, Cꢀ6b), 20.8 (CH3CO). HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for
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C48H43NO18Na 944.23723 ; Found 944.2391.
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Octyl 2,3,5,6ꢀOꢀbenzoylꢀβꢀDꢀgalactofuranosyl)ꢀ(1→3)ꢀ6ꢀOꢀacetylꢀαꢀDꢀmannopyranoside
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(8a): Synthesized according to general procedure starting from 6ꢀOꢀAcꢀmannopyranoside 4a
(51 mg, 0.15 mmol), galactofuranosyl bromide 1a (200 mg, 0.30 mmol), 2ꢀDPBA (34 mg,
0.15 mmol) and Ag2O (35 mg, 0.15 mmol). Reaction reached completion after 2 h.
Purification by column chromatography on silica gel afforded 8a (56 mg, 40%) as a white
solid. Further elution allowed isolating the corresponding orthoester 9a (68 mg, 49%).
Alternative protocol using 4a (44 mg, 0.13 mmol), 1a (176 mg, 0.27 mmol), 2ꢀDPBA (30 mg,
0.13 mmol) and AgOTf (34 mg, 0.13 mmol) as promoter gave 8a (70 mg, 57%) in mixture
with the octyl βꢀDꢀGalfꢀ(1
→4)ꢀDꢀManp regioisomer (ratio 4:1).
8a: 20 + 6 (c 1.5, CHCl3). 1H NMR (CDCl3): δH 8.13ꢀ7.88 (8H, m, HAr), 7.62ꢀ7.47 (4H, m,
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HAr), 7.46ꢀ7.28 (8H, m, HAr), 5.96 (1H, dt, J5b,6’b = 6.2 Hz, J5b,6b = 4.7 Hz, J5b,4b = 3.8 Hz, Hꢀ
5b), 5.73 (1H, dd, J3b,4b = 5.8 Hz, J3b,2b = 1.9 Hz, Hꢀ3b), 5.51ꢀ5.46 (2H, m, Hꢀ1b, Hꢀ2b), 4.91
(1H, dd, Hꢀ4b), 4.89 (1H, d, J1a,2a = 1.6 Hz, Hꢀ1a), 4.80 (1H, dd, J6b,6’b = 11.9 Hz, Hꢀ6b), 4.74
(1H, dd, Hꢀ6’b), 4.40 (1H, dd, J6a,6’a = 11.9 Hz, J6a,5a = 4.7 Hz, Hꢀ6a), 4.36 (1H, dd, J6’a,5a
=
2.8 Hz, Hꢀ6’a), 4.07 (1H, dd, J2a,3a = 3.3 Hz, Hꢀ2a), 3.95 (1H, dd, J3a,4a = 9.2 Hz, Hꢀ3a), 3.86
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(1H, dd, J4a,5a = 9.7 Hz, Hꢀ4a), 3.77 (1H, ddd, Hꢀ5a), 3.66 (1H, dt, J = 9.7 Hz, J = 6.8 Hz,
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OCH2), 3.42 (1H, dt, J = 6.6 Hz, OCH2), 2.11 (3H, s, COCH3) 1.56 (2H, m, OCH2CH2),
1.36–1.20 (10H, m, (CH2)5CH3), 0.87 (3H, t, 3J = 6.9, CH2CH3). 13C NMR (CDCl3): δC 171.5,
166.4, 166.2, 165.8, 165.7 (CO), 134.8, 133.8, 133.5, 133.3, 130.1, 130.1, 130.0, 129.9,
129.6, 129.5, 128.9, 128.7, 128.6, 128.6, 128.5, 128.0 (CAr), 104.4 (Cꢀ1b), 99.5 (Cꢀ1a), 83.1
(Cꢀ2b), 81.2 (Cꢀ4b), 78.8 (Cꢀ3a), 77.0 (Cꢀ3b), 70.4 (Cꢀ5a), 70.3 (Cꢀ5b), 68.6 (Cꢀ2a), 68.1
(OCH2), 66.0 (Cꢀ4a), 63.8 (Cꢀ6a), 63.2 (Cꢀ6b), 32.0, 29.5, 29.5, 29.3, 26.2, 22.8 [(CH2)6CH3],
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21.1 (COCH3), 14.2 (CH2CH3). HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C50H56O16Na
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935.34606 ; Found 935.3467.
