Synthesis of L-altrose and some derivatives

Article abstract of DOI:10.1002/ejoc.201200938

A convenient approach to the chemical synthesis of L-altrose (1) and its 6-deoxy derivative 2 has been developed by starting from D-galactose (9) and D-fucose (10), respectively. The 5-epimerization by a Mitsunobu inversion of the open-chain D-hexoses was the key step for these routes. Furthermore, the conversion of 2 into peracetylated TDP-6-deoxy-α-L-altrose (3a) was achieved by the cycloSal approach. However, the final deacetylation led to an unexpected side-reaction resulting in the previously unknown 6-deoxy-α-L-altropyranose 1,3-cyclophosphate (4).

Full text of DOI:10.1002/ejoc.201200938

Job/Unit: O20938
/KAP1
Date: 25-09-12 16:41:59
Pages: 12
FULL PAPER
DOI: 10.1002/ejoc.201200938
Synthesis of -Altrose and Some Derivatives
L
Nathalie Lunau[a] and Chris Meier*[a]
Keywords: Carbohydrates / Epimerization / Synthesis design / Phosphorylation
A convenient approach to the chemical synthesis of
(1) and its 6-deoxy derivative 2 has been developed by start-
ing from -galactose (9) and -fucose (10), respectively. The
5-epimerization by a Mitsunobu inversion of the open-chain
-hexoses was the key step for these routes. Furthermore,
L
-altrose
the conversion of 2 into peracetylated TDP-6-deoxy-α-L-
altrose (3a) was achieved by the cycloSal approach. How-
ever, the final deacetylation led to an unexpected side-reac-
D
D
tion resulting in the previously unknown 6-deoxy-α-
L-altrop-
D
yranose 1,3-cyclophosphate (4).
conjugates, and antibiotics.[4] For example, a few members
of the l-altro series are listed below: l-Altrose (1) is a com-
ponent of the extracellular polysaccharides of butyrivibrio
fibrisolvens strain CF3,[5] l-altruronic acid was found in the
O-specific region of LPSs of Proteus mirabilis O10, a hu-
man opportunistic pathogen causing urinary tract infec-
tions,[6] and the LPS O-antigens of Y. enterocolotica sero-
type O:3 and Pectinatus frisingensis consist of a homopoly-
mer of 6-deoxy-α-l-altrose (2), which is synthesized in a
glycosyltransferase-catalyzed reaction by using TDP-6-de-
oxy-α-l-altrose as glycosyl donor.[4,7]
In view of the major importance of l-hexoses in various
glycobiological processes in addition to the practical diffi-
culties of obtaining these rare sugars from natural sources,
there is still a need for new efficient approaches for their
chemical synthesis.
Introduction
Carbohydrates are essential for all living organisms. In
their main functions they serve as skeletal substance in
micro-organisms, plants, and animals (e.g., cellulose and
chitin), as fast mobilizable energy sources (e.g., starch and
glycogen), in cell–cell recognition, and form part of the nu-
cleosides of RNA and DNA. Furthermore, glycolipids and
glycoproteins are involved in the construction and conser-
vation of cell walls and play decisive roles in biological sig-
nal and recognition processes.[1]
The biosyntheses of structurally diverse polysaccharides
and glycoconjugates are catalyzed by inverting or nonin-
verting glycosyltransferases (GT) by using nucleoside di-
phosphate (NDP) sugars as donors. For biosynthetic stud-
ies of various glycoconjugates [e.g., lipopolysaccharides
(LPSs)] an efficient access to NDP-sugars as glycosyltrans-
ferase substrates is of crucial importance.[2]
Previously reported syntheses follow different methodol-
ogies, including de novo syntheses[8] as well as epimeriza-
tions of readily available d- or l-sugars or their deriva-
tives.[9] Guaragna et al. reported the conversion of a hetero-
cyclic three-carbon reagent with 2,3-O-isopropylidene-
l-glyceraldehyde to obtain a 2,3-unsaturated l-pyranoside
that can be further functionalized to afford the desired l-
hexose.[8a] Shan et al. achieved an asymmetric synthesis of
l-mannose and l-altrose via a common pyranone interme-
diate.[8b] This route relies on a Pd0-catalyzed glycosylation
reaction and a corresponding post-glycosylation transfor-
mation in which the control of absolute and relative stereo-
chemical configurations is achieved by Noyori reduction of
2-acylfuran and subsequent diastereoselective introduction
of further stereogenic centers. Adinolfi et al. obtained the
tert-butyl ester of l-altronic acid by Swern oxidation of
d-galactitol followed by a diastereoselective Tishenko reac-
tion of the resulting aldulose induced by OSmI2. The ester
was converted into an inseparable mixture of lactones with
the d- and l-configurations. After reduction, the two epi-
meric hemiacetals could be separated to yield d-galactose and
l-altrose, respectively.[9a]
A reliable and high-yielding general synthetic pathway
for the synthesis of anomerically defined NDP-sugars has
recently been developed by our group. In this approach,
strong acceptor bearing cycloSal-nucleotides serve as active
phosphate ester building blocks that were treated with an-
omerically pure glycopyranosyl phosphates to yield a large
variety of naturally occurring NDP-sugars as well as NDP-
sugar analogues. Most of the sugar 1-phosphates were gen-
erated by phosphorylation of commercially available
d-monosaccharides.[3]
In addition to the most common d-sugars, a range of
l-monosaccharides, amino-sugars, sugar acids as well as
various deoxy sugars are present as structural components
in numerous biologically important oligosaccharides, glyco-
[a] Organic Chemistry, Department of Chemistry, Faculty of
Sciences, University of Hamburg,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax: +49-40-42838-5592
E-mail: chris.meier@chemie.uni-hamburg.de
Homepage: www.chemie.uni-hamburg.de/oc/meier/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200938.
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Two of the most efficient methods for the synthesis of
l-hexoses were developed by Takahashi et al. and Hung et
al.[9b,9c] The former described the conversion of d-glycono-
1,5-lactones into the corresponding l-sugars in which the
key step of the synthesis is based on an intramolecular O-
alkylation of δ-hydroxyalkoxamates. Hung et al. reported
the epimerization of d-glucose to obtain l-idose, which was
then used as starting material in the synthesis of l-altrose
and l-mannose by a reaction sequence of four steps that
includes stereoselective hydroborations and hydrogenations
of olefins as the key steps.[9c]
All the syntheses outlined above have in common that
their application is not restricted to the synthesis of one
certain sugar, but rather provide access to various l-hexoses
depending on the reagents used. Because of their omnipres-
ence in natural products like starch, cellulose, and lactose,
many naturally occurring d-sugars, like d-glucose or d-ga-
lactose, are available almost without restriction and there-
fore are suitable as starting materials for large-scale prepa-
rations of l-hexoses.[9]
Scheme 1. Retrosynthesis of TDP-6-deoxy-l-altrose (3).
Although there are several approaches to the chemical
synthesis of l-altrose (1),[8a,9,10] only a few syntheses of its
6-deoxy derivative 2 have been reported so far.[8b,11]
For LPS biosynthesis studies and the development of po-
tential innovative agents for the treatment of Gram-negative
infections, there is a need for new synthetic approaches that
provide a multigram-scale access to 6-deoxy-l-altrose (2)
and thus to TDP-6-deoxy-β-l-altrose (3).
Herein we report an efficient chemical synthesis of l-al-
trose (1) as well as its 6-deoxy derivative 2 by a 5-epimeri-
zation of the commercially available d-galactose (9) and
d-fucose (10), respectively. An attempt was also made to
synthesize TDP-6-deoxy-α-l-altrose (3) from 6-deoxy-α-
l-altrose (2) by the cycloSal approach.
Scheme 2. 5-Epimerization of d-galactose 9 and d-fucose 10.
(2) the 5-epimerization 6-deoxy-d-galactose (d-fucose, 10;
Scheme 2). Although the former reaction sequence provides
access to two different rare sugars of the l-altro series, the
second approach has the advantage of being shorter. With
the exception of the deoxygenation reaction, both routes
follow the same reaction sequence.
To enable the 5-epimerization of 6-deoxy-d-galactose
(10) and d-galactose (9), the glycopyranoses have to be con-
verted into their open-chain forms. By modification of a
known method,[13] both glycopyranoses 9 and 10 were con-
verted first into their methyl glycopyranosides by a micro-
wave-assisted, acid-catalyzed reaction with methanol.[13]
Results and Discussion
For the synthesis of TDP-6-deoxy-l-altrose (3), two
building blocks were needed: 6-Deoxy-l-altropyranosyl
phosphate 5 and the 5-nitro-cycloSal triester 6 (Scheme 1).
The sugar phosphate 5 was envisaged to be generated by
the phosphorylation of 6-deoxy-l-altrose (2), which is a
commercially unavailable representative of the l-hexoses.
Synthesis of L-Altrose (1) and 6-Deoxy-L-altrose (2)
Our concept for the synthesis of l-altrose (1) and 6-de- The subsequent benzylation yielded the fully protected
oxy-l-altrose (2) was based on the 5-epimerization of sugars 11 and 12 in yields of 93 and 65%, respectively
d-galactose (9) and d-fucose (10), respectively (Scheme 2). (Scheme 3).
One powerful method for the inversion of the configuration
Selective cleavage of the methyl glycopyranosides with
of alcohols is the widely used Mitsunobu reaction in which acetic acid resulted in the anomeric compounds 13 (87%)
a hydroxy function is replaced by an acidic nucleophile un- and 14 (63%), which were the precursors for the following
der mild conditions by the combined use of an oxidizing ring-opening reaction. For this purpose, both sugars were
azo and a reducing phosphane reagent.[12]
converted into their acyclic diethyl dithioacetals with
Two different approaches to 6-deoxy-l-altrose (2) were ethanethiol under acidic conditions (CF3COOH).[14] In
studied: (1) The 5-epimerization of d-galactose (9) followed addition to products 15 (58%) and 16 (28%), in both cases
by a 6-deoxygenation of the resulting l-altrose (1) and anomeric mixtures of thioglycopyranosides 17 (34%) and
2
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Synthesis of l-Altrose and Some Derivatives
pared with the galactose derivative 15 due to the neigh-
boring methyl group characterized by a smaller electron-
withdrawing effect and steric hindrance. This might explain
why no benzyl migration was observed during the conver-
sion of galactose 13.
Scheme 4. Side-products isolated after acid-catalyzed ring-opening
with ethanethiol.
After successful separation of the different thio com-
pounds by silica gel column chromatography, the dithio-
acetals 15 and 16 were used in the following Mitsunobu
inversions, the key steps of both reaction sequences. Both
reactions yielded the benzoylated products 20 (71%) and 21
(61%), respectively. As a result of the acyclic structures of
20 and 21, it was not possible at this step to determine
whether or not the reaction proceeded under inversion of
the configuration at C-5. Therefore, the dithioacetals 20 and
21 were treated with mercury(II) chloride in the presence of
mercury(II) oxide in methanol to give the corresponding
dimethyl acetals 22 (95%) and 23 (89%) in high yields.[18]
For cyclization, the hydroxy group at C-5 was deprotected
by alkaline hydrolysis to give 24 and 25 in yields of 90 and
75%, respectively. Subsequent acid catalysis in diethyl ether
led to the benzylated l-altropyranosides 26 (83%) and 27
(93%), respectively.[18] The successful 5-epimerization lead-
ing to both target sugars 26 and 27 was verified by
1H NMR spectroscopy. Therefore, this approach has proved
suitable for the transformation of common d-sugars (5 and
6) into rare l-hexoses (1 and 2).
Scheme 3. Synthesis of l-altrose (1) and 6-deoxy-l-altrose (2).
To achieve an additional access to 6-deoxy-l-altropyr-
anoside (2) by the deoxygenation of 1, selective cleavage of
the 6-O-benzyl ether was required. According to the selec-
tive 6-O-debenzylation procedure developed by Yang et
al.,[19] treatment of 26 with 7 equiv. of zinc(II) chloride in
acetic anhydride and acetic acid yielded a mixture of methyl
18 (37%) were also isolated.[15] As intermediates in the for-
mation of diethyl dithioacetal, these can be reused under
the same conditions.
