Lactones are biologically active molecules that are found in pharmaceuticals including the cholesterol-lowering drugs Lovastatin and Simvastatin, and natural chemical signals, such as the beetle pheromone (R)-?-caprolactone. We have demonstrated the production of enantiomerically pure lactones utilizing biocatalysis as the key asymmetric step. Aldehydes with varying aromatic substituents under went sulfur protection, umpolung reversal of polarity and a series of SN2 reactions producing ?-keto nitriles. A library of twenty baker's yeast keto reductases, over expressed in engineered Escherichia coli, was screened for the enzymes' ability to reduce the ketone functionality of the gamma-keto-nitriles to the corresponding asymmetric alcohol. Enzymes that produce the highest enantiomeric excess are of the most interest and were chosen for scale up.  Since these reactions were performed with enzymes, the need for harsh solvents, reactants and catalysts was eliminated. After hydrolysis with base, protonation of the acid allowed for spontaneous cyclization to a lactone with the stereochemistry preserved.

Synthesis of γ-keto nitriles and a biocatlytic approach to asymmetric lactones

243rd National Meeting (2012)

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