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9a: 1H NMR (CDCl3): δH 7.97ꢀ7.91 (2H, m, HAr), 7.91ꢀ 7.83 (4H, m, HAr), 7.75ꢀ7.70 (2H, m,
HAr), 7.60ꢀ 7.54 (1H, m, HAr), 7.53ꢀ7.46 (2H, m, HAr), 7.42ꢀ7.36 (5H, m, HAr), 7.36ꢀ7.28 (4H,
m, HAr), 6.36 (1H, d, J1b,2b = 4.4 Hz, Hꢀ1b), 5.51 (1H, dd, J3b,4b = 4.2 Hz, J3b,2b = 1.5 Hz, Hꢀ
3b), 5.28 (1H, ddd, J5b,4b = 7.6 Hz, J5b,6’b = 5.0 Hz, J5b,6b = 3.9 Hz, Hꢀ5b), 5.23 (1H, dd, Hꢀ2b),
4.71 (1H, d, J1a,2a = 1.7 Hz, Hꢀ1a), 4.62 (1H, dd, Hꢀ4b), 4.51 (1H, dd, J6b,6’b = 12.4 Hz, Hꢀ6b),
4.42 (1H, dd, J6a,6’a = 12.1 Hz, J6a,5a = 4.6 Hz, Hꢀ6a), 4.33 (1H, dd, Hꢀ6’b), 4.27 (1H, dd, J6’a,5a
= 2.1 Hz, Hꢀ6’a), 3.90 (1H, dd, J3a,4a = 8.8 Hz, J3a,2a = 3.3 Hz, Hꢀ3a), 3.79ꢀ3.67 (2H, m, Hꢀ4a,
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H5a), 3.63ꢀ3.55 (2H, m, Hꢀ2a, OCH2), 3.33 (1H, dt, J = 9.7 Hz, J = 6.6 Hz, OCH2), 2.87
(1H, d, JOH,4a = 2.8 Hz, OH), 2.17 (1H, d, JOH,2a = 3.2 Hz, OH), 2.09 (3H, s, COCH3), 1.56ꢀ
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1.46 (2H, m, OCH2CH2), 1.31ꢀ1.23 (10H, m, (CH2)5CH3), 0.88 (3H, t, J = 6.9 Hz,
(CH2)5CH3). 13C NMR (CDCl3): δC 171.7 (COCH3), 165.8, 165.4, 165.3 (COPh), 136.6,
133.8, 133.2, 133.2, 130.1, 130.0, 129.9, 129.8, 129.6, 128.7, 128.6, 128.5, 128.4, 126.2 (CAr),
123.9 (PhCO3), 105.1 (Cꢀ1b), 99.3 (Cꢀ1a), 86.0 (Cꢀ2b), 83.1 (Cꢀ4b), 76.7 (Cꢀ3b), 74.5 (Cꢀ3a),
71.2 (Cꢀ5b), 70.6 (Cꢀ5a), 70.2 (Cꢀ2a), 68.0 (OCH2), 65.6 (Cꢀ4a), 63.7 (Cꢀ6a), 62.9 (Cꢀ6b),
31.9, 29.4, 29.4, 29.4, 26.2, 22.8 [(CH2)6CH3], 21.0 (COCH3), 14.2 [(CH2)6CH3]. HRMS
(ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C50H56O16Na 935.34606 ; Found 935.3465.
Thiotolyl
2,3,5,6ꢀOꢀbenzoylꢀβꢀDꢀgalactofuranosyl)ꢀ(1→3)ꢀ6ꢀOꢀacetylꢀαꢀDꢀ
mannopyranoside (8b): Synthesized according to general procedure starting from thiotolyl
6ꢀOꢀAcꢀmannopyranoside 4b (50 mg, 0.15 mmol), galactofuranosyl bromide 1a (200 mg,
0.30 mmol), 2ꢀDPBA (34 mg, 0.15 mmol) and Ag2O (35 mg, 0.15 mmol). Reaction reached
completion after 2 h. Purification by column chromatography on silica gel afforded 8b (131
mg, 96%) as a white solid.
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Alternative protocol using 4b (50 mg, 0.15 mmol), 1a (200 mg, 0.30 mmol), 2ꢀDPBA (34 mg,
0.14 mmol) and AgOTf (39 mg, 0.15 mmol) as promoter gave 8b (94 mg, 69%).
