Synthesis of arabinofuranose branched galactofuran tetrasaccharides, constituents of mycobacterial arabinogalactan

Article abstract of DOI:10.1039/c0ob00989j

Mycolyl-arabinogalactan (mAG) complex is a major component of the cell wall of Mycobacterium tuberculosis, the causative agent of tuberculosis disease. Due to the essentiality of the cell wall for mycobacterium viability, knowledge of the biosynthesis of

Full text of DOI:10.1039/c0ob00989j

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PAPER
Synthesis of arabinofuranose branched galactofuran tetrasaccharides,
constituents of mycobacterial arabinogalactan†
Luc´ıa Gandolfi-Donad´ıo, Malena Santos, Rosa M. de Lederkremer and Carola Gallo-Rodriguez*
Received 5th November 2010, Accepted 10th December 2010
DOI: 10.1039/c0ob00989j
Mycolyl-arabinogalactan (mAG) complex is a major component of the cell wall of Mycobacterium
tuberculosis, the causative agent of tuberculosis disease. Due to the essentiality of the cell wall for
mycobacterium viability, knowledge of the biosynthesis of the arabinogalactan is crucial for the
development of new therapeutic agents. In this context, we have synthesized two new branched
arabinogalactafuranose tetrasaccharides, decenyl b-D-Galf -(1→5)-b-D-Galf -(1→6)[a-D-Araf -
(1→5)]-b-D-Galf (1) and decenyl b-D-Galf -(1→6)-[a-D-Araf -(1→5)]-b-D-Galf -(1→5)-b-D-Galf (2),
as interesting tools for arabinofuranosyl transferase studies. The aldonolactone strategy for the
introduction of the internal D-Galf was employed, allowing the construction of oligosaccharides from
the non-reducing to the reducing end. Moreover, a one-pot procedure was developed for the synthesis
of trisaccharide lactone 21, precursor of 2, which involved a glycosylation-deprotection-glycosylation
sequence, through the use of TMSOTf as catalyst of the trichloroacetimidate method as well as
promoter of TBDMS deprotection.
complex (mAG-P). The sugar constituents of the AG are in the
furanose form; both are absent in mammals. The galactan region
Introduction
Among the worldwide infectious diseases, tuberculosis causes the
second most deaths after HIV/AIDS.1 There were 9.4 million
new cases in 2008, and although the estimated incidence rates
are falling very slowly, that year showed the highest multidrug-
resistant tuberculosis rate ever recorded.2 In fact, the emergence
of drug-resistant strains of Mycobacterium tuberculosis, together
with the widespread dissemination by global travel, encouraged
consists of a 30 unit linear polymer of alternating b-(1→5) and b-
(1→6)Galf , which are further branched by three arabinan chains
located at positions 8, 10 and 12 from the galactan reducing
end, through an a-D-Araf -(1→5)-D-Galf linkage.11 The 31 unit
long arabinan includes a-(1→5), a-(1→3) and b-(1→2) linkages.
Recently, a model of the entire primary structure of the my-
cobacterial mycolyl-arabinogalactan was proposed which includes
the search for new drugs. Better understanding the biology of
the localization of a succinyl ester residue and the identification
of an inner 14 unit linear arabinan region.12 Understanding the
biosynthesis of the arabinogalactan is important in the context of
new drug development against tuberculosis,13 taking into account
that the integrity of the mycobacterial cell wall is essential for
the viability of mycobacteria.14 Although extensive research has
been performed on the biosynthesis of the arabinogalactan, the
assembly of the polysaccharide was not fully elucidated. Questions
arise on the nature of the assembly that could be on a lipid
carrier, or by introduction of each Araf step-by-step from the
reducing to the non-reducing end or vice versa, or by attachment
of preformed oligosaccharide building blocks, etc.7 The assembly
of the mycolyl-arabinogalactan is sustained by an array of glyco-
syltranferases, some of which have been identified and partially
characterized.15,16
Mycobacteria will help in the development of better diagnosis
and more efficient drugs.3 There are gaps in the knowledge of
the biology of this pathogen, connected also with the life cycle.4
In this context, M. tuberculosis presents a complex cell wall,
rich in lipids and diverse polysaccharides,5–7 which acts as a
robust barrier that is difficult to penetrate. Recently, cryo-electron
microscopy showed that the outer membrane is a thick and
morphologically symmetrical lipid bilayer, despite the presence of
mycolic acids with asymmetrical hydrocarbon chains.8,9 Mycolic
acids are covalently linked to the arabinogalactan, which is
covalently linked to peptidoglycan through a phosphate ester
via a linker disaccharide a-D-GlcNAc-(1→3)-a-L-Rhap.10 This
entity is termed as the mycolyl-arabinogalactan-peptidoglycan
The arabinosyltransferases already characterized are: AftA that
transfers the first Araf to the galactan,17 AftB that completes the
arabinan synthesis by adding a terminal cap of b-Araf -(1→2);18
AftC involved in internal a-1,3-branching of AG19 and very
recently, AftD which also is an a-(1→3) branching enzyme of
AG and lipoarabinomannan (LAM);20 EmbA and EmbB proteins
CIHIDECAR, Departamento de Qu´ımica Orga´nica, Facultad de Ciencias
Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria,
Pabello´n II, 1428 Buenos Aires, Argentina. E-mail: cgallo@qo.fcen.uba.ar;
Fax: +54-11-4576-3352; Tel: +54-11-4576-3346
† Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra for compounds 1, 2, 6, 7, 12, 15, 16, 18–27. See DOI:
10.1039/c0ob00989j
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involved in the formation of the Ara6 motif of AG,21 and EmbC
required for the elongation of the arabinan domain in LAM.22
Synthetic oligosaccharides have been used as tools for the
characterization of these enzymes. For example, the use of
synthetic trisaccharides, constituents of galactofuranan (octyl
b-D-Galf -(1→6)-b-D-Galf -(1→5)-b-D-Galf and octyl b-D-Galf -
(1→5)-b-D-Galf -(1→6)-b-D-Galf ) were useful as substrates for
the transfer of the first Araf residue of the galactan back-
bone, by demonstration that the transference occurred not on
the O-5 of the non-reducing terminal Galf , but on the 6-O-
linked internal Galf .23 The enzymatic products, octyl glyco-
sides of b-D-Galf -(1→5)-b-D-Galf -(1→6)[a-D-Araf (1→5)]-b-D-
Galf and b-D-Galf -(1→6)-[a-D-Araf -(1→5)]-b-D-Galf -(1→5)-
b-D-Galf , were characterized by MALDI-TOF/TOF MS/MS
analysis of their methylated derivatives. Synthetic branched ara-
binose acceptor constituents of AG and LAM arabinan domains
were used to identify a novel arabinofuranosyl transferase activity
of internal a-D-Araf (1→5)transferase that follows an a-3,5-
branch in the acceptor.24 Recently, synthetic oligosaccharides
allowed the development of a plate-based assay to screen inhibitors
of AftB.25
as well as glycosylation methods,38,39 and the difficulty is in-
creased when internal galactofuranosyl linkages are required.
In this sense, the following methods have been employed for
internal linkage construction of several oligosaccharides:31–33,36,40–46
Koenings–Kno¨rr,40a cyanoorthoester,40b–d anomeric acetate,40e
trichloroacetimidate,31,36,41–43 and more recently, thioglycoside,32,44
2¢-carboxybenzyl-glycosides33,45,46 and glycosyl fluoride.33,46 Re-
cently, several galactofuranosyl trisaccharides have been obtained
as by-products by enzymatic procedures.47
From all the galactofuranosyl precursors used to date,32,39,48
we have chosen D-galactone-1,4-lactone as the template for the
internal galactofuranoses in oligosaccharides 1 and 2. We have
succeeded in the use of the glycosyl aldonolactone approach for
the synthesis of oligosaccharides which are constituents of Leish-
mania,41 and Trypanosoma cruzi,43 as well as M. tuberculosis.31,36 As
is known, D-galactono-1,4-lactone can be selectively substituted
and can act as an acceptor in a glycosylation reaction, with the
anomeric carbon virtually protected as a lactone. After reduction
of the lactone function, activation of the anomeric center can be
accomplished by the trichloroacetimidate method. This strategy
allows oligosaccharide construction from the non-reducing to the
reducing end.
The galactan domain of AG is apparently biosynthesized by two
bifunctional galactosyl transferases (GlfT1 and GlfT2).26 By the
use of synthetic acceptors such as galactofuranose trisaccharides
containing b-(1→6) and b-(1→5) linkages, the characterization
of the dual functionality of galactofuranosyl transferase GlfT2
was possible.27,28 Also, the galactofuranosyl transferase (GlfT1)
responsible for attaching the first unit of Galf to decaprenyl-P-P-
GlcNAc-Rha was characterized using synthetic acceptors.26
Additional arabinofuranosyl transferases involved in AG
biosynthesis still remain to be identified and characterized. The
synthesis of oligosaccharides which would allow the characteriza-
tion of these enzymes is required. Our laboratory and other groups
have been involved in the synthesis of oligosaccharide constituents
of the AG of M. tuberculosis, such as arabinan fragments,29,30 galac-
tan fragments,31,32 and more recently, galactan-linker-disaccharide
fragments.32,33 However, there are few reports on the synthesis
of oligosaccharides containing both units, Araf and Galf .34–36
We have synthesized the galactofuranose trisaccharides with
alternating linkages of mycobacterial galactan,31 and we have in-
corporated an Araf 37 in the synthesis of lineal a-D-Araf -(1→5)-b-
D-Galf -(1→5)-b-D-Galf -(1→6)-D-Galf .36 We now report the syn-
thesis of two branched arabinogalactofuranose tetrasaccharides,
decenyl b-D-Galf -(1→5)-b-D-Galf -(1→6)[a-D-Araf (1→5)]-b-D-
Galf (1) and decenyl b-D-Galf -(1→6)-[a-D-Araf -(1→5)]-b-D-
Galf -(1→5)-b-D-Galf (2) (Scheme 1), as useful tools to investigate
the influence of the position of the Araf on the transfer of another
Araf or Galf in the galactan. Compounds 1 and 2 are analogous
structures of those already isolated from the AfTA-promoted
glycosylation of a galactofuranose trisaccharide acceptor.23 In
addition, we also report a one-pot procedure for the preparation
of a branched trisaccharide precursor of 2.
We chose to synthethize 1 and 2 as decenyl glycosides be-
cause the double bound could be further functionalized. In this
sense, recently, galactofuranose-based acceptors for carbohydrate
polymerase GlfT2 have been synthetized by Grubbs olefin cross
metathesis from the corresponding allyl glycosides.49
Retrosynthetic analysis for tetrasaccharide 1 indicated a
2 + 2 retroglycosylation between the already synthesized dis-
accharide trichoroacetimidate 331 and disaccharide lactone 4
(Scheme 1). Compound 4 could be obtained by glycosylation of
D-galacto-1,4-lactone derivative 6 with O-2,3,5-tri-O-benzoyl-a-
D-arabinofuranosyl trichloroacetimidate (5), to give the desired
1,2-trans a-linkage by anchimeric assistance.
On the other hand, retrosynthetic analysis for oligosaccharide 2
indicated a 3 + 1 retroglycosylation between trisaccharide imidate
7 and the already synthesized lactone 831 (Scheme 1). Moreover,
trisaccharide 7 could be synthesized from disaccharide 4, also a
synthon for 1, and 2,3,5,6-tetra-O-benzoyl-b-D-galactofuranosyl
trichloroacetimidate (9).50 It is important to mention that once
the tetrasaccharide lactone was in hand, reduction of the lactone
function would allow either further elongation or decenyl glyco-
side derivatization.
