Direct, mild, and selective synthesis of unprotected dialdo-glycosides

Article abstract of DOI:10.1002/ejoc.200600288

A direct and highly convenient organocatalytic method for the preparation of 1,5-dialdo-pyranosides and 1,4-dialdo-furanosides is presented. The method relies on the chemoselective properties of TEMPO in combination with trichloroisocyanuric acid under very mild, basic conditions. Unprotected glycosides are prepared in a single step in high yields and are efficiently purified with the use of solid-phase imine capture. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600288

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200600288
Direct, Mild, and Selective Synthesis of Unprotected Dialdo-Glycosides
Marcus Angelin,[a] Magnus Hermansson,[a] Hai Dong,[a] and Olof Ramström*[a]
Keywords: Glycosides / Oxidation / Catalysis / Solid-phase / Imine capture
A direct and highly convenient organocatalytic method for
the preparation of 1,5-dialdo-pyranosides and 1,4-dialdo-fu-
glycosides are prepared in a single step in high yields and
are efficiently purified with the use of solid-phase imine cap-
ranosides is presented. The method relies on the chemoselec- ture.
tive properties of TEMPO in combination with trichloroisocy-
anuric acid under very mild, basic conditions. Unprotected
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
tecting group strategies, which results in moderate overall
yields and considerable amounts of waste products. With
the consideration of today’s demand from industry and so-
ciety for more efficient and environmentally adapted pro-
cesses, the design of simple, safe and effective synthetic
routes are becoming more important. Terms such as, toxic-
ity, atom efficiency and waste minimization are now invalu-
able parts of commercial and research focused synthesis.
In this study, we report a mild, simple and efficient
TEMPO-catalyzed oxidation of a range of unprotected
methyl glycosides (1–6) to their corresponding oxo deriva-
tives (7–12). The transformation is made in one single step
and products are isolated in high yield after a simple purifi-
cation step.
Introduction
For many applications in modern synthetic chemistry,
the pool of natural compounds is a useful source of build-
ing blocks. In particular, the diverse family of carbohydrates
provides complex, stereochemically pure structures at mod-
erate cost, and they can serve as reagents and scaffolds in a
variety of synthetic protocols.[1–4] Modified carbohydrates
are also important components in the development of ef-
ficient protein ligands and inhibitors.[5] The selective oxi-
dation of carbohydrate hydroxy groups is in this case a con-
venient way to introduce new functionalities into the struc-
tures and to adjust several of the carbohydrates’ fundamen-
tal chemical and physical properties. Oxidation of this pri-
mary hydroxy group to an aldehyde functionality produces
dialdo-glycosides. This is a highly useful route for the prep-
aration of reactive carbohydrate components with intact
carbon skeletons. These structures have proved advan-
tageous for a variety of reactions, including reductive amin-
ation protocols to produce N-linked glycosides and glyco-
conjugates,[6,7] glycoside oxime formation,[8] olefination re-
actions[9] and different polymerization protocols.[10,11]
The synthesis of 1,5-dialdo-pyranosides has been ad-
dressed over the years, and some enzymatic,[12–14] as well
as several synthetic,[12,15] pathways have been reported. The
enzymatic procedures use galactose oxidase and are
straightforward but are largely limited to galactose deriva-
tives because of the enzymatic specificity for this structure.
Purification of the resulting 1,5-dialdo-galactopyranosides
has also been reported to be difficult,[12] and crude mixtures
are often used in subsequent reactions. Synthetic pro-
cedures usually require several steps with sophisticated pro-
Results and Discussion
TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) is a very
mild oxidation agent that has been previously used in dif-
ferent green and environmentally benign systems.[16–18] Un-
der various conditions, it has been used catalytically and
stoichiometrically for the chemoselective oxidation of pri-
mary hydroxy groups to aldehydes, carboxylic acids and
mixtures thereof.[19–21] The general oxidation mechanism
has been the object of several detailed studies, and the cur-
rently accepted catalytic cycle in basic media is displayed in
Figure 1.[19] However, in order to stop at the aldehyde stage
the reaction must generally take place in nonaqueous sol-
vents, most commonly CH2Cl2, to avoid overoxidation to
the corresponding carboxylic acids.[22–25] These solvents are
generally incompatible with polar compounds because of
solubility issues, and oxidation is therefore performed with
protected structures.
[a] KTH
– Royal Institute of Technology, Department of
In order to avoid overoxidation and to overcome solubil-
ity issues, the use of alternative solvents was addressed in
this study. The reaction was found to be best carried out in
DMF (Scheme 1), which proved to be an efficient solvent
for this transformation as all reactants could be sufficiently
Chemistry,
Teknikringen 30, 10044 Stockholm, Sweden
Fax: +46-8-7912333,
E-mail: ramstrom@kth.se
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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M. Angelin, M. Hermansson, H. Dong, O. Ramström
SHORT COMMUNICATION
Table 1. Synthesis of methyl 1,5-hexodialdo-pyranosides and
methyl 1,4-pentodialdo-ribofuranoside.
Figure 1. Proposed mechanism for TEMPO-catalyzed alcohol oxi-
dation under basic (B) conditions.[19] [O] indicates secondary oxi-
dant.
dissolved. DMF is a very polar aprotic solvent that has not
previously been used in TEMPO-mediated reactions proba-
bly because of its tendency to degrade in oxidative environ-
ments. This phenomenon was also observed to a small ex-
tent under these mild conditions but was not pronounced
enough to prevent oxidation of the starting material. In ad-
dition, several alkaline compositions and common second-
ary oxidants were screened to further optimize the reaction
conditions, the majority of which, however, resulted in low
conversions or degradation of the final product. In very
weakly basic conditions, however, degradation could be
completely eliminated.
The differences in the reaction times of glycosides 1–6
should also be noticed. The most likely explanation for
these variations can be attributed to steric interference from
the neighbouring groups. Thus, riboside 5, which is the least
sterically congested molecule, showed the shortest reaction
time. Among the pyranosides, glucosides 1, 2 and 6 and
mannoside 4 all had similar rates, while galactoside 3 clearly
stood out as the least reactive structure. This could be due
to its axial hydroxy group in the 4-position which lies in
close proximity to the reaction centre and could interfere
with the reaction.
Scheme 1. TEMPO-catalyzed oxidation of unprotected glycosides.
Purification of unprotected dialdosides has been re-
ported to be difficult,[12] and their sensitive nature consider-
The most efficient system for the transformation of ably limits the options available for purification. In our
alcohols into aldehydes was finally identified to be at low case, both the separation from DMF and the actual purifi-
temperature with sodium hydrogencarbonate as the base cation were needed in order to isolate our desired com-
and TCC (trichloroisocyanuric acid) as secondary oxidant. pounds. This problem was solved with the use of amino-
TCC is known to be a very mild and safe oxidant,[26,27] and derivatized solid-phase extraction columns.
it has previously been used in TEMPO-based reac-
The procedure (Figure 2) is based on the reversible reac-
tions.[27,28] This combination together with TEMPO tion between aldehydes and primary amines to form a tem-
(2.5 mol-%) in DMF at 0 °C managed to raise the conver- porary imine functionality. After filtration, the reaction
sion of the reaction up to quantitative yields for the investi- mixture was passed through the derivatized silica column,
gated reactant glycosides (Table 1), without any observed which traps the glycosidic aldehyde in the column by its
decomposition.
conversion into an imine. The column was then washed
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Eur. J. Org. Chem. 2006, 4323–4326