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8b: 20 + 60 (c 1.15, CH2Cl2). 1H NMR (CDCl3): δH 8.11 (2H, dd, 3J = 8.4 Hz, 4J = 1.3 Hz,
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7.61ꢀ7.51 (4H, m, HAr), 7.46ꢀ7.31 (10H, m, HAr), 7.12 (2H, d, 3J = 8.0 Hz, HTol), 5.94 (1H, td,
J5b,6b = 5.3 Hz, J5b,4b = 3.6 Hz, Hꢀ5b), 5.73 (1H, dd, J3b,4b = 5.9 Hz, J3b,2b = 2.2 Hz, Hꢀ3b), 5.54
(1H, d, J1a,2a = 1.4 Hz, Hꢀ1a), 5.48 (1H, d, J1b,2b = 0.8 Hz, Hꢀ1b), 5.48 (1H, dd, Hꢀ2b), 4.92
(1H, dd, Hꢀ4b), 4.80 (2H, d, Hꢀ6b), 4.41 (1H, dd, J6a,6’a = 12.1 Hz, J6a,5a = 5.9 Hz, Hꢀ6a), 4.37ꢀ
4.30 (3H, m, Hꢀ2a, Hꢀ5a, Hꢀ6’a), 3.98ꢀ3.88 (2H, m, Hꢀ3a, Hꢀ4a), 3.19 (1H, d, JOH,4a = 3.8 Hz,
OH), 2.33 (3H, s, CH3), 2.07 (3H, s, COCH3). 13C NMR (CDCl3): δC 171.4, 166.5, 166.2,
165.8, 165.7 (CO), 138.1, 133.9, 133.6, 133.4, 132.5, 130.1, 130.0, 129.6, 129.5, 128.9,
128.7, 128.6 (CAr), 104.1 (Cꢀ1b), 87.8 (Cꢀ1a), 83.2 (Cꢀ2b), 81.4 (Cꢀ4b), 78.3 (Cꢀ3a), 77.0 (Cꢀ
3b), 71.4 (Cꢀ5a), 70.2 (Cꢀ5b), 69.6 (Cꢀ2a), 66.4 (Cꢀ4a), 63.8 (Cꢀ6a), 63.2 (Cꢀ6b), 21.3 (CH3),
21.0 (COCH3). HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C49H46O15SNa 929.24496 ;
Found 929.2455.
p
ꢀNitrophenyl (2, 3, 5, 6ꢀOꢀtetrabenzoylꢀβꢀDꢀgalactofuranosyl)ꢀ(1→3)ꢀ6ꢀOꢀacetylꢀβꢀDꢀ
galactopyranoside (17): Synthesized according to general procedure starting from pNP 6ꢀOꢀ
Acꢀgalactopyranoside 12 (52 mg, 0.15 mmol), galactofuranosyl bromide 1a (200 mg, 0.30
mmol), 2ꢀDPBA (34 mg, 0.15 mmol) and Ag2O (35 mg, 0.15 mmol). Reaction reached
completion after 2 h. Purification by column chromatography on silica gel afforded 17 (121
mg, 86%) as a white solid. 20 ꢀ 26.5 (c 1, CHCl3). 1H NMR (CDCl3): δH 8.20 (2H, d, J = 9.4
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Hz, HpNP), 8.12ꢀ8.06 (2H, m, HBz), 8.04ꢀ7.97 (4H, m, HBz), 7.95ꢀ7.89 (2H, m, HBz), 7.62ꢀ7.51
(3H, m, HBz), 7.47ꢀ7.29 (9H, m, HBz), 7.12 (2H, d, HpNP), 5.97 (1H, ddd, J5b,6’b = 6.3 Hz, J5b,6’b
= 5.0 Hz, J5b,4b = 3.8 Hz, Hꢀ5b), 5.75 (1H, dd, J3b,4b = 5.8 Hz, J3b,2b = 2.2 Hz, Hꢀ3b), 5.69 (1H,
d, J1b,2b = 0.9 Hz Hꢀ1b), 5.56 (1H, dd, Hꢀ2b), 4.99 (1H, d, J1a,2a = 7.8 Hz, Hꢀ1a), 4.83 (1H, dd,
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J6b,6’b = 11.8, Hꢀ6b), 4.80 (1H, dd, Hꢀ4b), 4.71 (1H, dd, Hꢀ6’b), 4.34 (1H, dd, J6a,6’a = 11.7 Hz,
J6a,5a = 7.6 Hz, Hꢀ6a), 4.24 (1H, dd, J6’a,5a = 4.8 Hz, Hꢀ6’a), 4.22 (1H, dd, J2a,3a = 9.4 Hz, Hꢀ
2a), 4.10 (1H, dd, J4a,3a = 3.4 Hz, J4a,5a = 1.1 Hz, Hꢀ4a), 3.86 (1H, ddd, Hꢀ5a), 3.79 (1H, dd,
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Hꢀ3a), 2.08 (3H, s, CH3). C NMR (CDCl3): δC 170.8, 166.3, 166.3, 165.8, 165.7 (COPh),
