A new C(1)-auxiliary for anomeric stereocontrol in the synthesis of alpha-sialyl glycosides.

Article abstract of DOI:10.1021/ol015854i

The installation of the novel N,N-dimethylglycolamide ester auxiliary onto the C(1)-position of protected neuraminic acid donors allows for the exploitation of C(1)-neighboring group participation to generate sialoside conjugates with good to excellent al

Full text of DOI:10.1021/ol015854i

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1665-1668
A New C(1)-Auxiliary for Anomeric
Stereocontrol in the Synthesis of
r-Sialyl Glycosides
Jannine M. Haberman and David Y. Gin*
Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
gin@scs.uiuc.edu
Received March 15, 2001
ABSTRACT
The installation of the novel N,N-dimethylglycolamide ester auxiliary onto the C(1)-position of protected neuraminic acid donors allows for the
exploitation of C(1)-neighboring group participation to generate sialoside conjugates with good to excellent r-selectivity under a variety of
sialylation protocols, including those that would otherwise lead to nonselective or â-selective sialoside products.
Oligosaccharides and glycoconjugates incorporating sialic
acid residues play important roles in a host of biological
processes, including, inter alia, immune response, cell
proliferation, cell differentiation, and oncogenesis.1 However,
complex mammalian sialosides are typically isolated in
exceedingly small quantities from natural sources; as a result,
chemical2 or enzymatic3 syntheses have been instrumental
in providing access to complex sialyl conjugates for use as
biochemical probes and/or potential therapeutic agents. Most
of the methods to synthesize sialic acid-containing oligo-
saccharides involve the use of glycosidic coupling strategies
in which a C(2)-ketal bond is constructed in a coupling event
(Scheme 1). Several glycosylation methods have been
Scheme 1
(1) (a) Dwek, R. A. Chem. ReV. 1996, 96, 683-720. (b) Lis, H.; Sharon,
N. Chem. ReV. 1998, 98, 637-674. (c) Mammen, M.; Choi, S.-K.;
Whitesides, G. M. Angew. Chem., Int. Ed. 1998, 37, 2754-2794. (d)
Simanek, E. E.; McGarvey, G. J.; Jablonowski, J. A.; Wong, C.-H. Chem.
ReV. 1998, 98, 833-862. (e) Ørntoft, T. F.; Vestergaard, E. M. Electro-
phoresis 1999, 20, 362-371.
employed for the synthesis of sialosides employing sialyl
donors 1 with specific anomeric latent leaving groups.2 In
this context, variable degrees of R/â selectivities are achieved
and these selectivities are highly dependent on the nature of
the substrates and reaction conditions. However, naturally
occurring sialosides incorporate an R-C(2)-stereochemistry
(equatorial), which is unfortunately not the thermodynami-
cally favored epimer as a consequence of the anomeric effect.
Thus, a critical and ongoing challenge in glycosylation
employing sialyl donors is control over anomeric stereo-
chemistry to generate R-linked sialyl conjugates with good
anomeric selectivity.
(2) (a) Okamoto, K.; Goto, T. Tetrahedron 1990, 46, 5835-5857. (b)
DeNinno, M. P. Synthesis 1991, 583-593. (c) Boons, G.-J.; Demchenko,
A. V. Chem. ReV. 2000, 100, 4539-4565.
(3) (a) Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C.-H. Chem. ReV.
1996, 96, 443-473. (b) Lio, R. C.; Thiem, J. Carbohydr. Res. 1999, 317,
180-190. (c) Palcic, M. M. Curr. Opin. Biotech. 1999, 10, 616-624. (d)
Nishimura, S.-I.; Matsuda, M.; Kitamura, H.; Nishimura, T. Chem. Commun.
1999, 1435-1436. (e) Mehta, S.; Gilbert, M.; Wakarchuk, W. W.; Whitfield,
D. M. Org. Lett. 2000, 2, 751-753. (f) Miyazaki, T.; Sato, H.; Sakakibara,
T.; Kajihara, Y. J. Am. Chem. Soc. 2000, 122, 5678-5694. (g) Koeller, K.
M.; Smith, M. E. B.; Huang, R.-F.; Wong, C.-H. J. Am. Chem. Soc. 2000,
122, 4241-4242.
10.1021/ol015854i CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/02/2001