Synthesis of decenyl b-D-Galf -(1→5)-b-D-Galf -(1→6)[a-D-Araf -
(1→5)]-b-D-Galf (1)
For the synthesis of disaccharide lactone 4, we have chosen to
start with the 6-O silyl derivative 6 (Scheme 2), taking into
account that it is a common intermediate for trisaccharide
7 (Scheme 1), precursor of oligosaccharide 2. Compound 6
was synthesized from 2,3-di-O-benzoyl-5,6-O-isopropylidene-D-
galactono-1,4-lactone (10).41,51 Hydrolysis of the isopropylidene
of 10 gave 11 (80%) which was selectively silylated on the primary
6-position with 1.2 equiv. of t-butyldiphenylchlorosilane and
imidazole in DMF to yield 6 (83%). The TBDPS group was
used due to its resistance to acid hydrolysis. On the other hand,
arabinofuranosyl imidate 5 was synthesized from 1,2,3,5-tetra-O-
benzoyl-a,b-D-arabinose (13), which is obtained in one step by
Results and discussion
Synthetic strategies
The synthesis of galactofuranosyl-containing oligosaccharides
involves the choice of convenient galactofuranosyl precursors
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Scheme 1 Retrosynthesis of the target tetrasaccharides 1 and 2.
benzoylation of arabinose in hot pyridine.37,52 Treatment of 13
confirmed the a furanosic linkage. In order to glycosidate the
6-position in this convergent synthesis, the TBDPS group was
removed by treatment of 15 with HF in CH3CN to give 4 in
65% yield. Glycosylation of 4 with disaccharide imidate 331 with
TMSOTf as catalyst in Cl2CH2 at -10 ◦C gave tetrasaccharide
lactone 16 in 58% yield after column chromatography. The
stereochemistry of the new glycosidic linkage was established
as b as indicated by the 13C NMR spectrum that showed
the anomeric new carbon at 105.3 ppm (internal Galf C-1¢),
together with the signals at 107.7 (Araf C-1¢¢¢) and 106.2
(terminal Galf C-1¢¢) ppm. The 1H NMR spectrum showed three
singlets assigned by HETCOR and COSY experiments to the
anomeric hydrogen of terminal Araf (d 5.77, H-1¢¢¢), terminal
with 32% HBr in AcOH, followed by bromide hydrolysis with
the assistance of Ag2CO3 gave the already described 1454 (92%),
53
which was activated as the trichloroacetimidate 554 by reaction
with trichloroacetonitrile and DBU.
Glycosylation of 6 with imidate 5 in the presence of TMSOTf
afforded disaccharide lactone 15 in 80% yield (Scheme 3). The 1H
NMR spectrum showed the resonance of H-1¢ as a singlet and
H-2 as a doublet with a small coupling constant (J = 1.7 Hz)
which are characteristic signals for a-D-Araf , with a 1,2-trans
disposition. The signal at 107.5 ppm in the 13C NMR spectrum
was assigned to the anomeric center (C-1¢), and together with
the downfield signals for C-2¢ and C-4¢ at 82.7 and 81.1 ppm,
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Scheme 2 Synthesis of tetrasaccharide 1 building blocks 5 and 6.
Scheme 3 Synthesis of tetrasaccharide 1.
Galf (d 5.61, H-1¢¢) and the internal Galf (d 4.98, H-1¢) which
confirmed the b configuration. A second fraction from the column
(34%) was identified as the corresponding opened lactone 2,3,5,6-
tetra-O-benzoyl-b-D-galactofuranosyl-(1→5)-3-O-acetyl-2,6-di-
O-pivaloyl-b-D-galactofuranosyl-(1→6)-[2,3,5-tri-O-benzoyl-a-
D-arabinofuranosyl-(1→5)]-2,3-di-O-benzoyl-D-galactonic acid
(17) which was converted into 16 upon warming in Cl3CH at 50 ◦C
for 5 h, raising the total glycosylation yield to 72%. The opened
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lactone byproduct 17 from the glycosylation reaction could not
be avoided even by quenching the reaction with 1 equivalent of
triethylamine. As shown by tlc, the opening occurred on column
purification of the crude mixture.
4 which was already employed for the synthesis of tetrasaccha-
ride 1.
Glycosylation
of
4
with
2,3,4,5-tetra-O-benzoyl-D-
galactofuranosyl trichloroacetimidate 9 yielded the crystalline
trisaccharide lactone 21 in 84% yield (Scheme 4). The two singlets
With tetrasaccharide lactone 16 in hand, reduction of the
lactone function with disiamylborane gave tetrasaccharide 18 in a
moderate yield of 43% as an a : b anomeric mixture in 0.23 : 0.77
ratio, as indicated by the integration of the H-5a (d 6.09) and
1
at 5.78 (Araf H-1¢¢) and 5.27 ppm (Galf H-1¢) in the H NMR
spectrum, as well as the anomeric signals at 107.7 (Araf C-1¢¢)
and 105.2 ppm (Galf C-1¢) indicated the 1,2-trans disposition for
the furanose moieties.
1
H-3b (d 5.83) signals in the H NMR spectrum. Activation of
the anomeric center of 18 with trichloroacetonitrile and DBU at
rt gave trichloroacetimidate 19 in 85% as a 9 : 1 b : a anomeric
mixture, as indicated by the integration of the anomeric signals
at 6.91 (J = 4.5 Hz) and 6.66 ppm in the 1H NMR spectrum. On
reaction of tetrasaccharide imidate 19 with 9-decen-1-ol in Cl2CH2
with TMSOTf as catalyst, decenyl glycoside 20 was obtained
as a single diastereomer b (75%). In the 1H NMR spectrum,
the anomeric hydrogen of the new glycosidic bond resonated at
5.24 ppm as a singlet in agreement with the b-configuration.
Accordingly, in the 13C NMR spectrum, the new anomeric C-1
appeared at 105.3 ppm, corroborating the diastereoselectivity of
the reaction. The other furanose anomeric centers appeared at
106.7 (C-1¢¢¢), 106.0 (C-1¢) and 105.8 (C-1¢¢). Assignments were
supported by COSY and HETCOR experiments. Deacylation of
20 by sodium methoxide in methanol yielded the desired decenyl
b-D-Galf -(1→5)-b-D-Galf -(1→6)[a-D-Araf (1→5)]-b-D-Galf (1)
(78%).
One-pot synthesis of trisaccharide lactone 21
Considerable efforts are being pursued to simplify the preparation
of complex oligosaccharides by one-pot multi-step approaches
involving different glycosylation strategies as well as minimizing
protective group manipulation.55 An interesting strategy combines
deprotection or manipulation of protecting groups with glyco-
sylation reactions employing the same catalyst, thus obtaining
branched oligosaccharides.56 In this sense, we envisioned the
synthesis of trisaccharide lactone 21 in a one-pot procedure by
the use of TMSOTf as glycosylation catalyst as well as promoter
for the removal of the silyl protecting group. Glycosylation by
the trichloroacetimidate method followed by silyl deprotection
with TMSOTf in a one-pot procedure was previously described.57
In our case, we planned the following one-pot procedure: (1)
glycosylation at O-5 of a D-galactone-1,4-lactone derivative with
Araf imidate 5, (2) removal of the silyl group at the 6-O position
and (3) glycosylation with Galf imidate 9 at the 6-O position
(Scheme 5). In this case, acid resistant 6-O-TBDPS in 6 was
replaced by TBDMS which can be removed by Lewis acids.58
Treatment of 11 with 1.2 equiv. of t-butyldimethylchlorosilane
and imidazole in DMF gave the acceptor 12 (95%, Scheme 2).
We first assayed the resistance to acid of the TBDMS group
of 12, and under standard glycosylation conditions (0.3 equiv.
TMSOTf, Cl2CH2, -15 ◦C), no product 11 was observed which
would result from silyl removal. However, on addition of 1
equiv. of TMSOTf, and after 1.5 h reaction, 11 was obtained
as the only product as shown by TLC. The resistance of the
arabinofuranosyl linkage to the TBDMS removal conditions
was also evaluated. On treatment of 2,3,5-tri-O-benzoyl-a-D-
Araf -(1→5)-2,6-di-O-pivaloyl-D-galactono-1,4-lactone37 with 1.3
equiv. TMSOTf for 2.5 h at -15 ◦C, no decomposition was
observed.
Synthesis of tetrasaccharide 2
For the synthesis of tetrasaccharide 2, our first target was the
synthesis of imidate 7, as shown in the retrosynthetic analysis
(Scheme 1). Whereas several groups have synthesized oligosaccha-
ride fragments from arabinan or galactan, few oligosaccharides
containing both units have been synthesized. This is the case
for a-D-Araf -(1→5)-[b-D-Galf -(1→6)]-D-Galf , which has been
synthesized by two different methodologies. The first involved a
sequential strategy with the introduction of the Araf moiety by
the trichloroacetimidate method at O-5 of a Galf derivative, then
deprotection of the 6-O position, followed by the introduction of
the galactofuranosyl moiety by the pentenyl method at position
6.34 This trisaccharide was obtained as its ethyl glycoside, which
is difficult to hydrolyze for further elongation. On the other hand,
this trisaccharide was also synthesized by a one-pot strategy from
3-O-benzoyl-1,2-O-isopropylidene-D-galactofuranose by selective
glycosylation of the primary OH-6 with Galf imidate 9, followed
by glycosylation with Araf imidate 5.35 In this case, further elon-
gation of the product would imply hydrolysis of the isopropylidene
group, and differentiation of OH-1 and OH-2.
Considering the aldonolactone approach, our first attempt
was the use of 2,3-di-O-benzoyl-D-galactono-1,4-lactone (11,
Scheme 2) in order to introduce the Galf at the primary 6-O
position, followed by the Araf at 5-position, taking into account
the previous report.35 However, in our hands, glycosylation of 11
with 1 equiv. of Galf imidate 9 resulted in low regioselectivity.
The disaccharide lactone obtained by monoglycosylation at OH-
6, and the corresponding monoglycosylation by-product at OH-5,
as well as the trisaccharide lactone, product of diglycosylation,
were obtained, even at temperatures as low as -78 ◦C. For that
reason, following the Gurjar strategy,34 we chose to use compound
With these results, and after several assays, we found that the
best one-pot conditions were: (1) glycosylation of 12 with 1 equiv.
of Araf imidate 5 using a small amount of TMSOTf (0.05 equiv.)
at -15 ◦C, which gave the corresponding disaccharide, (2) after
1.5 h, the temperature was raised to -8 ◦C and 1.3 equiv. of
TMSOTf were added, (3) after 1 h more, the mixture was cooled
◦
to -18 C and Galf imidate 9 was added. Under this procedure,
trisaccharide lactone 21 was obtained crystalline from the crude
reaction mixture in 50% overall yield.
It is important to mention that deprotection of the TB-
DMS group required a short time. Longer times resulted in
the formation of the transglycosylation by-product, 5,6-di-O-
(2,3,5-tri-O-benzoyl-a-D-arabinofuranosyl)-2,3-di-O-benzoyl-D-
galactono-1,4-lactone (data not shown).
The next step was the reduction of the lactone function
followed by activation of the furanose center. Treatment of 21
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Scheme 4 Synthesis of tetrasaccharide 2.
Scheme 5 One-pot strategy for the synthesis of 21.
with disiamylborane gave trisaccharide 22 as a 0.6 : 0.4 b : a
anomeric mixture. Activation of the anomeric center of 22 with
trichloroacetonitrile and DBU gave trichloroacetimidate 7 as a
9 : 1 b : a anomeric mixture, which was condensed with 2,6-di-O-
pivaloyl-D-galactono-1,4-lactone (8)31 (Scheme 4). The reaction
was carried out with TMSOTf as catalyst in Cl2CH2 and the
product of glycosylation on exocyclic OH-5 23 was obtained
regioselectively as expected in 71% yield. Prior to disiamylborane
reduction, 23 was acetylated to give 24. In the 1H NMR spectrum
of 24, the H-3 signal appeared shifted 1 ppm downfield compared
to the same signal in 23, confirming the regioselectivity of the
glycosylation. Reduction of the lactone function of 24 with
disiamylborane gave 25 as a b : a (0.7 : 0.3) anomeric mixture
(64%). Its imidate 26 (73%) was reacted with 9-decenol to yield
tetrasaccharide 27 in 94% yield. The H NMR spectrum of 27
1
showed the new anomeric center at 4.92 ppm as a singlet due to
the b-stereochemistry, together with the other anomeric signals
at 5.78 (Araf H-1¢¢¢), 5.58 (internal Galf H-1¢), and 5.35 ppm
(terminal Galf H-1¢¢). In the 13C NMR spectrum, the anomeric
centers appeared at 106.5 (C-1¢¢), 106.0 (C-1¢¢¢), 105.0 (C-1¢) and
105.4 ppm, the latter assigned to the new glycosidic center (C-
1). With tetrasaccharide 27 in hand, the last step was the total
deprotection by Zemplen procedure to afford the desired decenyl
glycoside 2 with 76% yield.
