Production of carbohydrate building blocks from red seaweed polysaccharides. Efficient conversion of galactans into C-glycosyl aldehydes

Article abstract of DOI:10.1039/b816606d

Agarans and carrageenans are abundant natural polysaccharides which are obtained on a large scale by water extraction from a variety of red seaweeds. These galactans, in addition to being valuable products for the pharmaceutical and food industries, are l

Full text of DOI:10.1039/b816606d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Production of carbohydrate building blocks from red seaweed
polysaccharides. Efficient conversion of galactans into C-glycosyl aldehydes†
Diogo R. B. Ducatti,a,b Alessandro Massi,*a Miguel D. Noseda,b Maria Eugeˆnia R. Duarteb and
Alessandro Dondoni*a
Received 22nd September 2008, Accepted 23rd October 2008
First published as an Advance Article on the web 26th November 2008
DOI: 10.1039/b816606d
Agarans and carrageenans are abundant natural polysaccharides which are obtained on a large scale by
water extraction from a variety of red seaweeds. These galactans, in addition to being valuable products
for the pharmaceutical and food industries, are low cost starting materials for the preparation of useful
and rare carbohydrate-based building blocks whose access by total synthesis is difficult and expensive.
The semisynthesis of two sets of C-glycosyl aldehydes with L- and D-configuration from agarose and
kappa-carrageenan respectively is described. Succinctly, the partial acid-catalyzed mercaptolysis of the
two galactans under mild conditions afforded agarobiose and carrabiose (b-D-Galp-(1→4)-3,6-
anhydro-aldehydo-L- and D-galactose, respectively) derivatives. Complete depolymerization of agarose
and kappa-carrageenan under harsher conditions produced 3,6-anhydro L- and D-galactose aldehyde
derivatives. Chain shortening of these products via alditol formation and oxidative carbon-carbon bond
cleavage furnished C-formyl a-L- and a-D-threofuranosides. The above C-glycosyl aldehydes were all
prepared on a meaningful preparative scale starting from gram quantities of galactans. Finally, a new
procedure for the preparation of the 2,3-O-benzyl L-threofuranose was established by Baeyer-Villiger
oxidation of the benzylated C-formyl a-L-threofuranoside here prepared from agarose.
variety of diseases. The regiochemistry of sulfate derivatization
Introduction
onto the carbohydrate moiety as well as the configuration of
Proteoglycans, glycoproteins, and glycolipids are important medi-
the carbon atom bearing the sulfate group are crucial for the
ators in specific cell-cell and cell-extracellular matrix interactions.
biological function of the whole molecule. Accordingly, several
The carbohydrate domain (mono- and oligosaccharide units)
sulfated glycomimetics have been prepared.13 Also, the synthesis
acts as an information carrier1 while it is responsible for many
of CBBs that display a chiral hydroxylated tetrahydrofuran moiety
functions performed by these glycoconjugates, such as neuronal
in their structure has attracted considerable attention14 due to their
development,2 tumor growth and metastasis,3 inflammation,4 viral
potential use in the preparation of bioactive compounds such as
and bacterial infection,5 immune response,6 and fertilization.7
antibiotics, nucleoside, and nucleotide analogues.15
Hence, the development of synthetic strategies toward natural
In parallel, synthetic organic chemists have widely recognized
oligosaccharides and their mimetics plays a pivotal role in
the great potential of carbohydrates as chiral ligands and aux-
biomedicinal chemistry.8 Carbohydrate-based building blocks
iliaries and, more recently, as organocatalysts in stereoselec-
(CBBs) are key molecules for the synthesis of glycomimetics. The
tive transformations.16 However, in many cases the scope of
glycidic portion may act not only as a mimetic of particular
carbohydrate-based strategies in the above mentioned areas is
biological motifs9 but also as a valuable scaffold10 by virtue
limited by the availability of CBBs at low cost and in sufficient
of its rich stereochemistry, rigid conformation, and ease of
amount. Moreover only the more abundant enantiomeric form is
functionalization. In particular, CBBs constituted of unusual
easily accessible. Therefore, the development of efficient routes
sugar residues and holding suitable chemical functionalities have
to CBBs with both natural and non-natural stereochemistry
been demonstrated to be ideal substrates for the production of
is of great relevance. Natural polysaccharides may constitute
chemical libraries as sources of molecular diversity.11 In this
valuable and low cost starting materials for the preparation of
context, the great relevance of the sulfate group in bioactive sul-
fated carbohydrates has been recently recognized.12 This chemical
functionality appears to be involved in many recognition processes
at the molecular level and participate in the development of a
CBBs. Remarkably, galactans from red seaweeds are interesting
biopolymers that are constituted of alternating (1→3)-linked
b-D-galactopyranose and (1→4)-linked a-D-galactopyranose
units, some which are sulfated at specific positions. Depending on
the configuration of the 4-linked units, galactans can be classified
as agarans (L-enantiomer) or carrageenans (D-enantiomer).17
Frequently, 4-linked units in galactans are displayed in the 3,6-
anhydro form. Agarose 1 ([→3)-b-D-Galp-(1→4)-3,6-anhydro-
a-L-Galp-(1→]n) and kappa-carrageenan 2 ([→3)-b-D-Galp-4-
sulfate-(1→4)-3,6-anhydro-a-D-Galp-(1→]n) are representative
examples of this sub-class of galactans (Fig. 1).17a,c Agarans and
aDipartimento di Chimica, Laboratorio di Chimica Organica, Universita`
di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy. E-mail: adn@
unife.it, msslsn@unife.it
bDepartamento de Bioqu´ımica e Biologia Molecular, Universidade Federal
do Parana´, Centro Polite´cnico, CEP 81-531-990, PO Box 19046, Curitiba,
Brazil
† Electronic supplementary information (ESI) available: Copies of the 1H
and 13C NMR spectra. See DOI: 10.1039/b816606d
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Fig. 1 Carbohydrate building blocks prepared from agarose 1 and kappa-carrageenan 2.
carrageenans are valuable products for the pharmaceutical and
food industries because they are used as gelling-stabilizing agents
and consumer products (e.g. gel matrices for chromatography, mi-
crobial and cell culture, and other biochemical assay supports).18
Hence, because of their broad use these galactans are produced
on a large scale. They are, therefore, low cost starting materials for
the production of useful and valuable CBBs.19
We would like to report in this paper the preparation of
CBBs 3–5 from agarose 1, and 7, 8, ent-4 and ent-5 from
kappa-carrageenan 2. These compounds constitute a set of
O-benzyl protected aldehydes displaying a threofuranosyl unit
in either the D or L enantiomeric form, and eventually bearing
the sulfate group in their structure (Fig. 1). Another common
feature of these derivatives is the presence of a hydrolytically
and enzymatically stable carbon-carbon bond at the anomeric
position of the threofuranose moiety. The synthesis of the rare
sugar L-threose 6 from 5 is also reported. The main interest in the
production of preparative amounts of 6 lies in its use as a starting
material for non-natural nucleotide synthesis and the subsequent
generation of (2¢,3¢)-a-L-threose nucleic acid (TNA) sequences.20
In fact, TNAs are capable of giving Watson-Crick base pairing
with complementary DNA or RNA sequences. Proposals about
the role of TNA as a progenitor of RNA have been recently
advanced.21
tans. However, these methods involve time consuming reactions
and laborious purifications steps.22 Hence, to overcome these limi-
tations and produce multigrams of the target CBB 3, we submitted
commercial agar (5 g scale), which is a source of agarose 1,23
to mild TFA (trifluoroacetic acid)-promoted hydrolysis according
to the procedure of Stevenson and Furneaux23 (Scheme 1). This
procedure mainly afforded a reducing disaccharide intermediate
(not shown) via selective 3,6-anhydro-a-galactosidic bond cleav-
age. This crude material was treated with ethanethiol (EtSH)
and concentrated HCl to give crude agarobiose dithioacetal 9.
Flash chromatography of a portion (100 mg) of this material
allowed the isolation of pure 9,24 which was characterized as
the peracetylated derivative 10.24 Crude dithioacetal 9 was then
perbenzylated under standard conditions (NaH/BnBr, DMF, 0 ◦C
to r.t., 1 h) to give disaccharide 11 in 52% isolated yield (from
agarose 1; 5 g scale). Carbonyl group unmasking of dithioacetal 11
was carried out under oxidative conditions using periodic acid,25
thus avoiding dithioacetal cleavage by harmful mercuric salts.
This transformation was performed at 0 ◦C in THF-Et2O and
produced the aldehyde 3 in 90% yield and almost pure form as
judged by 1H NMR and TLC analyses. The formation of a single
product indicated that the configuration at the C2 stereocenter
of the epimerizable 3 remained unaltered in the course of the
oxidation of 11. The preparation of peracetylated aldehyde 12 was
also investigated. Acetylation on a multigram scale of the crude
extract containing 9 proceeded readily under standard conditions
(Ac2O/pyridine) and afforded the derivative 10 in 59% isolated
yield. Unfortunately, the conversion of 10 to 12 by the above
periodic acid method generated a complex reaction mixture, from
which aldehyde 12 was isolated in 57% yield and 80% purity as
established by 1H NMR analysis.
Results and discussion
A. Semisynthesis of agarobiose derivative 3 and carrabiose
derivatives 7 and 8
Early studies on the elucidation of galactan’s structure were
troublesome because of the high instability of the 3,6-anhydro-
galactose unit under the harsh acidic conditions that were used
for the hydrolysis of the polysaccharide backbone.22 However,
approaches based on HCl-promoted mercaptolysis proved to
be successful in producing analytical samples and preparative
amounts of dithioacetal derivatives of the anhydro unit of galac-
The procedure depicted in Scheme 1 was then applied to
kappa-carrageenan 2 depolymerization.26 Accordingly, the two-
step mercaptolysis of 227 (5 g scale) produced a crude residue
which contained a mixture of 4¢-sulfated disaccharide 13a and
free-hydroxy disaccharide 13b in 5:1 ratio (Scheme 2). This ratio
was estimated after the isolation of pure 13a and 13b by analytical
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Scheme 1 Semisynthesis of CBB 3 derived from agarose 1.
flash chromatography and acetylation of the above crude material
(see Experimental Section). The presence of a sulfate group at
C4¢ of 13a was confirmed by ESI MS (negative-ion mode) and
1H NMR analyses. The MS spectrum showed an intense peak
at m/z 509 ([M - H]-), while the NMR spectrum displayed the
H4¢ signal shifted significantly downfield to 4.65 ppm. This result
unequivocally excluded sulfate group hydrolysis or migration
during the mercaptolysis of 2.
The crude material containing 13a and 13b was benzylated
under standard conditions to give the sulfated disaccharide 14a in
41% isolated yield from 2 (3 g scale) along with the perbenzylated
disaccharide 14b (7%). Unfortunately, unmasking of the latent
formyl group of 14a by periodic acid oxidation resulted in the
concomitant loss of the sulfate group and isolation of aldehyde
15 (83% yield). This unsatisfactory outcome was confirmed by 1H
NMR analysis of the 4¢-trichloroacetyl carbamate derivative of 15
which was generated in the NMR tube by using trichloroacetyl
isocyanate as a derivatizating agent (see Experimental Section).
