C-5 Modifications in N-acetyl-neuraminic acid: scope and limitations

doi:10.1016/j.carres.2008.04.007

Carbohydrate Research

Volume 343, Issues 10–11, 21 July 2008, Pages 1540-1552

https://doi.org/10.1016/j.carres.2008.04.007 Get rights and content

Abstract

Glycoconjugates containing sialic acid are involved in a large variety of biological phenomena, including cell–cell adhesion, recognition by viruses and bacteria, and oncogenesis. Therefore, they are important synthetic targets for the design of drugs and vaccines. In the last decades, different methodologies that improve yield and stereoselectivity in sialylation reactions have been investigated. This review summarizes the latest developments in the synthesis of C-5 modified sialic acid glycosyl donors and glycosyl acceptors and their application in the synthesis of α-sialosides.

Graphical abstract

Introduction

Glycoconjugates containing sialic acid are important synthetic targets due to their active participation in a wide variety of biological phenomena, ranging from cell–cell adhesion and recognition, to pathogen attack and oncogenesis.1, 2, 3, 4 The most widespread sialic acid is N-acetyl-neuraminic acid (Neu5Ac, Fig. 1), which is naturally found α-(2→3) or α-(2→6)-linked to galactose and α-(2→6)-linked to N-acetyl-galactosamine (e.g., α-Neu5Ac-(2→3)-Gal, α-Neu5Ac-(2→6)-Gal, and α-Neu5Ac-(2→6)-GalNAc). The disialosyl structures α-Neu5Ac-(2→8)-Neu5Ac and α-Neu5Ac-(2→9)-Neu5Ac have also been found as constituents of glycoproteins and glycolipids (Fig. 1).²

The stereoselective synthesis of α-sialosides in high yield is extremely challenging mainly due to the destabilizing presence of the C-1 carboxylic group and to the lack of a hydroxyl group at C-3. Thus, upon the departure of the leaving group, the resulting carbocation is not assisted by a stereocontrolling neighboring group and therefore an anomeric mixture is often produced. In addition, competition with E1 elimination and nucleophilic attack of water (hydrolysis) are other factors that decrease the overall yield (Scheme 1). The synthesis of the disialosyl structure α-Neu5Ac-(2→8)-Neu5Ac linkages is further complicated by the low reactivity of the hydroxyl group at C-8 in the sialosyl acceptor, which has been related to its involvement in H-bonds (Fig. 2).5, 6, 7, 8

To improve the glycosylation outcome toward the desired α-anomer, different strategies have been proposed in the past decades, including varying the nature of the leaving group, solvent, and promoters. Structurally modified derivatives at C-1, C-3, and C-5 have been also investigated.9, 10, 11, 12, 13 This review summarizes the most recent developments in the C-5 modification strategies for the synthesis of α-sialosides, and discusses their advantages and disadvantages. A detailed description of the following C-5 structural modifications is provided: N-acetylacetamido (NAc₂), azido (N₃), N-trifluoroacetyl (NHTFA); N-trichloroethoxycarbonyl (NHTroc), 5-N,4-O-oxazolidinone and its N-acetylated version. The last part of the review is dedicated to very recent or less exploited developments: the use of 1,5-lactams, 5-N-t-butoxycarbonylacetamido (NAcBoc), phthalimido (NPhth) and 5-N,7-O-oxazinone groups.

Section snippets

Acetamido deprotection methods: an overview

The majority of the N-modifications investigated requires a complete deprotection of the natural acetamido group to yield a free amine. The removal of the 5-N acetyl group can be accomplished under basic (hydrazine14, 15 sodium¹⁶ or barium¹⁷ hydroxide) or acidic conditions (methanesulfonic acid).¹⁸ In general, both conditions offer high yields of the deprotected product (∼70–90%); however, deprotection in acidic media offers the advantage of maintaining the methyl ester functionality (if

N-Acetylacetamido (NAc₂)

The introduction of an additional acetyl group is undoubtedly the most straightforward and simple procedure of all investigated C-5 modifications, as neither N-acetylation nor N-deacetylation requires additional synthetic steps for protecting group manipulations. The additional acetyl group at the C-5 position can, in fact, be easily introduced directly from the fully deprotected Neu5Ac with concomitant O-acetylation (or from the N-monoacetylated donor 1). It is removed under Zémplen

Azido (N₃)