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After 2 h, the mixture was quenched by addition of water
(10 mL). After dilution with CH2Cl2 (70 mL) and additional water
(60 mL), the organic phase was separated and washed with water
(4 ¥ 70 mL), dried (Na2SO4) and concentrated. The residue was
purified by column chromatography (toluene) to give 0.532 g of 6
(83% yield) as an amorphous solid: Rf 0.61 (2 : 1 hexane–EtOAc),
[a]D +41.6 (c 1, CHCl3),1H NMR (CDCl3, 500 MHz) d 8.12–7.37
(m, 20 H, aromatic), 6.14 (d, 1 H, J = 6.6 Hz, H-2), 6.13 (dd, 1 H,
J = 6.6, 6.2 Hz, H-3), 4.73 (dd, 1 H, J = 6.2, 1.9 Hz, H-4), 4.12
(m, 1 H, H-5), 3.91 (dd, 1 H, J = 6.6, 10.3 Hz, H-6a), 3.85 (dd,
1 H, J = 6.4, 10.3 Hz, H-6b), 1.09 (s, 9H, C(CH3)3); 13C NMR
(CDCl3, 125.8 MHz) d 168.7 (C-1), 165.6 (COPh), 165.2 (COPh),
135.5–127.8 (aromatic), 79.3 (C-4); 73.4, 72.6 (C-2, C-3); 69.9 (C-
5), 63.8 (C-6), 26.8 (C(CH3)3), 19.2 (C(CH3)3). Anal. Calcd for
C36H36O8Si: C 69.21; H 5.81; Found: C 69.15, H 5.71.
Conclusions
We have synthesized two branched arabinogalactan derivatives
as their decenyl glycosides 1 and 2, which constitute interesting
substrates for studies on arabinofuranosyl transferases. The
aldonolactone strategy was employed as the template of the
furanose ring, by sequential construction of the oligosaccharides
from the non-reducing end to the reducing end. The synthesis
of trisaccharide lactone 21, precursor of 2, was extended to a
one-pot procedure. The glycosylation-deprotection-glycosylation
strategy was possible by the use of TMSOTf as the catalyst for
the trichloroacetimidate method as well as the promoter for silyl
removal.
Experimental
2,3-Di-O-benzoyl-6-O-tert-butyldimethylsilyl-D-galactono-1,4-
lactone (12). To a stirred suspension of 2,3-di-O-benzoyl-D-
galactono-1,4-lactone (10) (577 mg, 1.44 mmol) and imidazole
(170 mg, 2.5 mmol) in DMF (7 mL) cooled to 0 ◦C, tert-
butyldimethylchlorosilane (262 mg, 1.74 mmol) was slowly added.
After 1.5 h, the mixture was quenched by addition of water
(10 mL). After dilution with CH2Cl2 (70 mL) and additional water
(60 mL), the organic phase was separated and washed with water
(4 ¥ 70 mL), dried (Na2SO4) and concentrated. The solid residue
was purified by recrystallization from 7 : 1 hexane–EtOAc to give
the first crop of 12 (0.623 g, 87% yield). The mother liquors were
concentrated under reduced pressure and the solid recrystallized
from 7 : 1 hexane–EtOAc to give a second crop of crystalline 12
(61 mg, 8% yield): mp 118 ◦C, Rf 0.61 (2 : 1 hexane–EtOAc), [a]D
General
TLC was performed on 0.2 mm silica gel 60 F254 aluminium
supported plates. Detection was effected by exposure to UV
light or by spraying with 5% (v/v) sulfuric acid in EtOH and
charring. Column chromatography was performed on silica gel
60 (230–400 mesh). NMR spectra were recorded with a Bruker
AVANCE II 500 spectrometer at 500 MHz (1H) and 125.8 MHz
(13C) or with a Bruker AC 200 at 200 MHz (1H) and 50.3 MHz
(13C). Chemical shifts are given relative to the signal of an
internal acetone standard at 2.16 ppm and 30.8 ppm for 1H
NMR and 13C NMR spectra when recorded in D2O. H and 13C
1
assignments were supported by COSY and HSQC experiments.
High resolution mass spectra (HRMS) were recorded on an
Agilent LCTOF with Windows XP-based OS and a APCI/ESI
ionization high resolution mass spectrometer analyzer or in a
BRUKER micrOTOF-Q II spectrometer. Melting points were
determined with a Fisher–Johns apparatus and are uncorrected.
Optical rotations were measured with a path length of 1 dm at
25 ◦C.
1
+68.1 (c 1, CHCl3), H NMR (CDCl3, 500 MHz) d 8.10–7.43
(m, 10 H, aromatic), 6.13 (t, 1 H, J = 6.6 Hz, H-3), 6.09 (d,
1 H, J = 7.1 Hz, H-2), 4.66 (dd, 1 H, J = 6.2, 2.2 Hz, H-4),
4.07 (m, 1 H, H-5), 3.83 (dd, 1 H, J = 6.6, 10.0 Hz, H-6a), 3.77
(dd, 1 H, J = 6.3, 10.0 Hz, H-6b), 0.89 (s, 9H, C(CH3)3); 0.09,
0.08 (2 ¥ CH3); 13C NMR (CDCl3, 125.8 MHz) d 168.8 (C-1),
165.7 (COPh), 165.2 (COPh), 133.9–128.3 (aromatic), 79.4, 73.4,
72.6, 69.9, 62.9, 25.8 (C(CH3)3), 18.2 (C(CH3)3), -5.5 (CH3). Anal.
Calcd for C26H32O8Si: C 62.38, H 6.44; Found: C 62.37, H 6.43.
2,3-Di-O-benzoyl-D-galactono-1,4-lactone (11). To a stirred
solution of 2,3-di-O-benzoyl-5,6-O-isopropylidene-D-galactono-
1,4-lactone51 (10, 1.6 g, 3.8 mmol) in HOAc (15 mL) at 80 ◦C
was slowly added H2O (2 mL) until turbidity, and heating was
continued for 1 h. The mixture was cooled and concentrated, and
the residue was subjected to successive dissolution and evaporation
with toluene (3 ¥ 10 mL). Column chromatography (3 : 1 toluene–
EtOAc) of the residue afforded 11 (1.17 g, 80%) as a solid which
after recrystallization from hexane–EtOAc (1.5 : 1) gave mp 118–
120 ◦C, [a]D +89.1 (c 1, CHCl3), Rf 0.38 (1 : 1 hexane–EtOAc); 1H
NMR (200 MHz, CDCl3): d 8.07–7.18 (m. 10 H, aromatic), 6.08
(m, 2 H, H-2, H-3), 4.66 (m, 1 H, H-4), 4.13 (m, 1 H, H-5), 3.86
(dd, 1H, J = 6.2, 11.2 Hz, H-6a), 3.75 (dd, 1H, J = 5.9, 11.2 Hz, H-
6b), 3.60 (bs, 1H, OH), 2.91 (bs, 1H, OH). 13C NMR (CDCl3, 25.3
MHz): d 169.0 (C-1), 165.8 (COPh), 165.3 (COPh), 133.9–128.5
(COPh), 80.3, 73.4, 72.7, 70.2, 62.9. Anal. Calcd for C20H18O8: C
62.17; H 4.70; Found: C 62.11, H 4.46.
2,3,5-Tri-O-benzoyl-a,b-D-arabinofuranose (14). A solution of
1,2,3,5-tetra-O-benzoyl-a,b-D-arabinofuranose37,52 (13) (455 mg,
0.80 mmol) in 32% (w/w) hydrogen bromide–glacial acetic acid
(1.5 mL) was stirred for 1 h at room temperature until the tlc
showed consumption of the starting material. The solution was
concentrated under reduced pressure and the residue coevaporated
with toluene (5 ¥ 5 mL). The crude solid was diluted in 10 : 1
acetone–water and the resulting solution was then warmed to
40 ◦C and Ag2CO3 (171 mg, 1.01 mmol) was slowly added. After
stirring at 50 ◦C for 1.5 h, the reaction mixture was diluted
with CH2Cl2 (50 mL) and filtered through Celite. The filtrate
was washed with water (3 ¥ 50 mL), the organic layer was
dried (Na2SO4), filtered and concentrated. The crude product was
purified by column chromatography (20 : 1 toluene–EtOAc) to give
0.339 g of 14 (92%) as an amorphous solid: Rf 0.19 (7 : 1 toluene–
1
2,3-Di-O-benzoyl-6-O-tert-butyldiphenylsilyl-D-galactono-1,4-
lactone (6). To
galactono-1,4-lactone (11, 400 mg, 0.99 mmol) and imidazole
(115 mg, 1.7 mmol) in DMF (4 mL) cooled to 0 ◦C, tert-
butyldiphenylchlorosilane (0.3 mL, 1.15 mmol) was slowly added.
EtOAc), [a]D -34.7 (c 1, CHCl3). H NMR (CDCl3, 200 MHz,
a
stirred solution of 2,3-di-O-benzoyl-D-
mixture of a and b anomers, 0.76 : 0.24, in accordance with lit.54);
13C NMR (CDCl3, 50.3 MHz) d 166.5–165.5 (COPh), 133.6–128.3
(aromatic), 100.9 (C-1a), 95.5 (C-1b), 82.5, 81.3, 78.9, 77.9, 76.5,
65.8 (C-5a), 63.9 (C-5b).
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2,3,5-Tri-O-benzoyl-a-D-arabinofuranosyl-(1→5)-2,3-di-O-ben-
zoyl-6-O-tert-butyldiphenylsilyl-D-galactono-1,4-lactone (15).
mmol), and 4 A powdered molecular sieves (0.5 g) in anhydr.
CH2Cl2 (8 mL) was cooled to -10 ◦C and then, TMSOTf (29
mL, 0.16 mmol) was slowly added. After 1 h of stirring, tlc
monitoring showed a main spot (Rf 0.47, 7 : 1 toluene–EtOAc)
and consumption of the starting materials. The mixture was
filtered into saturated aqueous NaHCO3 (100 mL) and then
extracted with CH2Cl2 (2 ¥ 100 mL). The organic layer was
washed with water (3 ¥ 100 mL), dried (Na2SO4), filtered and
concentrated under reduced pressure. The syrupy residue was
purified by column chromatography (80 : 1 toluene–EtOAc).
The first fraction of the column (Rf 0.47, 7 : 1 toluene–EtOAc)
was concentrated to give an amorphous solid identified as 16
A
vigorously stirred solution of dried 2,3,5-tri-O-benzoyl-D-
arabinofuranosyl trichloroacetimidate54 (5, 1.26 g, 2.07 mmol),
2,3-di-O-benzoyl-6-O-tert-butyldiphenylsilyl-D-galactono-1,4-
˚
lactone (6, 1.12 g, 1.75 mmol), and activated 4 A powdered
molecular sieves (0.7 g) in anhydr. CH2Cl2 (90 mL) was cooled to
-15 ◦C, and TMSOTf (105 mL, 0.58 mmol) was slowly added. After
2 h of stirring, the mixture was filtered into saturated aqueous
NaHCO3 (200 mL) and then extracted with CH2Cl2 (2 ¥ 200 mL).
