Sialic acid donors

no neighbouring substituent is present at C-3 to assist with the formation of the alternative thermodynamically more stable (3-glycoside. A wide spectrum of exquisite devices is available for the chemical synthesis of a-sialosides, and these utilize a variety of sialic acid donors. However, no single sialic acid donor is available that is applicable to every synthetic strategy. 

In this chapter, the chemistry of sialic acid is briefly reviewed and some advantages and problems of strategies described for the construction of the a-ketosidic linkage of sialic acid and complicated sialosides are presented. Experimental details are also provided to allow practical preparation of the chosen targets. 

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Scheme 20 Various Sialic Acid Donors for the Synthesis of Sialylated Building Blocks...

Despite the development of the exquisite methods for a-(2-8)-linked disialic acid synthesis discussed above, the assembly of the a-(2-8)-linked oligomer has been far from a success. Recently, Tanaka disclosed the unpredictable difficulty of the oligomer synthesis. As mentioned above, the coupling of A-Troc-protected sialic acid donor and acceptor successfully delivered the dimer of sialic acid. However, the A-Troc donor 163 was hardly incorporated into the A-Troc disialyl acceptor 164 the glycosylation produced the stereo mixture of trisial-ic acid 165 in 6% yield (O Scheme 45) [114]. 

In contrast to other monosaccharides, activated sialic acid donors are biosynthesized from A -acetylmannosamine (ManNAc) or directly from sialic acids (Sia), including A-acetylneuraminic acid (NeuAc), via a more complex pathway (21). ManNAc is phosphorylated at the at the 6-hydroxyl group and condensed with phosphoenolpyruvate to give A -acetylneuraminic acid-9-phosphate (NeuAc-9-P). Phosphate ester hydrolysis is followed by direct condensation with CTP to give CMP-NeuAc (Figure 3). Sialic acids can intercept this pathway directly via enzymatic reaction with CTP. 

Curiously, this chemical modification of Gonococci living in the host is possible by a sialyltransferase expressed by the bacterium itself and the sialic acid donor substrate, CMP-Neu5Ac, produced by the host. The properties of the sialyltransferase extracted from the bacteria have been reported [974]. It would be very interesting to compare the primary structure of this enzyme with those of host sialyltransferases. This mechanism is different from that used by trypanosomes for sialylation, although in both cases sialic acids are acquired from the host. 

Efficient, stereoselective sialylations are still a cumbersome challenge for synthetic carbohydrate chemists due to the lack of neighboring group participation of the sialic acid [29]. Transferase-catalyzed sialylations therefore offer a welcome synthetic alternative. To date, eight different sialic acid linkage types have been identified. Out of the more than a dozen different sialyltransferases - SiaT - that have been found and cloned [99] a rat liver a(2-6)SiaT (E.C.2.4.99.1) and porcine a(2-3)SiaT (E.C.2.4.99.4) are commercially available. The synthesis of the natural CMP-sialic acid donor and that of various derivatives have been described [39, 48, 100, 101]. The capability for transfer of donor analogs by a(2-6)SiaT and rat liver a(2-3)SiaT (E.C.2.4.99.6) has recently been compiled [28,48]. 

Sialic acid donors that have been reported to date can be classified into two major types based on the mode of chemical modification. These have been termed standard type and appended type donors (Figure 9.2). All of the donors have a suitable leaving group such as bromide, chloride, alkyl- or arylthio group (SMe, SEt, SPh, etc.) or phosphite group [OP(OEt)2 and OP(OBn)2] at the anomeric C-2 carbon. In the appended type donors an assisting nucleophilic functionality (auxiliary) is mounted at C-3 or C-1 to restrain the nucleophile from attacking the (3-face. In contrast, the standard type donors maintain the 3-deoxy structure. 

Notes and discussion. This protocol is applicable for the preparation of the title compound, which is a universal precursor to various types of sialic acid donors. Preparation of the acetyl derivatives can be performed on a large scale ( 100 g of sialic acid) in the laboratory. Usually the resulting acetate is subjected to the next reaction after only an aqueous work-up. Although this procedure gives a mixture of a- and (3-isomers in the ratio of 1 to 8, acetylation of the starting material with acetic anhydride-pyridine followed by esterification with diazomethane gives the P-acetate in 94%, which can be converted into the a-acetate via a two step-manipulation [9]. 

Full details have appeared on the use of 0-protected glycosyl phosphites for Lewis acid-catalysed glycosidation (cf. Synlett, 1993, 115). Again anomeric mixtures were produced, but reasonable yields resulted - especially when O-benzyl protection was employed with glucosyl, galactosyl and mannosyl donors and with 0-acetylated sialic acid donor. 

Fig. 22.3. Metabolism of free N-acetylneuraminic acid (= sialic acid) UDP-acetylglucos-amine 2-epimerase is inhibited by the activated sialic acid donor, CMP-N-acetylneur-aminic acid, which also provides N-acetylneuraminic acid for glycoconjugate synthesis. In sialuria (22.6) loss of feedback inhibition leads to overproduction of sialic acid. In sialic acid storage disorders (22.5.1 and 22.5.2) N-acetylneuraminic acid accumulates in the lysosomes due to a defect of a specific transporter (sialin)...

Table 1 Review of sialic acid donors with different leaving groups and C5 modifications...

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