Furthermore, in the case of the derivatization of d-fucose
14, a third compound was isolated, which was an isomer of
the acyclic diethyl dithioacetal 16, as judged by MS and
1H NMR spectroscopy. On the basis of 2D correlation
NMR experiments (H,H COSY, HSQC, and HMBC), we
proposed the formation of diastereomers 19 (32%) by an
acid-catalyzed intramolecular benzyl group O-4Ǟ5 mi-
gration in 16 (Scheme 4). Such migrations have previously
been observed as side-reactions during the acidic treatment
of benzyl-protected derivatives of various N-containing het-
erocycles (e.g., quinolines and indoles).[16] Moreover, sim-
ilar reaction conditions to those used for the ring opening
of 13 and 14 were also applied to benzyl cleavage.[17] For
example, Fuji et al. reported the removal of O-benzyl block-
ing groups by treatment with a hard Lewis acid like boron
6-O-acetyl-2,3,4-tri-O-benzyl-α/β-l-altropyranoside
(28;
37%) and 1,6-di-O-acetyl-2,3,4-tri-O-benzyl-α/β-l-altropyr-
anose (29; 29%), which were separated by silica gel column
chromatography. Subsequent alkaline hydrolysis of 28 re-
sulted in methyl 2,3,4-tri-O-benzyl-l-altropyranoside (30,
90%; Scheme 5). Several attempts were subsequently made
to introduce a good leaving group (e.g., tosylate, triflate)
into the C-6 position of 30, but they all failed for unknown
reasons. Thus, the following deoxygenation reactions yield-
ing 27 could not be performed.
Synthesis of TDP-6-deoxy-
L-altrose (3)
trifluoride–diethyl ether and
EtSH.[17a] The hydroxy group at the C-5 position of fucose
dithioacetal 16 may be preferred as benzyl acceptor com- cycloSal approach, two building blocks were needed: Sugar
a soft nucleophile like
For the synthesis of TDP-6-deoxy-l-altrose (3) by the
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N. Lunau, C. Meier
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phate triester 33 as an anomeric mixture (α/β ≈ 12:1).[21]
Unfortunately, even after repeated column chromatography
on silica gel by using different eluents, a complete separa-
tion of the benzyl-protected sugar phosphate 33 and the
dibenzyl N,N-diisopropylphosphoramidate, which was
formed by oxidation of the excess amidite starting material,
failed due to almost identical Rf values. The benzyl ethers
were cleaved by Pd(OH)2-catalyzed hydrogenolysis of 33 in
methanol. To obtain defined counterions for the subsequent
coupling reaction, a small amount of triethylamine was also
added. Under these reaction conditions not only the cleav-
age of the benzyl groups but also partial cleavage of acetyl
groups occurred. Repeated column chromatography on sil-
ica gel with a polar eluent gave pure α-5 (12% over three
steps) and α-5a (18% over three steps) and traces of β-5
(Scheme 6).
Because protecting groups in sugar phosphates affect the
solubility but not the performance and selectivity of cou-
pling reactions with cycoSal triesters,[3b,22] a mixture of both
phosphates 5 and 5a was used in the following conversion
to yield TDP-6-deoxy-l-altrose (3).
The last step in the synthesis of the TDP-sugar 3 was the
reaction of both 6-deoxy-α-l-altrosyl phosphates 5 and 5a
with 5-nitro-cycloSal-3Ј-O-acetylthymidine monophosphate
6 in DMF, which was performed according to the procedure
reported previously.[3b] After the complete conversion of tri-
ester 6, the solvent was removed, and the acetyl groups (of
both the sugar and nucleotide moieties) were cleaved by ba-
sic hydrolysis in a mixture of methanol, water, and triethyl-
amine (7:3:1). Finally, the resulting crude product was puri-
fied by reversed-phase chromatography with water as eluent
(Scheme 6).
Scheme 5. Synthesis of selective de-O-benzylated 30.
1-phosphate 5 and triester 6. 5-Nitro-cycloSal-3Ј-O-acetyl-
thymidine monophosphate 6 was synthesized by reaction of
3Ј-O-acetylthymidine 8 with 5-nitro-cycloSal-chlorophos-
phite 7, which was prepared as reported previously by start-
ing from 5-nitrosalicyl alcohol (Scheme 1).[20]
To generate the peracetylated 6-deoxy-α-l-altropyranosyl
phosphate 5, the benzyl ethers of 27 were cleaved by
Pd(OH)2-catalyzed hydrogenolysis in methanol followed by
peracetylation under standard conditions to yield 31 in
97% yield over two steps (Scheme 6).
Besides the reisolated deprotected sugar phosphate (δ =
2.11 ppm; the starting sugar-phosphate was used in excess),
the 31P NMR spectroscopic data obtained after RP
chromatography showed the presence of a mixture of three
different phosphorylated compounds, which could not be
separated in a first attempt: (1) TDP-6-deoxy-l-altrose [3;
2
2
δ = –13.73 (d, JPP = 20.2 Hz, Pβ), –11.45 (d, JPP
=
20.1 Hz, Pα) ppm], (2) thymidine monophosphate (δ =
2.24 ppm), and (3) a sugar-containing phosphorus species
of unknown structure (δ = 15.49 ppm). In the mixture, the
latter was the main compound, and the desired sugar nucle-
otide 3 was obtained only in very small amounts (ratio 8:1).
To separate both compounds, the mixture was once again
purified by preparative TLC. This second chromatography
resulted in the isolation of the pure byproduct but unfortu-
nately also in a complete loss of the desired TDP-sugar 3.
Based on the NMR and MS data, the byproduct was iden-
tified as being 6-deoxy-α-l-altropyranose 1,3-cyclophos-
phate (4). Such cyclic sugar phosphates are known as cleav-
age products of NDP-sugars under alkaline conditions.
Cleavage of the pyrophosphate bond and cyclization oc-
Scheme 6. Synthesis of TDP-6-deoxy-α-l-altrose (3) and its cleav-
age by basic deacetylation to yield the 1,3-cyclic phosphate 4.
Acid hydrolysis of the methyl glycoside 31 by treatment curred in an SN2-type reaction mechanism in which the
with TiBr4 resulted in 32 (66%), which was subsequently 3-hydroxy group attacked at the phosphate and displaced
treated with dibenzyl N,N-diisopropylphosphoramidite and TMP. Although 1,2-cyclic phosphates are well documented
DCI to give a phosphite intermediate, which was oxidized as cleavage products of NDP-sugars (e.g., UDP-glucose and
with m-chloroperbenzoic acid at 0 °C to give dibenzyl phos- ADP-glycero-β-d-manno-heptopyranose), 1,3-cyclic phos-
4
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Synthesis of l-Altrose and Some Derivatives
Instrumentation: 1H NMR spectroscopy was performed with a
Bruker AMX 400 or AV 400 spectrometer at 400 MHz. 13C NMR
spectra were recorded with a Bruker AMX 400 or AV 400 spec-
trometer at 101 MHz. 31P NMR spectra were recorded with a
Bruker AMX 400 spectrometer at 162 MHz (H3PO4 as external
standard). The spectra were recorded at room temperature. All 1H,
31P, and 13C NMR chemical shifts are quoted in parts per million
(ppm) downfield from tetramethylsilane and calibrated against sol-
vent signals. All 13C and 31P NMR spectra were recorded in the
proton-decoupled mode. HRMS were obtained with a VG Analyti-
phates are less known.[23] We assume that the formation of
the 1,3-cyclic phosphate 4 (six-membered ring) is dependent
on the configuration of the sugar moiety (1,3-diaxial posi-
tion of the hydroxy groups in the C4 conformation) of the
NDP-sugar 3.
Considering the strong basic conditions that were used
for the deacetylation of 3a, it is not surprising that the
1,3-cyclic phosphate 4 (and TMP) was the major product
obtained by the above-mentioned second reaction of the
1
previously formed 3. Because 4 is a cleavage product origi- cal VG/70–250F spectrometer. Freeze-drying of aqueous solutions
was performed by using a Christ-Alpha 2–4 lyophilizer. Microwave-
assisted reactions were performed in a CEM Discover® LabMate
system (CEM Corporation; open vessel mode). IR data were re-
corded with an Alpha-P FT-IR spectrometer (Bruker).
nating from TDP-sugar 3, it was possible to determine the
yield of the reaction of cycloSal triester 6 with the sugar
1-phosphates 5 and 5a from the quantity of the cyclic phos-
phate 4 obtained (68%, Scheme 6).
General Procedure 1. Synthesis of Methyl Glycopyranosides: The
corresponding monosaccharide was suspended in CH3OH. Am-
berlite® IR-120 (H+ form) was added, and the reaction mixture was
heated at reflux by irradiation with microwaves (150 W) for 20 min.
After complete conversion of the starting material (TLC control,
CH3CN/H2O, 5:1) the resin was filtered, and the solvent was re-
moved under reduced pressure. Because of their high purity, the
resulting anomeric mixtures of the methyl glycopyranosides could
be used in the following reactions without further purification.
Conclusions
We have successfully developed a reliable approach for
the chemical synthesis of methyl 2,3,4,6-tetra-O-benzyl-α/β-
l-altropyranoside (26) and its 6-deoxy derivative 27 by a
5-epimerization of commercially available d-galactose (9)
and d-fucose (10), respectively. Both synthetic pathways
were executed in eight steps in which 26 was obtained in a
high overall yield of 24%. Owing to the increased occur-
rence of secondary reactions (e.g., O-4Ǟ5-benzyl migration
in 16), the yield of the 6-deoxy derivative 27 was 4 %.
Although the precursor was available, we were unable to
synthesize TDP-6-deoxy-α-l-altrose (3), which is required
for biosynthesis studies of LPS, by the cycloSal approach.
In the final basic deacetylation and chromatography, de-
composition of the product 3a to yield the previously un-
known 6-deoxy-α-l-altropyranose 1,3-cyclophosphate (4)
was observed. We are currently investigating appropriate
conditions to prevent the cleavage of the target NDP-sugar
during the deacetylation process.
General Procedure 2. Synthesis of Benzyl Ethers: A solution of
1.0 equiv. of the corresponding methyl glycopyranoside in anhy-
drous DMF was treated with NaH (1.5 equiv. per hydroxy group)
at 0 °C whilst stirring under N2. The resulting suspension was
warmed to room temp. and stirred for 1 h. Then, on recooling to
0 °C, benzyl bromide (1.3 equiv.) was added, and the resulting sus-
pension was stirred at room temp. for 16 h. The reaction was
stopped by dropwise addition of CH3OH under ice cooling. After
removal of the solvents under reduced pressure, the residue was
diluted with EtOAc and washed with water. The aqueous phase
was extracted with EtOAc (3ϫ), and the combined organic phases
were dried with Na2SO4 and concentrated. The resulting residue
was purified on silica gel with PE/EtOAc (4:1, v/v) as eluent.
General Procedure 3. Synthesis of Diethyl Dithioacetals: A solution
of corresponding monosaccharide in EtSH was treated with tri-
fluoroacetic acid and stirred at room temp. for 16 h. The solution
was washed with sodium hydrogen carbonate solution until gas
evolution stopped. Diethyl ether was added and the aqueous phase
was extracted. After drying with Na2SO4, the solvent was removed
under reduced pressure, and the resulting oil was purified on silica
gel with PE/EtOAc (6:1, v/v) as eluent.
Experimental Section
General: Water-sensitive reactions were performed in flame-dried
glassware under nitrogen. Solvents were dried under the following
conditions: CH3CN and CH2Cl2 were distilled from calcium hy-
dride under nitrogen and stored over activated molecular sieves
(CH3CN: 3 Å; CH2Cl2: 4 Å), DMF was stored over activated mo-
lecular sieves (4 Å), and N,N-diisopropylethylamine (DIPEA) was
distilled from calcium hydride. Solvents for chromatography and
extractions [CH2Cl2, petroleum ether 50–70 (PE), ethyl acetate
(EtOAc), toluene, CH3CN, and CH3OH] were distilled before use.
