Tandem Bidirectional Chain Extensions

In principle, bifunctional aldehydes should be able to engage in twofold enzymatic aldol additions to both of their acceptor carbonyls in a fashion to be classified as a tandem reaction, that is, without the need for isolation of intermediates. Depending on the specificity of the enzyme used and on the functionalization in the starting material, the isomeric constitution as well as the absolute and relative stereochemistry should be deliberately addressable. Therefore, we engaged in a program to evaluate the scope and the Hmitations of such two-directional chain elongation processes for the construction of extended poly functional molecules [36]. 

With meso-conflgured dialdehyde precursors, the enantiotopic nature of the termini must give rise to a conflgurational terminus differentiation upon twofold chain extension because the catalyst-controlled diastereoselective aldol additions will break the inherent o symmetry. While the two enantiotopic termini cannot 

In both reactions with the meso substrates, no intermediary monoadduct could be detected. Consequently, a potential kinetic preference of the aldolase for either of the competing enantiotopic hydroxyaldehyde moieties within the starting substrates could not be investigated. No matter which of the enantiotopic aldehyde groups is attacked first, however, the second addition steps must be kinetically faster in each case, probably supported by the presence of an anionic charge in the intermediates, which should improve the substrate affinity to the enzyme. 

Structural relationships suggest that the extended carbohydrate scaffolds obtainable by such tandem aldolizations may be regarded as metabolically stable mimetics of oligosaccharides, in particular of C-glycosides that are hydrolytically stable. The latter class of compounds shares an interest for potential therapeutic applications with the class of so-called aza sugars that have commanded attention in recent years as potent glycoprocessing inhibitors for the treatment of diabetes and other metabolic disorders, as well as for the blocking of viral or microbial infection and metastasis. 

Strikingly, this unique technique of enzymatic bidirectional chain synthesis leads in most cases to enantio- and diastereomerically pure higher-carbon diketoses of high structural complexity from rather simple a,co-dialdehydes with good 

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Figure 10.32 Applications of bidirectional chain extension for the synthesis of disaccharide mimetics and of annulated and spirocyclic oligosaccharide mimetics using tandem enzymatic aldol additions, including racemate resolution under thermodynamic control.

Bidirectional chain extension of dihydroxy dialdehydes gives rise to carbon-linked disaccharide mimetics (e.g., 43, 45, 46) by simple one-pot operations [115,117]. The latter may be obtained as single diastereomers in good overall yield even from racemic precursors (especially cycloolefins), if the tandem aldolization reactions are conducted under conditions of thermodynamic control (Fig. 19). Typically, the thermodynamic advantage favors the trans (43) and equatorial attachments (45, 47) of the sugar ring by far, so that the... 

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