Enzymatic aldol additions

Figure 10.20 Substrate analogs of dihydroxyacetone phosphate accessible by the CPO oxidation method, and spontaneous, reversible formation of arsenate or vanadate analogs of dihydroxyacetone phosphate/n s/tu for enzymatic aldol additions.

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.

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]. 

W. D. Fessner and O. Eyrisch, One-pot synthesis of tagatose 1,6-bisphosphate by diastereoselec-tive enzymatic aldol addition, Angew. Chem. lnt. Ed. Engl. 31 56 (1992). 

Figure 19.5 Structure of the N-protected-3-aminopropanal for the enzymatic aldol addition.

Scheme 9. Sugar ring anulation by tandem enzymatic aldol additions to cyclic dihydroxydial-dehydes...

W. D. Fessner, G. Sinerius, A. Schneider, M. Dreyer, G. E. Schulz, J. Badia, and J. Arguilar, Diastereoselective enzymatic aldol additions L-Rhamnulose and L-fuculose 1-phosphate aldolases from E. coli, Angew. Chem, Int. Ed. Engl. 30 555 (1991). 

Spontaneous, reversible formation of arsenate and vanadate analogs of dihydroxyacetone phosphate in situ for enzymatic aldol additions. 

From a stereochemical point of view, the approach of the aldol acceptor to the enzyme-nucleophile complex is stereospecific, following an overall retention mechanism. On the other hand, the facial differentiation of the acceptor aldehyde carbonyl is usually high but, in some instances, depends on the substrate structure, and the stereochemical outcome does not always follow that of the natural acceptor. Although enzymatic aldol addition is a reversible reaction, for most applications, the C—C bond formation is favored for thermodynamic reasons because the primary aldol adducts can often form more stable cyclic ketal... 

FruA) from different sources, L-rhamnulose-l-phosphate aldolase (RhuA) and l-fuculose-l-phosphate aldolase (FucA) from E. coli have been extensively investigated and applied in the synthesis of carbohydrates and their derivatives such as deoxysug-ars, iminocyclitols and aminocyclitols [44]. An exception was D-tagatose-l,6-bisphos-phate aldolase (TagA), whose lack of stereoselection constitutes a major limitation of this aldolase, which frustrates the attempts to obtain the four possible stereoisomers from a single aldehyde, one of the hallmarks of enzymatic aldol additions [117,118]. 

Example of multistep chemo-enzymatic synthesis of pipecolic acid derivatives (60) and homoiminocyclitols (61) by two consecutive enzymatic aldol addition reactions (a) i-serine hydroxy-methyltransferase from Streptococcus thermophilus (lSHMTj ) (b) Cbz-OSu CHjCN/aqueous HCI (c) Cbz-OSu MeOH/SO CIj CaCI, NaBH, EtOH/THF CHjCN/aqueous HCI (d) o-threonine aldolase from Achromobacterxylosoxidans (oThrA j (e) FucA F131A (f) RhuA wild-type (g) acid phosphatase from potato type II and (h) H Pd/C. 

The discovery of the precise mechanism of the enzymatic aldol addition process in combination with the elucidation of enzyme structure is also of paramount importance. In this way, it becomes more practicable to elucidate the precise transition state(s) involved in the catalytic process, and this is of utmost significance in modifying rationally existing enzymes or de novo design new activities. 

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