Moreover, the TLC profile of the unmasking reaction indicated
that the sulfate group removal occurred before the formyl group
formation. Fortunately enough, this problem was solved by
Scheme 2 Semisynthesis of CBB 8 derived from kappa-carrageenan 2.
applying different oxidizing conditions. Accordingly, treatment of
14a with sodium nitrite and acetyl chloride in dichloromethane
and phosphate buffer at room temperature28 afforded the target
aldehyde 8 in a rewarding 88% isolated yield (Scheme 2). The 1H
NMR spectrum of 8 (DMSO-d6) at room temperature revealed
the presence of the aldehyde and its hydrated form, whereas at
higher temperatures (120–160 ◦C) partial epimerization at the
C2 stereocenter and loss of sulfate group were observed. Hence,
aldehyde 8 was conveniently converted into the corresponding al-
cohol 16 and this was fully characterized (Scheme 2). At this stage,
we were also interested in preparing the benzylated disaccharide
aldehyde 7, i.e. using the minor product that resulted from the
benzylation-oxidation sequence of the crude extract containing
13a and 13b (see Scheme 2 and Experimental Section). To this
end, we envisaged the desulfation of 14a and subsequent O-benzyl
protection as an alternative route to 7 (Scheme 3). While several
reagents have been reported for the desulfation of carbohydrates
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Scheme 3 Semisynthesis of CBB 7 from sulfated intermediate 14a.
and polysaccharides,29 chlorotrimethylsilane (CTMS) was selected
in this endeavor. Accordingly, treatment of 14a with CTMS in
pyridine at 100 ◦C afforded the 4¢-O-TMS protected disaccharide
17 in 78% isolated yield (column chromatography). It is worth
noting that this compound constitutes a valuable CBB in its
own right because the orthogonal protection of the 4¢-hydroxy
group of the b-Galp unit provides easy access to other classes
of carbohydrate molecules (library from library approach). The
conversion of disaccharide 17 into CBB 7 proceeded readily
as depicted in Scheme 3. The one-pot base (NaH)-promoted
TMS group removal and Bn group installation afforded the
intermediate 14b (88%), which in turn was submitted to the opti-
mized unmasking protocol with periodic acid to give the
target aldehyde 7 (90%).
Scheme 4 Semisynthesis of CBBs 4 and ent-4 from galactans.
Acetylation of a portion of each extract furnished the peracety-
lated derivatives of these products (56% and 30% overall yields
from 1 and 2, respectively; see Experimental Section), thereby
allowing us to evaluate the chemical efficiency of the optimized
mercaptolysis procedure. The substantially different yields of 18
and ent-18 are likely to be due to the lower hydrolysis rate of kappa-
carrageenan 2 in comparison with agarose 1. It is well known
that the presence of sulfate groups in carrageenan’s23,31 backbone
confers stability to both a- and b-glycosidic bonds through steric
and electronic interactions. In addition, the observed low solubility
of kappa-carrageenan 2 in the MeOH/EtSH mixture likely
contributed to decreasing the polysaccharide hydrolysis rate. As a
continuation of the synthetic plan, the crude extracts containing
18 and ent-18 were perbenzylated under standard conditions to
give 19 and ent-19. These intermediates were converted into the
target 3,6-anyhdro-L-galactose 4 and 3,6-anhydro-D-galactose ent-
4 aldehydes by the optimized periodate-based formyl unmasking
sequence described above (Scheme 4).
B. Semisynthesis of 3,6-anhydro L- and D-galactose aldehydes 4
and ent-4
Agarose 1 and kappa-carrageenan 2 were also considered as
starting materials for the preparation of aldehydes 4 and ent-4,
respectively. The approach toward these compounds required the
complete mercaptolysis of 1 and 2, i.e. acidic cleavage of both a-
and b-galactosidic bonds followed by dithioacetal formation of
the resulting 3,6-anhydro-galactose units. Previous studies were
reported as early as in the 1960s dealing with the complete
depolymerization of galactans22,30 by the use of concentrated HCl
and ethanethiol. However, in order to make the process developed
by Hama and co-workers30 operatively simple, we introduced
an important modification, namely the use of a lower excess of
stinky EtSH. Hence, agarose 123 and kappa-carrageenan 226,27
C. Semisynthesis of C-formyl a-L- and a-D-threofuranosides 5 and
ent-5, and Protected L-Threofuranose 6
◦
(6 g scale) were separately heated at 60 C for 17 h in a mixture
The development of efficient syntheses of C-formyl glycosides32
and their elaboration into bioactive C-oligosaccharides and
C-glycoconjugates33 have been actively pursued in one of our
laboratories over the course of the last two decades. Therefore,
of HCl/MeOH/EtSH (Scheme 4). After neutralization (NaOH),
diethyl ether extraction of the reaction mixtures afforded crude
extracts containing monosaccharide dithioacetals 18 and ent-18.
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the preparation of hitherto unreported C-glycosyl aldehyde 5 and
its enantiomer ent-5, featuring the rare threofuranosyl moiety, was
established as a further goal of this study. To this aim we planned
transforming agarose 1 and kappa-carrageenan 2 into alditols and
elaborating these intermediates into 5 and ent-5 via orthogonal
manipulation of the hydroxyl groups (Scheme 5). The strategy
was initially tested starting from agarose 1.23 This polysaccharide
(10 grams) was submitted to the double hydrolysis/reduction
protocol that was previously optimized on an analytical scale
for the quantitative determination (GC-MS analysis) of the
monosaccharide composition in galactans.23 Accordingly, the
mild acid hydrolysis of 1 by TFA at 80 ◦C resulted in selective
a-galactosidic bond cleavage to give a crude mixture that was
mainly constituted of the reducing disaccharide displaying the
3,6-anhydro-galactose residue as the terminal unit (not shown).
The subsequent reduction of the above mixture by NaBH4 in
MeOH afforded the crude alditol disaccharide 20, which in turn
was submitted to a second hydrolysis step under harsher condi-
tions (TFA, 120 ◦C) to promote the b-galactosidic bond cleavage.
This reaction sequence afforded the 3,6-anhydro-L-galactitol 21.34
A second reductive step (NaBH4) was also performed to convert
D-galactose into D-galactitol (not shown) and thus facilitate the
isolation of 21. A suitable work-up of the complex reaction mixture
by the use of ionic resins was then optimized (see Experimental
Section) to remove inorganic salts and D-galactitol from 21.
The satisfactory outcome of the whole procedure was confirmed
by acetylation of a portion (100 mg) of the crude residue and
recovery of acetylated 21 in 60% overall yield from agarose 1
(see Experimental Section). At this stage, the conversion of crude
21 into the target C-formyl a-L-threofuranoside 5 proceeded
rapidly through selective 1,2-O-isopropylidene protection, 4,5-O-
benzylation, acetonide removal, and final oxidation with periodic
acid (24% overall yield from 1; Scheme 5).
The numerous steps and the laborious purification of 21
prompted us to investigate a more efficient entry to 5 via a one-
carbon chain-shortening of 4. This approach involved the selective
C2 debenzylation of protected alditol 24 as the key step (Scheme 6).
This intermediate was readily prepared in almost quantitative yield
by NaBH4 reduction of aldehyde 4. Methods for the regioselective
deprotection of carbohydrate molecules are important tools to
access derivatives that display free hydroxy groups in definite
positions. Numerous reports dealing with this issue have been
reported over the years.35 Hence, after some experimentation
that involved the screening of several acid catalysts, we found
TFA was the optimal one to promote the selective C2 acetolysis
of 24. This transformation was effectively performed at 70 ◦C
by using a mixture of acetic anhydride and 5% TFA. Column
chromatography of the resulting crude material afforded the
diacetyl intermediate 25 as the main product in 72% isolated
yield. As previously postulated in similar studies on the selective
deprotection of pentofuranoses,35a a chelation effect of the Lewis
basic endocyclic oxygen and C2 benzylic oxygen atom on H+ ions
could be at the origin of the observed regioselectivity. Afterwards,
deacetylation of 25 under standard conditions (NaOMe/MeOH)
afforded the diol 23 (82%), which in turn was effectively oxidized
with periodic acid to give the target C-formyl a-L-threofuranoside
5 in 87% yield. The same strategy was employed for the synthesis
of the enantiomeric C-formyl a-D-threofuranoside ent-5 starting
from ent-4 (see Experimental Section).
Scheme 6 Semisynthesis of CBB 5 via selective debenzylation of interme-
diate 24.
As already mentioned, L-threofuranose derivative 6 is also a
valuable CBB, mainly because of its utilization in non-natural
nucleotide synthesis and TNA sequence generation.20 This rare
sugar is commercially available (Carbosynth: $400/g) and several
Scheme 5 Semisynthesis of CBB 5 via orthogonal protection of alditol
intermediate 21.
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procedures for its production have been reported in the
literature.21c,36 We envisaged the Baeyer-Villiger oxidation of
C-formyl a-L-threofuranoside 5 as a new route to 6 (Scheme 7).
Indeed, m-chloroperbenzoic acid (MCPBA) promoted the cleav-
age of the anomeric carbon-carbon bond of 5 to give the
O-formyl protected b-L-threofuranose 26 in 63% isolated yield.
The b-configuration at the anomeric position of 26 was tentatively
assigned by NMR analysis on the basis of the absence of NOE
on H3 upon H1 irradiation. The removal of the formyl protective
group from 26 was carried out under mild basic conditions (Et3N),
thus affording the target L-threofuranose derivative 6 in almost
quantitative yield.
a-cyano-4-hydroxycinnamic acid as the matrix. ESI MS analyses
were performed in negative-ion mode with samples dissolved in
a mixture of MeCN/H2O 1:1. Commercial agar,23 a source of
agarose 1, was purchased from Oxoid Limited (Hampshire, UK).
Kappa-carrageenan 2 was obtained from red algae Kappaphycus
alvarezii as described.26 Derivatives 6,37 18,22b,30 and 2138 are known
compounds and their spectroscopic data were identical to those
reported. Derivatives 9,24 10,24 13b,22c peracetylated-13b,22d and
ent-1822a are known compounds but only their optical rotation
values are reported.
b-D-Galactopyranosyl-(1→4)-3,6-anhydro-L-galactose diethyl
dithioacetal (9)
◦
Commercial agar (5 g)23 was first dissolved in hot (~90 C) H2O
(450 mL) and then 1M TFA solution (50 mL) was added in
◦
one portion. The resulting mixture was heated at 80 C for 3 h,
cooled to room temperature, diluted with H2O (500 mL), and then
concentrated under vacuum. The resulting residue was dissolved
in water (90 mL), diluted with i-PrOH (90 mL), and then filtered
through a glass-sintered filter. The filtrate was concentrated and
coevaporated with toluene three times to give a brown-yellow solid
(4.85 g). This material was dissolved in 37% HCl (7.2 mL) and
EtSH (3.2 mL) at 0 ◦C. The resulting mixture was then stirred
at 0 ◦C for 1h, neutralized with 1M NaOH solution, and kept
under a nitrogen flow to remove unreacted EtSH. The mixture
was then concentrated under vacuum to give a solid residue,
which was suspended in MeOH (100 mL), and filtered through
a glass-sintered filter. The filtrate was concentrated to afford a
crude material (5.01 g) containing the dithioacetal derivate 9. A
small amount of this crude material (100 mg) was eluted from a
column of silica gel with 7:1 AcOEt-MeOH to give 9 (60 mg, 59%
from starting agar)23 as a white amorphous solid. [a]D = -16.4 (c
Scheme 7 Semisynthesis of threofuranose derivative 6 from CBB 5.
Conclusions
In conclusion, we have reported a convenient utilization of natural
polysaccharides of marine origin through their transformation
into potentially valuable carbohydrate-based building blocks
which may serve as starting materials in C-glycoside synthesis.
The utility of these semisynthetic methods is demonstrated by their
being effective for the production of orthogonally functionalized
building blocks which are hardly accessible by total synthesis. It is
noteworthy that the opposite stereochemistry of the 3,6-anhydro-
galactose moiety that distinguishes the backbone of agarose from
kappa-carrageenan enables access to products which belong to
L- and D-series of carbohydrates. This great potential offers a wide
range of opportunities for studies in glycobiology and applications
in biomedicinal chemistry. The use of the herein described
CBBs for the synthesis of dihydropyrimidine-based artificial
C-nucleosides will be the subject of a forthcoming publication.