Column chromatography was performed on Merck silica gel 60,
230–400 mesh. Reversed-phase column chromatography was per-
formed on reverse-phase-18 silica gel with distilled water as the
eluent at room temperature in a glass column. Analytical TLC was
performed on Merck precoated aluminium plates (60 F254) with a
0.2 mm layer of silica gel containing a fluorescent indicator. All of
the synthesized compounds were visualized by dunking the TLC
plates in dilute sulfuric acid (10%) and subsequent heat treatment.
Preparative TLC was performed on Macherey–Nagel precoated
TLC plates (SIL G-200 UV254; 20ϫ20 cm) with a 2.0 mm layer of
General Procedure 4. Mitsunobu Inversion of Hydroxy Groups: Tri-
phenylphosphane (3.0 equiv.) was suspended in anhydrous diethyl
ether, and DIAD (2.8 equiv.) was added at 0 °C. After stirring at
0 °C for 30 min, the resulting suspension was added to a solution of
the corresponding alcohol (1 equiv.) and benzoic acid (3.0 equiv.) in
anhydrous diethyl ether. The reaction mixture was stirred at room
temp. for 20 h. Then the precipitate was filtered, washed with di-
ethyl ether, and the solvent was removed under reduced pressure.
The resulting oil was purified on silica gel with PE/EtOAc (6:1, v/
v) as eluent.
General Procedure 5. Synthesis of Dimethyl Acetals: Mercury(II)
oxide (3.2 equiv.) and mercury(II) chloride (2.5 equiv.) were added
to a solution of the corresponding diethyl dithioacetal (1 equiv.) in
anhydrous CH3OH. The resulting suspension was stirred at room
temp. for 20 h. After filtration through Celite, the solvent was re-
moved under reduced pressure. The residue was dissolved in diethyl
ether and washed with a saturated solution of NaI. The combined
silica gel and fluorescent indicator UV254
.
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organic phases were dried with Na2SO4 and concentrated. The re-
sulting syrup was purified on silica gel with toluene/acetone (25:1,
v/v) as eluent.
3
3
H, Bn-CH2), 4.14 (t, JHH = 6.5 Hz, 1 H, 5-H), 4.02 (dd, JHH
=
3
9.9, JHH = 3.5 Hz, 1 H, 2-H), 3.95–9.93 (m, 1 H, 4-H), 3.89 (dd,
3JHH = 9.9, JHH = 2.8 Hz, 1 H, 3-H), 3.59–3.45 (m, 2 H, 6-H),
3
2.93 (s, 1 H, OH) ppm. 13C NMR (101 MHz, CDCl3): δ = 138.6,
138.5, 138.2, 137.9 (each Cq), 128.4, 128.3, 128.2, 128.1, 128.0,
127.9, 127.8, 127.7, 127.6, 127.5, 127.4 (CHar), 91.9 (C-1), 78.7 (C-
3), 76.6 (C-2), 74.7 (C-4), 74.6, 73.6, 73.5, 72.9 (each Bn-CH2), 69.5
General Procedure 6. Hydogenolytic Cleavage of Benzyl Ethers: The
corresponding benzylated compound was dissolved in CH3OH. Af-
ter addition of a catalytic amount of Pd(OH)2 (20 wt.-% Pd), the
reaction mixture was stirred under H2 for 16 h. After complete con-
version of the starting material (TLC control, CH3CN/H2O, 5:1,
v/v), the Pd(OH)2 residues were filtered, and the solvent was re-
moved under reduced pressure.
(C-5), 68.9 (C-6) ppm. IR (ATR): ν = 3062, 3029, 2867, 1496, 1453,
˜
1363, 1208, 1059, 910, 732, 694, 599, 461 cm–1. HRMS (ESI): calcd.
for C34H36KO6 [M + K]+ 563.2404; found 563.2403.
+
General Procedure 7. Acidic Cleavage of Methyl α/β-Glycopyranos-
ides: The corresponding methyl α/β-glycopyranoside was dissolved
in a mixture of CH3COOH/HCl (1 m)/H2O (5:2:1) and the resulting
solution was heated at reflux by irradiation with microwaves
(150 W) for 1 h. After cooling to room temp., the solution was
extracted with CH2Cl2. The combined organic phases were washed
with sodium hydrogen carbonate until gas evolution stopped. After
drying with Na2SO4, the solvent was removed under reduced pres-
sure, and the resulting oil was purified on silica gel with PE/EtOAc
(4:1, v/v) as eluent.
2,3,4,6-Tetra-O-benzyl-
cording to general procedure 3, the reaction was conducted with
2,3,4,6-tetra-O-benzyl-α/β-d-galactopyranose (13; 23.90 g,
D-galactose Diethyl Dithioacetal (15): Ac-
44.20 mmol), ethanethiol (330 mL, 277 g, 4.46 mol), and trifluoro-
acetic acid (50 mL). Pure 15 was obtained as a yellow oil (16.59 g,
25.65 mmol, 58%). Rf (PE/EtOAc, 4:1, v/v) = 0.73. [α]2D0 = –13 (c
1
= 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.30–7.14 (m, 20
2
2
H, CHar), 4.81 (d, JHH = 11.0 Hz, 1 H, Bn-CH2), 4.61 (d, JHH
=
2
11.7 Hz, 1 H, Bn-CH2), 4.43 (d, JHH = 11.8 Hz, 1 H, Bn-CH2),
4.35 (d, 2JHH = 11.7 Hz, 1 H, Bn-CH2), 4.29 (dd, JHH = 6.8, 3JHH
3
= 4.0 Hz, 1 H, 3-H), 4.25 (d, 2JHH = 11.7 Hz, 1 H, Bn-CH2), 3.97–
General Procedure 8. Acidic Hydrolysis of Dimethyl Acetals: A cata-
lytic amount of p-toluenesulfonic acid was added to a solution of
the corresponding dimethyl acetal in anhydrous diethyl ether and
the solution was heated at reflux for 3.5 h. After cooling to room
temp., the reaction mixture was neutralized by the addition of
methanolic NaOH (1%), the solvent was removed under reduced
pressure, and the resulting oil was purified on silica gel with tolu-
ene/acetone (25:1, v/v) as eluent.
3
3
3.94 (m, 1 H, 5-H), 3.89 (dd, JHH = 6.8, JHH = 4.0 Hz, 1 H,
2-H), 3.83 (d, 3JHH = 4.0 Hz, 1 H, 1-H), 3.69 (dd, 3JHH = 3.9, 3JHH
= 1.7 Hz, 1 H, 4-H), 3.49–3.41 (m, 2 H, 6-H), 2.65–2.56 (m, 2 H,
3
Et-CH2), 2.51–2.42 (m, 2 H, Et-CH2), 1.11 (t, JHH = 7.5 Hz, 3 H,
3
Et-CH3), 1.07 (t, JHH = 7.4 Hz, 3 H, Et-CH3) ppm. 13C NMR
(101 MHz, CDCl3): δ = 138.8, 138.6, 138.5, 138.3 (each Cq), 128.2,
127.7, 127.5, 127.3 (CHar), 83.1 (C-2), 81.8 (C-3), 76.3 (C-4), 75.7,
75.0, 73.2, 72.4 (Bn-CH2), 70.6 (C-6), 70.1 (C-5), 53.7 (C-1), 24.9,
Methyl 2,3,4,6-Tetra-O-benzyl-α-D-galactoside (11): Methyl α-d-ga-
24.8 (Et-CH ), 14.5, 14.4 (each Et-CH ) ppm. IR (ATR): ν = 3029,
˜
2
3
lactopyranoside was synthesized according to general procedure 1.
The reaction was conducted with d-galactose (9; 5.00 g, 27.8 mol,
1 equiv.), CH3OH (150 mL), and Amberlite® IR 120 (H+; 50 mL).
The following O-benzylation was carried out according to general
procedure 2 with NaH (4.00 g, 167 mmol, 6 equiv.), DMF
(100 mL), and BnBr (20.5 mL, 24.8 g, 145 mmol, 5.2 equiv.). Pure
α-11 (14.34 g, 25.85 mmol, 93% over two steps) was obtained as a
2924, 2867, 1749, 1495, 1453, 1363, 1209, 1064, 819, 732, 694, 605,
+
460 cm–1. HRMS (ESI): calcd. for C38H46NaO5S2 [M + Na]+
669.2679; found 669.2686.
5-O-Benzoyl-2,3,4,6-tetra-O-benzyl-L-altrose Diethyl Dithioacetal
(20): According to general procedure 4, the reaction was conducted
with triphenylphosphane (12.65 g, 48.23 mmol, 2.9 equiv.), DIAD
(9.69 mL, 48.8 mmol, 3.0 equiv.), 2,3,4,6-tetra-O-benzyl-d-galac-
tose diethyl dithioacetal (15; 10.59 g, 16.37 mmol, 1 equiv.), benzoic
acid (6.02 g, 49.3 mmol, 3 equiv.), and diethyl ether (200 mL). Pure
20 was obtained as a yellow oil (8.73 g, 11.62 mmol, 71%). Rf (tolu-
ene/acetone, 25:1, v/v) = 0.82. [α]2D0 = +2 (c = 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 8.05 (d, 3JHH = 7.9 Hz, 2 H, Bz-
yellow
syrup.
Rf
(PE/EtOAc,
4:1,
v/v)
=
0.67.
[α]2D0 = +7 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
7.38–7.22 (m, 20 H, CHar), 4.92 (d, 2JHH = 11.5 Hz, 1 H, Bn-CH2),
4.84–4.80 (m, 2 H, Bn-CH2), 4.71 (d, JHH = 11.8 Hz, 1 H, Bn-
CH2), 4.66–4.65 (m, 2 H, 1-H, Bn-CH2), 4.56 (d, JHH = 11.5 Hz,
2
2
2
1 H, Bn-CH2), 4.46 (d, JHH = 11.8 Hz, 1 H, Bn-CH2), 4.38 (d,
2JHH = 11.8 Hz, 1 H, Bn-CH2), 4.04–4.01 (m, 1 H, 2-H), 3.93–3.86
3
CH), 7.59–7.55 (m, 1 H, Bz-CH), 7.45 (t, JHH = 7.6 Hz, 2 H, Bz-
3
(m, 3 H, 4-H, 3-H, 5-H), 3.51 (d, JHH = 6.4 Hz, 2 H, 6-H), 3.35
3
3
CH), 7.37–7.22 (m, 20 H, Bn-CH), 5.61 (td, JHH = 6.6, JHH
=
(s, 3 H, OCH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 138.9,
138.7, 138.5, 138.1 (each Cq), 128.5, 128.4, 128.3, 128.2, 128.1,
127.8, 127.7, 127.6, 127.5 (CHar), 98.9 (C-1), 79.2 (C-4), 76.5 (C-
2), 75.2 (C-3), 74.7, 73.5, 73.4, 73.3 (each Bn-CH2), 69.2 (C-5), 69.1
2
3.3 Hz, 1 H, 5-H), 4.84 (d, JHH = 11.2 Hz, 1 H, 2-Bn-CH2), 4.79
(d, 2JHH = 11.3 Hz, 1 H, 2-Bn-CH2), 4.71–4.64 (m, 4 H, 3-Bn-CH2,
4-Bn-CH2), 4.53 (d, 2JHH = 12.2 Hz, 1 H, 6-Bn-CH2), 4.46 (d, 2JHH
= 12.1 Hz, 1 H, 6-Bn-CH2), 4.30 (dd, JHH = 7.0, JHH = 4.3 Hz,
1 H, 3-H), 4.13 (d, JHH = 3.6 Hz, 1 H, 1-H), 4.09–4.05 (m, 2 H,
3
3
(C-6), 55.3 (OCH ) ppm. IR (ATR): ν = 3029, 2009, 1496, 1350,
˜
3
3
1194, 1093, 1044, 732, 694 cm–1. HRMS (ESI): calcd. for
3
3
4-H, 6-H), 4.02 (dd, JHH = 7.0, JHH = 3.6 Hz, 1 H, 2-H), 3.86
(dd, 2JHH = 11.1, 3JHH = 6.6 Hz, 1 H, 6-H), 2.76–2.58 (m, 2 H, Et-
CH2), 1.19 (t, 3JHH = 6.5 Hz, 3 H, Et-CH3), 1.16 (t, 3JHH = 6.5 Hz,
3 H, Et-CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 165.9
(C=O), 141.0 (Bn-Cq), 138.9, 138.7, 138.4, 138.1 (each Bn-Cq),
133.1 (Bz-CH), 129.9 (Bz-CH), 126.7 (Bz-CH), 128.5, 128.4, 128.3,
128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 127.5, 127.4, 127.1 (each
Bn-CH), 84.0 (C-2), 80.9 (C-3), 79.3 (C-4), 75.7 (Bn-CH2), 75.0
(Bn-CH2), 73.9 (C-5), 73.1 (Bn-CH2), 73.0 (Bn-CH2), 68.9 (C-6),
54.4 (C-1), 25.6, 25.0 (Et-CH2), 14.6, 14.5 (each Et-CH3) ppm. IR
+
C35H38NaO6 [M + Na]+ 577.2561; found 577.2561.