The organic layer was washed with water (3 ¥ 150 mL), dried
(Na2SO4), filtered and concentrated under reduced pressure. The
residue was purified by column chromatography (80 : 1 toluene–
EtOAc) to give 15 (1.50 g, 80%) as a syrup: Rf 0.68 (7 : 1 toluene–
1
(484 mg, 58%): [a]D +1.2 (c 1, CHCl3); H NMR (CDCl3, 500
MHz) d: 8.09-7.23 (m, 45 H, aromatic), 6.29 (d, 1 H, J = 6.7 Hz,
H-2), 6.19 (dd, 1H, J = 6.7, 6.0 Hz, H-3), 6.08 (m, 1 H, H-5¢¢), 5.77
(bs, 1 H, H-1¢¢¢), 5.72 (m, 2 H, H-3¢¢¢, H-3¢¢), 5.61 (bs, 1 H, H-1¢¢),
5.60 (d, 1 H, J = 2.1 Hz, H-2¢¢), 5.58 (d, 1 H, J = 2.1 Hz, H-2¢¢¢),
5.31 (dd, 1 H, J = 2.3, 6.2 Hz, H-3¢), 5.01 (d, 1 H, J = 2.3 Hz, H-2¢),
4.98 (s, 1 H, H-1¢), 4.87 (dd, 1 H, J = 1.6, 6.0 Hz, H-4), 4.83 (dd, 1
H, J = 3.6, 5.2 Hz, H-4¢¢), 4.78 (dd, 1 H, J = 5.4, 13.0 Hz, H-5a¢¢¢),
4.77 (dd, 1 H, J = 3.9, 12.0 Hz, H-6a¢¢), 4.73 (dd, 1 H, J = 7.3,
12.0 Hz, H-6b¢¢), 4.68 (m, 2 H, H-4¢¢¢, H-5b¢¢¢), 4.42 (m, 2 H, H-6a¢,
H-5), 4.37 (dd, 1 H, J = 3.2, 6.2 Hz, H-4¢), 4.30 (m, 2 H, H-5¢,
H-6b¢), 4.01 (t, J = 9.4 Hz, H-6a), 3.91 (dd, 1 H, J = 6.0, 9.4 Hz, H-
6b); 13C NMR (CDCl3, 125.8 MHz) d: 177.8, 177.3 (COC(CH3)3),
169.7 (COCH3), 168.8 (C-1), 166.1–165.1 (COPh), 133.8–128.2
(aromatic), 107.7 (C-1¢¢¢), 106.2 (C-1¢¢), 105.3 (C-1¢), 82.9 (C-2¢¢),
82.0 (C-2¢¢¢), 81.7 (C-4¢¢), 81.3 (C-2¢), 80.9 (C-4¢), 80.8 (C-4¢¢¢),
79.6 (C-4), 77.6 (C-3¢¢), 76.9 (C-3¢¢¢), 75.9 (C-3¢), 75.6 (C-5), 73.8
(C-3), 73.4 (C-5¢), 72.2 (C-2), 70.2 (C-5¢¢), 64.7 (C-6), 63.9 (C-
6¢); 63.6, 63.4 (C-5¢¢¢, C-6¢¢); 38.6 (C(CH3)3), 38.4 (C(CH3)3), 27.0
(C(CH3)3), 27.8(C(CH3)3), 20.3(CH3). Anal. Calcd for C98H92O32:
C 66.06; H 5.20; Found: C 65.81, H 5.08.
The lowest migrating component from the column (Rf 0.65,
EtOAc) was eluted with EtOAc and identified as 2,3,5,6-tetra-
O-benzoyl-b-D-galactofuranosyl-(1→5)-3-O-acetyl-2,6-di-O-
pivaloyl-b-D-galactofuranosyl-(1→6)-[2,3,5-tri-O-benzoyl-a-D-
arabinofuranosyl-(1→5)]-2,3-di-O-benzoyl-D-galactonic acid (17,
287 mg, 34%): [a]D -27.9 (c 1, CHCl3), 13C NMR (CDCl3, 125.8
MHz) d: 178.2 (C-1 and COC(CH3)3), 177.4 (COC(CH3)3, 170.0
(COCH3), 166.3, 166.1, 165.9, 165.8, 165.7, 165.6, 165.5, 165.4,
165.2 (9 x COPh), 133.8–128.2 (aromatic), 107.0 (C-1¢¢¢), 105.9 (C-
1¢¢), 105.4 (C-1¢), 82.3, 82.0, 81.9, 81.4, 81.2, 80.8, 77.9, 77.4, 75.9,
75.6, 72.9, 71.7, 70.3, 68.4, 65.6, 64.7, 63.9, 63.5; 38.7 (C(CH3)3),
38.5 (C(CH3)3), 27.0 (C(CH3)3), 26.8 (C(CH3)3), 20.2 (CH3).
HRMS (ESI) m/z calcd for C98H94O33Na (M+Na+) 1821.5570,
found 1821.5617.
1
EtOAc); [a]D -24.2 (c 1, CHCl3); H NMR (CDCl3, 500 MHz)
d: 8.09–7.24 (m, 35 H, aromatic), 6.24 (d, 1 H, J = 6.7 Hz, H-2),
6.15 (t, 1 H, J = 6.4 Hz, H-3), 5.61 (d, 1 H, J = 1.7, 5.2 Hz, H-3¢),
5.58 (s, 1 H, H-1¢), 5.53 (d, 1 H, J = 1.7 Hz, H-2¢), 5.01 (dd, 1 H,
J = 1.9, 6.1 Hz, H-4), 4.55 (dd, 1 H, J = 3.8, 12.0 Hz, H-5a¢), 4.49
(dd, 1 H, J = 4.4, 12.0 Hz, H-5b¢), 4.36 (m, 1 H, H-4¢), 4.23 (ddd,
1 H, J = 1.9, 5.2, 9.3 Hz, H-5), 4.03 (dd, 1 H, J = 5.2, 10.0 Hz,
H-6a), 3.97 (t, 1 H, J = 9.8 Hz, H-6b), 1.0 (s, 9 H, ((CH3)3CSi);
13C NMR (CDCl3, 125.8 MHz) d: 168.9 (C-1), 166.1, 165.7 (x2),
165.4, 165.2 (COPh), 135.4–127.8 (aromatic), 107.5 (C-1¢), 82.7
(C-2¢), 81.0 (C-4¢), 79.3 (C-4), 77.5 (C-5), 77.0 (C-3¢), 73.9 (C-3),
72.4 (C-2), 63.4 (C-5¢), 61.9 (C-6), 26.8 ((CH3)3C), 19.1 ((CH3)3C).
HRMS (ESI) m/z calcd for C62H56O15SiNa (M+Na+) 1091.3281,
found 1091.3268.
2,3,5-Tri-O-benzoyl-a-D-arabinofuranosyl-(1→5)-2,3-di-O-ben-
zoyl-D-galactono-1,4-lactone (4). A solution of 5% HF (48 wt%
in H2O) in acetonitrile (30 mL) was added to 15 (1.16 g, 1.01
mmol), and the resulting solution was stirred at 5 ◦C for 16 h,
and 20 ◦C for additional 3 h. The reaction mixture was poured
into saturated aq. NaHCO3 (150 mL), and extracted with CH2Cl2
(2 ¥ 100 mL). The organic layer was washed with water (3 ¥
100 mL) until pH 7, dried (Na2SO4), filtered, and concentrated
under reduced pressure. Purification by column chromatography
(10 : 1 toluene–EtOAc) yielded 4 (595 mg, 65%) as a foamy solid:
Rf 0.39 (4 : 1 toluene–EtOAc); [a]D +43.7 (c 1, CHCl3); 1H NMR
(CDCl3, 500 MHz) d: 8.09–7.16 (m, 25 H, aromatic), 6.17 (m, 2
H, H-2, H-3), 5.73 (bs, 1 H, H-1), 5.68 (dd, 1 H, J = 1.9, 4.9 Hz,
H-3¢), 5.66 (dd, 1 H, J = 0.6, 1.9 Hz, H-2¢), 4.80 (dd, 1 H, J = 3.4,
11.5 Hz, H-5a¢), 4.76 (m, 2 H, H-4, H-4¢), 4.66 (dd, 1 H, J = 5.55,
11.5 Hz, H-5b¢), 4.33 (ddd, 1 H, J = 2.4, 4.7, 7.7 Hz, H-5), 4.04
(dd, 1 H, J = 7.7, 12.0 Hz, H-6a), 3.86 (ddd, 1 H, J = 2.4, 8.0,
12.0 Hz, H-6b), 2.88 (d, 1 H, J = 8.0 Hz, OH); 13C NMR (CDCl3,
125.8 MHz) d: 168.7 (C-1), 166.1, 165.8, 165.7, 165.2 (COPh),
133.7–125.3 (aromatic), 107.7 (C-1¢), 82.4 (C-2¢), 81.5 (C-4¢), 80.5
(C-4), 80.1 (C-5), 76.8 (C-3¢), 74.0, 72.1 (C-3 and C-2), 63.7 (C-5¢),
62.8 (C-6). Anal. Calcd for C46H38O15: C 66.50; H 4.61; Found: C
66.62, H 4.42.
This fraction was concentrated, the residue was dissolved in
CHCl3 (15 mL) and the solution was heated for 5 h at 50 ◦C. Tlc
monitoring showed almost total conversion into 16 (Rf 0.47, 7 : 1
toluene–EtOAc). The solution was evaporated to dryness and the
resulting residue was purified by a short column chromatography
(40 : 1, toluene–EtOAc) to provide 116 mg of a product with the
same spectroscopic and physical data as 16 (14%).
2,3,5,6-Tetra-O-benzoyl-b-D-galactofuranosyl-(1→5)-3-O-ace-
tyl-2,6-di-O-pivaloyl-b-D-galactofuranosyl-(1→6)-[2,3,5-tri-O-
benzoyl-a-D-arabinofuranosyl-(1→5)]-2,3-di-O-benzoyl-D-gal-
actono-1,4-lactone (16). A vigorously stirred suspension of
2,3,5,6-tetra-O-benzoyl-b-D-galactofuranosyl-(1→5)-3-O-acetyl-
2,3,5,6-Tetra-O-benzoyl-b-D-galactofuranosyl-(1→5)-3-O-ace-
tyl-2,6-di-O-pivaloyl-b-D-galactofuranosyl-(1→6)-[2,3,5-tri-O-
benzoyl-a-D-arabinofuranosyl-(1→5)]-2,3-di-O-benzoyl-D-gal-
actofuranose (18). A solution of bis(2-butyl-3-methyl)borane
2,6-di-O-pivaloyl-b-D-galactofuranosyl
trichloroacetimidate31
(3, 592 mg, 0.53 mmol), disaccharide lactone 4 (391 mg, 0.47
2092 | Org. Biomol. Chem., 2011, 9, 2085–2097
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(1.28 mmol) in anhydr. THF (0.4 mL), cooled to 0 C under an
(NH, 0.90 H), 8.07–7.14 (m, 45 H), 6.91 (d, 0.10 H, J = 4.5 Hz,
H-1 a anomer), 6.66 (bs, 0.9 H, H-1 b anomer), 6.07 (m, 0.9 H,
H-5¢¢), 5.87 (dd, 0.9 H, J = 0.9, 4.6 Hz), 5.85 (bs, 0.9 H), 5.73 (bs,
0.9 H), 5.66–5.63 (m, 3.6 H), 6.39 (d, 0.9 H, J = 1.9 Hz), 5.29 (dd,
0.9 H, J = 2.7, 7.1 Hz), 5.02 (dd, 0.9 H, J = 0.5, 2.8 Hz), 4.96 (bs,
0.9 H), 4.86 (dd, 0.9 H, J = 3.6, 4.8 Hz), 4.72–4.65 (m, 7.2 H), 4.62
(dd, 0.9 H, J = 4.0, 11.4 Hz), 4.53 (m, 0.9 H), 4.49 (dd, 0.9 H, J =
3.1, 12.0), 4.32–4.25 (m, 1.8 H), 4.21 (m, 0.9 H), 4.09 (dd, 0.9 H,
J = 8.1, 9.2), 3.93 (dd, J = 6.3, 9.2 Hz), 1.86 (s, 3 H), 1.24, 0.95 (2 s,
18 H), 13C NMR (CDCl3, 125.8 MHz) d: 177.9 (COC(CH3)3),
177.3 (COC(CH3)3), 170.0 (COCH3), 166.1–165.1 (COPh), 160.2
(CONH), 133.5–125.3 (COPh), 107.1, 106.1, 105.7, 103.1, 85.6,
82.6, 82.4, 82.0, 81.7, 81.2, 80.6, 80.4, 77.9, 77.2, 76.9, 76.1, 75.3,
72.7, 70.4, 66.0, 65.4, 63.9, 63.5, 38.7, 38.3, 27.1, 26.8, 20.5.