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161.8 (CpNP), 142.9 (CpNP), 133.9, 133.6, 133.5, 130.1, 130.0, 129.9, 129.4, 128.7, 128.6,
128.5 (CBz), 125.7 (CpNP), 116.7 (CpNP), 107.9 (Cꢀ1b), 100.2 (Cꢀ1a), 83.1 (Cꢀ2b), 81.6 (Cꢀ4b),
80.7 (Cꢀ3a), 77.0 (Cꢀ3b), 72.9 (Cꢀ5a), 70.2 (Cꢀ2a, Cꢀ5b), 68.5 (Cꢀ4a), 63.0 (Cꢀ6a, Cꢀ6b), 20.9
(CH3). HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C48H43NO18Na 944.23723 ; Found
944.2368.
p
ꢀNitrophenyl (2, 3, 5, 6ꢀtetraꢀ
acetylꢀ2ꢀdeoxyꢀ ꢀgalactopyranoside (18): Synthesized according to general procedure
starting from pNP 6ꢀOꢀacetylꢀβꢀ ꢀNꢀacetylgalactosamine 14 (58 mg, 0.15 mmol),
OꢀbenzoylꢀβꢀDꢀgalactofuranosyl)ꢀ(1→3)ꢀ2ꢀacetamidoꢀ6ꢀOꢀ
β
ꢀD
D
galactofuranosyl bromide 1a (200 mg, 0.30 mmol), 2ꢀDPBA (34 mg, 0.15 mmol) and Ag2O
(35 mg, 0.15 mmol). Reaction reached completion after 2 h. Purification by column
chromatography on silica gel afforded 18 (14 mg, 10%) as a light brown solid. Further elution
allowed isolating the corresponding orthoester 18’ (54 mg, 37%).
Alternative protocol using 14 (58 mg, 0.15 mmol), 1a (200 mg, 0.30 mmol), 2ꢀDPBA (34 mg,
0.15 mmol) and AgOTf (39 mg, 0.15 mmol) as promoter gave 18 (80 mg, 55%) in mixture
with the pNP βꢀDꢀGalfꢀ(1→
4)ꢀDꢀGalNHAc regioisomer (ratio 4:1).
1
3
18: H NMR (CD3OD+CDCl3): δH 8.15 (2H, d, J = 9.2 Hz, HpNP), 8.10ꢀ8.03 (2H, m, HBz),
8.02ꢀ7.93 (4H, m, HBz), 7.87ꢀ7.81 (2H, m, HBz), 7.57ꢀ7.50 (3H, m, HBz), 7.44ꢀ7.27 (9H, m,
HBz), 7.06 (2H, d, HpNP), 5.95 (1H, ddd, J5b,6’b = 6.7 Hz, J5b,6b = 4.4 Hz, J5b,4b = 4.0 Hz, Hꢀ5b),
5.68 (1H, d, J1a,2a = 8.2 Hz, Hꢀ1a), 5.66 (1H, dd, J3b,4b = 5.4 Hz, J3b,2b = 1.9 Hz, Hꢀ3b), 5.43
(1H, d, Hꢀ2b), 5.37 (1H, s, Hꢀ1b), 4.84 (1H, dd, Hꢀ4b), 4.76 (1H, dd, J6b,6’b = 11.8 Hz, Hꢀ6b),
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4.67 (1H, dd, Hꢀ6’b), 4.49 (1H, dd, J3a,2a = 10.8 Hz, J3a,4a = 3.3 Hz, Hꢀ3a), 4.30 (1H, dd, J6a,6’a
= 11.7 Hz, J6a,5a = 7.9 Hz, Hꢀ6a), 4.16 (1H, dd, J6’a,5a = 4.5 Hz, Hꢀ6’a), 4.09 (1H, d, Hꢀ4a),
3.89 (1H, dd, Hꢀ5a), 3.80 (1H, dd, Hꢀ2a), 2.03 (3H, s, CH3), 1.93 (3H, s, CH3). 13C NMR
(CD3OD+CDCl3): δC 172.4, 171.0 (COCH3), 166.4, 166.2, 165.9, 165.9 (COPh), 161.9
(CpNP), 142.8 (CpNP), 133.9, 133.6, 133.5, 130.1, 130.0, 129.9, 129.8, 129.4, 128.7, 128.6,
128.5 (CBz), 125.7 (CpNP), 116.7 (CpNP), 107.9 (Cꢀ1b), 97.0 (Cꢀ1a), 83.0 (Cꢀ2b), 81.2 (Cꢀ4b),
77.4 (Cꢀ3b), 76.8 (Cꢀ3a), 72.8 (Cꢀ5a), 70.3 (Cꢀ5b), 68.2 (Cꢀ4a), 63.3 (Cꢀ6a, Cꢀ6b), 53.4 (Cꢀ
2a), 23.3, 20.8 (COCH3). HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C50H46N2O18Na
985.26378 ; Found 985.2646.