2,3,4,6-Tetra-O-benzyl-α/β-D-galactopyranose (13): According to
general procedure 7, the reaction was conducted with methyl
2,3,4,6-tetra-O-benzyl-α-d-galactoside 11 (20.19 g, 36.40 mmol),
CH3COOH (100 mL), 1 m HCl (40 mL), and H2O (20 mL). Pure
13 was obtained as a slightly yellow syrup (17.12 g, 31.7 mmol,
87%). Rf (PE/EtOAc, 3:1, v/v) = 0.33; anomeric ratio α/β ≈ 1:0.6.
Data for the α anomer: 1H NMR (400 MHz, CDCl3): δ = 7.39–
3
7.23 (m, 20 H, CHar), 5.26 (d, JHH = 3.5 Hz, 1 H, 1-H), 4.91 (d,
2
2JHH = 11.5 Hz, 1 H, Bn-CH2), 4.81 (d, JHH = 11.7 Hz, 1 H, Bn-
(ATR): ν = 2924, 2866, 1718, 1496, 1452, 1267, 1093, 1068, 1267,
˜
2
CH2), 4.75–4.72 (m, 2 H, Bn-CH2), 4.69 (d, JHH = 11.8 Hz, 1 H,
1093, 1068, 1025, 733, 695, 462 cm–1. HRMS (ESI): calcd. for
2
+
Bn-CH2), 4.56 (d, JHH = 11.5 Hz, 1 H, Bn-CH2), 4.47–4.37 (m, 2
C45H50NaO6S2 [M + Na]+ 773.2941; found 773.2938.
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20938
/KAP1
Date: 25-09-12 16:41:59
Pages: 12
Synthesis of l-Altrose and Some Derivatives
5-O-Benzoyl-2,3,4,6-tetra-O-benzyl- -altrose Dimethyl Acetal (22):
According to general procedure 5, the reaction was conducted with
5-O-benzoyl-2,3,4,6-tetra-O-benzyl-l-altrose diethyl dithioacetal
(20; 6.72 g, 8.95 mmol, 1 equiv.), HgO (6.13 g, 28.30 mmol,
3.2 equiv.), and HgCl2 (6.13 g, 22.6 mmol, 2.5 equiv.) in absolute
CH3OH (400 mL). Pure 22 was obtained as a yellow oil (5.87 g,
3
3
3
L
11.3, JHH = 5.6 Hz, 1 H, 6-H), 3.60 (dd, JHH = 4.9, JHH
=
1.4 Hz, 1 H, 2-H), 3.42 (s, 3 H, OCH3) ppm. 13C NMR (101 MHz,
CDCl3): δ = 138.9, 138.7, 138.4, 138.2 (each Cq), 128.5, 128.4,
128.2, 128.0, 127.9, 127.8, 127.7, 127.6 (CHar), 100.5 (C-1), 75.7
(C-2), 74.0 (C-3), 73.9 (Bn-CH2), 73.8 (C-4), 73.7 (C-5), 73.6 (Bn-
CH2), 73.0 (Bn-CH2), 71.9 (Bn-CH2), 70.3 (C-6), 57.1 (OCH3)
8.50 mmol, 95%). Rf (toluene/acetone, 25:1, v/v) = 0.58. [α]2D0
=
ppm. IR (ATR): ν = 3029, 2865, 1496, 1453, 1366, 1207, 1113,
˜
+1.2 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.04–8.02 1073, 1024, 910, 732, 695 cm–1. HRMS (ESI): calcd. for
3
+
(m, 2 H, Bz-CH), 7.59–7.55 (m, 1 H, Bz-CH), 7.44 (t, JHH
=
=
C35H38NaO6 [M + Na]+ 577.2561; found 577.2559.
Methyl 6-O-Acetyl-2,3,4-tri-O-benzyl-α/β- -altropyranoside (28)
and 1,6-Di-O-acetyl-2,3,4-tri-O-benzyl-α/β- -altropyranose (29):
3
7.7 Hz, 2 H, Bz-CH), 7.37–7.22 (m, 20 H, CHar), 5.82 (td, JHH
L
3
6.8, JHH = 3.5 Hz, 1 H, 5-H), 4.82–4.77 (m, 3 H, Bn-CH2), 4.70
L
2
2
(d, JHH = 11.5 Hz, 1 H, Bn-CH2), 4.55 (d, JHH = 11.6 Hz, 1 H,
Methyl 2,3,4,6-tetra-O-benzyl-α/β-l-altropyranoside (26; 120 mg,
0.216 mmol, 1 equiv.) was dissolved in Ac2O/AcOH (1 mL, 2:1).
Freshly fused ZnCl2 (208 mg, 1.53 mmol, 7 equiv.) dissolved in
Ac2O/AcOH (1 mL, 2:1) was added to this solution. The reaction
mixture was stirred at room temp., and the conversion was moni-
tored by TLC (PE/EtOAc, 3:1). After 1 h, the formation of another
product was observed, and the reaction was stopped by the ad-
dition of water despite the incomplete conversion of the staring
material. The mixture was extracted with CH2Cl2 (3ϫ), washed
with saturated aqueous sodium carbonate solution and then water,
dried with Na2SO4, and concentrated to give a syrup. Purification
by column chromatography on silica gel with PE/EtOAc (8:1 Ǟ
3:1, v/v) as eluent yielded methyl 6-O-acetyl-2,3,4-tri-O-benzyl-α/β-
l-altropyranoside (28; 40 mg, 79 μmol, 37%) and 1,6-di-O-acetyl-
2,3,4-tri-O-benzyl-α/β-l-altropyranose (29; 33 mg, 62 μmol, 29%)
as colorless syrups.
2
3
Bn-CH2), 4.53 (d, JHH = 12.1 Hz, 1 H, Bn-CH2), 4.50 (d, JHH
=
=
3
6.2 Hz, 1 H, 1-H), 4.46–4.41 (m, 2 H, Bn-CH2), 4.15 (dd, JHH
3
6.6, JHH = 2.9 Hz, 1 H, 4-H), 3.99–3.95 (m, 2 H, 3-H, 6-H), 3.90
2
3
3
(dd, JHH = 10.9, JHH = 6.8 Hz, 1 H, 6-H), 3.79 (dd, JHH = 6.2,
3JHH = 3.6 Hz, 1 H, 2-H), 3.39 (s, 3 H, OCH3), 3.28 (s, 3 H, OCH3)
ppm. 13C NMR (101 MHz, CDCl3): δ = 165.6 (C=O), 139.1, 138.7,
138.4, 138.3 (each Cq), 133.0 (Bz-CHc), 129.9 (Bz-CHa), 128.6,
128.5, 128.4, 128.3 (CHar), 128.0 (Bz-CHb), 128.9, 127.8, 127.6,
127.4 (Bn-CH), 105.6 (C-1), 79.0 (C-4), 78.9 (C-2), 78.7 (C-3), 74.2,
74.1 (each Bn-CH2), 73.7 (C-5), 73.2, 73.1 (each Bn-CH2), 68.9 (C-
6), 56.0, 54.5 (each OCH ) ppm. IR (ATR): ν = 2923, 2853, 1720,
˜
3
1453, 1269, 1093, 1069, 1026, 734, 711, 697 cm–1. HRMS (ESI):
calcd. for C43H46O8Na+ [M + Na]+ 713.3085; found 713.3081.
2,3,4,6-Tetra-O-benzyl-L-altrose Dimethyl Acetal (24): 5-O-Benzo-
yl-2,3,4,6-tetra-O-benzyl-l-altrose dimethyl acetal (22; 5.00 g,
7.24 mmol) was dissolved in methanolic NaOH (1%), and the solu-
tion was stirred at room temp. for 2 h. After neutralization by the
addition of HCl (1 m), the solvent was removed under reduced pres-
sure, and the resulting oil was purified on silica gel with toluene/
acetone (25:1, v/v) as eluent. Pure 24 was obtained as a colorless
oil (3.82 g, 6.52 mmol, 90%). Rf (toluene/acetone, 25:1, v/v) = 0.32.
[α]2D0 = –20 (c = 1.0, CH2Cl2/CH3OH, 1:1, v/v). 1H NMR
(400 MHz, CDCl3): δ = 7.33–7.20 (m, 20 H, CHar), 4.73–4.68 (m,
Methyl 6-O-Acetyl-2,3,4-tri-O-benzyl-α/β-L-altropyranoside (28): Rf
(PE/EtOAc, 3:1, v/v) = 0.42; anomeric ratio α/β ≈ 8:1. Data for
α anomer: H NMR (400 MHz, CDCl3): δ = 7.35–7.20 (m, 15 H,
CHar), 4.82 (d, JHH = 12.6 Hz, 1 H, Bn-CH2), 4.73 (d, JHH
1.1 Hz, 1 H, 1-H), 4.56–4.47 (m, 5 H, Bn-CH2), 4.42–4.33 (m, 3 H,
6-H, Bn-CH2), 4.26 (dd, JHH = 11.7, JHH = 5.4 Hz, 1 H, 6-H),
1
3
3
=
2
3
4.08–4.02 (m, 1 H, 5-H), 3.80–3.77 (m, 2 H, 3-H, 4-H), 3.66 (dd,
3JHH = 4.0, JHH = 1.1 Hz, 2 H, 2-H), 3.51 (s, 3 H, OCH3), 2.02
3
2
3 H, Bn-CH2), 4.62 (d, JHH = 11.4 Hz, 2 H, Bn-CH2), 4.52–4.45
(s, 3 H, COCH3) ppm. α-13C NMR (101 MHz, CDCl3): δ = 171.1
(C=O), 138.8, 138.2, 137.9 (each Cq), 128.9, 128.8, 128.7, 128.6,
128.5, 128.4, 128.2, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7 (CHar),
100.6 (C-1), 75.4 (C-2), 73.9 (Bn-CH2), 73.6 (C-4), 73.2 (Bn-CH2,
C-3), 73.1 (Bn-CH2), 71.8 (C-5), 64.4 (C-6), 57.2 (OCH3), 21.1
3
(m, 4 H, Bn-CH2), 4.40 (d, JHH = 5.3 Hz, 1 H, 1-H), 4.09–4.03
3
3
(m, 1 H, 5-H), 3.96 (t, JHH = 4.4 Hz, 1 H, 3-H), 3.83 (dd, JHH
=
3
3
6.5, JHH = 4.1 Hz, 1 H, 4-H), 3.78 (t, JHH = 5.0 Hz, 1 H, 2-H),
3.64–3.57 (m, 2 H, 6-H), 3.35 (s, 3 H, OCH3), 3.31 (s, 3 H, OCH3),
3
2.96 (d, JHH = 4.5 Hz, 1 H, OH) ppm. 13C NMR (101 MHz,
(COCH ) ppm. IR (ATR): ν = 3030, 2924, 2855, 1740, 1496, 1454,
˜
3
CDCl3): δ = 138.9, 138.7, 138.4, 138.2 (Aryl-Cq), 128.5, 128.4,
128.2, 128.0, 127.9, 127.9, 127.8, 127.7, 127.6 (CHar), 106.0 (C-1),
79.9 (C-3), 79.5 (C-4), 79.4 (C-2), 74.7 (Bn-CH2), 74.4 (Bn-CH2),
73.5 (Bn-CH2), 72.9 (Bn-CH2), 71.6 (C-6), 71.0 (C-5), 56.1 (OCH3),
1368, 1231, 1076, 1027, 803, 735, 697 cm–1. HRMS (ESI): calcd.
for C30H34NaO7 [M + Na]+ 529.2197; found 529.2195.