A vigorously stirred suspension of trichloroacetimidate 19
(100 mg, 0.052 mmol), 9-decen-1-ol (12.6 mL, 0.068 mmol), and
argon atmosphere, was added to a flask containing previously
dried compound 16 (381 mg, 0.21 mmol). The solution was
allowed to reach room temperature and stirring continued for 16 h.
Tlc showed partial consumption of compound 16, the mixture was
cooled to 0 ◦C and a solution of bis(2-butyl-3-methyl)borane (1.55
mmol) in anhydr. THF (2.2 mL) was added. The resulting solution
was stirred at room temperature for additional 12 h; tlc showed
total consumption of compound 16 and the mixture was processed
as previously described.59 The organic layer was washed with water,
dried (Na2SO4), and concentrated. Boric acid was eliminated by
coevaporation with MeOH (5 ¥ 3 mL) at rt. The residue was
purified by column chromatography (15 : 1, toluene–EtOAc) to
give 162 mg (43%) of syrupy 18 as a 0.77 : 0.23 b : a anomeric
mixture: Rf 0.6 (5 : 1 toluene–EtOAc); [a]D +2.9 (c 1, CHCl3); 1H
NMR (CDCl3, 500 MHz), only the assigned d are listed: 8.17–7.16
(m, 45 H, aromatic), 6.09 (m, 0.23 H, H-5¢¢a anomer), 6.04 (m, 0.77
H, H-5¢¢ b anomer), 5.87 (bs, 0.23 H, H-1¢¢¢ a anomer), 5.83 (dd,
0.77 H, J = 1.8, 5.9 Hz, H-3), 5.77 (bs, 0.77 H, H-1¢¢¢ b anomer),
5.75 (d, 0.77 H, J = 4.6 Hz, H-1 b anomer), 5.70 (dd, 0.23 H, J =
5.0, 11.7 Hz, H-1 a anomer), 5.67 (bs, 0.77 H, H-1¢¢), 5.66–5.63 (m,
2.31 H, H-2, H-3¢¢, H-3¢¢¢), 5.59 (d, 0.77 H, J = 1.6 Hz, H-2¢¢), 5.56
(d, 0.77 H, J = 2.3 Hz, H-2¢¢¢), 5.25 (dd, 0.77 H, J = 5.6, 1.6 Hz,
H-3¢), 5.06 (d, 0.77 H, J = 1.6 Hz, H-2¢), 5.03 (d, 0.77 H, J = 5.0 Hz,
OH), 4.98 (bs, 0.23 H, H-1¢a anomer), 4.96 (dd, 0.77 H, J = 1.7,
5.7 Hz, H-4¢¢), 4.95 (bs, 0.77 H, H-1¢), 4.79 (dd, 0.77 H, J = 3.7,
12.4 Hz, H-6a¢¢), 4.76–4.70 (m, 1.54 H, H-6a¢, H-5a¢¢¢), 4.67 (dd,
0.77 H, J = 7.6, 12.1 Hz, H-6b¢¢), 4.65 (m, 0.77 H, H-4¢¢¢), 4.63 (dd,
0.77 H, J = 5.0, 11.0 Hz, H-5b¢¢¢), 4.59 (dd, 0.77 H, J = 1.8, 5.9 Hz,
H-4), 4.47 (dd, 0.77 H, J = 3.4, 5.9 Hz, H-4¢), 4.44 (m, 0.77 H, H-5),
4.40 (m, 0.77 H, H-5¢), 4.22 (dd, 0.77 H, J = 7.5, 12.6 Hz, H-6b¢),
4.09 (dd, 0.77 H, J = 8.3, 9.9 Hz, H-6a), 3.84 (dd, 0.77 H, J = 5.45,
8.3 Hz, H-6b), 1.88 (s, 0.69 H, CH3 a anomer), 1.83 (s, 2.31 H, CH3
b anomer); 1.15, 1.04 (2 s, 13.9 H, C(CH3)3);1.14, 1.00 (2 s, 4.1 H,
C(CH3)3); 13C NMR (CDCl3, 125.8 MHz) d: 179.7 (COC(CH3)3),
177.3 (COC(CH3)3), 170.2 (COCH3), 166.3–165.2 (COPh), 133.5–
125.3 (aromatic), 107.6 (C-1¢¢¢ b anomer), 107.3 (C-1¢¢¢ a anomer),
105.8 (C-1¢¢ a anomer), 105.4 (C-1¢ a anomer), 105.1 (C-1¢¢ b
anomer), 103.9 (C-1¢ b anomer), 100.5 (C-1 b anomer), 95.1 (C-1
a anomer), 83.6 (C-2), 82.6 (C-2¢¢¢), 82.3 (C-2¢¢), 82.1 (C-4¢), 81.4
(C-4¢¢), 81.2 (C-4), 80.9 (C-2¢), 80.1 (C-4¢¢¢), 77.9 (C-3¢¢*), 77.5 (C-
3), 77.4 (C-3¢¢¢*), 76.0 (C-3¢), 75.4 (C-5), 72.6 (C-5¢), 70.5 (C-5¢¢),
66.9 (C-6¢), 63.7 (C-6¢¢, C-6, C-5¢¢¢), 38.9, 39.5, (COC(CH3)3), 27.1,
27.0, 26.9, 26.8 (COC(CH3)3), 21.5, 20.3 (CH3). HRMS (ESI) m/z
calcd for C98H94O32Na (M+Na+) 1805.5620, found 1805.5684.
˚
4 A powdered molecular sieves (0.2 g) in freshly anhydr. CH2Cl2
(2 mL) was cooled to -15 ◦C and TMSOTf (2.8 mL, 0.016 mmol)
was slowly added. After 30 min of stirring, the mixture was diluted
with CH2Cl2 (10 mL) and filtered into saturated aq. NaHCO3
(10 mL). The organic layer was washed with water (3 ¥ 10 mL),
filtered, and evaporated under reduced pressure. The product was
washed with cold hexane (2 ¥ 0.7 mL) to eliminate the alcohol
affording 20 as a chromatographically homogeneous syrup (75 mg,
75%): Rf 0.49 (7 : 1, toluene–EtOAc); [a]D -14.1 (c 1, CHCl3); 1H
NMR (CDCl3, 500 MHz) d 8.09–7.24 (m, 45 H, aromatic), 6.07
(ddd, 1 H, J = 3.5, 3.8, 7.7 Hz, H-5¢¢), 5.78 (ddt, 1 H, J = 6.6, 10.3,
16.9 Hz, CH-ethylenic), 5.79 (bs, 1 H, H-1¢¢¢), 5.75 (dd, 1 H, J =
1.6, 5.4 Hz, H-3), 5.68 (dd, 1 H, J = 1.6, 5.5 Hz, H-3¢¢¢), 5.66 (dd,
1 H, J = 1.7, 5.4 Hz, H-3¢¢), 5.64 (s, 1 H, H-1¢¢), 5.60 (d, 1 H, J =
1.6 Hz, H-2¢¢¢), 5.59 (d, 1 H, J = 1.7 Hz, H-2¢¢), 5.52 (d, 1 H, J =
1.6 Hz, H-2), 5.32 (dd, 1 H, J = 2.4, 6.6 Hz, H-3¢), 5.24 (s, 1 H,
H-1), 5.05 (d, 1 H, J = 2.4 Hz, H-2¢), 5.01 (s, 1 H, H-1¢), 4.96 (ddt,
1 H, J = 1.6, 2.2, 17.2 Hz, CH2-ethylenic), 4.90 (ddt, 1 H, J = 1.3,
2.0, 10.2 Hz, CH2-ethylenic), 4.88 (dd, 1 H, J = 3.5, 5.4 Hz, H-4¢¢),
4.79 (m, 1 H, H-4¢¢¢), 4.77 (dd, 1 H, J = 3.4, 11.9 Hz, H-5a¢¢¢), 4.74
(dd, 1 H, J = 3.8, 12.1 Hz, H-6a¢¢), 4.69 (dd, 1 H, J = 7.7, 12.1 Hz,
H-6b¢¢), 4.65 (dd, 1 H, J = 3.8, 11.9 Hz, H-5b¢¢¢), 4.47 (ddd, 1 H,
J = 3.7, 6.2, 6.8 Hz, H-5), 4.41 (dd, 1 H, J = 3.7, 5.4 Hz, H-4), 4.39
(dd, 1 H, J = 3.4, 11.4 Hz, H-6a¢), 4.31 (dd, 1 H, J = 3.0, 6.5 Hz,
H-4¢), 4.28 (dd, 1 H, J = 7.1, 11.4 Hz, H-6b¢), 4.26 (m, 1 H, H-5¢),
4.04 (dd, 1 H, J = 6.2, 10.1 Hz, H-6a), 3.81 (dd, 1 H, J = 6.8,
10.1 Hz, H-6b), 3.74 (dt, 1 H, J = 6.7, 9.7 Hz, CH2O), 3.49 (dt, 1
H, J = 6.5, 9.7 Hz, CH2O), 2.01 (m, 2 H, CH2), 1.89 (s, 3 H, CH3),
1.61 (m, 2 H, CH2), 1.38–1.22 (m, 10 H, CH2), 1.12, 0.96 (2 s, 18
H, ((CH3)3CCO); 13C NMR (CDCl3, 125.8 MHz): d 177.8, 177.1
((CH3)3CCO), 170.0 (CH3CO), 166.1–165.1 (COPh), 139.2 (CH-
ethylenic), 133.5–128.3 (aromatic), 114.1 (CH2-ethylenic), 106.7
(C-1¢¢¢), 106.0 (C-1¢), 105.8 (C-1¢¢), 105.3 (C-1), 82.7 (C-2¢¢), 82.3
(C-2), 82.2 (C-4), 82.1 (C-4¢¢), 82.0 (C-2¢¢¢), 81.6 (C-4¢¢¢), 80.8 (C-
2¢), 80.2 (C-4¢), 77.9 (C-3¢¢), 77.5 (C-3¢¢¢), 77.3 (C-3), 76.1 (C-3¢),
75.3 (C-5), 72.7 (C-5¢), 70.3 (C-5¢¢), 67.6 (CH2O), 67.0 (C-6), 64.5
(C-6¢), 63.8 (C-6¢¢), 63.4 (C-5¢¢¢), 38.7 (2 x (CH3)3CCO), 29.7, 29.5,
29.4, 29.1, 28.9, 26.1 (7 ¥ CH2), 27.0, 26.7 ((CH3)3CCO), 20.4
(CH3). HRMS (ESI) m/z calcd for C108H113O32 (M+H+) 1921.7210,
found 1921.7251.
9-Decenyl 2,3,5,6-tetra-O-benzoyl-b-D-galactofuranosyl-(1→5)-
3-O-acetyl-2,6-di-O-pivaloyl-b-D-galactofuranosyl-(1→6)-[2,3,5-
tri-O-benzoyl-a-D-arabinofuranosyl-(1→5)]-2,3-di-O-benzoyl-b-D-
galactofuranoside (20). To a stirred solution of 18 (146 mg, 0.082
mmol) and trichloroacetonitrile (42 mL, 0.41 mmol) in anhydr.
◦
CH2Cl2 (5 mL) cooled to 0 C, DBU (6.1 mL, 0.041 mmol) was
slowly added. After 1 h, the solution was carefully concentrated
under reduced pressure at rt and the residue was purified by
column chromatography (20 : 1 : 0.2 toluene–EtOAc–TEA) to
give 131 mg (85%) of syrupy trichloroacetimidate 19 as a 9 : 1 b : a
anomeric mixture: Rf 0.68 (5 : 1 : 0.05 toluene–EtOAc–TEA);1H
NMR (CDCl3, 200 MHz) for the b anomer, only diagnostic
signals are listed for the a anomer, d 9.01 (NH, 0.10 H), 8.82
9-Decenyl b-D-galactofuranosyl-(1→5)-b-D-galactofuranosyl-
(1→6)-[a-D-arabinofuranosyl-(1→5)]-b-D-galactofuranoside (1).