Increased R-selectivity has been achieved in several
instances where sialosyl couplings have been performed in
acetonitrile solvent, capitalizing on the generation of a
putative sialyl â-nitrilium species as a reactive intermediate.4
High4c,5 to moderate6 R-selectivities have been achieved,
although yields are variable depending on the nature of the
sialyl activating reagents and their compatibility with nitrile
solvents. Neighboring group participation has also been
extensively investigated as a means of influencing anomeric
selectivity in the sialylation process. Traditionally, C(3)-
neighboring group effects have been employed to control
anomeric selectivity in sialosyl couplings; yet, this is not
possible without elaborate derivatization of the sialyl donor.
For example, protected neuraminic acid glycals (derived from
protection and C(2)-C(3) elimination of neuraminic acid)7
are typically oxidized to introduce a heteroatom substituent
at the C(3) position (i.e., halogen,8 sulfide,7,9-13 selenide,9
or oxygen substituents12,14). The resulting donor is then
employed in the sialylation of the glycosyl acceptor followed
by reductive removal of the C(3)-auxiliary to afford the
desired fully protected sialyl conjugate. Although good
R-selectivities can be obtained in many cases, the protracted
multistep protocol in this approach severely detracts from
the overall efficiency and broad utility of this strategy.
While the bulk of the advances to address this crucial
problem of R-selective sialylation have involved multistep
C(3)-derivatization, reports on the use of auxiliary function-
alities at the C(1)-carboxylic acid position have been
limited.15 We report herein a new C(1)-auxiliary for neigh-
boring group participation in glycosidic couplings with sialyl
donors for the preparation of R-sialyl conjugates. In this
context, a C(1)-N,N-dimethylglycolamide auxiliary (-OCH2-
CONMe2) (i.e., 3, Scheme 2) was employed because of its
structural simplicity and its likelihood to participate favorably
in the coupling event to enhance R-selectivity. It was
anticipated that when a C(1)-derivatized sialyl donor such
Scheme 2
as 3 (Scheme 2) is activated under various glycosylation
conditions, the resulting C(2)-oxocarbenium intermediate can
be stabilized by the neighboring N,N-dimethylglycolamide
carbonyl group from either an axial (â) orientation (i.e., 4)
or from an equatorial (R) orientation (i.e., 5). Of these two
putative reactive intermediates, 4 is likely to predominate
due to the anomeric effect. More importantly, however, 4 is
also likely to be more reactive toward the acceptor (Nu-H)
since approach of Nu-H from the â-face (i.e., 5) would be
sterically disfavored relative to nucleophilic attack on the
R-face (i.e., 4), resulting in the preferred formation of the
desired R-sialoside 6R.
This hypothesis was verified by performing a series of
comparative sialylations with 4,7,8,9-tetra-O-acetylneuramin-
ic acid donors incorporating either the traditional methyl ester
protective group at C(1) (7, Figure 1) or the N,N-dimethyl-
glycolamide auxiliary at C(1) (8). The sialyl acceptors
include simple alkyl alcohols such as cyclohexanol (9) and
cholesterol (10), as well as carbohydrate-derived nucleophiles
such as methyl 2,3,4-tetra-O-benzyl-R-D-glucopyranoside
(11) and the diol acceptor methyl 2,6-di-O-benzyl-R-D-
galactopyranose (12), a carbohydrate acceptor relevant to
many naturally occurring gangliosides.
(4) For the nitrile effect in O-glycosylation reactions, see: (a) Schmidt,
R. R.; Ru¨cker, E. Tetrahedron Lett. 1980, 21, 1421-1424. (b) Schmidt, R.
R.; Behrendt, M.; Toepfer, A. Synlett 1990, 694. For examples of the nitrile
effect in sialylation, see: (c) Hasegawa, A.; Ohki, H.; Nagahama, T.; Ishida,
H.; Kiso, M. Carbohydr. Res. 1991, 212, 277-281. (d) Birberg, W.; Lo¨nn,
H. Tetrahedron Lett. 1991, 32, 7457-7458. See also ref 2c.
(5) Murase, T.; Ishida, H.; Kiso, M.; Hasegawa, A. Carbohydr. Res. 1988,
184, C1-C4.
(6) Kanie, O.; Kiso, M.; Hasegawa, A. J. Carbohydr. Chem. 1988, 7,
501-506.
(7) Erce´govec, T.; Magnusson, G. J. Org. Chem. 1995, 60, 3378-3384,
and references therein.
(8) Okamoto, K.; Kondo, T.; Goto, T. Tetrahedron 1987, 43, 5909-
5918.
(9) Ito, Y.; Ogawa, T. Tetrahedron 1990, 46, 89-102.
(10) Martichonok, V.; Whitesides, G. M. J. Am. Chem. Soc. 1996, 118,
8187-8191.
Three distinct methods for sialylation were employed to
assess the generality of this neighboring group participation
strategy. These include the use of sialyl chlorides, sulfides,
and phosphites.2,16 The resultant yields and anomeric selec-
(11) Erce´govec, T.; Magnusson, G. J. Org. Chem. 1996, 61, 179-184.
(12) Castro-Palomino, J. C.; Tsvetkov, Y. E.; Schmidt, R. R. J. Am.
Chem. Soc. 1998, 120, 5434-5440.
(13) Hossain, N.; Magnusson, G. Tetrahedron Lett. 1999, 40, 2217-
2220.
(14) Okamoto, K.; Kondo, T.; Goto, T. Tetrahedron 1987, 43, 5919-
(16) The sialyl donors 7 and 8 were prepared according to established
protocols that proceed under thermodynamic control to provide selectivity
for the â-anomers (see ref 2). The preparation of the chloride and diethyl
phosphite donors of 7 afforded exclusively the â-anomers, while the
preparation of the ethyl thioglycoside of 7 afforded a 6:1 mixture of â:R-
anomers. The preparation of the corresponding donors of 8 all led to the
formation of a single anomer whose spectral data are consistent with the
C(2) â-configuration (see ref 2a and Supporting Information).
5928.
(15) For the use of alkylthioalkyl ester auxiliaries, see: (a) Takahashi,
T.; Tsukamoto, H.; Yamada, H. Tetrahedron Lett. 1997, 38, 8223-8226.
For the use of a 2-furanyl substituent as a masked C(1)-carboxylate
functionality in glycosylations with C(5)-epi-sialic acid donors, see: (b)
Danishefsky, S. J.; DeNinno, M. P.; Chen, S. J. Am. Chem. Soc. 1988,
110, 3929-3940.
1666
Org. Lett., Vol. 3, No. 11, 2001