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18’: 1H NMR (CDCl3): δH 8.14 (2H, d, 3J = 9.3 Hz, HpNP), 7.93ꢀ7.88 (2H, m, HBz), 7.86ꢀ7.80
(4H, m, HBz), 7.73ꢀ7.68 (2H, m, HBz), 7.59ꢀ7.46 (3H, m, HBz), 7.43ꢀ7.27 (9H, m, HBz), 7.04
(2H, d, HpNP), 6.21 (1H, d, J1b,2b = 4.3 Hz, Hꢀ1b), 5.84 (1H, d, J1a,2a = 8.3 Hz, Hꢀ1a), 5.76 (1H,
d, J=7.0, NH), 5.40 (1H, dd, J3b,4b = 5.4 Hz, J3b,2b = 1.8 Hz, Hꢀ3b), 5.19 (1H, ddd, J5b,4b = 7.0
Hz, J5b,6’b = 5.3 Hz, J5b,6b = 3.7 Hz, Hꢀ5b), 5.10 (1H, dd, Hꢀ2b), 4.63 (1H, dd, J3a,2a = 10.6 Hz,
J3a,4a = 3.0 Hz, Hꢀ3a), 4.51 (1H, dd, Hꢀ4b), 4.42 (1H, dd, J6b,6’b = 12.4 Hz, Hꢀ6b), 4.32 (2H, d,
J6a, 5a = 6.2 Hz, Hꢀ6a), 4.24 (1H, dd, Hꢀ6’b), 4.10 (1H, t, J4a,3a = J4a,OH = 3.0 Hz, Hꢀ4a), 3.92
(1H, t, Hꢀ5a), 3.54 (1H, ddd, J2a,NH = 7.0 Hz, Hꢀ2a), 2.46 (1H, d, OH), 2.07 (3H, s, OCOCH3),
13
1.98 (3H, s, NHCOCH3). C NMR (CDCl3): δC 171.9 (NHCO), 170.9 (OCO), 165.8, 165.4
(COPh), 161.9 (CpNP), 142.9 (CpNP), 137.4, 133.9, 133.3, 133.2, 130.2, 129.9, 129.8, 129.5,
128.7, 128.6, 128.5, 128.4, 126.2 (CAr), 125.8 (CpNP), 124.8 (PhCO3), 116.7 (CpNP), 104.5 (Cꢀ
1b), 96.6 (Cꢀ1a), 86.4 (Cꢀ2b), 81.2 (Cꢀ4b), 76.4 (Cꢀ3b), 72.7 (Cꢀ5a), 71.0 (Cꢀ5b), 70.0 (Cꢀ3a),
68.2 (Cꢀ4a), 63.2 (Cꢀ6a), 62.7 (Cꢀ6b), 53.9 (Cꢀ2a), 24.0 (NHCOCH3), 21.0 (OCOCH3).
HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C50H46N2O18Na 985.26378 ; Found 985.2632.
p
ꢀNitrophenyl
(2,
3,
5,
6ꢀtetraꢀ
O
ꢀbenzoylꢀ
β
ꢀDꢀgalactofuranosyl)ꢀ(1
→
3)ꢀαꢀ
Lꢀ
rhamnopyranoside (19): Synthesized according to general procedure starting from pNP
αꢀ
Lꢀ
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rhamnopyranoside 15 (43 mg, 0.15 mmol), galactofuranosyl bromide 1a (200 mg, 0.30
mmol), 2ꢀDPBA (34 mg, 0.15 mmol) and Ag2O (35 mg, 0.15 mmol). Reaction reached
completion after 2 h. Purification by column chromatography on silica gel afforded 19 (58
mg, 45%) as a light brown foam. Further elution allowed isolating the corresponding
orthoester 19’ (43 mg, 33%).
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Alternative protocol using 15 (43 mg, 0.15 mmol), 1a (200 mg, 0.30 mmol), 2ꢀDPBA (34 mg,
0.15 mmol) and AgOTf (39 mg, 0.15 mmol) as promoter gave 19 (77 mg, 59%) in mixture
with the pNP βꢀDꢀGalfꢀ(1→4)ꢀLꢀRhap regioisomer (ratio 9:1).
3
19: 20 ꢀ90 (c 0.8, CHCl3). 1H NMR (CDCl3): δH 8.20 (2H, d, J = 9.3 Hz, HpNP), 8.10 (2H,
ʞ
ʟ
͸
dd, 3J = 8.4 Hz, 4J = 1.3 Hz, HBz), 8.05ꢀ7.90 (6H, m, HBz), 7.62ꢀ7.48 (4H, m, HBz), 7.47ꢀ7.40
(2H, m, HBz), 7.39ꢀ7.31 (6H, m, HBz), 7.11 (2H, d, HpNP), 5.94 (1H, ddd, J5b,6’b = 6.2 Hz, J5b,6b
= 5.6 Hz, J5b,4b = 3.5 Hz, Hꢀ5b), 5.78 (1H, dd, J3b,4b = 6.2 Hz, J3b,2b = 2.7 Hz, Hꢀ3b), 5.65 (1H,
d, J1b,2b = 1.1 Hz, Hꢀ1b), 5.54 (1H, dd, Hꢀ2b), 5.49 (1H, d, J1a,2a = 1.9 Hz, Hꢀ1a), 4.87 (1H, dd,
J6b,6’b = 11.8 Hz, Hꢀ6b), 4.84 (1H, dd, Hꢀ4b), 4.69 (1H, dd, Hꢀ6’b), 4.26 (1H, dd, J2a,3a = 3.4
Hz, Hꢀ2a), 4.05 (1H, dd, J3a,4a = 9.3 Hz, Hꢀ3a), 3.81 (1H, t, J4a,3a = J4a,5a = 9.3 Hz, Hꢀ4a), 3.71
13
(1H, qd, J5a,CH3 = 6.2 Hz, Hꢀ5a), 3.12 (1H, s, OH), 2.86 (1H, s, OH), 1.31 (3H, d, CH3). C
NMR (CDCl3): δC 166.6, 166.5, 165.8, 165.7 (COPh), 161.0 (CpNP), 142.7 (CpNP), 134.9,
134.0, 133.9, 133.7, 133.5, 130.2, 130.1, 130.0, 129.9, 129.4, 128.7, 128.7, 128.7, 128.6,
128.5, 128.1 (CPh), 125.9 (CpNP), 116.4 (CpNP), 108.6 (Cꢀ1b), 97.8 (Cꢀ1a), 83.9 (Cꢀ2b), 81.0
(Cꢀ3a,Cꢀ4b), 76.7 (Cꢀ3b), 71.3 (Cꢀ4a), 70.3 (Cꢀ2a), 70.1 (Cꢀ5b), 69.4 (Cꢀ5a), 63.0 (Cꢀ6b),
17.8. (CH3). HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for C46H41NO16Na 886.23175 ; Found
886.2322.
