Dihydroxyacetone-dependent aldolases aldol reactions

Figure 12 Aldol reactions catalyzed in vivo by the four stereocomplementary dihydroxyacetone-dependent aldolases.

In nature, most aldolases are rooted in the sugar metabolic cycle and accept highly functionalized substrates for the aldol reaction. Nevertheless, the scope of enzymatic aldol reactions is limited, since aldolases strictly distinguish between the acceptor and the donor, yielding almost exclusively one product, and is furthermore restricted to only a few different possible natural donors. According to the donor molecules, aldolases are grouped in dihydroxyacetone phosphate-, phosphoenolpyruvate- or pyruvate-, acetaldehyde-, and glycine-dependent aldolases [41]. 

Fructose 1,6-biphosphate aldolase from rabbit muscle in nature reversibly catalyzes the addition of dihydroxyacetone phosphate (DHAP) to D-glyceraldehyde 3-phosphate. The tolerance of this DHAP-dependent enzyme towards various aldehyde acceptors made it a versatile tool in the synthesis of monosaccharides and sugar analogs [188], but also of alkaloids [189] and other natural products. For example, the enzyme-mediated aldol reaction of DHAP and an aldehyde is a key step in the total synthesis of the microbial elicitor (—)-syringolide 2 (Fig. 35a) [190]. 

In vivo, six known DHAP-dependent aldolases are known to catalyze the reversible enanotioselective aldol addition of dihydroxyacetone phosphate to an acceptor aldehyde. The group is comprised of fructose 1,6-diphosphate (FDP) aldolase (EC 4.1.2.13), L-fuculose 1-phosphate (Fuc 1-P) aldolase (EC 4.1.2.17), tagatose 1,6-diphosphate (TDP) aldolase (EC 4.1.2.2), ketotetrose phosphate aldolase (EC 4.1.2.2), L-rhamnulose 1-phosphate (Rha 1-P) aldolase (EC 4.1.2.19), and phospho-5-keto-2-deoxygluconate aldolase (EC 4.1.2.29). The in vivo catalyzed reactions of this group are shown in Scheme 5.3. 

A comprehensive review (260 refs.) on the synthesis of carbohydrates from noncarbohydrate sources covers the use of benzene-derived diols and products of Sharpless asymmetric oxidation as starting materials, Dodoni s thiazole and Vogel s naked sugar approaches, as well as the application of enzyme-catalysed aldol condensations. The preparation of monosaccharides by enzyme-catalysed aldol condensations is also discussed in a review on recent advances in the chemoenzymic synthesis of carbohydrates and carbohydrate mimetics, in parts of reviews on the formation of carbon-carbon bonds by enzymic asymmetric synthesis and on carbohydrate-mediated biochemical recognition processes as potential targets for drug development, as well as in connection with the introduction of three Aldol Reaction Kits that provide dihydroxyacetone phosphate-dependent aldolases (27 refs.). A further review deals with the synthesis of carbohydrates by application of the nitrile oxide 1,3-dipolar cycloaddition (13 refs.). ... 

Scheme 2.192 Aldol reaction catalyzed by dihydroxyacetone-dependent fhictose-6-phosphate aldolase...

Here we recount the latest research on chemoenzymatic multistep and cascade strategies for the synthesis of iminocyclitols, carbohydrates, and deoxysugars from N-protected ami noaldehydes, hydroxyaldehydes, and simple alkylaldehydes, respectively. The key step in all of them is the stereoselective aldol addition reaction of dihydroxyacetone phosphate (DHAP) and its unphosphorylated analogs to the acceptor aldehydes using DH AP-dependent and dihydroxyacetone- (DH A)-utilizing aldolases, respectively, as biocatalysts. 

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