Merging Organolithium Chemistry and Stereoselective Biocatalysis: Transformation of Aromatic Nitriles into Chiral Alcohols

Abstract

AbstractThe combination of RLi‐mediated organic transformations (under air and at room temperature) with a subsequent stereoselective biocatalytic reaction is for the first time presented. Most of the previous asymmetric chemoenzymatic routes have been limited to the concomitant or sequential combination of transition metals/organocatalysts with enzymes. However, the use of polar organometallic reagents (RLi) in the design of these stereoselective hybrid protocols has been totally neglected, as far as we are concerned. Thus, in this work, the combination of organolithium chemistry and asymmetric biocatalysis is described for the first time in a one‐pot fashion. The chemoenzymatic approach converts a series of nitriles into chiral alcohols consisting of two steps, where the key item was the finding of suitable conditions to adapt the reactivities of organolithiums and alcohol dehydrogenases (ADHs) in the same recipient. The organolithium addition occurred with total chemoselectivity (no side reactions were observed) under neat conditions and room temperature leading to the corresponding imines, which were hydrolyzed using a buffer, and adjusting the pH for the subsequent ADH action. Commercial and made in house overexpressed ADHs allowed to produce chiral alcohols with excellent selectivities and good overall yields. The different behavior displayed for the reductive enzymes in the presence of diethyl ether clearly influenced in the decision to let the organolithium solvent evaporate under open‐air conditions before developing the bioreduction step. Our results demonstrate the importance of the fine orchestration of the reaction conditions for the development of efficient hybrid chemoenzymatic cascades without the need of intermediate isolation/purification steps or compartmentalization of the different synthetic systems.