Conversion of the C-5 position of N-acetyl-neuraminic acid into an azido (N₃) group has been accomplished by enzymatic26, 27, 28, 29, 30 and chemical methods.31, 32, 33, 34 In general, enzymatic synthesis of 5-azido sialic acid can be accomplished by treatment of the 2-azido-2-deoxy mannose precursor in the presence of sodium pyruvate and N-acetyl-neuraminic acid aldolase. As example of chemical methods, it is possible to convert thiosialosyl donors 16a,b in azido-bearing donors 17a,b using

Trifluoroacetamido (NHTFA)

The introduction of a trifluoroacetyl group can be accomplished by complete deprotection in acidic conditions followed by selective N-acylation with methyl trifluoroacetate in the presence of triethylamine and O-acetylation.18, 40 Thus, conversion of sialosyl donor 1 into 5-trifluoroacetamido donor 28 was accomplished in three steps in 73% yield (Scheme 9).²² The removal of the TFA group can be performed under basic conditions in the presence of sodium hydroxide.²²

For the synthesis of an

Trichloroethoxycarbonyl (NHTroc)

The introduction of trichloroethoxycarbonyl group at C-5 has been described by Wu and co-workers⁴⁶ and Kiso and co-workers⁴⁷ via deprotection of the N-acetyl phenylthioglycoside derivative 46 under acidic conditions and selective N-protection using succinimidyl 2,2,2-trichloroethyl carbonate or trichloroethylchloroformate, respectively (Scheme 13). Conversion of N-Troc derivatives into the corresponding free amine can be easily accomplished in the presence of zinc in acetic acid.⁴⁷

The higher

5-N,4-O-oxazolidinone group and its N-acetylated version

Modification at C-5 of thiophenyl sialosyl donor 46 by introduction of a trans-fused oxazolidinone ring can be accomplished by deprotection in acidic medium followed by N-functionalization by treatment with p-nitrophenylchloroformate (NPCC), and then O-acetylation to afford glycosyl donor 57.⁵⁴ Additionally N-acetylation of 57 with acetyl chloride in diisopropylethylamine (DIPEA) leads to compound 58 in 94% yield (Scheme 16).⁵⁵ Removal of oxazolidinone in 57 can be performed in the presence of

Miscellaneous substituents

Modifications of the C-5 acetyl group into other conventional protecting groups, such as N-t-butyloxycarbonyl (Boc),¹⁷N-benzyloxycarbonyl (Cbz,Z),⁵⁸ phthalimido (NPhth),59, 60, 61 and N-t-butyloxycarbonylacetamido (NAcBoc)62, 63 as well as into less conventional polycyclic compounds, such as 1,5 lactam⁴⁴ (as sialosyl acceptor) and 5,7-N,O oxazinanone protected sialosyl donor⁶⁴ have been recently reported. For example, combination of NAcBoc modification and laurylthiol leaving group as in

Conclusions

Although it is clear that modifications at the C-5 position of N-acetyl-neuraminic acid influences reactivity and stereoselectivity in glycosylation reactions, each protecting group has to be selected based on the nature of the desired glycosidic bond, for example (2→3) and (2→6), as well as the nature of the glycosyl acceptor (e.g., protecting groups). In addition, the glycosylation yields and stereoselectivities have to compensate for the number of added steps required for the protection and

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ReviewC-5 Modifications in N-acetyl-neuraminic acid: scope and limitations

Abstract

Graphical abstract

Introduction

Section snippets

Acetamido deprotection methods: an overview

N-Acetylacetamido (NAc2)

Azido (N3)

Trifluoroacetamido (NHTFA)

Trichloroethoxycarbonyl (NHTroc)

5-N,4-O-oxazolidinone group and its N-acetylated version

Miscellaneous substituents

Conclusions

Int. Rev. Cytol.

Tetrahedron Lett.

Tetrahedron Lett.

Carbohydr. Res.

Tetrahedron Lett.

Carbohydr. Res.

Tetrahedron Lett.

Tetrahedron Lett.

Carbohydr. Res.

Carbohydr. Res.

Carbohydr. Res.

Carbohydr. Res.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron

Carbohydr. Res.

Carbohydr. Res.

Tetrahedron Lett.

Tetrahedron

Glycoconjugate J.

Biology of Sialic Acids

J. Am. Chem. Soc.

Pure Appl. Chem.

Chem. Rev.

Curr. Org. Synth.

ACS Symp. Ser.

Russ. J. Bioorg. Chem.

J. Carbohydr. Chem.

Chem. Eur. J.

Review
C-5 Modifications in N-acetyl-neuraminic acid: scope and limitations

N-Acetylacetamido (NAc₂)

Azido (N₃)