0.7, MeOH) (lit.24 [a]D = -20.9 (c 1.4, MeOH)); Rf = 0.16 (7:1
1
AcOEt-MeOH). H NMR (CD3OD): d = 4.41 (d, 1 H, J1¢,2¢
=
7.5 Hz, H-1¢), 4.34 (dd, 1 H, J2,3 = 3.5, J3,4 = 4.0 Hz, H-3), 4.29-
4.26 (m, 2 H, H-4, H-5), 4.00 (d, 1 H, J1,2 = 8.5 Hz, H-1), 3.93
(dd, 1 H, J5,6a = 4.5, J6a,6b = 9.5 Hz, H-6a), 3.86-3.84 (m, 2 H,
H-2, H-4¢), 3.80-3.70 (m, 3 H, H-6b, H-6a¢, H-6b¢), 3.55-3.50 (m,
2 H, H-5¢, H-2¢), 3.47 (dd, 1 H, J2¢,3¢ = 10.0, J3¢,4¢ = 3.5 Hz, H-3¢),
2.80-2.61 (m, 4 H, SCH2CH3), 1.25, 1.24 (2 t, 6 H, J = 7.5 Hz,
SCH2CH3). 13C NMR: d = 103.0, 86.1, 83.9, 75.8, 75.6, 73.8, 73.4,
73.0, 71.2, 68.9, 61.3, 54.4, 24.8, 24.6, 13.7, 13.6. MALDI-TOF
MS: 453.1 (M+ + Na). Anal. Calcd for C16H30O9S2 (430.13): C,
44.64; H, 7.02; S, 14.90. Found: C, 44.72; H, 7.00; S, 14.99.
2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl-(1→4)-2,5-di-O-
Experimental section
acetyl-3,6-anhydro-L-galactose diethyl dithioacetal (10)
Reactions were monitored by TLC on silica gel 60 F254 with
detection by charring either with sulfuric acid (conc. H2SO4/EtOH
1:9) or 0.5% orcinol in conc. H2SO4/EtOH 1:20. Flash column
chromatography was performed on silica gel 60 (230–400 mesh).
A mixture of crude material (125 mg) containing compound
9, pyridine (2.2 mL), and Ac2O (2.0 mL) was stirred at room
temperature for 12 h, then concentrated, and coevaporated with
toluene three times. The resulting residue was eluted from a column
of silica gel with 1:1 cyclohexane-AcOEt to give 10 (120 mg, 59%
from starting agar)23 as a colorless syrup. [a]D = -7.4 (c 0.8, CHCl3)
(lit.24 [a]D = -11.8 (c 1.0, CHCl3)); Rf = 0.28 (1:1 cyclohexane-
AcOEt). 1H NMR: d = 5.39 (dd, 1 H, J3¢,4¢ = 3.5, J4¢,5¢ = 1.0 Hz,
H-4¢), 5.35 (dd, 1 H, J1,2 = 9.2, J2,3 = 2.7 Hz, H-2), 5.18 (dd, 1
H, J1¢,2¢ = 8.0, J2¢,3¢ = 10.5 Hz, H-2¢), 5.02 (dd, 1 H, H-3¢), 5.00
Optical rotations were measured at 20
2
◦C in the stated
1
solvent; [a]D values are given in 10-1 deg cm2 g-1. H (300 MHz)
and 13C (75 MHz) NMR spectra were recorded for CDCl3
solutions at room temperature unless otherwise specified. Peaks
1
assignments were aided by H–1H COSY and gradient-HMQC
experiments. MALDI-TOF mass spectra were acquired using
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(m, 1 H, H-5), 4.59 (d, 1 H, H-1¢), 4.47 (dd, 1 H, J3,4 = 5.0 Hz,
H-3), 4.22 (dd, 1 H, J5¢,6b¢ = 7.2, J6a¢,6b¢ = 11.0 Hz, H-6b¢), 4.12 (dd,
J5¢,6a¢ = 6.0 Hz, H-6a¢), 4.06 (d, 1 H, H-1), 4.00-3.94 (m, 3 H, H-5¢,
H-6b, H-6a), 3.89 (dd, 1 H, J4,5 = 1.5 Hz, H-4), 2.78-2.58 (m, 4 H,
SCH2CH3), 2.14, 2.13, 2.08, 2.06, 2.04, 1.97 (6 s, 18 H, COCH3),
1.26, 1.23 (2 t, 6 H, J = 7.5 Hz, SCH2CH3). 13C NMR: d = 170.3,
170.2, 170.1, 169.9, 169.4, 101.6, 86.0, 83.0, 79.5, 72.5, 71.1, 70.9,
70.6, 68.6, 66.9, 61.0, 52.0, 25.0, 24.8, 20.8, 20.7,20.6, 20.5, 20.4,
14.2, 14.1. MALDI-TOF MS: 721.3 (M+ + K). Anal. Calcd for
C28H42O15S2 (682.20): C, 49.26; H, 6.20; S, 9.39. Found: C, 49.39;
H, 6.25; S, 9.31.
AcOEt as the eluent. [a]D = -28.8 (c 2.4, CHCl3); Rf = 0.26
(3.3:1cyclohexane-AcOEt).1H NMR: d = 9.67 (d,1 H, H-1), 7.38-
7.18 (m, 30 H, Ph), 4.93, 4.86, 4.77 (3 d, 3 H, J = 12.0 Hz, PhCH2),
4.73 (s, 1 H, PhCH2), 4.70 (d, 2 H, J = 12.0 Hz, PhCH2), 4.61,
4.51 (2 d, 2 H, PhCH2), 4.42-4.30 (m, 6 H, PhCH2, H-4, H-3),
4.21 (dd, 1 H, J1,2 = 1.0, J2,3 = 3.0 Hz, H-2), 4.11 (m, 1 H, H-5),
4.09 (d, 1 H, J1¢,2¢ = 8 Hz, H-1¢), 3.97 (dd, 1 H, J5,6b = 4.0, J6a,6b
=
10.0 Hz, H-6b), 3.83 (dd, 1 H, J5,6a = 5.0 Hz, H-6a), 3.80 (dd, 1 H,
H-4¢), 3.77 (dd, 1 H, J
= 10.0 Hz, H-2¢), 3.47 (dd, 1 H, J5¢,6b¢
=
2¢,3¢
6.5, J6a¢,6b¢ = 9.5 Hz, H-6b¢), 3.40 (dd, 1 H, J3¢,4¢ = 3.0 Hz, H-3¢),
3.37 (dd, 1 H, J5¢,6a¢ = 6.0 Hz, H-6a¢), 3.27 (ddd, 1 H, H-5¢). 13C
NMR: d = 202.5, 138.6, 138.3, 138.2, 137.8, 137.6, 137.4, 128.4,
128.3, 128.2, 128.1, 127.9, 127.7, 127.6, 127.5, 104.0, 84.9, 83.8,
83.4, 82.2, 81.9, 79.1, 75.1, 74.5, 73.5, 73.4, 73.3, 73.0, 72.9, 71.5,
71.4, 69.2. MALDI-TOF MS: 887.4 (M+ + Na). Anal. Calcd for
C54H56O10 (864.39): C, 74.98; H, 6.53. Found: C, 74.87; H, 6.57.
The above described procedure was repeated starting from 2.50 g
of the crude material containing 9 to give 2.40 g of 10.
2,3,4,6-Tetra-O-benzyl-b-D-galactopyranosyl-(1→4)-2,5-di-O-
benzyl-3,6-anhydro-L-galactose diethyl dithioacetal (11)
To a cooled (0 ◦C), stirred mixture of the crude material (4.17 g)
containing compound 9 (~2.51 g, 5.84 mmol) and DMF (80 mL)
was added portionwise NaH (2.80 g, 70.1 mmol of a 60%
suspension in mineral oil) and, after 30 min, benzyl bromide
(5.4 mL, 45.5 mmol). The mixture was stirred at room temperature
for 40 min, then treated with MeOH (10 mL), stirred for an
additional 10 min, diluted with H2O (100 mL), and extracted
with Et2O (3 ¥ 100 mL). The combined organic phases were dried
(Na2SO4), concentrated, and eluted from a column of silica gel
with 5:1 cyclohexane-AcOEt to give 11 (5.1 g, 52% from starting
agar)23 as a white amorphous solid. [a]D = -3.4 (c 0.9, CHCl3);
Rf = 0.19 (5:1cyclohexane-AcOEt).1H NMR: d = 7.40-7.20 (m,
30 H, Ph), 4.94, 4.89, 4.84, 4.78 (4 d, 5 H, J = 11.5 Hz, PhCH2),
4.72 (s, 2 H, PhCH2), 4.57, 4.43, 4.39, 4.37 (4 d, 5 H, J = 11.5 Hz,
PhCH2), 4.35 (d, 1 H, J1¢,2¢ = 7.5 Hz, H-1¢), 4.33-4.28 (m, 2 H,
H-3, H-4), 4.12 (d, 1 H, J1,2 = 5.9 Hz, H-1), 4.07 (m, 1 H, H-5),
3.95 (dd, 1 H, J5,6b = 3.0, J6a,6b = 9.5 Hz, H-6b), 3.90 (dd, 1 H,
J3¢,4¢ = 3.0 Hz, H-4¢), 3.86 (dd, 1 H, J2,3 = 4.5 Hz, H-2), 3.80 (dd,
1 H, J5,6a = 5.0 Hz, H-6a), 3.76 (dd, 1 H, J2¢,3¢ = 9.5 Hz, H-2¢),
3.57 (dd, 1 H, J5¢,6b¢ = 7.5, J6a¢,6b¢ = 9.0 Hz, H-6b¢), 3.51 (dd, 1 H,
J5¢,6a¢ = 5.0 Hz, H-6a¢), 3.48-3.43 (m, 2 H, H-5¢, H-3¢), 2.70-2.50
(m, 4 H, SCH2CH3), 1.27, 1.23 (2 t, 6 H, J = 7.5 Hz, SCH2CH3).
13C NMR: d = 138.6, 138.4, 138.3, 137.8, 137.6, 128.4, 128.3,
128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.2,
102.6, 84.3, 83.0, 82.0, 81.9, 79.2, 75.1, 74.8, 74.6, 73.5, 73.2, 72.8,
71.4, 71.2, 68.3, 53.3, 26.0, 25.3, 14.4, 14.3. MALDI-TOF MS:
1009.3 (M+ + K). Anal. Calcd for C58H66O9S2 (970.41): C, 71.72;
H, 6.85; S, 6.60. Found: C, 71.60; H, 6.88; S, 6.69.
2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl-(1→4)-2,5-di-O-
acetyl-3,6-anhydro-aldehydo-L-galactose (12)
To a cooled (0 ◦C), stirred mixture of 10 (409 mg, 0.60 mmol),
THF (1.2 mL), and Et2O (3 mL) a solution of H5IO6 (274 mg,
1.20 mmol) in THF (0.6 mL) was added dropwise. The resulting
mixture was warmed to room temperature, stirred for 20 min,
diluted with 1M phosphate buffer (25 mL), and extracted with
CHCl3 (80 mL). The organic phase was washed with 10% aqueous
Na2SO3 solution (2 ¥ 25 mL), dried (Na2SO4), concentrated, and
eluted from a column of silica gel with 1:2 cyclohexane-AcOEt to
give aldehyde 12 (197 mg, 57%) at least 80% pure as established
1
1
by H NMR analysis. H NMR: d = 9.58 (s, 1 H, H-1), 5.41
(d, 1 H, J2,3 = 3.5 Hz, H-2), 5.39 (dd, 1 H, J3¢,4¢ = 3.5, J4¢,5¢
=
1.0 Hz, H-4¢), 5.18 (dd, 1 H, J1¢,2¢ = 8.0, J2¢3¢ = 10.5 Hz, H-2¢), 5.02
(dd, 1 H, H-3¢), 5.00 (ddd, 1 H, H-5), 4.65 (d, 1 H, H-1¢), 4.38
(t, 1 H, J3,4 = 4.0 Hz, H-3), 4.20-4.14 (m, 2 H, H-4, H-6a¢), 4.09
(dd, 1 H, J5¢,6b¢ = 6.5, J6a¢,6b¢ = 11.5 Hz, H-6b¢), 3.99 (dd, 1 H, J5,6b
=
2.0, J6a,6b = 10.5 Hz, H-6b), 3.93 (dd, 1 H, J5,6a = 4.5 Hz, H-6a),
3.92 (ddd, 1 H, H-5¢), 2.25, 2.18, 2.12, 2.09, 2.04, 2.00 (6 s, 18 H,
COCH3). 13C NMR: d = 195.9, 170.4, 170.3, 107.2, 170.0, 169.4,
101.3, 84.1, 82.1, 78.6, 76.4, 71.4, 71.1, 70.6, 68.5, 67.0, 61.4, 61.4,
20.9, 20.6, 20.5. MALDI-TOF MS: 615.6 (M+ + Na).
