Protecting group free glycosidations using p-toluenesulfonohydrazide donors

Article abstract of DOI:10.1021/ol801232f

(Figure Presented) N-Glycopyranosylsulfonohydrazides are introduced as glycosyl donors for protecting group free synthesis of O-glycosides, glycosyl azides, and oxazolines. Mono- and disaccharides containing a reducing terminal N-acelylglucosamine residue were condensed with p-toluenesulfonylhydrazide to give the desired β-D-pyranose donors. These donors can be activated with NBS and then glycosidated with the desired alcohol or transformed to the oxazoline or glycosyl azide.

Full text of DOI:10.1021/ol801232f

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3461-3463
Protecting Group Free Glycosidations
Using p-Toluenesulfonohydrazide
Donors
Anna V. Gudmundsdottir and Mark Nitz*
Department of Chemistry, UniVersity of Toronto, Toronto, ON, Canada M5S 3H6
mnitz@chem.utoronto.ca
Received June 2, 2008
ABSTRACT
N′-Glycopyranosylsulfonohydrazides are introduced as glycosyl donors for protecting group free synthesis of O-glycosides, glycosyl azides,
and oxazolines. Mono- and disaccharides containing a reducing terminal N-acetylglucosamine residue were condensed with p-toluenesulfo-
nylhydrazide to give the desired ꢀ-D-pyranose donors. These donors can be activated with NBS and then glycosidated with the desired
alcohol or transformed to the oxazoline or glycosyl azide.
In 1893, Fischer’s group reported the acid-catalyzed con-
densation reaction between glucose and methanol to yield
methyl R-D-glucopyranoside in what is now commonly
known as the Fischer glycosidation.1 Since Fischer’s report,
immense progress has been made in the synthetic methods
available to generate complex carbohydrates. These methods
have enabled the stereocontrolled synthesis of glycans as
large as the recently reported docosanasaccharide.2 These
impressive advances have been facilitated by the develop-
ment of versatile protecting group strategies and powerful
glycosylation conditions.3
Despite the advances of modern carbohydrate chemistry,
the Fischer glycosidation is still the method of choice for
forming simple glycosides because it can be carried out in a
single synthetic step and it requires no protecting group
manipulations. Many researchers have explored variations
on Fischer’s initial conditions, but in general, the limitations
of the reaction, including the formation of mainly the
thermodynamic pyranoside products and the strong acid
catalysis required, have not been circumvented.4 Other
excellent examples of efficient protecting group free glyco-
sylations have been reported, but in most cases, the synthesis
of the glycosyl donors for these reactions has required
protecting group chemistry.5
The use of N′-glycosyltoluenesulfonohydrazides (GSHs) as
glycosyl donors offers numerous advantages: they do not require
protecting group chemistry for their synthesis, require only a
modest excess of alcohol for glycosidation, and can be activated
by readily available reagents. Furthermore, the conditions for
glycosyl donor formation and glycosidation are suitably mild
that they can be carried out with oligosaccharides. Protected
derivatives of GSHs have been investigated by Vasella et al.
as precursors of lactone hydrazones.6 But, GSHs have not
previously been investigated as glycosyl donors.
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E. M.; Murugesan, S.; Linhardt, R. J. Carbohydr. Res. 2007, 342, 614–
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374–406. (b) Galonic, D. P.; Gin, D. Y. Nature 2007, 446, 1000–1007. (c)
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10.1021/ol801232f CCC: $40.75
Published on Web 07/11/2008
2008 American Chemical Society

In this report we focus on N′-(2-acetamido-2-deoxy-ꢀ-D-
glucopyranosyl)-p-toluenesulfonohydrazide donors, as reducing
terminal N-acetylglucosamine (GlcNAc) residues are found in
a wide variety of biologically important oligosaccharides. The
acetamido group at C-2 of GlcNAc is also known to aid in
stereochemical control of glycosidation reactions.7
The condensation reactions between aldoses and sulfo-
nylhydrazides have been used extensively for the character-
ization and labeling of mono and oligosaccharides.8 The
crystal structures of a series of N′-glycosyl-p-toluensulfono-
hydrazides have been reported.9
Using 1H NMR, the equilibrium constant for the conden-
sation of N-acetylglucosamine and p-toluenesulfonylhy-
drazide to form the N′-glycosyl-p-toluenesulfonohydrazide
(1) in aqueous solution was determined to be approximately
30 M-1; thus, concentrated conditions or excess hydrazide
is required to drive the reaction to completion.10 Under
nonaqueous conditions, the reaction proceeds to completion
in the presence of only a small excess of the desired
hydrazide with mild acid catalysis (Scheme 1). Monosac-
The oxidations of N′-alkylsulfonohydrazides have been
proposed to proceed through diazene intermediates.11,12 Acyl
hydrazides have been used extensively in peptide chemistry
as convenient precursors to carboxylic acids, thioesters,
amides, and esters via their oxidization to form acyl
diazenes.13 Following a similar reaction mechanism, oxida-
tion of the glycosyl donors (1-3) with NBS would lead to
a glycosyl diazene (Scheme 2). Elimination of sulfinic acid
Scheme 2. Proposed Mechanism of
N′-Glycosylsulfonohydrazide Activation
Scheme 1. Formation of Glycosyl Donors
and nitrogen gas would then give the oxocarbenium ion. The
evolution of gas is clearly evident during these glycosidation
reactions. The oxocarbenium ion is then trapped by the
incoming alcohol wherein the stereochemistry of the attack
is biased by the neighboring acetamido group. The sulfinic
acid generated in the reaction undergoes further oxidation
in situ to generate the sulfonyl halide, and thus, it is necessary
to use 2 equiv of oxidizing agent to achieve complete
glycosidation. Mass spectral analysis of crude reaction
mixtures gave masses consistent with the formation of methyl
toluenesulfonate likely resulting from methanol attack on the
sulfonyl halide.
Previously, Vasella et al. have shown that it is possible to
form lactone hydrazones from protected N′-glycosyl-p-
toluenesulfonohydrazides under similar oxidation conditions
to those used here. The tautomerization of the unprotected
diazene to form the lactone hydrazone was only observed
with donor 1 when the oxidation was carried out at low
temperatures in the presence of a moderately strong base
(e.g., DBU, DIPEA).6
Activation of the glycosyl donors (1-3) in the presence
of a moderate excess (20 equiv) of the desired alcohol leads
to good yields of the ꢀ-D-O-glycopyranosides (4-15) (Table
1). Small amounts of the R-glycosides are also formed,
despite the neighboring acetamido group. The R-glycoside
charide donor 1 was synthesized on a multigram scale in a
suspension of DMF with a small excess of hydrazide (1.2
equiv) and a catalytic amount of acetic acid. The product
could be easily isolated via precipitation with diethyl ether.
The disaccharide donors 2 and 3 were formed on a milligram
scale and could be readily purified with reversed-phase
chromatography. Under these conditions only the cyclic ꢀ-D-
pyranosyl donors were observed and the acyclic hydrazones
were not present in quantities sufficient to be observed by
NMR spectroscopy. The donors (1-3) are stable under
ambient conditions and undergo slow hydrolysis when
dissolved in a neutral aqueous solution.
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(10) See the Supporting Information.
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Org. Lett., Vol. 10, No. 16, 2008