19’: 1H NMR (CDCl3): δH 8.14 (2H, d, 3J = 9.2 Hz, HpNP), 7.96ꢀ7.91 (2H, m, HBz), 7.89ꢀ7.84
(4H, m, HBz), 7.79ꢀ7.73 (2H, m, HBz), 7.61ꢀ7.55 (1H, m, HBz), 7.54ꢀ7.48 (2H, m, HBz), 7.44ꢀ
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7.30 (9H, m, HBz), 7.05 (2H, d, HpNP), 6.36 (1H, d, J1b,2b = 4.2 Hz, Hꢀ1b), 5.53ꢀ5.49 (2H, m,
Hꢀ1a, Hꢀ3b), 5.28ꢀ5.23 (1H, m, Hꢀ5b), 5.25 (1H, dd, J2b,3b = 1.5 Hz, Hꢀ2b), 4.63 (1H, dd,
J4b,3b = 7.5 Hz, J4b,5b = 4.6 Hz, Hꢀ4b), 4.51 (1H, dd, J6b,6’b = 12.5 Hz, J6b,5b = 3.7 Hz, Hꢀ6b),
4.32 (1H, dd, J6’b,5b = 5.3 Hz, Hꢀ6’b), 4.06 (1H, t, JOH,2a = J2a,3a = 3.1 Hz, Hꢀ2a), 4.00 (1H, dd,
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J3a,4a = 8.8 Hz, Hꢀ3a), 3.69ꢀ3.57 (2H, m, Hꢀ4a, Hꢀ5a), 2.59 (1H, d, OH), 2.52 (1H, d, JOH,4a
=
13
2.4 Hz, OH), 1.26 (3H, d, JCH3,5a = 1.0 Hz, CH3). C NMR (CDCl3): δC 165.8, 165.5, 165.4
(COPh), 161.0 (CpNP), 142.7 (CpNP), 136.6, 134.0, 133.3, 130.1, 129.9, 129.8, 128.7, 128.6,
128.5, 128.4, 126.2 (CBz), 125.9 (CpNP), 124.3 (PhCO3), 116.3 (CpNP), 104.8 (Cꢀ1b), 97.7 (Cꢀ
1a), 86.2 (Cꢀ2b), 82.4 (Cꢀ4b), 76.6 (Cꢀ3b), 74.4 (Cꢀ3a), 71.1 (Cꢀ5b), 70.5 (Cꢀ4a), 70.0 (Cꢀ5a),
69.7 (Cꢀ2a), 62.9 (Cꢀ6b), 17.8 (CH3). HRMS (ESI/QꢀTOF) m/z: [M+Na]+ Calcd for
C46H41NO16Na 886.23175 ; Found 886.2318.
4ꢀNitrophenyl
2,3,5,6ꢀtetraꢀ
Oꢀbenzoylꢀβꢀ
Dꢀgalactofuranosylꢀ(1→6)ꢀβꢀ
D
ꢀ
galactofuranoside (20): Synthesized according to general procedure starting from pNP
β
ꢀD
ꢀ
galactofuranoside 16 (20 mg, 67 µmol), galactofuranosyl bromide 1a (88 mg, 0.13 mmol), 2ꢀ
DPBA (15 mg, 67 µmol) and Ag2O (15 mg, 67 µmol). Reaction reached completion after 2 h.
Purification by column chromatography on silica gel afforded 20 (7 mg, 12%) as a white
solid. Further elution allowed isolating the corresponding orthoester 20’ (35 mg, 56%).
Alternative protocol using 16 (20 mg, 67 µmol), 1a (88 mg, 0.13 mmol), 2ꢀDPBA (15 mg, 65
µmol) and AgOTf (16 mg, 65 µmol) as promoter yielded a 7:1 inseparable mixture of 20 and
pNP βꢀDꢀGalfꢀ(1→5)ꢀDꢀGalf (51% overall yield, 30 mg, 34 ꢁmol).
