The pyruvate aldolases use pyruvate as the nucleophilic component in stereoselective aldol condensations, producing a 4-hydroxy-2-ketobutyrate framework. We have examined the 2-keto-3-deoxy-6-phosphogluconate (KDPG) aldolases from Pseudomonas putida, Escherichia coli, and Zymomonas mobilis for utility as synthetic reagents. Unlike other pyruvate aldolases examined to date, the KDPG aldolases accept short-chain, non-carbohydrate electrophilic aldehydes as substrates, providing a general methodology for the construction of the 4-hydroxy-2-ketobutyrate skeleton. The three aldolases differ markedly with respect to enzyme stability, pH optima, stability in organic cosolvent mixtures, substrate specificity, and diastereoselectivity during aldol condensation. All three enzymes show broad substrate specificity with regard to the electrophilic component. The primary requirements for substrate activity appear to be minimal steric hindrance and the presence of electron-withdrawing substituents at C2. The aldolases from Pseudomonas and Escherichia are also specific for the d-stereochemical configuration at C2, while the enzyme from Zymomonas displays no stereochemical discrimination with regard to the electrophilic substrate. Nucleophiles other than pyruvate are accepted as nucleophilic substrates by all three enzymes, provided the electrophile is sufficiently reactive. In preparative scale reactions with three unnatural electrophiles, the three enzymes show varying degrees of stereochemical fidelity. In most cases, a single diastereomer of the aldol adduct was produced, although in one case, a diastereomeric excess of 50% was observed. In all cases, the diastereoselectivity is exclusively kinetic in origin, despite the reversibility of some reactions. The enzymes are remarkably tolerant of added cosolvent:  all three showed >60% of native activity in 30% DMSO and DMF. By appropriate choice of enzyme, the KDPG aldolases offer exceptional utility for stereocontrolled carbon−carbon bond formation under a wide range of experimental conditions.

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Codeinone (3) was efficiently and directly converted to 14-hydroxycodeinone (1) by catalytic air oxidation in aqueous solution. A number of simple manganese and copper salts were identified to be effective catalysts, including MnSO4, KMnO4, and CuSO4. An appropriate reducing agent, such as sodium thiosulfate, is required in the reaction mixture presumably for the reduction of a detrimental peroxide intermediate. This discovery allows the more abundant codeine to be employed as the starting material for the synthesis of 14-hydroxylated opiate drugs without recourse to a thebaine-like intermediate. These discoveries were inspired from our study of microbial transformation of codeine to 14-hydroxycodeine by Mycobacterium neoaurum, where we found the actual 14-hydroxylation step is a chemical reaction rather than an enzymatic reaction, as previously believed.