4-O-Sulfonato-b-D-galactopyranosyl-(1→4)-3,6-anhydro-D-
galactose diethyl dithioacetal (13a) and b-D-galactopyranosyl-
(1→4)-3,6-anhydro-D-galactose diethyl dithioacetal (13b)
Kappa-carrageenan26 2 (5 g) was first dissolved in hot (~90 ◦C)
H2O (450 mL) and then 1M TFA solution (50 mL) was added in
one portion. The resulting mixture was heated at 80 C for 3 h,
2,3,4,6-Tetra-O-benzyl-b-D-galactopyranosyl-(1→4)-2,5-di-O-
benzyl-3,6-anhydro-aldehydo-L-galactose (3)
◦
cooled to room temperature, diluted with H2O (500 mL), and then
concentrated under vacuum. The resulting residue was dissolved
in water (90 mL), diluted with i-PrOH (90 mL), and then filtered
through a glass-sintered filter. The filtrate was concentrated and
coevaporated with toluene three times to give a brown-yellow solid
(4.60 g). This material was dissolved in 37% HCl (5.3 mL) and
EtSH (3.5 mL) at 0 ◦C. The resulting mixture was then stirred
at 0 ◦C for 1h, neutralized with 1M NaOH, and kept under a
nitrogen flow to remove unreacted EtSH. The mixture was then
concentrated under vacuum to give a solid residue, which was sus-
pended in MeOH (100 mL), and filtered through a glass-sintered
To a cooled (0 ◦C), stirred mixture of 11 (582 mg, 0.60 mmol),
THF (1.2 mL), and Et2O (3 mL) a solution of H5IO6 (274 mg,
1.20 mmol) in THF (0.6 mL) was added dropwise. The resulting
mixture was warmed to room temperature, stirred for 20 min,
diluted with 1M phosphate buffer (25 mL), and extracted with
Et2O (80 mL). The organic phase was washed with 10% aqueous
Na2SO3 solution (2 ¥ 25 mL), dried (Na2SO4), and concentrated
to give 3 (467 mg, 90%) as a white amorphous solid at least 95%
pure as established by 1H NMR analysis. An analytical sample of
3 was obtained by flash chromatography with 3.3:1 cyclohexane-
582 | Org. Biomol. Chem., 2009, 7, 576–588
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filter. The filtrate was concentrated to afford a crude material
(5.00 g) containing the dithioacetal derivates 13a and 13b. A small
amount of the above crude material (250 mg) was eluted from
a column of silica gel with 14:2:1 AcOEt-MeOH–H2O and then
with 10:2:1 AcOEt-MeOH-H2O to give firstly 13b (25 mg, 10%
from starting kappa-carrageenan)27 as a white amorphous solid.
[a]D = 7.4 (c 0.8, MeOH) (lit.22c [a]D = 14.0 (c 2.0, H2O)); Rf = 0.30
(14:2:1 AcOEt-MeOH-H2O). 1H NMR (CD3OD): d = 4.42-4.37
(m, 2 H, H-5, H-3), 4.34 (d, 1 H, J1¢,2¢ = 7.5 Hz, H-1¢), 4.16 (dd, 1
H, J = 3.0 and 5 Hz, H-4), 4.00 (d, 1 H, J1,2 = 8.5 Hz, H-1), 3.95
(dd, 1 H, J5,6b = 5.5, J6a,6b = 9.5 Hz, H-6b), 3.82-3.75 (m, 4 H, H-2,
H-4¢, H-6b¢, H-6a), 3.70 (dd, 1 H, J5¢,6a¢ = 4.5, J6a¢,6b¢ = 11.5 Hz,
H-6a¢), 3.56 (ddd, 1 H, H-5¢), 3.54 (dd, 1 H, J2¢,3¢ = 9.5 Hz, H-2¢),
3.47 (dd, 1 H, J3¢,4¢ = 3.5 Hz, H-3¢), 2.80-2.60 (m, 4 H, SCH2CH3),
1.28, 1.27 (2 t, 6 H, J = 7.5 Hz, SCH2CH3). 13C NMR (CD3OD):
d = 104.0, 87.8, 76.2, 75.8, 73.8, 73.2, 72.1, 71.2, 69.1, 61.5, 54.2,
24.8, 24.6, 13.8, 13.7. MALDI-TOF MS: 453.2 (M+ + Na). Anal.
Calcd for C16H30O9S2 (430.13): C, 44.64; H, 7.02; S, 14.90. Found:
C, 44.73; H, 7.08; S, 14.85.
Eluted second was 13a (147 mg, 48% from starting kappa-
carrageenan)27 as a white amorphous solid. [a]D = 7.5 (c
1.2, MeOH); Rf = 0.27 (10:2:1 AcOEt-MeOH-H2O).1H NMR
(CD3OD): d = 4.65 (dd, 1 H, J3¢4¢ = 3.5 Hz, H-4¢), 4.40-4.35 (m, 2
H, H-3, H-5), 4.36 (d, 1 H, J1¢,2¢ = 7.5 Hz, H-1¢), 4.14 (dd, 1 H, J =
3.0 and 4.5 Hz, H-4), 4.00 (d, 1 H, J1,2 = 8.5 Hz, H-1), 3.94 (dd,
1 H, J5,6b = 5.5, J6a,6b = 9.5 Hz, H-6b), 3.80-3.70 (m, 5 H, H-5¢,
H-2, H-6a, H-6b¢, H-6a¢), 3.62 (dd, 1 H, J2¢,3¢ = 10.0 Hz, H-3¢),
3.53 (dd, 1 H, H-2¢), 2.80–2.61 (m, 4 H, SCH2CH3), 1.25, 1.24 (2
t, 6 H, J = 7.5 Hz, SCH2CH3). 13C NMR (CD3OD): d = 105.1,
88.9, 84.4, 77.4, 76.8, 76.0, 74.4, 73.0, 62.3, 55.8, 26.0, 25.7, 14.9,
14.8. ESI MS: 509.4 (M - H).
(M+ + K). Anal. Calcd for C28H42O15S2 (682.20): C, 49.26; H, 6.20;
S, 9.39. Found: C, 49.18; H, 6.26; S, 9.30.
Eluted second was peracetylated-13a (164 mg, 48%) as a
colorless syrup. [a]D = 17.9 (c 2.0, MeOH); Rf = 0.23 (10:1 AcOEt-
MeOH). 1H NMR (CD3OD): d = 5.32 (ddd, 1 H, H-5), 5.19 (dd,
1 H, J1¢,2¢ = 8.0, J2¢3¢ = 10.5 Hz, H-2¢), 5.17 (dd, 1 H, J1,2 = 7.8,
J2,3 = 4.0 Hz, H-2), 4.92 (dd, 1 H, J3¢,4¢ = 3.5 Hz, H-3¢), 4.83 (dd,
1 H, H-4¢), 4.71 (d, 1 H, H-1¢), 4.40 (dd, 1 H, J6a¢,6b¢ = 12.0, J5¢,6a¢
4.5 Hz, H-6a¢), 4.31 (t, 1 H, J = 4.0 Hz, H-3), 4.23 (dd, 1 H, J5¢,6b¢
=
=
7.5 Hz, H-6b¢), 4.13 (dd, 1 H, J3,4 = 4.0 Hz, H-4), 4.09 (d, 1 H,
H-1), 4.00 (dd, 1 H, J5,6a = 4.5, J6a,6b = 10.5 Hz, H-6a), 3.99 (ddd,
1 H, H-5¢), 3.86 (dd, 1 H, H-6b), 2.80-2.60 (m, 4 H, SCH2CH3),
2.14, 2.11, 2.10, 2.06, 2.05 (5 s, 15 H, COCH3), 1.29, 1.27 (2 t,
6 H, J = 7.5 Hz, SCH2CH3). 13C NMR (CD3OD): d = 172.6,
172.0, 171.7, 171.2, 102.9, 86.6, 84.1, 80.0, 74.1, 73.5, 73.0, 72.8,
70.2, 64.6, 53.0, 26.1, 26.0, 21.0, 20.9, 14.8, 14.6. ESI MS: 719.8
(M - H).
2,3,6-Tri-O-benzyl-4-O-sulfonato-b-D-galactopyranosyl-(1→4)-
2,5-di-O-benzyl-3,6-anhydro-D-galactose diethyl dithioacetal (14a)
Treatment of the crude material (3.0 g) containing 13a (~1.77 g,
3.32 mmol) and 13b (~298 mg, 0.69 mmol) as described for
the preparation of 11 gave after column chromatography (10:1
AcOEt-MeOH) derivative 14a (2.78 g, 41% from starting kappa-
carrageenan)27 as a yellow amorphous solid. [a]D = 30.7 (c 1.0,
1
MeOH); Rf = 0.50 (10:1 AcOEt-MeOH). H NMR (CD3OD):
d = 7.50-7.20 (m, 25 H, Ph), 4.97 (d, 1 H, J = 11.5 Hz, PhCH2),
4.91 (dd, 1 H, J3¢,4¢ = 2.0 Hz, H-4¢), 4.81, 4.73, 4.70, 4.65, 4.56 (5
d, 5 H, J = 11.5 Hz, PhCH2), 4.55-4.52 (m, 2 H, H-1¢, H-4), 4.52,
4.49, 4.48 (3 d, 4 H, J = 11.5 Hz, PhCH2), 4.35 (dd, 1 H, J2,3
5.5, J3,4 = 3.0 Hz, H-3), 4.29 (ddd, 1 H, H-5), 4.00 (d, 1 H, J1,2
=
=
5.0 Hz, H-1), 3.99 (dd, 1 H, H-6b), 3.90 (dd, 1 H, J5¢,6a¢ = 4.5,
J6a¢,6b¢ = 10.5 Hz, H-6a¢), 3.89 (dd, 1 H, J5,6a = 4.5, H-6a), 3.88 (dd,
1 H, H-2), 3.81 (dd, 1 H, J5¢,6b¢ = 7.5 Hz, H-6b¢), 3.66 (dd, 1 H, H-
5¢), 3.57-3.54 (m, 2 H, H-2¢, H-3¢), 2.60-2.40 (m, 4 H, SCH2CH3),
1.09, 1.05 (2 t, 6 H, J = 7.5 Hz, SCH2CH3). 13C NMR (CD3OD):
d = 139.0, 138.6, 138.5, 138.4, 128.4, 128.2, 128.1, 128.0, 127.9,
127.8, 127.4, 127.3, 127.2, 103.2, 86.1, 84.3, 83.7, 81.3, 79.8, 78.6,
74.9, 74.7, 73.6, 73.1, 73.0, 71.7, 71.5, 71.3, 70.3, 53.3, 25.5, 25.3,
13.7, 13.5. ESI MS: 960.1 (M - H).