Table 1. Glycosidation Yields and Selectivitiesa
Scheme 3. Formation of Glycosyl Azide via Oxazoline
reducing terminal oxazolines for use as substrates for
endoglucosaminidases to allow the preparation of homoge-
neous N-linked glycoproteins.17
The unprotected oxazolines are also considerably more
reactive glycosyl donors than their protected counterparts.15
Acetyl-protected oxazolines generally require a strong lewis
acid catalyst (i.e., TMSOTf) for glycoside formation, and
thus, they are not used extensively in glycoside synthesis.18
In contrast, the unprotected oxazoline 15, formed in situ,
can be glycosidated with azide, with only lutidinium
hydrochloride present as an acid catalyst, to give 16 in 73%
yield. It was not possible to form the glycosyl azide directly
in the glycosylation reaction as NaN3, TBAN3, and TMSN3
were incompatible with the conditions necessary for activa-
tion of the glycosyl donors. Thus, this method may provide
a useful route to generate glycosyl azides from isolated
oligosaccharides for the formation of novel N-linked glyco-
conjugates.19,20
a Reaction conditions: (a) NBS (2.4 equiv), alcohol (20 equiv), in DMF
at rt; (b) NIS (2.4 equiv), alcohol (20 equiv), in DMF at rt.
is likely the result of participation by the solvent resulting
in an alternative ion pair.14 Other products produced in the
reaction included the free hemiacetal, resulting from hy-
drolysis, and trace amounts of the glycosyl sulfone, resulting
from the reaction of the oxocarbenium ion with the generated
sulfinic acid. Higher yields of the allyl glycoside (7) were
obtained using NIS (20% vs 75%), presumably due to
competing electrophilic addition to the alkene. The desired
glycosides could be readily purified using flash chromatog-
raphy on silica gel.
In conclusion, GSH glycosyl donors can be formed in high
yield under mild conditions and can be readily activated to form
a wide range of glycosides without the use of protecting groups.
The simplicity of the approach suggests it can be extended to
large oligosaccharides isolated from natural sources or those
generated by chemoenzymatic synthesis. We are currently
exploring the use of this reaction with glycosyl donors other
than those based on N-acetylglucosamine.
When this approach is compared to the facile formation
of ꢀ-D-2-acetamido-2-deoxyglucopyranosides recently in-
troduced by Cai et al., the current approach gives similar
yields but requires a smaller excess of the alcohols.15
Furthermore, disaccharide donors (2, 3) can be glycosidated
with efficiency equal to that of the monosaccharides as was
observed with glycosides 11-14.
Although the formation of oxazolines was not observed
in the glycosidation reactions, oxazolines could be formed
under the conditions shown in Scheme 3. It was essential to
have the chloride anion present in the reaction for clean
conversion of glycosyl donor 1 to the oxazoline 15. The
requirement for chloride ions suggests the reaction may
proceed through an intermediary glycosyl chloride. 1H NMR
spectroscopy shows the transient formation of a low-field
absorption at 6.3 ppm (Figure 2S, Supporting Information),
consistent with the generation of an R-glycopyranosyl
chloride. Halide exchange is rapid under these conditions,
and the ꢀ-glycosyl chloride would then proceed to the
oxazoline (Figure 1S, Supporting Information).16 This ox-
azoline synthesis may provide a useful route to generate
Acknowledgment. Funding from the Natural Science &
Engineering Research Council of Canada is gratefully acknowl-
edged.
Supporting Information Available: Figures 1S and 2S,
experimental procedures, and 1H and 13C NMR spectra.This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL801232F
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