+
1,6-Di-O-acetyl-2,3,4-tri-O-benzyl-α/β-L-altropyranose (29): Rf (PE/
EtOAc, 3:1, v/v) = 0.46; anomeric ratio α/β ≈ 1:0.3. Data for α
55.4 (OCH ) ppm. IR (ATR): ν = 3030, 2867, 1493, 1453, 1325,
˜
3
anomer: 1H NMR (400 MHz, CDCl3): δ = 7.35–7.24 (m, 15 H,
1150, 1073, 923, 881, 747, 698, 595 cm–1. HRMS (ESI): calcd. for
2
C36H42NaO7 [M + Na]+ 609.2823; found 609.2835.
+
CHar), 6.24 (s, 1 H, 1-H), 4.66 (d, JHH = 11.8 Hz, 1 H, Bn-CH2),
2
3
4.60–4.45 (m, 5 H, Bn-CH2), 4.42 (dd, JHH = 8.9, JHH = 3.1 Hz,
Methyl 2,3,4,6-Tetra-O-benzyl-α/β-L-altropyranoside (26): Accord-
3
3
1 H, 6-H), 4.33 (dd, JHH = 6.0, JHH = 4.3 Hz, 1 H, 4-H), 4.13–
4.09 (m, 2 H, 6-H, 2-H), 4.03 (d, JHH = 1.1 Hz, 1 H, 3-H), 3.75
ing to general procedure 8, the reaction was conducted with 2,3,4,6-
tetra-O-benzyl-l-altrose dimethyl acetal (24; 3.03 g, 5.16 mmol)
and p-toluenesulfonic acid (10 mg) in diethyl ether (200 mL). Pure
26 was obtained as a yellow oil (2.28 mg, 4.29 mmol, 83%). Rf
(toluene/acetone, 25:1, v/v) = 0.70; anomeric ratio: α/β ≈ 10:1. Data
3
3
3
(dt, JHH = 5.7, JHH = 3.7 Hz, 1 H, 5-H), 2.06 (s, 3 H, COCH3),
2.04 (s, 3 H, COCH3) ppm. 13C NMR (101 MHz, CDCl3): δ =
170.9, 170.17 (each C=O), 138.1, 137.7, 137.4 (each Cq), 128.7,
128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6
(CHar), 100.9 (C-1), 86.5 (C-3), 84.7 (C-4), 83.3 (C-2), 76.2 (C-5),
72.8, 72.0, 71.9 (each Bn-CH2), 62.8 (C-6), 21.4, 21.0 (each
1
for α anomer: H NMR (400 MHz, CDCl3): δ = 7.34–7.20 (m, 20
2
3
H, CHar), 4.80 (d, JHH = 12.5 Hz, 1 H, Bn-CH2), 4.73 (d, JHH
=
1.4 Hz, 1 H, 1-H), 4.61 (d, 2JHH = 12.1 Hz, 1 H, Bn-CH2), 4.57 (d,
COCH ) ppm. IR (ATR): ν = 3030, 2918, 1743, 1496, 1454, 1370,
˜
3
2JHH = 12.1 Hz, 1 H, Bn-CH2), 4.55 (d, JHH = 12.0 Hz, 1 H, Bn-
2
1226, 1101, 1046, 1008, 908, 727, 696, 602 cm–1. HRMS (ESI):
2
2
CH2), 4.53 (d, JHH = 12.5 Hz, 1 H,Bn-CH2), 4.48 (d, JHH
=
calcd. for C31H34O8Na+ [M + Na]+ 557.2146; found 557.2137.
12.1 Hz, 1 H, Bn-CH2), 4.43–4.40 (m, 2 H, Bn-CH2), 4.07 (ddd,
3
3
3
3JHH = 8.7, JHH = 5.6, JHH = 3.1 Hz, 1 H, 5-H), 3.82 (t, JHH
=
Methyl 2,3,4-Tri-O-benzyl-α/β-
acetyl-2,3,4-tri-O-benzyl-α/β-l-altropyranoside
0.051 mmol) was dissolved in methanolic NaOH (1%, 3 mL), and
L-altropyranoside (30): Methyl 6-O-
2.7 Hz, 1 H, 4-H), 3.79 (dd, 3JHH = 4.5, JHH = 3.1 Hz, 1 H, 6-H),
3.75 (dd, JHH = 4.9, JHH = 2.7 Hz, 1 H, 3-H), 3.71 (dd, JHH
(28; 26 mg,
3
3
3
2
=
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20938
/KAP1
Date: 25-09-12 16:41:59
Pages: 12
N. Lunau, C. Meier
FULL PAPER
+
the mixture was stirred at room temp. for 1 h. Then the reaction
mixture was neutralized by the addition of HCl (1 m), extracted
with CH2Cl2, dried with Na2SO4, and the solvent was removed
under reduced pressure. Purification by column chromatography
on silica gel with PE/EtOAc (2:1, v/v) as eluent yielded pure 30 as
a colorless syrup (19 mg, 0.041 mmol, 90%). Rf (PE/EtOAc, 2:1,
v/v) = 0.17; anomeric ratio α/β ≈ 3:1. Data for α anomer: 1H NMR
(400 MHz, CDCl3): δ = 7.33–7.20 (m, 15 H, CHar), 4.79–4.76 (m,
460 cm–1. HRMS (ESI): calcd. for C27H30NaO5 [M + Na]+
457.1991; found 457.1988.
2,3,4-Tri-O-benzyl-6-deoxy-
According to general procedure 3, the reaction was conducted with
2,3,4-tri-O-benzyl-6-deoxy-d-galactopyranose (14; 7.10 g,
D-galactose Diethyl Dithioacetal (16):
16.3 mmol), ethanethiol (126 mL, 2.41 mol), and trifluoroacetic
acid (13 mL). Besides the desired diethyl dithioacetal 16 (2.47 g,
4.56 mmol, 28%), the reaction yielded diethyl dithioacetal 19
(2.82 g, 5.22 mmol, 32%) and thioglycoside 18 (2.89 g, 6.03 mmol,
37%).
2 H, 1-H, Bn-CH2), 4.59–4.41 (m, 5 H, Bn-CH2), 3.95–3.89 (m,
2 H, 4-H, 6-H), 3.82–3.75 (m, 2 H, 5-H, 6-H), 3.73 (t, JHH
3
=
3.39 Hz, 1 H, 3-H), 3.62–3.59 (m, 1 H, 2-H), 3.53 (s, 3 H, OCH3)
ppm. 13C NMR (101 MHz, CDCl3): δ = 138.5, 138.2, 138.0 (each
Cq), 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0,
127.9, 127.8 (CHar), 100.5 (C-1), 75.5 (C-2), 74.0 (Bn-CH2), 73.8
(C-3), 73.6 (C-5), 73.2 (C-4), 73.1 (Bn-CH2), 72.0 (Bn-CH2), 63.0
2,3,4-Tri-O-benzyl-6-deoxy-D-galactose Diethyl Dithioacetal (16):
Rf (PE/EtOAc, 4:1, v/v) = 0.68. [α]2D0 = –13 (c = 1, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.40–7.26 (m, 15 H, CHar), 4.82–
2
4.80 (m, 4 H, 2,3-Bn-CH2), 4.74 (d, JHH = 11.6 Hz, 1 H, 4-Bn-
(C-6), 57.4 (OCH ) ppm. IR (ATR): ν = 3442, 2923, 1496, 1454,
˜
2
3
3
CH2), 4.59 (d, JHH = 11.6 Hz, 1 H, 4-Bn-CH2), 4.28 (dd, JHH
=
1363, 1206, 1075, 1028, 735, 698 cm–1. HRMS (ESI): calcd. for
3
6.0, JHH = 4.6 Hz, 1 H, 3-H), 4.05–4.01 (m, 1 H, 5-H), 3.97–3.93
C28H32O6Na+ [M + Na]+ 487.2091; found 487.2091.
3
(m, 2 H, 2-H, 1-H), 3.48–3.46 (m, 1 H, 4-H), 3.17 (d, JHH
=
4.7 Hz, 1 H, OH), 2.71–2.59 (m, 4 H, Et-CH2), 1.19–1.23 (m, 9 H,
Et-CH3, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 138.8,
138.4, 138.2 (Aryl-Cq), 128.6, 128.5, 128.4, 128.3, 123.2, 128.1,
128.0, 127.9, 127.8 (CHar), 83.0 (C-2), 82.1 (C-4), 81.3 (C-3), 75.4
(3-Bn-CH2), 74.8 (2-Bn-CH2), 73.5 (4-Bn-CH2), 67.4 (C-5), 54.0
(C-1), 25.5, 25.4 (each Et-CH2), 20.1 (CH3), 14.6 (2 Et-CH3) ppm.
Methyl 2,3,4-Tri-O-benzyl-6-deoxy-α/β-D-galactopyranoside (12):
Methyl 6-deoxy-α/β-d-galactopyranoside was synthesized accord-
ing to general procedure 1. The reaction was conducted with
d-fucose (10; 6.90 g, 42.0 mol, 1 equiv.), CH3OH (150 mL), and
Amberlite® IR 120 (H+; 50 mL). The subsequent O-benzylation
was carried out according to general procedure 2 with methyl 6-
deoxy-α/β-d-galactopyranoside (7.40 g, 41.5 mmol, 1 equiv.), NaH
(5.97 g, 0.249 mol, 6 equiv.), anhydrous DMF (200 mL), and BnBr
(25.4 mL, 214 mmol, 5.1 equiv.). Pure 12 (12.05 g, 26.86 mmol,
65% over two steps) was obtained as a yellow syrup. Rf (PE/EtOAc,
4:1, v/v) = 0.51; anomeric ratio: α/β ≈ 1:0.9. Data for α anomer:
1H NMR (400 MHz, CDCl3): δ = 7.41–7.26 (m, 15 H, CHar), 4.98
IR (ATR): ν = 3029, 2978, 2922, 2853, 1496, 1373, 1206, 1067,
˜
+
1026, 732, 694, 459 cm–1. HRMS (ESI): calcd. for C31H40NaO4S2
[M + Na]+ 563.2266; found 563.2258.