2,3,6-Tri-O-acetyl-4-O-sulfonato-b-D-galactopyranosyl-(1→4)-
2,5-di-O-acetyl-3,6-anhydro-D-galactose diethyl dithioacetal
(peracetylated-13a) and 2,3,4,6-tetra-O-acetyl-b-D-
galactopyranosyl-(1→4)-2,5-di-O-acetyl-3,6-anhydro-
D-galactose diethyl dithioacetal (peracetylated-13b)
A mixture of the crude material (200 mg) containing compounds
13a and 13b, pyridine (2.2 mL), and Ac2O (2.0 mL) was stirred at
room temperature for 12 h, then concentrated, and coevaporated
with toluene three times. The resulting residue was eluted from a
column of silica gel with 1:1 cyclohexane-AcOEt and then with
10:1 AcOEt-MeOH to give firstly peracetylated-13b (31 mg, 10%
2,3,4,6-Tetra-O-benzyl-b-D-galactopyranosyl-(1→4)-2,5-di-O-
benzyl-3,6-anhydro-D-galactose diethyl dithioacetal (14b).
Route A (Scheme 2)
from starting kappa-carrageenan)27 as a colorless syrup. [a]D
=
-2.6 (c 0.6, CHCl3) (lit.22d [a]D = -4.0 (c 1.2, CHCl3)); Rf = 0.3
Treatment of crude material (3.0 g) containing 13a (~1.77 g,
3.32 mmol) and 13b (~298 mg, 0.69 mmol) as described for
the preparation of 11 gave after column chromatography (5:1
cyclohexane-AcOEt) derivative 14b (469 mg, 7% from starting
kappa-carrageenan)27 as a colorless syrup. [a]D = 7.1 (c 0.5,
CHCl3); Rf = 0.41 (5:1 cyclohexane-AcOEt). 1H NMR: d = 7.40-
7.20 (m, 30 H, Ph), 4.93, 4.89, 4.79, 4.72, 4.71, 4.68, 4.61 (7 d, 8
H, J = 12.0 Hz, PhCH2), 4.52-4.45 (m, 4 H, H-4, H-1¢, 2 PhCH2),
4.38 (t, 1 H, J2,3 = 4.5 Hz, H-3), 4.50 (s, 2 H, PhCH2), 4.28 (m, 1
H, H-5), 4.03 (d, 1 H, J1,2 = 5.5 Hz, H-1), 4.02 (dd, 1 H, H-6b),
3.91 (dd, 1 H, J5,6a = 4.5, J6a,6b = 10.0 Hz, H-6a), 3.88 (dd, 1 H,
J3¢,4¢ = 3.0 Hz, H-4¢), 3.84 (t, 1 H, H-2), 3.78 (dd, 1 H, J1¢.2¢ = 8.0,
J2¢,3¢ = 9.5 Hz, H-2¢), 3.54 (dd, 1 H, J5¢,6b¢ = 9.0, J6a¢,6b¢ = 10.5 Hz,
1
(1:1 cyclohexane-AcOEt). H NMR: d = 5.39 (dd, 1 H, J3¢,4¢
=
3.5 Hz, H-4¢), 5.31 (ddd, 1 H, H-5), 5.20 (dd, 1 H, J1¢,2¢ = 8.0 Hz,
J2¢,3¢ = 10.5 Hz, H-2¢), 5.12 (dd, 1 H, J1,2 = 9.5, J2,3 = 2.5 Hz,
H-2), 5.02 (dd, 1 H, H-3¢), 4.63 (d, 1 H, H-1¢), 4.38 (dd, 1 H, J3,4
=
5.0 Hz, H-3), 4.13 (dd, 1 H, J5¢,6b¢ = 4.5, J6a¢,6b¢ = 11.0 Hz, H-6b¢),
4.11 (dd, 1 H, J5¢,6a¢ = 7.0 Hz, H-6a¢), 4.05 (d, 1 H, H-1), 4.02 (dd,
1 H, J5,6a = 4.5, J6a,6b = 10.5 Hz, H-6a), 3.98-3.92 (m, 3 H, H-4,
H-6b, H-5¢), 2.78-2.60 (m, 4 H, SCH2CH3), 2.21, 2.17, 2.12, 2.10,
2.05, 2.00 (6 s, 18 H, COCH3), 1.28, 1.27 (2 t, 6 H, J = 7.5 Hz,
SCH2CH3). 13C NMR: d = 170.7, 170.5, 170.3, 169.8, 101.9,
86.0, 82.5, 79.0, 72.7, 72.3, 71.2, 71.0, 68.7, 67.1, 61.3, 52.3, 25.3,
25.0, 21.2, 21.0, 20.9, 20.8, 14.6, 14.4. MALDI-TOF MS: 721.2
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H-6b¢), 3.48-3.42 (m, 3 H, H-6a¢, H-5¢, H-3¢), 2.70-2.50 (m, 4 H,
SCH2CH3), 1.19, 1.16 (2 t, 6 H, J = 7.5 Hz, SCH2CH3). 13C NMR:
d = 138.7, 138.6, 138.5, 138.2, 137.8, 128.4, 128.3, 128.2, 128.1,
127.9, 127.8, 127.5, 127.4, 127.3, 103.2, 85.0, 84.2, 83.8, 82.2, 81.3,
79.1, 75.0, 74.6, 74.5, 73.4, 73.3, 73.2, 73.1, 71.7, 71.2, 68.4, 53.2,
25.6, 25.4, 14.4, 14.2. MALDI-TOF MS: 993.4 (M+ + Na). Anal.
Calcd for C58H66O9S2 (970.41): C, 71.72; H, 6.85; S, 6.60. Found:
C, 71.84; H, 6.80; S, 6.69.
2,3,6-Tri-O-benzyl-4-O-sulfonato-b-D-galactopyranosyl-(1→4)-
2,5-di-O-benzyl-3,6-anhydro-D-galactitol (16)
To a stirred solution of aldehyde 8 (88 mg, 0.10 mmol) in MeOH
(5.0 mL) NaBH4 (8 mg, 0.20 mmol) was added in one portion.
The resulting mixture was stirred at room temperature for 1 h,
diluted with AcOH (0.50 mL), stirred for an additional 10 min,
concentrated, and then eluted from a column of silica gel with 15:1
AcOEt-MeOH to give 16 (66 mg, 75%) as a white amorphous solid.
[a]D = 38.5 (c 0.8, acetone); Rf = 0.20 (15:1AcOEt-MeOH).1H
NMR (CD3OD): d = 7.50-7.10 (m, 25 H, Ph), 4.97 (d, 1 H, J =
12.0 Hz, PhCH2), 4.85 (dd, 1 H, J3¢,4¢ = 3.0 Hz, H-4¢), 4.73, 4.70,
4.64 (3 d, 3 H, J = 12.0 Hz, PhCH2), 4.60 (s, 1 H, PhCH2), 4.55,
Route B (Scheme 3)
To a cooled (0 ◦C), stirred solution of 17 (476 mg, 0.50 mmol) was
added portionwise NaH (40 mg, 1.00 mmol of a 60% suspension in
mineral oil) and, after 30 min, benzyl bromide (77 mL, 0.65 mmol).
The mixture was stirred at room temperature for 40 min, then
treated with MeOH (1 mL), stirred for an additional 10 min,
diluted with H2O (20 mL), and extracted with Et2O (3 ¥ 50 mL).
The combined organic phases were dried (Na2SO4), concentrated,
and eluted from a column of silica gel with 5:1 cyclohexane-AcOEt
to give 14b (427 mg, 88%).
4.53, 4.51, 4.45 (4 d, 5 H, J = 12.0 Hz, PhCH2), 4.35 (dd, 1 H, J3,4
=
4.0 Hz, H-4), 4.31 (d, 1 H, J1¢,2¢ = 7.5 Hz, H-1¢), 4.21 (ddd, 1 H,
H-5), 3.98 (t, 1 H, H-3), 3.94 (dd, 1 H, J6a,6b = 10.0 Hz, H-6b), 3.88
(dd, 1 H, J5¢,6a¢ = 4.5, J6a¢,6b¢ = 10.5 Hz, H-6a¢), 3.81 (dd, 1 H, J5,6a
=
4.5 Hz, H-6a), 3.78 (dd, 1 H, J5¢,6b¢ = 7.5 Hz, H-6b¢), 3.69 (dd, 1 H,
J1a,2 = 3.5, J1a,1b = 10.0 Hz, H-1a), 3.65 (ddd, 1 H, H-2), 3.60 (dd,
1 H, J1b,2 = 5.5 Hz, H-1b), 3.55 (dd, 1 H, J2¢3¢ = 9.5 Hz, H-2¢), 3.51
(ddd, 1 H, H-5¢), 3.45 (dd, 1 H, H-3¢). 13C NMR (CD3OD): d =
140.2, 140.0, 139.7, 139.6, 129.5, 129.4, 129.3, 129.1, 129.0, 128.9,
128.6, 128.5, 128.4, 104.2 86.1, 85.5, 84.6, 80.8, 79.9, 79.7, 76.2,
74.7, 74.3, 74.0, 73.0, 72.3, 72.2, 71.5, 62.8. ESI MS: 855.8 (M - H).
2,3,6-Tri-O-benzyl-b-D-galactopyranosyl-(1→4)-2,5-di-O-benzyl-
3,6-anhydro-aldehydo-D-galactose (15)
Treatment of 14a (196 mg, 0.20 mmol) as described for the
preparation of 3 gave 15 (128 mg, 835) at least 95% pure as
2,3,6-Tri-O-benzyl-4-O-trimethylsilyl-b-D-galactopyranosyl-
(1→4)-2,5-di-O-benzyl-3,6-anhydro-D-galactose diethyl
dithioacetal (17)
1
1
established by H NMR analysis. H NMR (acetone-d6): d =
9.63 (d, 1 H, H-1), 7.50-7.20 (m, 25 H, Ph), 4.83, 4.77, 4.76, 4.74,
4.66, 4.63, 4.56 (7 d, 7 H, J = 12.0 Hz, PhCH2), 4.54-4.50 (m,
4 H, 3 PhCH2, H-4), 4.52 (d, 1 H, J1¢,2¢ = 8.0 Hz, H-1¢), 4.31
(ddd, 1 H, H-5), 4.21 (t, 1H, J = 4.5 Hz, H-3), 4.17 (dd, 1 H,
J2,3 = 5.0 Hz, H-2), 4.13 (dd, 1 H, J3¢,4¢ = 3.5 Hz, H-4¢), 3.96 (dd,
A mixture of 14a (659 mg, 0.67 mmol), chlorotrimethylsilane
(4.3 mL, 33.5 mmol), and pyridine (10 mL) was warmed to 100 ◦C,
stirred at this temperature for 3 h, cooled to room temperature,
concentrated, and coevaporated with toluene three times. The
resulting residue was eluted from a column of silica gel with 8:1
cyclohexane-AcOEt to give 17 (498 mg, 78%) as a colorless syrup.
