Sialyl donors

Another effective a-selective sialylation involves the use of a 5-N,4-0-carbonyl-protected sialyl donor, which could efficiently be used for the preparation of an a(2,8)-tetrasialoside. It was found that the 5-N,4-0-carbonyl protecting group improves the reactivity of the C-8 hydroxyl group of the sialyl acceptor [168]. 

Wong and coworkers showed that 5-azido sialyl donors protected with O-acetyl ester are useful for a-selective glycosylations of primary hydroxyls (Scheme 4.6e) [169]. It was proposed that the linear and electron-withdrawing nature of the C-5 azido moiety stabilizes the reactive axial acetonitrile adduct to allow the incoming nucleophile to approach the a-face in an SN2-like fashion. In addition, a chemose-lective glycosylation method has been developed for the synthesis of NeuAca-(2 —> 9) NeuAc as thioglycoside donor for use in the subsequent glycosylations [169]. 

Synthesis of Sialylated 2-Azido-2-deoxyglycosyl Amino Acids Using Sialyl Donors without C3 Participating Groups... 

Scheme 21 Synthesis of the 2,6-Sialyl TN-Antigen Building Block Using a Sialyl Donor without a C3 Participating Group[125l...

Almost all types of leaving groups have been explored in sialyl donors with, until recently, two notable exceptions the venerable imidates and the sulfoxides. While the preparation of stable, isolable sialyl trichloroacetimidates has still to be demonstrated, the recent innovation of the Biao Yu group—the (V-phenyltrifluoroacctimidatcs—has proven equal to the task and has provided access to new potent class of sialyl donors [27], Stable sulfoxides of sialyl thioglycosides have also been described recently and employed as glycosyl donors on activation with triflic anhydride (Tf20) [28], The S-benzoxazolyl (.S -Box) thiosialosides constitute another recent addition to the armory of sialyl donors [29, 30],... 

The most important advances in stereoselective sialylation in the last 15 years, beginning with the work of Geert-Jan Boons and Alexei Demchenko in 1998 [31], have centered around the discovery that modification of the N5 protecting group influences both the reactivity of sialyl donors and the stereoselectivity of their coupling reactions. In view of their importance to the field, the most important features of modifications of the N5 protecting groups are discussed in some detail here even if they have been reviewed previously [32, 33],... 

SCHEME 5.7 Use of a phthalimide-protected sialyl donor. All, allyl Phth, phthaloyl. 

Various other types of amine protection have been investigated as replacements for the native V-acetyl group in sialyl donors including Boc [54], allyloxycarbonyl [55], 9-fluorenylmethylcarbonyl [55], trichloroacetyl [55], and Cbz [55, 56] groups, but no particular advantages of these systems are apparent at present. 

Following a brief initial report by Carlo Unverzagt [57], 5-azido-based sialyl donors were prepared by various groups and their reactivity investigated [58-61],... 

FIGURE 5.4 RRVs of various sialyl donors relative to 4-tolyl peracetyl-a-D-thiomannopy-ranoside. 

OTHER CYCLIC AND BICYCLIC PROTECTING SYSTEMS FOR SIALYL DONORS... 

SCHEME 5.18 Use of a tricyclic sialyl donor and the influence of the acceptor protecting system on stereoselectivity. PMP, p-methoxyphenyl. 

Crich and coworkers used a mass spectral method to investigate the influence of the oxazolidinone ring and its. -acety I counterpart on the activation of sialyl donors [22], They found that a minimum cone voltage of 78 V is required to cause fragmentation of the glycosyl phosphate 76 under electrospray ionization conditions (Fig. 5.6). The comparable oxazolidinone phosphate (77) did not undergo mass spectral fragmentation... 

INFLUENCE OF HYDROXY PROTECTING GROUPS ON SIALYL DONOR REACTIVITY 147... 

The ability of the 4-0,5-iV-oxazolidinone group to limit glycal formation prompted Crich and coworkers to revisit the use of electrophilic sialyl donors for the formation of C-sialosides. Their effort resulted in the discovery that the /V-acetyloxazolidone-protected dibutylphosphates, on activation with TMSOTf at -78°C in the presence of... 

An efficient a-sialylation that took advantage of the highly reactive sialyl donors having C5 cyclic imides, especially phthalimide (NPhth), by virtue of the fixed-dipole moment effects, was also reported [42], For example, the use of the sialyl donor 4 and acceptor 6 at -78°C supplied the sialoside 7 as a only with 92% yield on 50 mg scale. The scale-up in batch process, however, significantly decreased the yield and stereoselectivity. This decrease in sialylation efficiency might be a result of... 

Efficient activation of the N-acetylated sialyl donor required l.Oequiv. of the Lewis acid under -78°C, giving the disaccharide 16 in 77% yield with excellent a selectivity (a/p=96/4, Table 8.2, entry 1). The conditions in entry 1 were reproducible under the microfluidic conditions (entry 2, 89% yield, a/p=94/6). Because the excess donor 15 inhibited the purification of sialoside 16 from the glycal by-product due to similar polarities on silica gel, the ratio between the donor and the acceptor... 

Linhardt employed Reformatsky-type additions to carbon electrophiles (see Chapter 5, Section 5.5) in a solid-phase synthesis of C-sialosides.43 Immobilised sialyl donor 9 was treated with Sml2 in the presence of ketone and aldehyde... 

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