Mixture of Diastereomers of Diethyl Dithioacetal 19: Rf (PE/
EtOAc, 4:1, v/v) = 0.74. [α]2D0 = –45 (c = 1, CHCl3). 1H NMR
2
(400 MHz, CDCl3): δ = 7.33–7.14 (m, 15 H, CHar), 4.81 (d, JHH
2
2
2
(d, JHH = 11.6 Hz, 1 H, Bn-CH2), 4.88 (d, JHH = 12.0 Hz, 1 H,
= 11.1 Hz, 1 H, 2-Bn-CH2), 4.72 (d, JHH = 11.1 Hz, 1 H, 2-Bn-
2
2
2
Bn-CH2), 4.93 (d, JHH = 12.1 Hz, 1 H, Bn-CH2), 4.75–4.71 (m, 2
H, Bn-CH2), 4.68–4.64 (m, 1 H, 1-H, Bn-CH2), 4.04 (dd, JHH
CH2), 4.63 (d, JHH = 11.6 Hz, 1 H, 3-Bn-CH2), 4.56 (d, JHH
=
3
11.6 Hz, 1 H, 4-Bn-CH2), 4.36 (d, 2JHH = 11.6 Hz, 1 H, 3-Bn-CH2),
4.24 (d, JHH = 11.6 Hz, 1 H, 4-Bn-CH2), 4.09 (d, JHH = 6.2 Hz,
1 H, 1-H), 4.01 (dd, JHH = 8.7, JHH = 4.1 Hz, 1 H, 3-H), 3.94
=
=
3
3
3
2
3
10.1, JHH = 3.6 Hz, 1 H, 2-H), 3.93 (dd, JHH = 10.1, JHH
2.8 Hz, 1 H, 3-H), 3.84 (q, 3JHH = 6.4 Hz, 1 H, 5-H), 3.64 (d, 3JHH
3
3
3
3
3
3
= 2.4 Hz, 1 H, 4-H), 3.54 (s, 3 H, OCH3), 1.12 (d, JHH = 6.4 Hz,
(dd, JHH = 6.2, JHH = 4.1 Hz, 1 H, 2-H), 3.79 (dq, JHH = 6.2,
3 H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 139.1, 138.8,
138.7 (each Cq), 128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9,
127.8, 127.7, 127.6 (CHar), 98.9 (C-1), 79.6 (C-3), 78.1 (C-4), 76.5
(C-2), 75.0, 73.6, 73.5 (each Bn-CH2), 66.2 (C-5), 55.4 (OCH3),
3JHH = 1.4 Hz, 1 H, 5-H), 3.54 (dt, JHH = 8.7, JHH = 1.6 Hz, 1
3
3
3
H, 4-H), 2.66–2.39 (m, 4 H, Et-CH2), 2.40 (d, JHH = 8.7 Hz, 1 H,
OH), 1.24 (d, 3JHH = 6.3 Hz, 1 H, CH3), 1.14 (dt, 3JHH = 7.4, 3JHH
= 2.8 Hz, 6 H, Et-CH3) ppm. 13C NMR (101 MHz, CDCl3): δ =
138.8, 138.7, 138.5 (Cq), 128.6, 128.5, 128.4, 128.3, 123.2, 128.1,
128.0, 127.9, 127.8, 127.6, 127.5 (CHar), 82.8 (C-2), 79.0 (C-3), 75.3
(C-4), 75.2 (2-Bn-CH2), 74.0 (3-Bn-CH2), 73.0 (C-5), 70.4 (5-Bn-
CH2), 53.8 (C-1), 25.9, 25.1 (each Et-CH2), 16.3 (CH3), 14.6, 14.5
16.8 (CH ) ppm. IR (ATR): ν = 3029, 2768, 1606, 1495, 1453, 1369,
˜
3
1099, 1042, 945, 733, 695, 613, 451 cm–1. HRMS (ESI): calcd. for
C28H32NaO5 [M + Na]+ 471.2147; found 471.2135.
+
2,3,4-Tri-O-benzyl-6-deoxy-α/β-D-galactopyranose (14): According
(each Et-CH ) ppm. IR (ATR): ν = 3029, 2978, 2922, 2853, 1496,
˜
3
to general procedure 7, the reaction was conducted with methyl
2,3,4-tri-O-benzyl-6-deoxy-α/β-d-galactopyranoside (12; 12.05 g,
26.86 mmol), AcOH (200 mL), 1 m HCl (80 mL), and H2O
(40 mL). Pure 14 was obtained as a slightly yellow syrup (7.28 g,
16.8 mmol, 63%). Rf (PE/EtOAc, 4:1, v/v) = 0.20; anomeric ratio:
1373, 1206, 1067, 1026, 732, 694, 459 cm–1. HRMS (ESI): calcd.
for C31H40NaO4S2 [M + Na]+ 563.2266; found 563.2238.
+
Ethyl 2,3,5-Tri-O-benzyl-6-deoxy-α/β-D-thiogalactopyranoside (18):
Rf (PE/EtOAc, 4:1, v/v) = 0.82. Data for α anomer: 1H NMR
1
3
α/β ≈ 1:0.7. Data for α anomer: H NMR (400 MHz, CDCl3): δ =
(400 MHz, CDCl3): δ = 7.33–7.16 (m, 15 H, CHar), 5.39 (d, JHH
2
7.40–7.28 (m, 15 H, CHar), 5.27 (d, 3JHH = 3.6 Hz, 1 H, 1-H), 4.98 = 5.5 Hz, 1 H, 1-H), 4.91 (d, JHH = 11.6 Hz, 1 H, Bn-CH2), 4.79
2
2
2
(d, JHH = 11.6 Hz, 1 H, Bn-CH2), 4.84–4.81 (m, 2 H, Bn-CH2),
(d, JHH = 11.9 Hz, 1 H, Bn-CH2), 4.68 (d, JHH = 11.7 Hz, 1 H,
2
2
3
3
4.76 (d, JHH = 11.7 Hz, 1 H, Bn-CH2), 4.72 (d, JHH = 11.7 Hz,
Bn-CH2), 4.64–4.57 (m, 3 H, Bn-CH2), 4.21 (dd, JHH = 9.9, JHH
2
3
1 H, Bn-CH2), 4.67 (d, JHH = 11.5 Hz, 1 H, Bn-CH2), 4.11–4.09 = 5.5 Hz, 1 H, 2-H), 4.12 (q, JHH = 6.4 Hz, 1 H, 5-H), 3.71 (dd,
3
3
3
3
(m, 1 H, 5-H), 4.04 (dd, JHH = 9.9, JHH = 3.6 Hz, 1 H, 2-H),
3JHH = 9.9, JHH = 2.8 Hz, 1 H, 3-H), 3.56 (d, JHH = 2.1 Hz, 1
3
3
3
3
3.90 (dd, JHH = 9.9, JHH = 2.8 Hz, 1 H, 3-H), 3.67 (d, JHH
=
H, 4-H), 2.53–2.37 (m, 2 H, Et-CH2), 1.19 (t, JHH = 7.4 Hz, 3 H,
1.9 Hz, 1 H, 4-H), 1.14 (d, JHH = 6.5 Hz, 3 H, CH3) ppm. 13C Et-CH3), 1.06 (d, JHH = 6.5 Hz, 1 H, CH3) ppm. 13C NMR
3
3
NMR (101 MHz, CDCl3): δ = 138.8, 138.7, 138.3 (each Cq), 128.7,
(101 MHz, CDCl3): δ = 139.0, 138.7, 138.4 (Cq), 128.5, 128.4,
128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.6 (CHar),
128.4, 128.3, 128.0, 127.9, 127.8, 128.7, 127.6, 127.5 (CHar), 83.5
92.0 (C-1), 79.2 (C-4), 77.3 (C-3), 76.7 (C-2), 66.8 (C-5), 74.9, 73.7, (C-1), 79.9 (C-3), 77.9 (C-4), 76.2 (C-2), 75.0, 73.5, 72.5 (each Bn-
73.1 (each Bn-CH ), 16.9 (CH ) ppm. IR (ATR): ν = 3403, 3030, CH2), 66.7 (C-5), 23.8 (Et-CH2), 16.7 (CH3), 14.9 (Et-CH3) ppm.
˜
2
3
2931, 2869, 1496, 1453, 1206, 1092, 999, 910, 733, 695, 607, 505,
IR (ATR): ν = 2871, 1496, 1453, 1360, 1207, 1066, 1027, 910, 732,
˜
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20938
/KAP1
Date: 25-09-12 16:41:59
Pages: 12
Synthesis of l-Altrose and Some Derivatives
695, 637, 595, 460 cm–1. HRMS (ESI): calcd. for C29H34NaO4S2
[M + Na]+ 501.2070; found 501.2060.
25:1, v/v) = 0.22. [α]2D3 = –11 (c = 1.0, CHCl3). 1H NMR (400 MHz,
+
2
CDCl3): δ = 7.26–7.18 (m, 20 H, CHar), 4.74 (d, JHH = 11.5 Hz,
2
1 H, 2-Bn-CH2), 4.67–4.63 (m, 2 H, 3-Bn-CH2), 4.59 (d, JHH
=
5-O-Benzoyl-2,3,4-tri-O-benzyl-6-deoxy-
L-altrose
Diethyl
Di-
11.5 Hz, 1 H, 2-Bn-CH2), 4.50 (d, 2JHH = 11.5 Hz, 1 H, 4-Bn-CH2),
thioacetal (21): According to general procedure 4, the reaction was
conducted with triphenylphosphane (7.61 g, 30.0 mmol, 3.3 equiv.),
DIAD (5.80 mL, 5.97 g, 29.5 mmol, 3.2 equiv.), 2,3,4-tri-O-benzyl-
6-deoxy-l-altrose diethyl dithioacetal (16; 5.26 g, 9.23 mmol,
1 equiv.), benzoic acid (3.66 g, 30.0 mmol, 3.3 equiv.), and absolute
diethyl ether (250 mL). Pure 21 was obtained as a yellow oil (3.63 g,
5.63 mmol, 61%). Rf (PE/EtOAc, 4:1, v/v) = 0.86. [α]2D3 = +3 (c =
2.6, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.01–8.00 (m, 2 H,
Bz-CH), 7.58–7.54 (m, 1 H, Bz-CH), 7.45–7.42 (m, 2 H, Bz-CH),
4.46–4.42 (m, 2 H, 4-Bn-CH2, 1-H), 3.96–3.92 (m, 1 H, 5-H), 3.87
3
3
3
(t, JHH = 4.2 Hz, 1 H, 3-H), 3.68 (dd, JHH = 5.8, JHH = 3.8 Hz,
3
3
1 H, 2-H), 3.48 (dd, JHH = 6.9, JHH = 4.9 Hz, 1 H, 4-H), 3.37 (s,
3
3 H, OCH3), 3.29 (s, 3 H, OCH3), 2.73 (d, JHH = 3.7 Hz, 1 H,
OH), 1.19 (d, 3JHH = 6.3 Hz, 3 H, CH3) ppm. 13C NMR (101 MHz,
CDCl3): δ = 138.7, 138.7, 138.5 (each Cq), 128.5, 128.4, 128.3,
128.1, 127.9, 127.8, 127.6 (CHar), 105.9 (C-1), 83.7 (C-4), 80.1 (C-
3), 79.1 (C-2), 72.6 (3-Bn-CH2), 74.1 (2-Bn-CH2), 73.4 (4-Bn-CH2),
68.3 (C-5), 56.2, 54.9 (each OCH3), 19.5 (CH3) ppm. IR (ATR):
3
3
7.39–7.23 (m, 15 H, CHar), 5.47 (dq, JHH = 6.4, JHH = 2.6 Hz, 1
ν = 3271, 2096, 2932, 1497, 1454, 1394, 1330, 1206, 1089, 1070,
˜
2
H, 5-H), 4.85 (d, JHH = 11.6 Hz, 1 H, 4-Bn-CH2), 4.82–4.79 (m,
1027, 734, 697 cm–1. HRMS (ESI): calcd. for C29H36NaO6 [M +
+
5 H, Bn-CH2), 4.63 (d, 2JHH = 11.5 Hz, 1 H, 4-Bn-CH2), 4.18–4.15
Na]+ 503.2410; found 503.2406.