[a]D = 18.6 (c 0.6, CHCl3); Rf = 0.28 (8:1 cyclohexane-AcOEt).1H
NMR: d = 7.40-7.20 (m, 25 H, Ph), 4.86, 4.79, 4.71, 4.70, 4.68,
4.67 (6 d, 6 H, J = 11.5 Hz, PhCH2), 4.51-4.46 (m, 4 H, 3 PhCH2,
H-4), 4.44 (d, 1 H, J1¢,2¢ = 8.0 Hz, H-1¢), 4.42 (d, 1 H, J = 11.5 Hz,
PhCH2), 4.40 (t, 1 H, H-3), 4.29 (ddd, 1 H, H-5), 4.06 (dd, 1 H,
J3¢,4¢ = 3.0 Hz, H-4¢), 4.04 (d, 1 H, J1,2 = 6.0 Hz, H-1), 4.03 (dd, 1 H,
H-6b), 3.92 (dd, 1 H, J5,6a = 4.5, J6a,6b = 10.0 Hz, H-6a), 3.82 (dd,
1 H, J2,3 = 4.5 Hz, H-2), 3.66 (dd, 1 H, J2¢,3¢ = 9.5 Hz, H-2¢), 3.60
(dd, 1 H, J5¢,6a¢ = 9.0, J6a¢,6b¢ = 10.0 Hz, H-6a¢), 3.44 (dd, 2 H, H-5¢,
H-6b¢), 3.28 (dd, 1 H, H-3¢), 2.70-2.51 (m, 4 H, SCH2CH3), 1.19,
1.16 (2 t, 6 H, J = 7.5 Hz, SCH2CH3), 0.10 (s, 9 H, SiCH3). 13C
NMR: d = 138.7, 138.4, 138.3, 138.2, 137.9, 128.4, 128.3, 128.2,
128.1, 128.0, 127.8, 127.5, 127.4, 103.4, 84.9, 84.0, 81.3, 81.1, 78.6,
74.8, 74.5, 73.6, 73.5, 71.7, 71.2, 68.7, 68.5, 53.2, 25.6, 25.5, 14.4,
14.2, 0.6; MALDI-TOF MS: 975.3 (M+ + Na). Anal. Calcd for
C54H68O9S2Si (952.41): C, 68.03; H, 7.19; S, 6.73; Si, 2.95. Found:
C, 68.12; H, 7.10; S, 6.84; Si, 2.90.
1 H, J5,6b = 2.0, J6a,6b = 10.0 Hz, H-6b), 3.87 (dd, 1 H, J5,6a
=
4.5 Hz, H-6a), 3.76 (dd, 1 H, J5¢.6a¢ = 5.0, J6a¢,6b¢ = 10.0 Hz, H-
6a¢), 3.64 (dd, 1 H, J5¢,6b¢ = 3.0 Hz, H-6b¢), 3.64 (ddd, 1 H, H-5¢),
3.62 (dd, 1 H, J2¢,3¢ = 9.5 Hz, H-2¢), 3.52 (dd, 1 H, H-3¢). 13C
NMR (acetone-d6): d = 201.4, 139.6, 139.2, 139.0, 138.8, 138.3,
128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.5, 103.7, 84.2,
83.9, 83.6, 82.6, 81.4, 78.8, 74.8, 73.6, 73.1, 72.9, 72.0, 71.4, 70.9,
69.6, 66.2.
The 4¢-trichloroacetyl carbamate derivative of 15 was generated
in the NMR tube by adding trichloroacetyl isocyanate (5 mL) to a
CDCl3 solution of 15 (10 mg).
2,3,6-Tri-O-benzyl-4-O-sulfonato-b-D-galactopyranosyl-(1→4)-
2,5-di-O-benzyl-3,6-anhydro-D-aldehydo-galactose (8)
To a cooled (0 ◦C), stirred solution of sodium nitrite (104 mg,
1.50 mmol) in CH2Cl2 (4.0 mL) AcCl (107 mL, 1.50 mmol) was
added dropwise. The resulting mixture was stirred at 0 ◦C for
10 min, and then a solution of 14a (492 mg, 0.50 mmol) in CH2Cl2
(3.0 mL) was slowly added. The mixture was stirred at 0 ◦C for an
additional 5 min, then diluted with 1M phosphate buffer (pH =
7.0) (2.0 mL), stirred at the same temperature for 1 h, and then
extracted with Et2O (80 mL). The organic phase was washed with
1M phosphate buffer (pH = 7.0) (3 ¥ 25 mL), concentrated, and
eluted from a column of silica gel with 15:1 AcOEt-MeOH to give
aldehyde 8 and its hydrate form (385 mg, 88%) as a colorless syrup.
Compound 17 easily decomposes by loss of TMS group when
it is stored at room temperature.
2,3,4,6-Tetra-O-benzyl-b-D-galactopyranosyl-(1→4)-2,5-di-O-
benzyl-3,6-anhydro-aldehydo-D-galactose (7)
1
Rf = 0.34 (15:1 AcOEt-MeOH). H NMR (DMSO-d6) selected
Treatment of 14b (427 mg, 0.44 mmol) as described for the
preparation of 3 gave 7 (342 mg, 90%) as a colorless syrup at
data: d = 9.55 (s, 1 H, CHO). ESI MS: 853.3 (M - H).
584 | Org. Biomol. Chem., 2009, 7, 576–588
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least 95% pure as established by 1H NMR analysis. An analytical
sample of 7 was obtained by flash chromatography with 3.3:1
cyclohexane-AcOEt as the eluent. [a]D = 6.3 (c 1.0, CHCl3).1H
NMR: d = 9.59 (d, 1 H, J1,2 = 1.0 Hz, H-1), 7.40-7.20 (m, 30 H,
Ph), 4.94, 4.81, 4.76, (3 d, 3 H, J = 12.0 Hz, PhCH2), 4.73 (s, 3
H, PhCH2), 4.72, 4.64, 4.55, 4.54, 4.45 (5 d, 5 H, J = 12.0 Hz,
chromatography (3:1 cyclohexane-AcOEt) peracetylated-18
(198 mg, 56% from starting agar).23 [a]D = 9.0 (c 2.5, CHCl3);
Rf = 0.30 (3:1 cyclohexane-AcOEt).1H NMR: d = 5.40 (dd, 1 H,
J1,2 = 8.0, J2,3 = 4.0 Hz, H-2), 5.19 (ddd, 1 H, J4,5 = 1.5, J5,6b
=
2.5, J5,6a = 5.0 Hz, H-5), 5.03 (ddd, 1 H, J3,4 = 4.0 Hz, H-4), 4.47
(t, 1 H, H-3), 4.12 (d, 1 H, H-1), 4.11 (dd, 1 H, J6a,6b = 11.0 Hz,
H-6b), 4.00 (dd, 1 H, H-6a), 2.81-2.63 (m, 4 H, SCH2CH3), 2.19,
2.12, 2.11 (3 s, 9 H, COCH3), 1.29, 1.26 (2 t, 6 H, J = 7.5 Hz,
SCH2CH3). 13C NMR: d = 170.1, 170.0, 82.5, 78.9, 78.2, 72.5,
72.1, 52.0, 25.1, 24.7, 20.9, 20.8, 14.3, 14.1. MALDI-TOF MS:
433.1 (M+ + K). Anal. Calcd for C16H26O7S2 (394.11): C, 48.71;
H, 6.64; S, 16.26. Found: C, 48.80; H, 6.61; S, 16.20.
PhCH2), 4.40-4.38 (d, 2 H, H-4, PhCH2), 4.31 (d, 1 H, J1¢,2¢
8.0 Hz, H-1¢), 4.26 (m, 1 H, H-5), 4.18 (dd, 1 H, J2,3 = 5.5, J3,4
=
=
3.5 Hz, H-3), 4.04 (dd, 1 H, H-6b), 4.01 (dd, 1 H, H-2), 3.90 (dd,
1 H, H-4¢), 3.88 (dd, 1 H, J5,6a = 4.0, J6a,6b = 10.0 Hz, H-6a), 3.77
(dd, 1 H, J2¢,3¢ = 9.5 Hz, H-2¢), 3.56 (dd, 1 H, J5¢,6b¢ = 5.5, J6a¢,6b¢
=
9.0 Hz, H-6b¢), 3.49 (dd, 1 H, J5¢,6a¢ = 5.5 Hz, H-6a¢), 3.47-3.42 (m,
2 H, H-5¢, H-3¢). 13C NMR: d = 202.0, 138.8, 138.6, 138.1, 138.0,
137.4, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 103.8,
84.2, 83.5, 83.4, 82.4, 82.1, 79.3, 75.4, 74.8, 73.7, 73.5, 73.3, 73.2,
72.5, 71.2, 68.7. MALDI-TOF MS: 887.3 (M+ + Na). Anal. Calcd
for C54H56O10 (864.39): C, 74.98; H, 6.53. Found: C, 74.89; H, 6.59.
2,4,5-Tri-O-acetyl-3,6-anhydro-D-galactose diethyl dithioacetal
(peracetylated-ent-18)
Treatment of crude extract (200 mg) containing ent-18 as de-
scribed for the preparation of peracetylated-13a gave after column
chromatography (3:1 cyclohexane-AcOEt) peracetylated-ent-18
(126 mg, 30% from starting kappa-carrageenan).27 [a]D = -9.4
(c 2.3, CHCl3). MALDI-TOF MS: 417.1 (M+ + Na). Anal. Calcd
for C16H26O7S2 (394.11): C, 48.71; H, 6.64; S, 16.26. Found: C,
48.79; H, 6.69; S, 16.20.
3,6-Anhydro-L-galactose diethyl dithioacetal (18)
A mixture of commercial agar23 (6.0 g), EtSH (9.0 mL), 37% HCl
◦
(3.0 mL), and MeOH (48 mL) was warmed to 60 C and stirred
at this temperature for 17 h. The mixture was then cooled to
room temperature, neutralized with 1M NaOH solution, and kept
under a nitrogen flow to remove unreacted EtSH. The mixture was
then concentrated under vacuum to give a solid residue, which
was suspended in H2O (80 mL) and then extracted with Et2O
(5 ¥ 100 mL). The combined organic phases were dried (Na2SO4)
and concentrated to give a crude extract (3.18 g) containing the
dithioacetal derivative 18. A small amount of the crude extract
(140 mg) was eluted from a column of silica gel with 1:3.3
cyclohexane-AcOEt to give 18 (94 mg, 56% from starting agar).23
[a]D = -14.9 (c 0.4, MeOH); [a]D = 10.0 (c 1.0, H2O); (lit.22b [a]D =
14.4 (c 1.2, H2O); Rf = 0.28 (1:3.3 cyclohexane-AcOEt). 1H NMR
(acetone-d6): d = 4.21 (t, 1 H, H-3), 4.11 (t, 1 H, H-4), 4.02 (ddd, 1
H, H-5), 3.97 (d, 1 H, J1,2 = 8.5 Hz, H-1), 3.87 (dd, 1 H, J5,6a = 4.0,
J6a,6b = 9.5 Hz, H-6a), 3.74 (dd, 1 H, J5,6b = 2.0 Hz, H-6b), 3.72
(dd, 1 H, J2,3 = 2.5 Hz, H-2), 2.75-2.60 (m, 4 H, SCH2CH3), 1.21,
1.20 (2 t, 6 H, J = 7.5 Hz, SCH2CH3). 13C NMR (acetone-d6): d =
85.5, 79.2, 77.3, 73.7, 73.6, 54.7, 24.9, 24.8, 14.2, 14.1. MALDI-
TOF MS: 307.1 (M+ + K). Anal. Calcd for C10H20O4S2 (268.08):
C, 44.75; H, 7.51; S, 23.89. Found: C, 44.87; H, 7.48; S, 23.81.