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Compound 20 (57 mg, 0.030 mmol) was suspended in 0.52 M
sodium methoxide in methanol (0.83 mL) and then cooled
at 0 ◦C. After stirring for 1 h at 0 ◦C, the resulting solution
was warmed to room temperature, stirred for 2 h, and a 9 : 1
MeOH–H2O solution (2 mL) was added. The solution was passed
through a column containing (H+) resin (1.5 mL) and the column
washed with MeOH–H2O (9 : 1). The combined eluates were
evaporated and the remaining methyl benzoate eliminated by five
successive coevaporations with water. The residue was dissolved
in water and purified through a C18-cartridge. Evaporation of
solvent gave 1 (18 mg, 78%) as a hygroscopic syrup. Rf 0.79
(n-propanol–EtOH–H2O, 7 : 1 : 1); [a]D -52.6 (c 1, H2O); 1H
NMR (D2O, 500 MHz) d: 5.86 (ddt, 1 H, J = 6.2, 10.0, 16.9 Hz,
CH-ethylenic), 5.15 (bs, 1 H), 5.14 (bs, 1 H), 4.99 (ddt, 1 H, J =
1.5, 1.9, 17.1 Hz, CH2-ethylenic), 4.94 (bs, 1 H), 4.92 (bs, 1 H),
4.91 (ddt, 1 H, J = 1.3, 2.6, 10.4 Hz, CH2-ethylenic), 4.10–3.83
(14 H), 3.79–3.59 (8 H), 3.51 (ddt, 1 H, J = 6.2, 9.4 Hz, CH2O),
2.00 (m, 2 H, CH2), 1.55 (m, 2 H, CH2), 1.34–1.29 (m, 10 H,
CH2 ¥ 5). 13C NMR (D2O, 125.8 MHz): d 139.8 (CH-ethylenic),
114.5 (CH2-ethylenic), 109.2 (C-1¢¢¢), 108.2, 107.7, 107.4, 84.4,
83.2, 82.4, 82.3, 81.8, 81.7 (x 3), 77.3, 77.1, 77.0 (x 2), 76.9, 76.8,
76.4, 71.1 (CH2O), 69.2, 67.9, 63.4, 61.8, 61.7, 33.7, 29.2, 29.1,
28.9, 28.8, 28.7, 25.7.
One-pot preparation of trisaccharide lactone 21. A suspension
of 2,3,5-tri-O-benzoyl-D-arabinofuranosyl trichloroacetimidate
(5, 501 mg, 0.83 mmol), 2,3-di-O-benzoyl-6-O-tert-
butyldimethylsilyl-D-galactono-1,4-lactone (12, 413 mg, 0.83
˚
mmol) and 4 A powdered molecular sieves (1.2 g) in anhydr.
◦
CH2Cl2 (40 mL) was cooled to -15 C. The mixture was stirred
for 5 min and TMSOTf (7.5 mL, 0.041 mmol) was slowly added.
After stirring for 1.5 h, tlc showed almost total consumption of 5
and the appearance of a main spot (Rf 0.74; 10 : 1 toluene–EtOAc)
of
2,3,5-tri-O-benzoyl-a-D-arabinofuranosyl-(1→5)-2,3-di-O-
benzoyl-6-O-tert-butyldimethylsilyl-D-galactono-1,4-lactone. The
reaction mixture was warmed to -8 C and additional TMSOTf
◦
(195.4 mL, 1.08 mmol) was slowly added. Silyl ether hydrolysis was
◦
monitored by tlc and after 1 h of stirring at -8 C showed total
disappearance of the silylated disaccharide and the appearance
of disaccharide 4 (Rf 0.09; toluene–EtOAc, 10 : 1). Therefore, the
mixture was cooled to -18 ◦C and a solution of donor 9 (764 mg,
1.03 mmol) in anhydr. CH2Cl2 (40 mL) was slowly added. The
stirring continued for 2 h at -15 ◦C and 12 h at -30 ◦C. The
reaction mixture was diluted with CH2Cl2 (50 mL) and filtered
into saturated aq. NaHCO3 (150 mL). The organic layer was
washed with water (3 ¥ 150 mL), filtered, and evaporated under
reduced pressure to give a syrupy product which was dissolved in
boiling EtOH (185 mL). After the first crystals appeared at room
temperature, the mixture was kept at 2 ◦C for 12 h and 21 was
obtained (452 mg, 39%). The mother liquors were kept at 2 ◦C for
additional 12 h and a second crop of crystals (123 mg, 11%) was
filtered and characterized as 21.
HRMS (ESI) m/z calcd for C33H58O20Na (M+Na+) 797.34137,
found 797.34138.
2,3,5,6-Tetra-O-benzoyl-b-D-galactofuranosyl-(1→6)-[2,3,5-tri-
O-benzoyl-a-D-arabinofuranosyl-(1→5)]-2,3-di-O-benzoyl-D-gal-
actono-1,4-lactone (21).
A
vigorously stirred suspension
2,3,5,6-Tetra-O-benzoyl-b-D-galactofuranosyl-(1→6)-[2,3,5-tri-
O-benzoyl-a-D-arabinofuranosyl-(1→5)]-2,3-di-O-benzoyl-D-gal-
actofuranose (22). A solution of bis(2-butyl-3-methyl)borane
(4.64 mmol) in anhydr. THF (1.55 mL), cooled to 0 ◦C and
under an argon atmosphere, was added to a flask containing
previously dried 21 (493 mg, 0.35 mmol). The solution was allowed
to reach room temperature and stirring continued for 16 h. The tlc
showed total consumption of 21 and the mixture was processed
as previously described.59 The product was purified by column
chromatography (25 : 1, toluene–EtOAc) to give 326 mg (66%) of
syrupy 22 as a 0.59 : 0.41 b : a anomeric mixture: Rf 0.38 (7 : 1
toluene–EtOAc); [a]D +14.4 (c 1, CHCl3); 1H NMR (CDCl3, 500
MHz) d: 8.18–7.17 (m, 45 H, aromatic), 6.11 (m, 0.4 H, H-5¢ a
anomer), 6.07 (dd, 0.4 H, J = 5.3, 6.6 Hz, H-3a), 6.01 (m, 0.6 H,
H-5¢ b anomer), 5.88 (dd, 0.6 H, J = 2.1, 6.0 Hz, H-3b), 5.87 (s,
0.4 H, H-1¢¢a), 5.82 (d, 0.6 H, J = 2.3 Hz, H-1b), 5.80 (s, 0.6 H,
H-1¢¢b), 5.76 (dd, 0.4 H, J = 2.7, 6.2 Hz, H-3¢¢a), 5.66 (dd, 0.4 H,
J = 4.9, 12.0 Hz, H-1a), 5.65–5.55 (m, 3.6 H, H-2 ab, H-2¢¢ab,
H-3b, H-3¢ab), 5.42 (d, 0.4 H, J = 0.9 Hz, H-2¢a), 5.40 (d, 0.6
H, J = 0.9 Hz, H-2¢b), 5.26 (s, 0.4 H, H-1¢a), 5.21 (s, 0.6 H, H-
1¢b), 5.05 (dd, 0.6 H, J = 3.4, 5.6 Hz, H-4¢b), 5.01 (dd, 0.4 H, J =
2.7, 12.3 Hz), 4.81–4.59 (m, 6,6 H, H-4ab, H-4¢¢ab, H-6a¢ab, H-
6b¢ab, H-5a¢¢ab, H-5b¢¢ ab, OH-b), 4.53–4.44 (m, 1.4 H, H-4¢a,
H-5ab), 4.29 (d, 0.4 H, J = 12.0 Hz, OH-a), 4.21 (t, 0.6 H, J =
8.3 Hz, H-6a b), 4.14 (m, 0.4 H, H-6a a), 3.91 (dd, 0.6 H, J =
5.4, 8.3 Hz, H-6bb), 3.87 (dd, 0.4 H, J = 5.9, 9.1 Hz, H-6ba).13C
NMR (CDCl3, 125.8 MHz): d 167.0–165.3 (COPh), 133.4–128.3
(aromatic), 107.6 (C-1¢¢ b anomer), 107.4 (C-1¢ a anomer), 105.0
(C-1¢ a anomer), 105.0 (C-1¢ a anomer), 104.3 (C-1¢ b anomer),
100.6 (C-1 b anomer), 95.1 (C-1 a anomer), 83.7, 83.5, 82.6, 81.7,
of
2,3,5,6-tetra-O-benzoyl-b-D-galactofuranosyl
trichloro-
acetimidate50 (9, 877 mg, 1.18 mmol), disaccharide lactone 4
˚
(820 mg, 0.99 mmol), and 4 A powdered molecular sieves (1.2 g)
in anhydr. CH2Cl2 (70 mL) was cooled to -15 C and TMSOTf
◦
(64 mL, 0.35 mmol) was slowly added. After 1.5 h of stirring,
the mixture was diluted with CH2Cl2 (50 mL) and filtered into
saturated aq. NaHCO3 (120 mL). The organic layer was washed
with water (3 ¥ 150 mL), dried (Na2SO4), filtered, and evaporated
under reduced pressure. The residue was purified by column
chromatography (30 : 1, toluene–EtOAc) to give 1.22 g (84%) of
21 as an amorphous solid which crystallized from hot EtOH: mp
89–90 ◦C, Rf 0.58 (7 : 1, toluene–EtOAc); [a]D +9.23 (c 1, CHCl3);
1H NMR (CDCl3, 500 MHz) d 8.12–7.14 (m, 45 H, aromatic),
6.18 (dd, 1 H, J = 6.2, 7.1 Hz, H-3), 6.10 (ddd, 1 H, J = 4.0,
4.4, 7.2 Hz, H-5¢), 6.06 (dd, 1 H, J = 7.1 Hz, H-2), 5.78 (bs, 1
H, H-1¢¢), 5.69 (dd, 1 H, J = 2.1, 5.2 Hz, H-3¢¢), 5.61 (d, 1 H,
J = 2.1 Hz, H-2¢¢), 5.59 (dd, 1 H, J = 1.3, 4.8 Hz, H-3¢), 5.42 (d,
1 H, J = 1.3 Hz, H-2¢), 5.27 (bs, 1 H, H-1¢), 4.88 (dd, 1 H, J =
1.9, 6.2 Hz, H-4), 4.78 (dd, 1 H, J = 7.2, 12.2 Hz, H-6a¢), 4.75
(dd, 1 H, J = 4.0, 5.2 Hz, H-4¢), 4.75 (dd, 1 H, J = 4.4, 12.2 Hz,
H-6b¢), 4.74 (dd, 1 H, J = 5.6, 8.6 Hz, H-5a¢¢), 4.70–4.66 (m, 2 H,
H-4¢¢, H-5b¢¢), 4.46 (ddd, 1 H, J = 1.9, 5.9, 9.5 Hz, H-5), 4.09 (t, 1
H, J = 9.5 Hz, H-6a), 3.97 (dd, 1 H, J = 5.9, 9.5 Hz, H-6b). 13C
NMR (CDCl3, 125.8 MHz): d 168.5 (C-1), 166.1–165.2 (COPh),
133.8–125.3 (aromatic), 107.7 (C-1¢¢), 105.2 (C-1¢), 82.9 (C-2¢¢),
82.0 (C-4¢), 81.7 (C-2¢), 80.7 (C-4¢¢), 79.3 (C-4), 77.6 (C-3¢), 76.9
(C-3¢¢), 75.2 (C-5), 73.5 (C-3), 72.0 (C-2), 70.4 (C-5¢), 64.5 (C-6),
63.7 (C-6¢), 63.6 (C-5¢¢). Anal. Calcd for C80H64O24. 1/2H2O: C
67.74; H 4.62; Found: C 67.65, H 4.45.
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81.6, 81.5, 81.3, 80.2, 80.1, 80.0, 77.7, 77.5, 77.3, 76.3, 75.8, 75.4,
70.8, 70.4, 64.8, 64.5, 63.9, 63.8, 63.5. Anal. Calcd for C80H66O24:
C 68.08; H 4.71; Found: C 67.56, H 4.50.
HRMS (ESI) m/z calcd for C96H91O31 (M+H+) 1739.5539,
found 1739.5543.