Direct, Mild, and Selective Synthesis of Unprotected Dialdo-Glycosides
with THF to remove DMF and the impurities from the
SHORT COMMUNICATION
Experimental Section
reaction mixture. Subsequently, a THF/water gradient was
applied to hydrolyze the imine bond and to elute the alde-
hyde in its pure (hydrated) form. Finally, the aldehyde was
isolated by freeze-drying the appropriate fractions. Al-
though this purification procedure generally generated pure
product, occasional traces (5–10%) of an impurity from the
unwanted hydrolysis of the column were observed. This was
General Methods: All commercially available starting materials and
solvents were of reagent grade and dried prior to use. Chemical
reactions were monitored by thin-layer chromatography with pre-
coated silica gel 60 (0.25 mm thickness) plates (Macherey–Nagel).
Solid-phase extraction was performed with Sep-Pak® NH2 car-
tridges (6 CC, 1 g) (Waters Corporation). 1H- and 13C NMR spec-
tra were recorded with a Bruker Avance 400 instrument or a Bruker
DMX 500 instrument at 298 K in D2O, with the residual signals
from H2O (1H NMR: δ = 4.70 ppm) as an internal standard. 1H
NMR peak assignments were made by first order analysis of the
spectra, supported by standard 1H-1H correlation spectroscopy
(COSY). High resolution mass spectra (HRMS) were performed
by the Chemical Center, Lund Institute of Technology, Lund, Swe-
den. All compounds were analyzed in their hydrate form.
1
visualized by TLC analysis as well as by H NMR spec-
troscopy, and was confirmed by passing water through un-
used columns. This impurity did cause some mixed frac-
tions in the elution process, which limited the yield. This
problem could probably be eliminated by small adjustments
in the manufacture of the column, which would render the
possibility of even higher yields.
Representative Oxidation: Sodium hydrogencarbonate (650 mg,
7.74 mmol) and TEMPO (1 mg, 6.40 µmol) were added to a stirred
solution of methyl α--mannopyranoside (4, 50 mg, 0.257 mmol) in
DMF (50 mL). The reaction was cooled to 0 °C and TCC (45 mg,
0.196 mmol) was added. After 7 h of continuous stirring at 0 °C,
the reaction mixture was filtered and passed through a Sep-Pak®
amino-derivatized solid-phase extraction column (1 g, 6 mL). The
column was washed with THF (40 mL), and the product was eluted
with a THF/H2O gradient (1Ǟ30% H2O). Fractions that con-
tained the product (TLC analysis) were freeze-dried to yield the
desired aldehyde (42 mg, 85%).
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic data of compounds 7 to 12.
Acknowledgments
This study was supported by the Swedish Research Council and the
Carl Trygger Foundation. MA gratefully acknowledges financial
support through the Royal Institute of Technology’s Excellence
Award.
Figure 2. Efficient solid-phase capture/release of dialdo-glycosides.
The reaction was generally optimized for laboratory-
scale transformations at milligram glycoside amounts.
However, the reaction was also performed in gram-scale
quantities for some of the substrates, which resulted in sim-
ilar conversions and reaction rates. This demonstrates that
the procedure is a possible candidate for large-scale or in-
dustrial applications. The solid-phase columns are also very
adaptable to large-scale syntheses, with the possibility of
multiple reuses and recycling of the solvent.
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SHORT COMMUNICATION
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Received: March 31, 2006
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Published Online: August 15, 2006
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