2,4,5-Tri-O-benzyl-3,6-anhydro-L-galactose diethyl dithioacetal
(19)
Treatment of crude extract (2.31 g) containing 18 (~1.56 g,
5.81 mmol) as described for the preparation of 11 gave after
column chromatography (15:1 cyclohexane-AcOEt) 19 (2.80 g,
50% from starting agar)23 as a colorless syrup. [a]D = -29.3 (c
0.6, CHCl3); Rf = 0.17 (15:1 cyclohexane-AcOEt).1H NMR: d =
4.83, 4.62, 4.56, 4.51, 4.48, 4.47 (6 d, 6 H, J = 12.0 Hz, PhCH2),
4.30 (t, 1 H, J2,3 = 5.0 Hz, H-3), 4.14-4.09 (m, 2 H, H-4, H-5),
4.02 (dd, 1 H, J5,6b = 2.5, J6a,6b = 10.0 Hz, H-6b), 3.99 (d, 1 H,
J1,2 = 5.5 Hz, H-1), 3.91 (dd, 1 H, J5,6a = 4.5 Hz, H-6a), 3.76 (t,
1 H, H-2), 2.73-2.53 (m, 4 H, SCH2CH3), 1.21, 1.18 (2 t, 6 H,
J = 7.5 Hz, SCH2CH3). 13C NMR: d = 138.3, 137.8, 128.4, 128.2,
128.0, 127.9, 127.8, 127.7, 127.5, 84.2, 83.6, 81.9, 74.7, 71.8, 71.4,
71.3, 53.1, 25.6, 25.5, 14.4, 14.3. MALDI-TOF MS: 561.2 (M+ +
Na). Anal. Calcd for C31H38O4S2 (538.22): C, 69.11; H, 7.11; S,
11.90. Found: C, 69.02; H, 7.18; S, 11.99.
2,4,5-Tri-O-benzyl-3,6-anhydro-D-galactose diethyl dithioacetal
(ent-19)
3,6-Anhydro-D-galactose diethyl dithioacetal (ent-18)
Treatment of kappa-carrageenan26 (6.0 g) as described for the
preparation of 18 gave a crude extract (2.60 g) containing the
dithioacetal derivative ent-18. A small amount of the crude extract
(240 mg) was eluted from a column of silica gel with 1:3.3
cyclohexane-AcOEt to give ent-18 (102 mg, 30% from kappa-
carrageenan).27 [a]D = 14.6 (c 0.4, MeOH); [a]D = -10.6 (c 1.1,
H2O); (lit.22a [a]D = -10.0 (c 1.0, H2O)). Anal. Calcd for C10H20O4S2
(268.08): C, 44.75; H, 7.51; S, 23.89. Found: C, 44.82; H, 7.45; S,
23.94.
Treatment of crude extract (2.20 g) containing ent-18 (~943 mg,
3.52 mmol) as described for the preparation of 11 gave after
column chromatography (15:1 cyclohexane-AcOEt) ent-19 (1.77 g,
28% from starting kappa-carrageenan)27 as a colorless syrup.
[a]D = 28.9 (c 0.5, CHCl3); Rf = 0.17 (15:1 cyclohexane-AcOEt).
MALDI-TOF MS: 561.6 (M+ + Na). Anal. Calcd for C31H38O4S2
(538.22): C, 69.11; H, 7.11; S, 11.90. Found: C, 69.22; H, 7.04; S,
11.98.
2,4,5-Tri-O-acetyl-3,6-anhydro-L-galactose diethyl dithioacetal
(peracetylated-18)
2,4,5-Tri-O-benzyl-3,6-anhydro-aldehydo-L-galactose (4) and
2,4,5-Tri-O-benzyl-3,6-anhydro-aldehydo-D-galactose (ent-4)
Treatment of crude extract (200 mg) containing 18 as described
for the preparation of peracetylated-13a gave after column
Treatment of 19 or ent-19 (1.22 g, 2.26 mmol) as described for the
preparation of 3 gave 4 or ent-4 (0.94 g, 95%) as a colorless syrup
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at least 95% pure as established by 1H NMR analysis. Analytical
samples of each aldehyde were obtained by flash chromatography
with 5:1 cyclohexane-AcOEt as the eluent. 4: [a]D = -24.4 (c 1.0,
CHCl3); Rf = 0.26 (5:1 cyclohexane-AcOEt). 1H NMR: d = 9.68
(d, 1 H, J1,2 = 1.4 Hz, H-1), 7.40-7.20 (m, 15 H, Ph), 4.74, 4.56,
4.48, 4.45, 4.43 (5 d, 6 H, J = 12.0 Hz, PhCH2), 4.17-4.10 (m,
2 H, H-5, H-3), 4.07-4.01 (m, 2 H, H-4, H-6b), 3.97 (dd, 1 H,
J2,3 = 5.0 Hz, H-2), 3.88 (dd, 1 H, J5,6a = 4.8, J6a,6b = 10.5 Hz, H-
6a). 13C NMR: d = 202.0, 137.5, 137.0, 128.5, 128.4, 128.3, 128.2
127.8, 127.7, 83.4, 83.0, 82.6, 82.3, 73.2, 71.9, 71.9, 71.1. MALDI-
TOF MS: 471.3 (M+ + K). Anal. Calcd for C27H28O5 (432.19):
C, 74.98; H, 6.53. Found: C, 75.00; H, 6.54. ent-4: [a]D = 24.6 (c
1.0, CHCl3). MALDI-TOF MS: 471.8 (M+ + K). Anal. Calcd for
C27H28O5 (432.19): C, 74.98; H, 6.53. Found: C, 75.04; H, 6.59.
J5,6a = 4.5, J5,6b = 3.5 Hz, H-5), 5.11 (dd, 1 H, J3,4 = 3.0 Hz, H-4),
4.37 (dd, 1 H, J1a,1b = 12.0 Hz, H-1a), 4.18 (dd, 1 H, H-1b), 4.06
(dd, 1 H, J6a,6b = 11.0 Hz, H-6a), 4.00-3.94 (m, 2 H, H-6b, H-3),
2.15, 2.13, 2.11, 2.08 (4 s, 12 H, COCH3).13C NMR: d = 170.8,
170.4, 170.0, 82.3, 78.2, 78.1, 72.3, 70.0, 63.0, 21.2, 20.9. MALDI-
TOF MS: 355.1 (M+ + Na). Anal. Calcd for C14H20O9 (332.11): C,
50.60; H, 6.07. Found: C, 50.72; H, 6.10.
1,2-O-Isopropylidene-3,6-anhydro-L-galactitol (22)
A mixture of crude material (2.0 g) containing compound 21
(~1.39 g, 8.50 mmol), acetone (200 mL), and 98% H2SO4 (4.0 mL)
was stirred at room temperature for 24 h, diluted with H2O
(100 mL), cooled to 0 ◦C, neutralized with Na2CO3 salt, and
then concentrated. The resulting residue was suspended in acetone
(100 mL), filtered through a glass-sintered, concentrated, and
eluted from a column of silica gel with 20:1 CH2Cl2-acetone to
give 22 (1.13 g, 39% from starting agar)23 as a colorless syrup.
[a]D = -27.7 (c 2.4, CHCl3), Rf = 0.20 (20:1 CH2Cl2-acetone).1H
NMR: d = 4.28 (ddd, 1 H, J1a,2 = 7.5, J1b,2 = 6.5, J2,3 = 2.5 Hz,
H-2), 4.14 (dd, 1 H, H-4), 4.07 (dd, 1 H, J1a,1b = 8.5 Hz, H1b), 4.03
(dd, 1 H, J5,6a = 3.5, J6a,6b = 9.0 Hz, H-6a), 4.00 (m, 1 H, H-5), 3.98
(dd, 1 H, H-1a), 3.88 (dd, 1 H, H-6b), 3.79 (dd, 1 H, H-3), 1.40,
1.35 (2 s, 6 H, CMe2). 13C NMR: d = 109.6, 84.3, 79.1, 77.1, 76.2,
74.0, 65.7, 25.6, 25.3. MALDI-TOF MS: 243.1 (M+ + K). Anal.
Calcd for C9H16O5 (204.10): C, 52.93; H, 7.90. Found: C, 52.88;
H, 7.98.
1,4-Anhydro-D-galactitol or 3,6-Anhydro-L-galactitol (21)34
Commercial agar (10 g)23 was first dissolved in hot (~90 ◦C) H2O
(900 mL) and then 1M TFA solution (100 mL) wa◦s added in
one portion. The resulting mixture was heated at 80 C for 3 h,
cooled to room temperature, diluted with H2O (800 mL), and then
concentrated. The resulting residue was coevaporated with toluene
three times to give a syrup. This material was dissolved in H2O
(100 mL), cooled to 0 ◦C and then NaBH4 (1.90 g, 50.0 mmol)
was added in one portion. The resulting mixture was stirred at
room temperature for 1 h, diluted with AcOH (~4.0 mL, pH
~4.0), stirred for an additional 10 min, and concentrated. The
residue was coevaporated with MeOH (3 ¥ 50 mL) to give a
yellow syrup containing disaccharide 20. This crude material was
dissolved in 2M TFA solution (250 mL) and the resulting mixture
was heated at 120 ◦C for 3 h, cooled to room temperature, diluted
with H2O (300 mL), and then concentrated. The resulting residue
was coevaporated with toluene three times to give a syrup. This
material was dissolved in H2O (100 mL), cooled to 0 ◦C and
then NaBH4 (1.90 g, 50.0 mmol) was added in one portion. The
resulting mixture was then stirred at room temperature for 1 h,
diluted with AcOH (~ 4.0 mL, pH~4.0), stirred for an additional
10 min, and concentrated to give a syrup. This material was
suspended in MeOH (30 mL) and acetone (100 mL), and then
filtered through a glass-sintered filter. The filtrate was concentrated
to afford a residue that was diluted with H2O (30 mL) and treated
with Dowex 1 ¥ 8 OH- form (64.8 g). The resulting mixture was
stirred for 10 min, filtered through a glass-sintered filter, and
washed thoroughly with H2O. The combined filtrates were then
treated with Amberlite IR120 H+ form (64.8 g), stirred for 10 min,
filtered through a glass-sintered filter, and washed thoroughly with
H2O. The combined filtrates were concentrated to give a crude
material (3.36 g) mainly constituted of the anhydro alditol 21.
1H and 13C NMR (D2O) data of 21 were consistent with those
previously reported.38
4,5-Di-O-benzyl-3,6-anhydro-L-galactitol (23). Route A
(Scheme 5)
Treatment of 22 (742 mg, 3.63 mmol) as described for
the preparation of 11 gave after column chromatography
(5:1 cyclohexane-AcOEt) 1,2-O-isopropylidene-4,5-di-O-benzyl-
3,6-anhydro-L-galactitol intermediate (1.40 g, 100%) as a colorless
syrup. [a]D = -10.0 (c 0.4, CHCl3); Rf = 0.16 (5:1 cyclohexane-
AcOEt).1H NMR: d = 7.40-7.20 (m, 10 H, Ph), 4.56 (d, 2H, J =
12 Hz, PhCH2), 4.49, 4.47 (2 d, 2 H, J = 12 Hz, PhCH2), 4.24
(ddd, 1 H, J1b,2 = 6.5, J1a,2 = 7.0 Hz, H-2), 4.10-4.05 (m, 2 H, H-5,
H-6b), 3.91-3.76 (m, 5 H, H-6a, H-1b, H-3, H-4, H1a), 1.43, 1.35
(2 s, 6 H CMe2).13C NMR: d = 137.4, 137.2, 128.3, 127.8, 127.7,
127.6, 109.4, 84.5, 84.2, 82.8, 75.9, 71.7, 71.2, 71.1, 65.3, 26.4, 25.0.
A mixture of the above benzylated intermediate (1.00 g,
2.60 mmol), AcOH (16 mL), and H2O (4 mL) was warmed to
100 ◦C, stirred at this temperature for 1 h, cooled to room temper-
ature, concentrated, and coevaporated with toluene three times.
The resulting residue was eluted from a column of silica gel with
1:2 cyclohexane-AcOEt to give 23 (626 mg, 70%) as a colorless
syrup. [a]D = -22.6 (c 1.0, CHCl3); Rf = 0.28 (1:2 cyclohexane-
AcOEt).1H NMR: d = 7.40-7.30 (m, 10 H, Ph), 4.57 (d, 1 H,
PhCH2), 4.54 (d, 3 H, PhCH2), 4.15 (m, 1 H, H-4), 4.09-4.04 (m,
2 H, H-5, H-6b), 3.95 (dd, 1 H, J2,3 = 4.0, J3,4 = 3.5 Hz, H-3), 3.89
1,2,4,5-Tetra-O-acetyl-3,6-anhydro-L-galactitol (peracetylated-21)
Treatment of the crude material (185 mg) containing 21 as
described for the preparation of peracetylated-13a gave after
column chromatography (20:1 CH2Cl2-acetone) peracetylated-21
(261 mg, 60% from starting agar).23 [a]D = 28.0 (c 1.7, CHCl3);
Rf = 0.28 (20:1 CH2Cl2-acetone).1H NMR: d = 5.38 (ddd, 1
H, J1a,2 = 4.0, J1b,2 = 7.0, J2,3 = 5.0 Hz, H-2), 5.16 (ddd, 1 H,
(dd, 1 H, J5,6a = 4.0, J6a,6b = 10.5 Hz, H-6a), 3.77 (m, 1 H, J1a,2 =
4.5, J1b,2 = 5.0 Hz, H-2), 3.68 (dd, 1 H, J1a,1b = 11.0 Hz, H-1b),
3.64 (dd, 1 H, H-1a). 13C NMR: d = 137.6, 137.4, 128.8, 128.4,
128.2, 128.0, 85.2, 84.4, 82.6, 72.3, 72.0, 71.5, 64.6. MALDI-TOF
MS: 383.1 (M+ + K). Anal. Calcd for C20H24O5 (344.16): C, 69.75;
H, 7.02. Found: C, 69.63; H, 7.09.