Table 1. Glycosidic Couplings
Figure 1. Carbohydrate coupling partners.
tivities of the sialylation reactions are summarized in Table
1. To assess the true extent of the influence of the new C(1)-
auxiliary, the comparative glycosylation reactions were
performed in the absence of acetonitrile to avoid possible
perturbations in R-selectivity due to nitrile solvent effects.
In these reactions, it is clear that the C(1)-N,N-dimethyl-
glycolamide auxiliary (XA) exerts a dramatic effect in
favoring R-sialylation of nucleophilic acceptors under various
glycosylation reaction conditions. For example, the coupling
of cyclohexanol (9) with the sialyl chloride donor 7
incorporating the C(1)-methyl ester proceeded with good
R-selectivity (entry 1, 13; 5:1, R:â); yet, the incorporation
of the C(1) auxiliary XA on the sialyl donor (8) in the
identical coupling protocol provided a significant enhance-
ment in R-selectivity of the product sialoside (entry 1, 14;
10:1, R:â).
More dramatic illustrations of the favorable stereochemical
influence of XA arise in the sialylation examples where no
anomeric selectivity is obtained when a methyl ester
functionality resides at C(1) of the donor (entries 3, 4, 6,
and 7; sialosides 15, 17, 17, and 19, respectively). However,
with the C(1)-XA auxiliary present in the donor, high
R-selectivities are achieved (entries 3, 4, 6, and 7; sialosides
16, 18, 18, and 20, respectively). Finally, striking examples
of the positive influence of the C(1)-XA auxiliary were also
exhibited in entries 2, 5, 8, and 9, wherein the anomeric
selectivities of the coupling reactions are reversed from being
selective for the â-anomer in the absence of the C(1)-
auxiliary to being selective for the R-anomer when XA is
incorporated in the sialyl donor. It is worth noting that the
sialosyl coupling reactions with the C(1)-XA derived sialosyl
donors (8) proceeded with comparable if not better efficien-
cies (i.e., entry 7) when compared to their C(1)-methyl ester-
derived counterparts (7).17
a Reagents: A ) AgOTf (1.4 equiv), PhCH3, -20 °C; B ) NIS (3 equiv),
TfOH (cat.), CH2Cl2, -50 °C; C ) TMSOTf (cat.), -40 °C, CH2Cl2. b XA
) OCH2CONMe2. c A 6:1 â:R anomeric mixture of the ethyl thioglycoside
of 7 was employed.
The utility of this C(1) participatory strategy relies also
on the efficiency with which the auxiliary can be installed
onto the sialyl donor and subsequently removed to liberate
the free C(1)-carboxylic acid after the coupling event.
Introduction of the N,N-dimethylglycolamide auxiliary onto
penta-O-acetylneuraminic acid (22) is easily accomplished
via a convenient protocol (Scheme 3). 2-Methanesulfonyl-
oxy-N,N-dimethylacetamide (24), derived from the treatment
of readily available 2-hydroxy-N,N-dimethylacetamide with
(17) For the low-yield preparation of 19 in entry 7, the corresponding
C(2)-C(3) sialic acid glycal was also isolated with 22% recovery. In all of
the other sialosyl coupling reactions, the formation of the byproduct
corresponding to C(2)-C(3) elimination of the donor was minimal (0-
10%). It is likely that the participatory nature of the C(1)-XA auxiliary also
helps to minimize the C(3) elimination pathway by providing added
stabilization to the putative sialosyl C(2)-oxocarbenium intermediate.
Org. Lett., Vol. 3, No. 11, 2001
1667