2,3,5,6-Tetra-O-benzoyl-b-D-galactofuranosyl-(1→6)-[2,3,5-tri-
O-benzoyl-a-D-arabinofuranosyl-(1→5)]-2,3-di-O-benzoyl-b-D-
galactofuranosyl-(1→5)-3-O-acetyl-2,6-di-O-pivaloyl-D -gal-
actono-1,4-lactone (24). To a solution of 23 (259 mg, 0.15
mmol) in dry pyridine (1.2 mL), cooled at 0 ◦C, was added acetic
anhydride (1.2 mL) dropwise and the mixture was stirred at room
2,3,5,6-Tetra-O-benzoyl-b-D-galactofuranosyl-(1→6)-[2,3,5-
tri-O-benzoyl-a-D-arabinofuranosyl-(1→5)]-2,3-di-O-benzoyl-b-
D-galactofuranosyl-(1→5)-2,6-di-O-pivaloyl-D-galactono-1,4-lac-
tone (23). To a stirred solution of 22 (490 mg, 0.35 mmol) and
trichloroacetonitrile (0.17 mL, 1.74 mmol) in anhydr. CH2Cl2
(20 mL) cooled to 0 ◦C, DBU (26 mL, 0.17 mmol) was
slowly added. After 1 h, the solution was carefully concentrated
under reduced pressure at rt and the residue was purified
by column chromatography (20 : 1 : 0.2 toluene–EtOAc–TEA) to
give O-(2,3,5,6-O-(tetra-O-benzoyl-b-D-galactofuranosyl-(1→6)-
[2,3,5-tri-O-benzoyl-a-D-arabinofuranosyl-(1→5)]-2,3-di-O-
benzoyl-D-galactofuranosyl) trichloroacetimidate (7) as a syrup
(522 mg, 97%): Rf 0.70 (5 : 1 : 0.05 toluene–EtOAc–TEA);1H NMR
(CDCl3, 500 MHz) d 8.77 (s, 0.88 H, NH), 8.55 (s, 0.12 H, NH),
8.11–7.14 (m, 45 H), 6.68 (bs, 0.88 H, H-1 b anomer), 6.65 (d, 0.12
H, J = 4.5 Hz, H-1 a anomer), 6.25 (m, 0.12 H), 6.17 (m, 0.12 H,
H-5¢¢), 6.06 (m, 0.88 H, H-5¢¢), 5.89 (d, 0.88 H, J = 4.2 Hz), 5.83
(d, 0.88 H, J = 1.1 Hz), 5.74 (s, 0.88 H), 5.61 (dd, 0.88 H, J = 1.7,
4.9 Hz), 5.58 (dd, 0.88 H, J = 1.5, 5.6 Hz), 5.39 (d, 0.9 H, J =
1.7 Hz), 5.38 (d, 0.88 H, J = 1.5 Hz), 5.28 (s, 0.88 H), 4.81–4.49
(m, 8 H), 4.24 (dd, 0.88 H, J = 7.8, 9.4 Hz), 3.95 (dd, 0.88 H,
J = 5.7, 9.4 Hz), 13C NMR (CDCl3, 125.8 MHz) d: 166.1–165.2
(COPh), 160.5 (CONH), 133.5–125.3 (COPh), 107.0, 105.6, 103.3,
86.0, 82.5, 82.1, 81.4, 81.1, 80.8, 77.2, 76.8, 75.4, 70.1, 66.0, 64.1,
63.6.
◦
temperature for 40 min. After cooling to 0 C, the reaction was
quenched by slow addition of MeOH (2.7 mL) and the stirring
continued for 30 min at room temperature. The solution was
diluted with CH2Cl2 (30 mL) and then sequentially washed with
10% HCl (2 ¥ 40 mL), water (2 ¥ 40 mL), satd. aq. NaHCO3
(2 ¥ 40 mL), water (2 ¥ 40 mL), dried (Na2SO4), filtered, and
then concentrated. The crude product was purified by column
chromatography (30 : 1, toluene–EtOAc) to give 24 (174 mg, 67%)
as a syrup; Rf 0.58 (5 : 1 toluene–EtOAc); [a]D -22.0 (c 1, CHCl3);
1H NMR (CDCl3, 500 MHz) d 8.05–7.17 (m, 45 H, aromatic),
6.10 (m, 1 H, H-5¢¢), 5.81 (dd, 1 H, J = 1.5, 4.5 Hz, H-3¢), 5.77 (t,
1 H, J = 7.7 Hz, H-3), 5.73 (bs, 1 H, H-1¢¢¢), 5.63 (dd, 1 H, J =
1.5, 6.0 Hz, H-3¢¢¢), 5.61 (d, 1 H, J = 8.0 Hz, H-2), 5.57 (dd, 1
H, J = 1.5, 5.3 Hz, H-3¢¢), 5.53 (d, 1 H, J = 1.5 Hz, H-2¢¢¢), 5.49
(bs, 1 H, H-1¢), 5.48 (d, 1 H, J = 1.5 Hz, H-2¢), 5.43 (d, 1 H, J =
1.5 Hz, H-2¢¢), 5.35 (s, 1 H, H-1¢¢), 4.86 (m, 1 H, H-4¢¢¢), 4.78
(dd, 1 H, J = 3.2, 5.3 Hz, H-4¢¢), 4.75 (dd, 1 H, J = 3.7, 12.0 Hz,
H-5a¢¢¢), 4.72–4.65 (m, 4 H, H-4¢, H-5b¢¢¢, H-6a¢¢, H-6b¢¢), 4.55
(dd, 1 H, J = 3.4, 7.8 Hz, H-4), 4.41 (m, 1 H, H-5¢), 4.35 (dd, 1 H,
J = 6.1, 10.9 Hz, H-6a), 4.30 (m, 2 H, H-5, H-6b), 4.17 (dd, 1 H,
J = 4.6, 10.8 Hz, H-6a¢), 3.81 (dd, 1 H, J = 6.5, 10.8 Hz, H-6b¢),
2.00 (s, 3 H, CH3), 1.14, 0.97 (2 s, 18 H, ((CH3)3CCO)). 13C NMR
(CDCl3, 125.8 MHz): d 177.8 ((CH3)3CCO); 169.4, 168.8 (C-1,
COCH3), 165.7–165.1 (COPh), 133.5–125.3 (aromatic), 106.4
(C-1¢¢), 106.3 (C-1¢¢¢), 105.5 (C-1¢), 85.0 (C-4¢), 82.5 (C-2¢¢¢), 81.9
(C-2¢, C-2¢¢), 81.6 (C-4¢¢), 80.8 (C-4¢¢¢), 77.7 (C-3¢¢¢), 77.6 (C-3¢¢),
77.2 (C-4), 76.6 (C-3¢), 76.2 (C-5¢), 72.3 (C-2, C-5), 72.1 (C-3),
70.3 (C-5¢¢), 67.8 (C-6¢), 63.8 (C-6¢¢), 63.5 (C-5¢¢¢), 62.2 (C-6); 38.7,
38.4 (COC(CH3)3); 27.0, 26.6 (COC(CH3)3), 20.4 (CH3).
A vigorously stirred suspension of trichloroacetimidate 7
(340 mg, 0.22 mmol), 2,6-di-O-pivaloyl-D-galactono-1,4-lactone31
˚
(8, 91.4 mg, 0.26 mmol), and 4 A powdered molecular sieves
◦
(0.5 g) in freshly anhydr. CH2Cl2 (18 mL) was cooled to -15 C
and TMSOTf (12 mL, 0.066 mmol) was slowly added. After 2 h
of stirring, the mixture was diluted with CH2Cl2 (25 mL) and
processed as usual. The product was purified by a short column
chromatography (20 : 1, toluene–EtOAc and then 10 : 1, toluene–
EtOAc) to give 270 mg (71%) of syrupy 23: Rf 0.46 (5 : 1, toluene–
EtOAc); [a]D -21.4 (c 1, CHCl3); 1H NMR (CDCl3, 500 MHz) d
8.07–7.19 (m, 45 H, aromatic), 6.13 (m, 1 H, H-5¢¢), 5.84 (dd, 1 H,
J = 1.2, 3.8 Hz, H-3¢), 5.75 (bs, 1 H, H-1¢¢¢), 5.70 (dd, 1 H, J = 1.6,
5.5 Hz, H-3¢¢¢), 5.56 (dd, 1 H, J = 1.4, 5.0 Hz, H-3¢¢), 5.52 (d, 1
H, J = 8.7 Hz, H-2), 5.49 (s, 1 H, H-1¢¢), 5.47 (d, 1 H, J = 1.2 Hz,
H-2¢), 5.43 (d, 1 H, J = 1.6 Hz, H-2¢¢¢), 5.42 (d, 1 H, J = 1.4 Hz,
H-2¢¢), 5.37 (s, 1 H, H-1¢¢), 4.87 (dd, 1 H, J = 3.2, 5.0 Hz, H-4¢¢),
4.85–4.82 (m, 2 H, H-3, H-4¢¢¢), 4.80–4.74 (m, 2 H, H-5a¢¢¢, H-6a¢¢),
4.72 (dd, 1 H, J = 7.6, 11.9 Hz, H-6b¢¢), 4.69 (dd, 1 H, J = 4.4,
12.1 Hz, H-5b¢¢¢), 4.62 (dd, 1 H, J = 3.8, 7.2 Hz, H-4¢), 4.40 (dd, 1
H, J = 6.9, 10.7 Hz, H-6a), 4.38–4.34 (m, 2 H, H-5¢, H-6b), 4.33
(dd, 1 H, J = 2.1, 8.0 Hz, H-4), 4.22 (ddd, 1 H, J = 2.1, 6.3, 6.9 Hz,
H-5), 4.18 (dd, 1 H, J = 6.4, 10.7 Hz, H-6a¢), 3.79 (dd, 1 H, J = 5.6,
10.7 Hz, H-6b¢), 1.18, 0.98 (2 s, 18 H, ((CH3)3CCO)). 13C NMR
(CDCl3, 125.8 MHz): d 177.3, 177.1 ((CH3)3CCO), 168.8 (C-1),
166.6–165.0 (COPh), 133.5–128.3 (aromatic), 106.7 (C-1¢), 106.4
(C-1¢¢¢), 106.2 (C-1¢¢), 86.8 (C-4¢), 83.4 (C-2¢¢¢), 81.8 (C-4¢¢, C-2¢¢),
81.4 (C-2¢), 80.5 (C-4¢¢¢), 79.5 (C-4), 77.7 (C-3¢¢), 77.2 (C-3¢¢), 76.1
(C-3¢, C-5¢), 74.6 (C-2), 73.2 (C-5), 71.5 (C-3), 70.3 (C-5¢¢), 67.2 (C-
6¢), 63.8, 63.3 (C-5¢¢¢, C-6¢¢), 63.0 (C-6); 38.7, 38.4 (COC(CH3)3);
27.0, 26.7 (COC(CH3)3).
HRMS (ESI) m/z calcd for C98H93O32 (M+H+) 1781.5645,
found 1781.5631.
