Glycosylations auxiliaries

Scheme 5 Stereoselective 1,2-cis-glycosylations with chiral auxiliaries at C-2 of glycopyranosyl donors.

Chiacchio et al. (43,44) investigated the synthesis of isoxazolidinylthymines by the use of various C-functionalized chiral nitrones in order to enforce enantioselec-tion in their cycloaddition reactions with vinyl acetate (Scheme 1.3). They found, as in the work of Merino et al. (40), that asymmetric induction is at best partial with dipoles whose chiral auxiliary does not maintain a fixed geometry and so cannot completely direct the addition to the nitrone. After poor results with menthol ester-and methyl lactate-based nitrones, they were able to prepare and separate isoxazo-lidine 8a and its diastereomer 8b in near quantitative yield using the A-glycosyl... 

Y. Itoh and T. Ogawa, Highly stereoselective glycosylation of W-acetylneuraminic acid aided by a phenylthio substituent as a stereocontrolling auxiliary. Tetrahedron Lett. 29 3981 (1988). 

In order to have a milder cleavage of the chiral auxiliary, various other glycosyl-amines have been introduced, such as 2-acetamido-3,4,6-tri-0-acetyl-l-amino-2-deoxy-/i-D-glucopyranose 30 [38], 2,3,4,6-tetra-0-alkyl-/i-D-glucopyranosylamines 31 [39] and l-amino-5-desoxy-5-thio-2,3,4-tri-0-isobutanoyl-/ -D-xylopyranose 32 [40] (Scheme 1.14). 

H. Kunz Stereoselective syntheses using carbohydrates as chiral auxiliaries G. W. Hart Ubiquitous and temporal glycosylation of nuclear and cytoplasmic proteins... 

New strategies for preparing either 1,2-cis- or 1,2-trans-glycosides stereoselectively have been reported.61 A chiral auxiliary containing a nucleophile is used to control the anomeric selectivity of the glycosylation. A sample reaction is shown in Scheme 8. 

A novel strategy for stereoselective glycosylations has been reported in which a chiral auxiliary at the 2-position of a glycosyl donor is used (Scheme 126).189 Upon formation of an oxonium ion, participation of the nucleophilic moiety of the auxiliary is (g) selective and depedent on the chirality. 

SCHEME 3.2 Stereoselective glycosylation by using chiral auxiliaries. 

SPOS also benefited from other technical improvements such as the on-resin analytical methods [112], the capture-release purification technique [113], and hydrophobically assisted switching phase [114], Recently, chiral auxiliary-mediated 1,2-n.v-glycosylations were introduced to SPOS, allowing for the efficient and stereoselective assembly of oligosaccharides [115] (see Chapter 7). 

In many cases, the substrate to be subjected to asymmetric conversion is coupled to the carbohydrate via the anomeric position. For the synthesis of amino compounds, the substrate is linked to the carbohydrate as a derivative of a glycosyl-amine. After completion of the asymmetric synthesis the product can be detached from the carbohydrate auxiliary by acidic hydrolysis. In most cases auxiliary and product can be separated by extraction or recrystallization techniques, and the carbohydrate auxiliary readily regenerated from its recovered detachment derivative. 

An alternative stereoselective synthesis of chiral heterocycles based on carbohydrate-induced stereodifferentiation includes nucleophilic addition reactions on heterocyclic systems already bound to the carbohydrate auxiliary. An example of this strategy has been shown by stereoselective addition of Grignard reagents to carbohydrate-linked 4-pyridones [61]. For this purpose, trimethylsiloxypyridine was glycosylated regioselectively using pivaloyl-protected glycosyl fluorides. 

Carbohydrate-derived auxiliaries exhibit an efficient stereoselective potential in a number of nucleophilic addition reactions on prochiral imines. a-Amino acids, P amino acids and their derivatives can be synthesized in few synthetic steps, and with high enantiomeric purity. A variety of chiral heterocycles can readily be obtained from glycosyl imines by stereoselective transformations, providing evidence that carbohydrates have now been established as useful auxiliaries in stereoselective syntheses of various interesting classes of chiral compounds. 

Chemical synthesis of sialosides is considered one of the most difficult glycosylation reactions because of a hindered tertiary anomeric carbon and the lack of a participating auxiliary functionality in the carbon next to the anomeric carbon in sialic acids (55, 56). Sialyltransferase-catalyzed glycosylation is believed to be the most efficient approach for the production of sialic acid-containing structures. 

A glycosyl chiral auxiliary can be easily removed from cycloadducts of A -glycosylnitrones such as 330 by acidic treatment or with hydroxylamine, to afford N-unsubstituted isoxazolidines <2003EJ04152, 2004T9997>. 

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