Enzyme-catalyzed aldol addition derivatives

Several cyditol derivatives of varying ring size, for example, (69)/(70), have been prepared based on an enzymatic aldolization as the initial step. Substrates carrying suitably installed C,H-acidic functional groups such as nitro, ester, phosphonate (or halogen) functionalities made use of facile intramolecular nucleophilic (or radical) cyclization reactions ensuing, or subsequent to, the enzyme-catalyzed aldol addition (Figure 10.27) [134—137]. 

Another promising route was reported in patent and open hterature by both DSM and Diversa [13, 14]. This route employs a 2-deoxy-D-ribose 5-phosphate aldolase (DERA) that catalyzes a tandem aldol addition in which two equivalents of acetaldehyde (AA) are added in sequence to chloroacetaldehyde (CIAA) to produce a lactol derivative that is similar to the 3,5-dihydoxy side chain of synthetic statins (Figure 6.2e). Diversa screened environmental libraries for novel wild-type DERAs and identified an enzyme that was both tolerant to increased substrate concentrations and more active than DERA from E. coli in the target reaction [13]. 

The Evans Cu(II)- and Sn(II)-catalyzed processes are unique in their ability to mediate aldol additions to pyruvate. Thus, the process provides convenient access to tertiary a-hydroxy esters, a class of chiral compounds not otherwise readily accessed with known methods in asymmetric catalysis. The process has been extended further to include a-dike-tone 101 (Eqs. 8B2.22 and 8B2.23). It is remarkable that the Cu(II) and Sn(II) complexes display enzyme-like group selectivity, as the complexes can differentiate between ethyl and methyl groups in the addition of thiopropionate-derived Z-silyl ketene acetal to 101. As discussed above, either syn or anti diastereomers may be prepared by selection of the Cu(II) or Sn(II) catalyst, respectively. 

Transketolase is one of several enzymes that catalyze reactions of intermediates with a negative charge on what was initially a carbonyl carbon atom. All such enzymes require thiamine pyrophosphate (TPP) as a cofactor (chapter 10). The transketolase reaction is initiated by addition of the thiamine pyrophosphate anion to the carbonyl of a ketose phosphate, for example xylulose-5-phosphate (fig. 12.33). The adduct next undergoes an aldol-like cleavage. Carbons 1 and 2 are retained on the enzyme in the form of the glycol-aldehyde derivative of TPP. This intermediate condenses with the carbonyl of another aldolase. If the reactants are xylulose-5-phosphate and ribose-5-phosphate, the products are glyceraldehyde-3-phosphate and the seven-carbon ketose, sedoheptulose-7-phosphate (see fig. 12.33). 

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