Synthesis of homogalacturonan fragments

HG is one of the major pectic polysaccharides of the plant primary cell wall. It is a homopolymer of a-(1^4) linked D-galacturonic acids, containing as many as 200 galacturonic acid units and measuring up to 100 nm long (Fig. 3.5). Methyl and acetyl ester are distributed throughout HG and contribute significantly to its gelling behaviour and the ripening process of fruit and vegetables. Efforts to synthesize fragments of HG, and selectively methyl-esterified versions thereof, have provided access to a variety of fragments ranging from di- to dodecasaccharides (Table 3.1).

Figure 3.5 Structure of homogalacturonan (HG). Methyl esters, which can be randomly positioned along the polysaccharide chain, are not shown.

Figure 3.5 Structure of homogalacturonan (HG). Methyl esters, which can be randomly positioned along the polysaccharide chain, are not shown.

Figure 3.6 (A) The 'direct glycosylation with galacturonic acid derivatives' strategy. (B) The 'late stage oxidation of primary OH groups' strategy. P, P1 and P2 denote protecting groups for hydroxyl and carboxyl functional groups; LG is a leaving group at anomeric centres of glycosyl donors.

From a synthetic point of view, two quite different strategies have been employed to obtain oligouronic acids, as shown in Fig. 3.6 . In the - direct glycosylation with galacturonic acid derivatives' strategy, the first step is to perform a glycosylation reaction in which suitably protected derivatives of esters of galacturonic acid are coupled. Subsequent deprotection provides the oligogalacturonide. In contrast, the first step in the 'late stage oxidation of primary hydroxyl groups' strategy is the glycosylation reaction in which suitable protected galactopyranosides are coupled. The synthesis proceeds with deprotection and selective oxidation of the primary hydroxyl groups (in the presence of secondary hydroxyl groups) to the carboxylic acid oxidation level of the required oligogalacturonide. These strategies are general for synthesis of all glycouronides and their principles have been reviewed (van den Bos et al. 2007).

3.5.1 Synthesis of oligogalacturonides by direct glycosylation with galacturonic acid derivatives

It should be noted that, due to the electron-withdrawing carboxylic acid group, galacturonic acid derivatives used in glycan synthesis are substantially less reactive than the corresponding galactose derivatives, which impacts on the choice of protecting and leaving groups and promoter reagents used. The best results obtained in the synthesis of homogalacturonide disaccharides have been achieved by use of thiophenyl galacturonides as

Figure 3.7 Synthesis of protected trigalacturonide.

glycosyl donors (Fig. 3.4C) (Magaud et al. 1997; Magaud et al. 1998), which is itself prepared by selective oxidation of galactose derivatives in two steps (Fig. 3.7). Syntheses of trigalacturonide applying the same thioglycosyl donors and a disaccharide acceptor proceeded with lower efficiency (Fig. 3.7) (Magaud et al. 1997; Kramer et al. 2000). Understandably, therefore, no syntheses of higher oligomers have been reported using this approach.

3.5.2 Synthesis of oligogalacturonides by a late stage oxidation approach

The second strategy which has been applied to the construction of oligoga-lacturonides is based on post-glycosylation oxidation of the initially synthesized neutral a-(1^4)-galactooligosaccharides. Galactopyranose-based building blocks used for this synthesis possess a temporary protecting group at the primary hydroxyl group, which can be removed selectively and the free alcohol oxidized into a carboxyl group at a later stage of the oligosac-charide assembly. Two synthetic approaches have been employed with the post-glycosylation oxidation strategy: convergent block synthesis and reiterative monomer addition. Several important examples of oligogalacturo-nide synthesis based on the post-glycosylation oxidation strategy are outlined below.

3.5.2.1 The convergent block synthesis approach

An impressive total synthesis of dodecagalacturonic acid employing construction of neutral galactododecaoside followed by oxidation of all 12 primary hydroxyl groups has been described (Fig. 3.8) (Nakahara & Ogawa 1990a; Nakahara & Ogawa 1990b). The common glycosylation methodology, based on glycosyl fluorides as glycosyl donors, was adopted throughout the whole synthesis. As well as imparting good overall reactivity, the use of non-participating benzyl protecting groups also helps to produce the required 1,2-ds-stereoselectivity during glycosylation. Only three types of

Figure 3.8 Synthesis of dodecagalacturonic acid 3.8.1 (Nakahara & Ogawa 1990a). Structural formulae are shown for starting monosaccharide building blocks (top), protected galacto-oligosaccharide and final product (bottom). The convergent block strategy is illustrated using cartoon representation.

Figure 3.8 Synthesis of dodecagalacturonic acid 3.8.1 (Nakahara & Ogawa 1990a). Structural formulae are shown for starting monosaccharide building blocks (top), protected galacto-oligosaccharide and final product (bottom). The convergent block strategy is illustrated using cartoon representation.

temporary protecting groups were employed for hydroxyl functionalities, including acetates for 0-6 of galactose units. Temporary acetates allowed selective deprotection and oxidation of primary hydroxyl groups. Readily available starting monosaccharide building blocks were used in a highly convergent scheme to assemble a 12-mer galactooligosaccharide as shown in Fig. 3.8. Deacetylation of the 12-mer followed by two-step oxidation led to protected dodecagalacturonic acid, which was finally deprotected to give target 12-mer 3.8.1.

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