3
20: 1H NMR (CD3OD): δH 8.11ꢀ8.06 (4H, m, HpNP, HBz), 7.93ꢀ7.81 (6H, 3 dd, J = 8.3 Hz, 4J
3
4
= 1.2 Hz, HBz), 7.66 (1H, td, J = 7.3 Hz, J = 1.2 Hz, HBz), 7.56ꢀ7.22 (11H, m, HBz), 7.03
3
(2H, d, J = 9.3 Hz, HpNP), 5.77 (1H, ddd, J5b,6b = 7.1 Hz, J5b,4b = J5b,6’b = 3.5 Hz, Hꢀ5b), 5.61
(1H, d, J1a,2a = 2.4 Hz, Hꢀ1a), 5.51 (1H, d, J3b,4b = 4.7 Hz, Hꢀ3b), 5.41 (1H, s, Hꢀ1b), 5.39 (1H,
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s, Hꢀ2b), 4.60 (1H, dd, J6b,6’b = 12.1 Hz, Hꢀ6b), 4.42ꢀ4.36 (2H, m, Hꢀ6’b, Hꢀ4b), 4.34 (1H, dd,
J4a,3a = 7.1 Hz, J4a,5a = 1.9 Hz, Hꢀ4a), 4.27 (1H, dd, J3a,2a = 4.9 Hz, Hꢀ3a), 4.15 (1H, dd, Hꢀ2a),
4.04 (1H, ddd, J5a,6’a = 8.6 Hz, J5a,6a = 6.2 Hz, Hꢀ5a), 3.92 (1H, app. t., J6a,6’a = 8.6 Hz, Hꢀ6a),
3.63 (1H, ddd, Hꢀ6’a). 13C NMR (CDCl3) δC 167.6, 167.2, 167.1, 166.8 (COPh), 163.4 (CpNP),
143.6 (CpNP), 134.9, 134.7, 134.6, 134.4, 131.1, 130.8, 130.7, 130.4, 130.3, 129.9, 129.7,
129.5 (CBz), 126.7, 117.4 (CpNP), 107.6 (Cꢀ1a), 106.3 (Cꢀ1b), 84.5 (Cꢀ4a), 83.4 (Cꢀ2a), 83.3
(Cꢀ4b), 83.2 (Cꢀ2b), 79.0 (Cꢀ3b), 77.1 (Cꢀ3a), 71.7 (Cꢀ5b), 68.8 (Cꢀ5a), 67.4 (Cꢀ6a), 64.9 (Cꢀ
6b).
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20’: 1H NMR (CD3OD) δH 8.14 (2H, d, 3J = 9.3 Hz, HpNP), 7.96, 7.83, 7.62 (8H, 3 d, J = 7.9
Hz, HAr), 7.54ꢀ7.27 (12H, m, HAr), 7.18 (2H, d, HpNP), 6.06 (1H, d, J1b,2b = 4.2 Hz, Hꢀ1b), 5.64
(1H, d, J1a,2a = 1.8 Hz, Hꢀ1a), 5.51 (1H, d, J3b,4b = 3.3 Hz, Hꢀ3b), 5.43ꢀ5.38 (1H, m, Hꢀ5b),
5.10 (1H, d, Hꢀ2b), 4.66ꢀ4.59 (2H, m, Hꢀ4b, Hꢀ6b), 4.43 (1H, dd, J6’b,6b = 12.4 Hz, J6’b,5b = 5.5
Hz, Hꢀ6’b), 4.27 (1H, dd, J2a,3a = 4.0 Hz, Hꢀ2a), 4.18 (1H, dd, J3a,4a = 6.4 Hz, Hꢀ3a), 4.11 (1H,
dd, J4a,5a = 2.5 Hz, Hꢀ4a), 3.86 (1H, app. td., J5a,6a = 6.8 Hz, Hꢀ5a), 3.51 (1H, dd, J6a,6’a = 9.4
13
Hz, Hꢀ6a), 3.40 (1H, dd, Hꢀ6’a). C NMR (CDCl3) δC 167.1, 166.7, 166.7 (COPh), 163.2,
143.5 (CpNP), 137.2, 134.7, 134.2, 130.7, 130.6, 130.5, 130.5, 130.3, 130.1, 129.6, 129.4,
129.3, 129.1, 127.5 (CAr), 126.5 (CpNP), 124.6 (CO3Ph), 117.5 (CpNP), 107.5 (Cꢀ1a), 106.5(Cꢀ
1b), 86.8 (Cꢀ2b), 85.2 (Cꢀ4a), 84.6 (Cꢀ4b), 83.3 (Cꢀ2a), 77.9, 77.8(Cꢀ3b, Cꢀ3a), 72.7 (Cꢀ5b),
69.2 (Cꢀ5a), 64.9 (Cꢀ6a), 64.0 (Cꢀ6b).
Acknowledgment. We are grateful to CNRS and the “Ministère de l’enseignement supérieur
et de la recherche” for financial supports, We thanks the “Centre Regional des Mesures
Physiques de l’Ouest (Université de Rennes 1)” for the registration of the mass spectra. This
work was supported by the French Agence Nationale de la Recherche (ANRꢀ10ꢀBLANꢀ
0718).
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Supporting Information Available: Details of the computational calculations and H and
13C NMR spectra of all new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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