2,3,5,6-Tetra-O-benzoyl-b-D-galactofuranosyl-(1→6)-[2,3,5-
tri-O-benzoyl-a-D-arabinofuranosyl-(1→5)]-2,3-di-O-benzoyl-b-
D-galactofuranosyl-(1→5)-3-O-acetyl-2,6-di-O-pivaloyl-a,b-D-
galactofuranose (25). A solution of bis(2-butyl-3-methyl)borane
(0.47 mmol) in anhydr. THF (0.13 mL), cooled to 0 ◦C and under
an argon atmosphere, was added to a flask containing previously
dried compound 24 (70 mg, 0.04 mmol). The solution was allowed
to reach room temperature and stirring continued for 16 h when tlc
showed partial consumption of 24. The mixture was cooled to 0 ◦C
and more solution of bis(2-butyl-3-methyl)borane (0.47 mmol) in
anhydr. THF (0.13 mL) was added. The resulting solution was
allowed to reach room temperature and the stirring continued
for additional 16 h. The tlc showed total consumption of 24 and
the mixture was processed as previously described.59 The product
was purified by column chromatography (12 : 1, toluene–EtOAc)
to give 64 mg (64%) of syrupy 25 as a 0.71 : 0.29 b : a anomeric
mixture: Rf 0.52 (5 : 1 toluene–EtOAc); [a]D - 6.3 (c 1, CHCl3); 1H
NMR (CDCl3, 500 MHz), only the assigned value are listed, d:
8.106–7.18 (m, 45 H, aromatic), 6.11 (m, 0.71 H, H-5¢¢b anomer),
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6.05 (m, 0.29 H, H-5¢¢ a anomer), 5.84 (dd, 0.29 H, J = 1.9, 5.6 Hz,
H-3¢¢¢), 5.82 (bs, 1 H, H-1¢¢¢), 5.79 (dd, 0.79 H, J = 1.3, 5.6 Hz, H-3¢¢¢
b anomer), 5.66 (m, 0.71 H, H-3¢¢ b anomer), 5.61 (bs, 0.29 H, H-1¢
a anomer), 5.51 (s, 0.71 H, H-1¢), 5.36 (bs, 0.29 H, H-1¢ a anomer),
5.33 (m, 1.71 H, H-1¢¢ b anomer, H-1 b anomer, H-1 a anomer),
5.23 (dd, 0.71 H, J = 1.4, 5.1 Hz, H-3 b anomer), 1.96, 1.32 (2 s,
CH3), 1.14, 1.13, 1.11, 1.06 (4 s, 18 H, C(CH3)3); 13C NMR (CDCl3,
125.8 MHz) d: 178.0 (COC(CH3)3), 177.1 (COC(CH3)3), 169.8
(COCH3), 166.4–165.3 (COPh), 133.4–128.2 (aromatic), 106.5 (C-
1¢¢¢ b anomer), 106.3 (C-1¢¢¢ a anomer), 105.7 (C-1¢¢), 105.4 (C-1¢
a anomer), 105.6 (C-1¢ b anomer), 105.0 (C-1¢ a anomer), 100.5
(C-1 b anomer), 95.3 (C-1 a anomer), 82.9, 82.7, 82.3, 82.1, 82.0,
81.7 (x 2), 81.5, 81.3, 80.8, 80.4, 79.1, 77.6, 76.4, 75.3, 74.7, 70.1,
66.8, 64.2, 63.8, 63.5; 38.7, 38.5, 38.4 (COC(CH3)3); 27.1, 27.0,
26.9, (COC(CH3)3); 21.5, 20.3 (CH3). HRMS (ESI) m/z calcd for
C98H94O32Na (M+Na+) 1805.5620, found 1805.5573.
H-4), 4.14 (dd, 1 H, J = 3.8, 10.8 Hz, H-6a¢), 3.87 (dd, 1 H, J = 7.2,
10.9 Hz, H-6b¢), 3.62 (dt, 1 H, J = 6.8, 9.6 Hz, CH2O), 3.36 (dt, 1
H, J = 6.6, 9.6 Hz, CH2O), 2.01 (m, 2 H, CH2), 1.93 (s, 3 H, CH3),
1.50 (m, 2 H, CH2), 1.36–1.22 (m, 10 H, CH2), 1.11, 1.07 (2 s, 18
H, ((CH3)3CCO)). 13C NMR (CDCl3, 125.8 MHz): d 177.9, 177.4
((CH3)3CCO), 169.9 (CH3CO), 166.0–165.2 (COPh), 139.2 (CH-
ethylenic), 133.4–128.2 (aromatic), 114.1 (CH2-ethylenic), 106.5
(C-1¢¢), 106.0 (C-1¢¢¢), 105.4 (C-1), 105.0 (C-1¢), 83.2 (C-4¢), 82.6
(C-2¢¢¢), 82.2 (C-2¢), 82.0 (C-2¢¢), 81.7 (C-2), 81.5 (C-4¢¢), 80.7 (C-
4¢¢¢), 80.2 (C-4), 77.7 (C-3¢¢), 77.4 (C-3¢), 77.2 (C-3¢¢¢), 76.2 (C-3),
75.4 (C-5¢), 72.5 (C-5), 70.3 (C-5¢¢), 68.0 (C-6¢), 67.6 (CH2O), 63.8
(C-6), 63.7 (C-6¢), 63.4 (C-5¢¢¢), 38.6 (2 x (CH3)3CCO), 33.8, 29.4,
29.5, 29.3, 29.1, 28.9, 27.0, 26.8, 26.0; 27.0, 26.7 ((CH3)3CCO),
26.0, 20.6 (CH3).
HRMS (ESI) m/z calcd for C108H112O32Na (M+Na+) 1943.7029,
found 1943.7091.
9-Decenyl b-D-galactofuranosyl-(1→6)-[a-D-arabinofuranosyl-
9-Decenyl 2,3,5,6-tetra-O-benzoyl-b-D-galactofuranosyl-(1→6)-
[2,3,5-tri-O-benzoyl-a-D-arabinofuranosyl-(1→5)]-2,3-di-O-ben-
zoyl-b-D-galactofuranosyl-(1→5)-3-O-acetyl-2,6-di-O-pivaloyl-b-
D-galactofuranoside (27). To a stirred solution of 25 (86 mg, 0.048
mmol) and trichloroacetonitrile (36 mL, 0.36 mmol) in anhydr.
(1→5)]-b-D-galactofuranosyl-(1→5)-b-D-galactofuranoside
(2).
Compound 27 (52 mg, 0.027 mmol) was suspended in 0.49 M
sodium methoxide in methanol solution (0.79 mL) and then
cooled at 0 ◦C. After stirring for 1 h at 0 ◦C, the resulting solution
was warmed to room temperature, stirred for 2.5 h, and 9 : 1
MeOH–H2O solution (2 mL) was added. The solution was passed
through a column containing Amberlite IR-120 plus (H+) resin
(1.5 mL) and the column washed with MeOH–H2O (9 : 1). The
combined eluates were evaporated and the remaining methyl
benzoate was eliminated by five successive coevaporations with
water (1 mL). The residue was dissolved in water, further purified
through a StrataTM C18-E cartridge, and the solution evaporated.
Glycoside 2 (16 mg, 76%) was obtained as a hygroscopic syrup. Rf
0.62 (n-propanol–EtOH–H2O, 7 : 1 : 1); [a]D -37.9 (c 1, H2O); 1H
NMR (D2O, 500 MHz) d: 5.78 (m, 1 H, CH-ethylenic), 5.20 (bs,
1 H), 5.18 (bs, 1 H), 4.98 (bs, 1 H), 4.97 (m, 1 H, CH2-ethylenic),
4.87 (bs, 1 H), 4.90 (m, 1 H, CH2-ethylenic), 4.58–3.88 (14 H),
3.80–3.60 (8 H), 3.43 (m, 1 H, CH2O), 2.00 (m, 2 H, CH2), 1.53
(m, 2 H, CH2), 1.33–1.25 (m, 10 H, CH2 ¥ 5). 13C NMR (D2O,
125.8 MHz): d 139.7 (CH-ethylenic), 114.7 (CH2-ethylenic),
109.1, 108.3, 107.9 (x 2), 84.4, 83.5, 83.2, 82.1 (x 2), 82.0, 81.7,
81.6, 77.4, 77.3, 77.2, 77.0, 76.4, 71.4, 68.8 (CH2O), 68.2, 63.4,
62.7, 61.8, 34.2, 30.8, 30.3, 29.8, 29.5, 29.3, 26.3. HRMS (ESI)
m/z calcd for C33H58O20Na (M+Na+) 797.3414, found 797.3416.
◦
CH2Cl2 (5 mL) cooled to 0 C, DBU (5.4 mL, 0.036 mmol) was
slowly added. After 2 h, the solution was carefully concentrated
under reduced pressure at rt and the residue was purified by
column chromatography (25 : 1 : 0.2 toluene–EtOAc–TEA) to give
trichloroacetimidate 26 (68 mg, 73%) as a syrup: Rf 0.45 (5 : 1 : 0.05
toluene–EtOAc–TEA);1H NMR (CDCl3, 200 MHz) d 8.54 (s, 1
H, NH), 8.07-7.15 (m, 45 H), 6.26 (s, 1 H, H-1 b anomer), 6.04
(m, 1 H, H-5¢¢), 5.78 (m, 2 H), 5.62 (m, 2 H), 5.55 (d, 1 H, J =
1.8 Hz), 5.53 (s, 1 H), 5.51 (d, 1 H, J = 1.3 Hz), 5.45 (d, 1 H, J =
1.5 Hz), 5.36 (m, 2 H), 5.33 (dd, 1 H, J = 0.5, 2.0 Hz), 4.88 (m, 1
H), 4.75–4.68 (m, 5 H), 4.64 (dd, 1 H, J = 4.1, 12.0 Hz), 4.53 (m, 1
H), 4.47 (t, 1 H, J = 5.3 Hz), 4.37 (dd, 1 H, J = 3.9, 11.4 Hz), 4.32
(m, 1 H), 4.25 (dd, 1 H, J = 6.6, 1.4 Hz), 4.17 (dd, 1 H, J = 3.7,
11.0 Hz), 4.89 (dd, 1 H, J = 7.1, 11.0 Hz), 1.93 (s, 3 H), 1.25, 1.22
(2 s, 18 H).
A vigorously stirred suspension of trichloroacetimidate 26
(63 mg, 0.033 mmol), 9-decen-1-ol (8.1 mL, 0.044 mmol), and
˚
4 A powdered molecular sieves (0.2 g) in freshly anhydr. CH2Cl2
(2 mL) was cooled to -15 ◦C and TMSOTf (1.8 mL, 0.010 mmol)
was slowly added. After 2 h of stirring, the mixture was diluted
with CH2Cl2 (10 mL) and processed as above. The product was
washed with cold hexane (6 ¥ 0.7 mL) to eliminate the alcohol to
afford 27 as a chromatographically homogeneous syrup (60 mg,
94%): Rf 0.62 (7 : 1, toluene–EtOAc); [a]D -14.9 (c 1, CHCl3);
1H NMR (CDCl3, 500 MHz) d 8.06—7.17 (m, 45 H, aromatic),
6.03 (m, 1 H, H-5¢¢), 5.80 (ddt, 1 H, J = 6.7, 10.8, 17.0 Hz, CH-
ethylenic), 5.78 (bs, 1 H, H-1¢¢¢), 5.63 (dd, 1 H, J = 1.6, 5.3 Hz,
H-3¢¢¢), 5.61 (dd, 1 H, J = 1.6, 5.4 Hz, H-3¢¢), 5.58 (m, 2H, H-1¢,
H-2¢), 5.50 (d, 1H, J = 1.6 Hz, H, H-2¢¢¢), 5.45 (d, 1H, J = 1.6 Hz,
H, H-2¢¢), 5.35 (m, 1 H, H-1¢¢), 5.31 (dd, 1 H, J = 2.5, 6.5 Hz,
H-3), 5.06 (dd, 1 H, J = 1.0, 2.5 Hz, H-2), 4.98 (ddt, 1 H, J = 1.6,
2.2, 17.0 Hz, CH2-ethylenic), 4.92 (ddt, 1 H, J = 1.2, 2.2, 10.3 Hz,
CH2-ethylenic), 4.92 (bs, 1 H, H-1), 4.88 (dt, 1 H, J = 3.8, 5.9 Hz,
H-5¢), 4.74 (dd, 1 H, J = 3.6, 12.0 Hz, H-6a¢¢), 4.71 (dd, 1 H, J =
3.3, 5.4 Hz, H-4¢¢), 4.70–4.67 (m, 3 H, H-5a¢¢, H-5b¢¢, H-4¢¢¢), 4.65
(dd, 1 H, J = 4.1, 12.0 Hz, H-6b¢¢¢), 4.51 (m, 1 H, H-5¢), 4.37 (m,
H-6a), 4.31 (m, 2 H, H-5, H-6b), 4.27 (dd, 1 H, J = 3.6, 6.5 Hz,
Acknowledgements
This work was supported by grants from Agencia Nacional de
Promocio´n Cient´ıfica y Tecnolo´gica, Universidad de Buenos Aires
and CONICET. R. M. de Lederkremer and C. Gallo-Rodriguez
are research members of CONICET.
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