Substrate-engineering approach to the stereoselective chemo-multienzymatic cascade synthesis of Nicotiana tabacum lactone

A multistep stereoselective synthesis of each stereoisomer of Nicotiana tabacum lactone is reported. A two steps reduction of an α,β-unsaturated ketoester gives the corresponding key intermediate ethyl 4-hydroxy-3-methylpentanoate. This one pot synthesis was catalyzed by a multienzymatic system comprising an ene-reductase (ER) and an alcohol dehydrogenase (ADH). This cascade process was highly chemoselective and stereoselective. In the last step, treatment of the hydroxyester with trifluoroacetic acid gives the γ-lactone in a very high overall yield (up to 78%) and with an excellent stereoselectivity (de > 94%, ee > 98%). The access to each stereoisomer was achieved by a substrate engineering approach and by selecting a Prelog or an anti-Prelog ADH. Furthermore, computational studies of the binding modes of the substrates into the catalytic site of ene-reductases have been carried out, giving an insight of the observed enantiodivergence.

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