3
3
(m, 1 H, 3-H), 4.12 (d, JHH = 4.0 Hz, 1 H, 1-H), 3.99 (dd, JHH
3
3
3
= 6.5, JHH = 4.1 Hz, 1 H, 2-H), 3.92 (dd, JHH = 5.6, JHH
2.7 Hz, 1 H, 4-H), 2.71–2.56 (m, 4 H, Et-CH2), 1.43 (d, JHH
=
=
Methyl 2,3,4-Tri-O-benzyl-6-deoxy-α/β-L-altropyranoside (27): Ac-
3
cording to general procedure 8, the reaction was conducted with
2,3,4-tri-O-benzyl-6-deoxy-l-altrose dimethyl acetal (25; 1.29 g,
2.69 mmol) and p-toluenesulfonic acid (10 mg) in anhydrous diethyl
ether (100 mL). Pure 27 was obtained as a yellow oil (1.12 mg,
2.50 μmol, 93%). Rf (toluene/acetone, 25:1, v/v) = 0.55; anomeric
ratio: α/β ≈ 1:0.13. Data for the α anomer. [α]2D4 = +22 (c = 0.74,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.35–7.20 (m, 15 H,
3
3
6.3 Hz, 1 H, CH3), 1.17 (dt, JHH = 7.4, JHH = 3.2 Hz, 6 H, Et-
CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 160.4 (C=O), 139.0
(2-Aryl-Cq), 138.7 (3Aryl-Cq), 138.5 (4-Aryl-Cq), 133.2, 129.8 (each
Bz-Cq), 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8,
127.5 (CHar), 84.1 (C-2), 81.6 (C-4), 80.2 (C-3), 75.7 (2-Bn-CH2),
74.9 (3-Bn-CH2), 73.5 (4-Bn-CH2), 72.5 (C-5), 54.7 (C-1), 25.6, 25.4
(each Et-CH2), 15.3 (CH3), 14.7, 14.6 (each Et-CH3) ppm. IR
3
3
CHar), 4.82 (d, JHH = 12.7 Hz, 1 H, Bn-CH2), 4.70 (d, JHH
=
(ATR): ν = 3062, 3030, 2963, 2868, 1715, 1496, 1271, 1211, 1090,
˜
1.2 Hz, 1 H, 1-H), 4.55–4.39 (m, 5 H, Bn-CH2), 3.97–3.90 (m, 1 H,
+
1067, 734, 711 cm–1. HRMS (ESI): calcd. for C38H44NaO5S2 [M
3-H), 3.72–3.70 (m, 1 H, 5-H), 3.63 (dd, 3JHH = 4.2, 3JHH = 1.1 Hz,
+
+ Na]+ 667.2528; found 667.2522; calcd. for C38H48NO5S2 [M +
3
3
1 H, 2-H), 3.51 (s, 3 H, OCH3), 3.47 (dd, JHH = 9.2, JHH
=
NH4]+ 662.2968; found 662.2968.
3
2.9 Hz, 1 H, 4-H),1.32 (d, JHH = 6.3 Hz, 3 H, CH3) ppm.
13C NMR (101 MHz, CDCl3): δ = 138.9, 138.4, 138.3 (each Cq),
128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7 (CHar),
100.4 (C-1), 78.5 (C-4), 75.6 (C-2), 74.0 (Bn-CH2), 73.7 (C-3), 72.9,
72.0 (each Bn-CH2), 69.4 (C-5), 57.0 (OCH3), 18.3 (CH3) ppm. IR
5-O-Benzoyl-2,3,4-tri-O-benzyl-6-deoxy-L-altrose Dimethyl Acetal
(23): According to general procedure 5, the reaction was conducted
with 5-O-benzoyl-2,3,4-tri-O-benzyl-6-deoxy-l-altrose diethyl di-
thioacetal (16; 3.26 g, 5.06 mmol, 1 equiv.), HgO (3.33 g,
15.4 mmol, 3.0 equiv.), and HgCl2 (3.33 g, 12.3 mmol, 2.4 equiv.)
in absolute CH3OH (200 mL). Pure 23 was obtained as a yellow
oil (2.63 g, 4.50 mmol, 89%). Rf (toluene/acetone, 25:1, v/v) = 0.43.
[α]2D3 = –1 (c = 1.2, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.00
(ATR): ν = 3029, 2897, 1496, 1453, 1390, 1367, 1327, 1245, 1210,
˜
+
1090, 1053, 736, 698 cm–1. HRMS (ESI): calcd. for C28H32NaO5
[M + Na]+ 471.2142; found 471.2132.
Methyl
2,3,4-Tri-O-acetyl-6-deoxy-α/β-L-altropyranoside
(31):
3
3
(d, JHH = 7.8 Hz, 2 H, Bz-CH), 7.55 (t, JHH = 7.4 Hz, 1 H, Bz-
CH), 7.45–7.41 (m, 2 H, Bz-CH), 7.37–7.22 (m, 15 H, CHar), 5.60
(dq, 3JHH = 6.2, 3JHH = 1.5 Hz, 1 H, 5-H), 4.90 (d, 2JHH = 11.5 Hz,
Methyl
2,3,4-tri-O-benzyl-6-deoxy-α/β-l-altropyranoside
(27;
1.10 g, 2.45 mmol, 1 equiv.) was dissolved in methanol (50 mL),
Pd(OH)2/C (20 wt.-% Pd) was added, and the reaction mixture was
stirred under H2 at room temp. for 24 h. After filtration and re-
moval of the solvent under reduced pressure, the methyl 6-deoxy-α/
β-l-altropyranoside obtained was dissolved in anhydrous pyridine
(30 mL), Ac2O was added (2.10 mL, 22.1 mmol, 9 equiv.), and the
solution was stirred at room temp. for 18 h. The solvent was re-
moved under reduced pressure. The resulting oil was dissolved in
EtOAc, washed with water and brine, dried with Na2SO4, and con-
centrated. Pure 31 (720 mg, 2.37 μmol, 97% over two steps) was
obtained as a yellow syrup after column chromatography on silica
gel with PE/EtOAc (1:1, v/v) as eluent. Rf (PE/EtOAc, 1:1, v/v) =
0.30; anomeric ratio: α/β ≈ 1:11. Data for α anomer: [α]2D4 = +34 (c
= 0.35, CHCl3). Data for β anomer: 1H NMR (400 MHz, CDCl3):
δ = 5.39 (dd, 3JHH = 5.4, 3JHH = 3.2 Hz, 1 H, 3-H), 5.10 (dd, 3JHH
2
1 H, 4-Bn-CH2), 4.84 (d, JHH = 11.7 Hz, 1 H, 2-Bn-CH2), 4.75 (s,
2 H, 3-Bn-CH2), 4.58–4.55 (m, 2 H, 1-H, 2-Bn-CH2), 4.42 (d, 2JHH
3
3
= 11.5 Hz, 1 H, 4-Bn-CH2), 4.08 (dd, JHH = 7.6, JHH = 1.8 Hz,
3
3
3
1 H, 4-H), 3.83 (ddd, JHH = 10.5, JHH = 7.1, JHH = 2.9 Hz,
2 H, 3-H, 2-H), 3.42 (s, 3 H, OCH3), 3.34 (s, 3 H, OCH3), 1.38 (d,
3JHH = 6.5 Hz, 3 H, CH3) ppm. 13C NMR (101 MHz, CDCl3):
δ = 165.6 (C=O), 139.1, 138.7, 138.4 (each Cq), 133.0 (Bz-CH),
129.7 (Bz-CH), 128.5, 128.4, 128.3, 128.2, 127.8, 127.7, 127.6, 127.4
(CHar), 105.6 (C-1), 80.2 (C-4), 78.9 (C-3), 78.3 (C-2), 74.2 (2-Bn-
CH2), 73.9 (3-Bn-CH2), 73.4 (4-Bn-CH2), 72.8 (C-5), 56.2, 54.3
(each OCH ), 14.5 (CH ) ppm. IR (ATR): ν = 3030, 2933, 1715,
˜
3
3
1496, 1452, 1272, 1068, 1026, 734, 712, 697 cm–1. HRMS (ESI):
calcd. for C36H40NaO7 [M + Na]+ 607.2672; found 607.2675;
+
calcd. for C36H44NO7 [M + NH4]+ 602.3112; found 602.3125.
+
3
3
3
= 5.5, JHH = 1.7 Hz, 1 H, 2-H), 4.95 (dd, JHH = 8.0, JHH
=
3
2,3,4-Tri-O-benzyl-6-deoxy-L-altrose Dimethyl Acetal (25): 5-O- 3.1 Hz, 1 H, 4-H), 4.81 (d, JHH = 1.7 Hz, 1 H, 1-H), 4.00–3.93
Benzoyl-2,3,4-tri-O-benzyl-6-deoxy-l-altrose dimethyl acetal (23;
2.06 g, 3.53 mmol) was dissolved in methanolic NaOH (1%,
400 mL), and the solution was stirred at room temp. for 2 h. After
neutralization by the addition of 1 m HCl, the solvent was removed
under reduced pressure, and the resulting oil was purified on silica
gel with toluene/acetone (25:1, v/v) as eluent. Pure 25 was obtained
as a colorless oil (1.27 g, 2.65 mmol, 75%). Rf (toluene/acetone,
(m, 1 H, 5-H), 3.50 (s, 3 H, OCH3), 2.10, 2.10, 2.03 (each s, 3
3
H, COCH3), 1.33 (d, JHH = 6.5 Hz, 3 H, CH3) ppm. 13C NMR
(101 MHz, CDCl3): δ = 169.7, 169.6, 169.0 (each C=O), 98.7 (C-
1), 71.1 (C-4), 69.5 (C-5), 68.7 (C-2), 67.1 (C-3), 57.0 (OCH3), 21.0,
20.9, 20.8 (each COCH ), 18.2 (CH ) ppm. IR (ATR): ν = 2926,
˜
3
3
1749, 1371, 1219, 1173, 1059, 1027, 940 cm–1. HRMS (ESI): calcd.
for C13H20NaO8 [M + Na]+ 327.1056; found 327.1053.
+
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O20938
/KAP1
Date: 25-09-12 16:41:59
Pages: 12
N. Lunau, C. Meier
FULL PAPER
2,3,4-Tri-O-acetyl-6-deoxy-α/β-
L
-altropyranose (32): Titanium(IV)
1372, 1223, 1174, 1059, 982, 825, 592 cm–1. HRMS (ESI): calcd.
for C12H18O11P– [M]– 369.0592; found 369.0600.
bromide (106 mg, 0.288 mmol, 2.9 equiv.) was added to a solution
of methyl 2,3,4-tri-O-acetyl-6-deoxy-l-altropyranoside (31; 30 mg,
0.098 mmol) in CH2Cl2/EtOAc (9:1, v/v, 2 mL). The reaction mix-
ture was stirred at room temp. for 16 h, neutralized by the addition
of sodium acetate, stirred at room temp. for 15 min, suspended with
CH2Cl2, washed with ice-cold water (5ϫ), dried with Na2SO4, and
concentrated. Pure 32 (19 mg, 0.065 mmol, 66%) was obtained as
a yellow syrup after column chromatography on silica gel with PE/
EtOAc (1:1, v/v) as eluent. Rf (toluene/acetone, 9:2, v/v) = 0.20;
anomeric ratio: α/β ≈ 1:0.8. Data for α anomer: 1H NMR
(400 MHz, CDCl3): δ = 5.32–5.30 (m, 1 H, 3-H), 5.02–5.01 (m, 1
Sodium Salt of 3,4-Di-O-acetyl-6-deoxy-α-L-altropyranosyl Phos-
phate (α-5a): Rf (CH3CN/H2O, 5:1, v/v) = 0.30. 1H NMR
3
(400 MHz, D2O): δ = 5.48 (d, JHP = 8.6 Hz, 1 H, 1-H), 5.37–5.35
3
3
(m, 1 H, 3-H), 4.93 (dd, JHH = 8.5, JHH = 2.9 Hz, 1 H, 4-H),
3
3
3
4.16 (qd, JHH = 13.2, JHH = 6.4 Hz, 1 H, 5-H), 3.99 (d, JHH
=
3
5.0 Hz, 1 H, 2-H), 2.16, 2.09 (each s, 3 H, COCH3), 1.30 (d, JHH
= 6.6 Hz, 3 H, CH3) ppm. 13C NMR (101 MHz, D2O): δ = 173.1,
2
173.0 (each C=O), 94.1 (d, JCP = 3.9 Hz, C-1), 70.7 (C-4), 69.9
3
(C-5), 69.3 (C-3), 68.0 (d, JCP = 6.3 Hz, C-2), 20.2 (2 COCH3),
17.2 (CH3) ppm. 31P NMR (162 MHz, D2O): δ = –0.61 ppm. IR
3
H, 1-H), 4.98–4.94 (m, 2 H, 4-H), 4.30 (quint, JHH = 6.7 Hz, 1 H,
(ATR): ν = 3648, 2987, 2901, 1748, 1507, 1456, 1249, 1228, 1066,
˜
5-H), 3.39–3.37 (m, 1 H, OH), 2.20, 2.13, 2.04 (each: s, 3 H,
COCH3), 1.27–1.25 (m, 3 H, CH3) ppm. Data for α anomer: 13C
NMR (101 MHz, CDCl3): δ = 170.3, 169.9, 169.3 (each C=O), 92.1
(C-1), 70.3 (C-2), 70.2 (C-4), 67.6 (C-3), 64.0 (C-5), 21.0, 20.9, 20.8
(each COCH3), 17.1 (CH3) ppm. Data for β anomer: 1H NMR
923 cm–1. HRMS (ESI): calcd. for C10H16O10P– [M]– 327.0487;
found 327.0492.