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Route B (Scheme 6)
15 H, Ph), 4.71, 4.68, 4.54, 4.53, 4.51, 4.50 (6 d, 6 H, J = 12.0 Hz,
PhCH2), 4.16 (dd, 1 H, J3,4 = 4.5 Hz, H-4), 4.09 (dd, 1 H, H-6b),
4.07 (m, 1 H, H-5), 4.03 (t, 1 H, H-3), 3.88 (dd, 1 H, J5,6a = 4.5,
J6a,6b = 10.5 Hz, H-6a), 3.76 (dd, 1 H, J1a,2 = 6.0, J1a,1b = 12.5 Hz,
H-1a), 3.72-3.67 (m, 2 H, H-2, H-1b). 13C NMR: d = 138.2, 137.5,
137.4, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 84.8, 83.8, 83.0,
78.1, 72.6, 71.9, 71.4, 71.3, 61.8. MALDI-TOF MS: 457.2 (M+ +
Na). Anal. Calcd for C27H30O5 (434.21): C, 74.63; H, 6.96. Found:
C, 74.66; H, 6.98. ent-24: [a]D = -8.3 (c 2.4, CHCl3). MALDI-
TOF MS: 457.5 (M+ + Na). Anal. Calcd for C27H30O5 (434.21): C,
74.63; H, 6.96. Found: C, 74.55; H, 7.01.
Metallic sodium (61 mg, 2.65 mmol) was carefully added to MeOH
(5 mL). The resulting mixture was stirred at room temperature
under nitrogen until complete consumption of metallic sodium,
and then a solution of 25 (570 mg, 1.33 mmol) in MeOH
(15 mL) was slowly added. The mixture was stirred at room
temperature for an additional 30 min, neutralized with Amberlite
IR120 (H+ form, 5.0 g), filtered through a glass-sintered filter,
and washed thoroughly with MeOH. The combined filtrates were
concentrated, and eluted from a column of silica gel with 1:2
cyclohexane-AcOEt to give 23 (380 mg, 83%).
1,2-Di-O-acetyl-4,5-di-O-benzyl-3,6-anhydro-L-galactitol (25) and
1,2-di-O-acetyl-4,5-di-O-benzyl-3,6-anhydro-D-galactitol (ent-25)
4,5-Di-O-benzyl-3,6-anhydro-D-galactitol (ent-23)
Metallic sodium (61 mg, 2.65 mmol) was carefully added to MeOH
(5 mL). The resulting mixture was stirred at room temperature
under nitrogen until complete consumption of metallic sodium,
and then a solution of ent-25 (570 mg, 1.33 mmol) in MeOH
(15 mL) was slowly added. The mixture was stirred at room
temperature for an additional 30 min, neutralized with Amberlite
IR120 (H+ form, 5.0 g), filtered through a glass-sintered filter,
and washed thoroughly with MeOH. The combined filtrates were
concentrated, and eluted from a column of silica gel with 1:2
cyclohexane-AcOEt to give ent-23 (380 mg, 83%) as a colorless
syrup. [a]D = 22.4 (c 1.2, CHCl3). MALDI-TOF MS: 367.5 (M+ +
Na). Anal. Calcd for C20H24O5 (344.16): C, 69.75; H, 7.02. Found:
C, 69.82; H, 7.08.
A mixture of 24 or ent-24 (800 mg, 1.80 mmol) in Ac2O-TFA
20:1 (42 mL) was heated at 70 ◦C for 8 h, then cooled to room
temperature, and then coevaporated with toluene three times. The
resulting brown syrup was eluted from a column of silica gel
with 3:1 cyclohexane-AcOEt to afford 25 or ent-25 (570 mg, 72%)
1
slightly contaminated by uncharacterized byproducts. H NMR:
d = 7.40-7.20 (m, 10 H, Ph), 5.33 (ddd, 1 H, J1a,2 = 7.0, J1b,2
=
4.0 Hz, H-2), 4.54, 4.52, 4.51, 4.45 (4 d, 4 H, J = 12.0 Hz, PhCH2),
4.32 (dd, 1 H, J1a,1b = 12.0 Hz, H-1b), 4.15 (dd, 1 H, H-1a), 4.09-
4.01 (m, 2 H, H-5, H-6b), 3.98-3.93 (m 2 H, H-3, H-4), 3.90 (dd,
1 H, J5,6a = 4.5, J6a,6b = 10.5 Hz, H-6a), 2.06, 2.05 (2 s, 6 H,
OCCH3). 13C NMR: d = 170.5, 170.4, 137.5, 137.3, 128.4, 128.0,
127.9, 127.8, 84.4, 82.7, 82.2, 72.1, 71.6, 71.4, 70.5, 63.0, 20.9, 20.7.
MALDI-TOF MS: 467.5 (M+ + K).
3,4-Di-O-benzyl-2,5-anhydro-aldehydo-L-lyxose (5) and
3,4-di-O-benzyl-2,5-anhydro-aldehydo-D-lyxose (ent-5)
Formyl 2,3-di-O-benzyl-b-L-threose (26)
Treatment of 23 or ent-23 (623 mg, 1.81 mmol) as described for the
preparation of 3 gave 5 or ent-5 (492 mg, 87%) as a colorless syrup
at least 95% pure as established by 1H NMR analysis. Analytical
samples of each aldehyde were obtained by flash chromatography
with 3.3:1 cyclohexane-AcOEt as the eluent. 5: [a]D = 19.6 (c 1.8,
CHCl3); Rf = 0.20 (3.3:1 cyclohexane-AcOEt).1H NMR: d = 9.63
(d, 1 H, J1,2 = 1.0 Hz, H-1), 7.40-7.20 (m, 10 H, Ph), 4.66, 4.54,
4.44 (d, 3 H, J = 12.0 Hz, PhCH2), 4.40 (s, 1 H, PhCH2), 4.37 (s,
To a cooled (0 ◦C), stirred mixture of aldehyde 5 (210 mg,
0.67 mmol), CH2Cl2 (5 mL), and NaHCO3 (146 mg, 1.74 mmol),
mCPBA (324 mg, 1.88 mmol) was added in one-portion. The
resulting mixture was stirred at 0 ◦C for 30 minutes, diluted with
CH2Cl2 (40 mL), then washed with brine (15 mL) and saturated
aqueous NaHCO3 solution (3 ¥ 15 mL). The organic phase was
dried (Na2SO4), concentrated, and eluted from a column of silica
gel with 6.7:1 cyclohexane-AcOEt to give 26 (138 mg, 63%) as
colorless syrup. [a]D = -12.9 (c 0.9, CHCl3); Rf = 0.43 (6.7:1
cyclohexane-AcOEt).1H NMR: d = 8.10 (s, 1 H, CHO), 7.41-7.29
(m, 10 H, Ph), 6.32 (s, 1 H, H-1), 4.69, 4.59, 4.53, 4.51 (4 d, 4 H,
J = 12.0 Hz, PhCH2), 4.34 (dd, 1 H, J3,4a = 5.5, J4a,4b = 9.5 Hz,
H-4a), 4.17 (ddd, 1 H, H-3), 4.15 (s, 1 H, H-2), 4.05 (dd, 1 H,
J3,4b = 4.5 Hz, H-4b).13C NMR: d = 159.9, 137.2, 137.0, 128.5,
128.1, 128.0, 127.9, 127.8, 100.4, 86.0, 81.7, 73.2, 72.1. MALDI-
TOF MS: 351.1 (M+ + Na). Anal. Calcd for C19H20O5 (328.13): C,
69.50; H, 6.14. Found: C, 69.62; H, 6.05.
1 H, H-2), 4.22 (s, 1 H, H-3), 4.16 (dd, 1 H, J4,5b = 1.0, J5a,5b
=
10.0 Hz, H-5b), 4.12 (dd, 1 H, J4,5a = 3.0 Hz, H-5a), 4.04 (ddd, 1
H, H-4). 13C NMR: d = 203.0, 137.1, 137.0, 128.6, 128.5, 128.1,
128.0, 127.7, 87.0, 84.6, 80.5, 72.7, 71.8, 70.9. MALDI-TOF MS:
351.1 (M+ + K). Anal. Calcd for C19H20O4 (312.14): C, 73.06; H,
6.45. Found: C, 73.09; H, 6.46. ent-5: [a]D = -19.3 (c 1.5, CHCl3).
MALDI-TOF MS: 351.8 (M+ + K). Anal. Calcd for C19H20O4
(312.14): C, 73.06; H, 6.45. Found: C, 73.11; H, 6.48.
2,4,5-Tri-O-benzyl-3,6-anhydro-L-galactitol (24) and
2,4,5-tri-O-benzyl-3,6-anhydro-D-galactitol (ent-24)
2,3-Di-O-benzyl-L-threose (6)
To a cooled (0 ◦C), stirred solution of aldehyde 4 or ent-4 (886 mg,
2.05 mmol) in MeOH (10 mL) NaBH4 (156 mg, 2.40 mmol) was
added in one portion. The resulting mixture was stirred at room
temperature for 1 h, diluted with AcOH (1 mL), stirred for an
additional 10 min, concentrated, and then eluted from a column
of silica gel with 1.6:1 cyclohexane-AcOEt to give 24 or ent-24
(837 mg, 94%) as a colorless syrup. 24: [a]D = 8.5 (c 1.4, CHCl3);
Rf = 0.34 (8:5 cyclohexane-AcOEt). 1H NMR: d = 7.40-7.25 (m,
A mixture of 26 (138 mg, 0.42 mmol), MeOH (10 mL), and Et3N
(10 mL) was stirred at room temperature for 30 minutes, and then
concentrated to give crude 6 (120 mg, 95%) at least 95% pure
1
as established by H NMR analysis. An analytical sample of 6
was obtained by column chromatography with 3.3:1 cyclohexane-
AcOEt as the eluent. Analytical and spectroscopic data of 6 were
consistent with those previously reported.37
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See: (a) A. G. Gonc¸alves, M. D. Noseda, M. E. R. Duarte and T. B.
Grindley, J. Org. Chem., 2007, 72, 9896–9904; (b) A. G. Gonc¸alves,
M. D. Noseda, M. E. R. Duarte and T. B. Grindley, Carbohydr. Res.,
2006, 341, 1753–1757; (c) A. G. Gonc¸alves, D. R. B. Ducatti, R. G.
Paranha, M. E. R. Duarte and M. D. Noseda, Carbohydr. Res., 2005,
340, 2123–2134.
Acknowledgements
M.D.N. and M.E.R.D. are research members of the National
Research Council of Brazil (CNPq). D.R.B.D. is grateful for
a scholarship from CAPES (PDEE-CAPES, Brazil) to spend
ten months at University of Ferrara. A. D. and A. M. greatly
acknowledge the University of Ferrara for financial support.
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Nature, 2002, 418, 214–221; (c) K.-U. Scho¨ning, P. Scholz, X. Wu, S.
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588 | Org. Biomol. Chem., 2009, 7, 576–588
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