all of the neuraminic acid protective groups are cleanly
removed, and the corresponding sialyl conjugate 25 is
isolated in quantitative yield following LH-20 Sephadex
chromatography.18
Scheme 3a
A new auxiliary for neighboring group participation in
sialic acid couplings has been established via the installation
of the N,N-dimethylacetamide ester auxiliary (XA) onto the
C(1)-position of protected neuraminic acids. This allows for
the exploitation of C(1)-neighboring group participation to
generate sialoside conjugates with good to excellent R-se-
lectivity under a variety of sialylation protocols, including
those that would otherwise lead to nonselective or â-selective
sialoside products in the absence of the new C(1)-XA
auxiliary. Moreover, since the auxiliary XA also functions
as a convenient and inexpensive C(1)-protective group, this
approach obviates the need for multistep derivatizations that
are required for the traditional C(3)-neighboring group
participation strategies. Efforts are currently underway to
explore the use of these and other C(1)-auxiliary motifs and
apply them to the synthesis of bioactive gangliosides.
a Reagents and conditions: (a) Ac2O, pyridine, 88%; (b)
MeSO3CH2CONMe2 (24), Cs2CO3, DMF, 88%.
methanesulfonyl chloride (Et3N, CH2Cl2, 23 °C, 88%), is
reacted with the cesium carboxylate of 22 to afford the XA-
derived neuraminic acid 23 in 88% yield. Conversion of 23
to the appropriate sialyl donors 8 can then be accomplished
by well-established methods.2 Following the coupling event,
removal of the auxiliary XA is equally simple and efficient
(Scheme 4), requiring hydrolysis conditions that are typically
Acknowledgment. This research was supported by the
National Institutes of Health (GM-58833), the Arnold and
Mabel Beckman Foundation (BYI), Glaxo Wellcome Inc.,
and the Alfred P. Sloan Foundation.
Scheme 4
Supporting Information Available: Experimental details
and spectral/analytical data for the glycoside products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL015854I
(18) The structures of the sialosides 13-20 were verified by base
hydrolysis of all ester functionalities within the product sialyl conjugates
and comparison of the products with literature structural data. For 13-14,
see ref 6. For 15-18, see ref 8. For 19 and 20, see: Thiem, J.; Sauerbrei,
B. Angew. Chem. 1991, 103, 1521-1523.
used for saponification of C(1)-methyl ester-derived neuramin-
ic acids. For example, when the sialosyl conjugate 18 is
treated with a mixture of 1 N NaOH(aq) and MeOH (2:1 v/v),
1668
Org. Lett., Vol. 3, No. 11, 2001