6-Deoxy-α-
L-altropyranose 1,3-Cyclophosphate (4) via TDP-6-de-
oxy-α- -altropyranose (3) as Intermediate: The reaction was carried
L
3
out under nitrogen. After intense drying in vacuo for 36 h, a mix-
ture of 2,3,4-tri-O-acetyl-6-deoxy-α-l-altropyranosyl phosphate (5;
11 mg, 31 μmol) and 3,4-di-O-acetyl-6-deoxy-α-l-altropyranosyl
phosphate (5a; 20 mg, 51 μmol) was dissolved in dry DMF (1 mL).
After storage over activated molecular sieves (4 Å), a solution of
5-nitro-cycloSal-3Ј-O-acetylthymidine monophosphate (6; 26 mg,
41 μmol, 1 equiv.) in dry DMF (1 mL) was added over 15 min, and
the reaction mixture was stirred at room temp. for 24 h. The solvent
was removed under reduced pressure. To cleave all the acetyl groups
in the crude product of 3a, the residue was dissolved in a mixture
of CH3OH/H2O/Et3N (7:3:1, v/v), and the mixture was stirred at
room temp. for 16 h. After removing the solvent in vacuo, the crude
mixture was purified by RP18 chromatography using water as elu-
ent. In addition to de-O-acetylated α-l-altropyranosyl phosphate,
which was accessed in this reaction, thymidine monophosphate and
6-deoxy-α-l-altropyranose 1,3-cyclophosphate sodium salt (4)
(7.0 mg, 28 μmol, 68%) were obtained as colorless foams. The de-
sired 3 was only obtained in traces (Ͻ1 mg, Ͻ 3%, colorless foam),
which prevented a complete characterization.
(400 MHz, CDCl3): δ = 5.39 (t, JHH = 3.6 Hz, 1 H, 3-H), 5.18 (d,
3JHH = 8.3 Hz, 1 H, 1-H), 4.98–4.94 (m, 1 H, 2-H), 4.83 (dd, JHH
3
3
= 9.6, JHH = 3.1 Hz, 1 H, 4-H), 4.02–3.96 (m, 1 H, 5-H), 3.39–
3.37 (m, 1 H, OH), 2.20, 2.12, 2.04 (each s, 3 H, COCH3), 1.27–
1.25 (m, 3 H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.3,
169.9, 169.3 (each C=O), 91.6 (C-1), 70.3 (C-2), 70.2 (C-4), 69.8
(C-5), 67.3 (C-3), 21.0, 20.9, 20.8 (each COCH3), 17.9 (CH3) ppm.
IR (ATR): ν = 3436, 2981, 2939, 1742, 1432, 1370, 1213, 1047, 943,
˜
912, 732 cm–1. HRMS (ESI): calcd. for C12H18NaO8 [M + Na]+
+
313.0894; found 313.0895.
Sodium Salt of 2,3,4-Tri-O-acetyl-6-deoxy-L-altropyranosyl Phos-
phate (5): 2,3,4-Tri-O-acetyl-6-deoxy-α/β-l-altropyranose (32;
116 mg, 0.400 mmol, 1 equiv.) was dissolved in anhydrous CH2Cl2
(5 mL), and 4,5-dicyanoimidazole (DCI) (58 mg, 0.49 mmol,
1.2 equiv.) was added. The reaction mixture was cooled to 0 °C,
and
dibenzyl
N,N-diisopropylphosphoramidite
(0.20 mL,
0.61 mmol, 1.5 equiv.) was added dropwise. The reaction mixture
was then warmed to room temp. and stirred for 2 h. Then, m-chlo-
roperbenzoic acid (139 mg, 0.805 mmol, 2 equiv.) was added at
0 °C, and the reaction mixture was stirred at room temp. for
30 min. After diluting with Et2O, the organic phase was washed
with sodium sulfite, brine, and water, dried with Na2SO4, and con-
centrated. Because of their almost identical Rf values, a mixture of
33 and dibenzyl N,N-diisopropylphosphoramidate was obtained as
a yellow syrup after repeated column chromatography on silica gel
with PE/EtOAc (1:1, v/v) or toluene/acetone (9:2, v/v) as eluent.
This inseparable mixture was then dissolved in methanol (5 mL),
Pd(OH)2/C (20 wt.-% Pd) and a few drops Et3N were added, and
the reaction mixture was stirred under H2 at room temp. for 24 h.
After filtration, the solvent was removed under reduced pressure.
Repeated column chromatography on silica gel with CH3CN/H2O
(5:1, v/v) as eluent gave pure α-5 (18 mg, 46 μmol, 12% over three
steps), pure α-5a (25 mg, 71 μmol, 18% over three steps), and traces
of β-5 as colorless foams.
Sodium Salt of TDP-6-deoxy-α-L-altropyranose (3): Data taken
from the spectra of the crude reaction mixture. Rf [iPrOH/NH4OAc
(1 m), 2:1, v/v] = 0.15. 31P NMR (162 MHz, D2O): δ = –13.73 (d,
2
2JPP = 20.2 Hz, Pβ), –11.45 (d, JPP = 20.1 Hz, Pα) ppm. HRMS
(ESI): calcd. for C16H25N2O15P2 [M]– 547.0739; found 547.0736.
–
Sodium Salt of 6-Deoxy-α-
L-altropyranosyl-1,3-cyclophosphate (4):
Rf [iPrOH/NH4OAc (1 m), 2:1, v/v] = 0.62. 1H NMR (400 MHz,
3
3
D2O): δ = 5.61 (dd, JHP = 21.5, JHH = 2.8 Hz, 1 H, 1-H), 4.46–
3
4.44 (m, 1 H, 2-H), 4.25 (t, JHH = 3.1 Hz, 1 H, 3-H), 3.97 (dd,
3
3
3
3JHH = 8.0, JHH = 6.5 Hz, 1 H, 5-H), 3.71 (dd, JHH = 8.0, JHH
= 3.1 Hz, 1 H, 4-H), 1.30 (d, JHH = 6.5 Hz, 3 H, CH3) ppm. 13C
3
4
NMR (101 MHz, D2O): δ = 95.4 (C-1), 78.2 (d, JCP = 1.3 Hz, C-
2), 69.5 (C-5), 69.4 (C-4), 67.7 (d, 3JCP = 10.9 Hz, C-3), 17.2 (CH3)
ppm. 31P NMR (162 MHz, D2O, 1H-decoupled): δ = 15.49 ppm.
31P NMR (162 MHz, D2O, 1H-coupled): δ = 15.49 (d, JPH
=
3
21.1 Hz) ppm. IR (ATR): ν = 3335, 2933, 2477, 1561, 1406, 1245,
˜
Sodium Salt of 2,3,4-Tri-O-acetyl-6-deoxy-α-L-altropyranosyl Phos-
1121, 1022, 651, 621, 496 cm–1. HRMS (ESI): calcd. for C6H10O7P–
[M]– 225.0170; found 225.0172.
phate (α-5): Rf (CH3CN/H2O, 5:1, v/v) = 0.47. 1H NMR (400 MHz,
D2O): δ = 5.63 (dd, 3JHP = 9.0, 3JHH = 1.7 Hz, 1 H, 1-H), 5.46 (dd,
3JHH = 4.9, JHH = 3.3 Hz, 1 H, 3-H), 5.18 (dd, JHH = 5.1, JHH Sodium Salt of 6-Deoxy-α-
L-altropyranosyl Phosphate (5b): Rf
3
3
3
3
3
= 1.7 Hz, 1 H, 2-H), 5.94 (dd, JHH = 8.7, JHH = 3.3 Hz, 1 H, 4-
[iPrOH/NH4OAc (1 m), 2:1, v/v] = 0.05. 1H NMR (400 MHz,
D2O): δ = 5.33 (d, 3JHP = 8.7 Hz, 1 H, 1-H), 4.05 (t, 3JHH = 3.6 Hz,
3
3
H), 4.16 (qd, JHH = 12.9, JHH = 6.4 Hz, 1 H, 5-H), 2.24, 2.22,
2.12 (each s, 3 H, COCH3), 1.35 (d, JHH = 6.4 Hz, 3 H, CH3) 1 H, 3-H), 3.93 (d, 3JHH = 3.5 Hz, 1 H, 2-H), 3.90 (dd, 3JHH = 9.7,
3
3
3
ppm. 13C NMR (101 MHz, D2O): δ = 173.0, 172.8, 172.6 (each
C=O), 94.4 (d, 2JCP = 3.0 Hz, C-1), 70.7 (C-4), 69.9 (C-5), 69.2 (C-
3JHH = 6.4 Hz, 1 H, 5-H), 3.55 (dd, JHH = 9.6, JHH = 3.2 Hz, 1
H, 4-H), 1.30 (d, JHH = 6.4 Hz, 3 H, CH3) ppm. 13C NMR
3
2), 66.9 (C-3), 20.2, 20.1, 20.0 (each COCH3), 17.2 (CH3) ppm. 31
P
(101 MHz, D2O): δ = 93.2 (C-1), 70.3 (C-2), 70.2 (C-3), 69.6 (C-5),
NMR (162 MHz, D O): δ = –0.79 ppm. IR (ATR): ν = 2987, 1748, 69.5 (C-4), 17.3 (CH3) ppm. 31P NMR (162 MHz, CDCl3): δ =
˜
2
10
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Job/Unit: O20938
/KAP1
Date: 25-09-12 16:41:59
Pages: 12
Synthesis of l-Altrose and Some Derivatives
J. Am. Chem. Soc. 2000, 122, 2995–3000; c) S.-C. Hung, C.-C.
2.11 ppm. IR (ATR): ν = 3337, 2482, 1378, 1068, 971, 872, 817,
˜
617, 528 cm–1. HRMS (ESI): calcd. for C6H12O8P– [M]– 243.0275;
found 243.0275.
Wang, S. R. Thopate, Tetrahedron Lett. 2000, 41, 3119–3122.
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Supporting Information (see footnote on the first page of this arti-
1
cle): H, 13C and 31P NMR spectra for compounds 4, 5a, 11, 12,
22, 23, 26, and 27.
Acknowledgments
The authors thank the University of Hamburg for financial sup-
port.
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Received: July 16, 2012
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11

Job/Unit: O20938
/KAP1
Date: 25-09-12 16:41:59
Pages: 12
N. Lunau, C. Meier
FULL PAPER
Activated Sugars
N. Lunau, C. Meier* ....................... 1–12
Synthesis of l-Altrose and Some Deriva-
tives
Keywords: Carbohydrates / Epimerization /
Synthesis design / Phosphorylation
A synthesis of l-altrose and its 6-deoxy de-
rivative has been developed by starting
from d-galactose and d-fucose, respectively.
After 1-phosphorylation, the intermediate
was treated with 5-nitro-cycloSal-TMP to
give the peracetylated TDP-6-deoxy-α-l-al-
trose. The final deprotection led to an un-
expected side-reaction resulting in the pre-
viously unknown 6-deoxy-α-l-altropyr-
anose 1,3-cyclophosphate.
12
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