One-pot chemoenzymatic synthesis of enantiopure aryl- and alkyl-azaarenes pharmaceutical intermediates

One-pot reactions are distinctive processes in which multiple sequential reactions occur within a single reaction vessel. Crucially, each reaction begins only after the completion of the previous one, ultimately yielding the desired final product without requiring intermediate purification. This approach not only shortens the overall synthesis time but also enhances total yield and minimizes chemical waste, making it a more environmentally sustainable strategy [1,2]. Following this successful approach, a one-pot reaction was designed and set up in two steps for the preparation of enantio-enriched 3,3-azaaryl-1-aryl-propanols and 3,3-azaaryl-1-alkyl-propanols containing a pyridine core. The first step of the one-pot protocol provided the addition of phenyl boronic acid to a carbonyl-activated alkenyl azaarenes (1-4) using [Rh(coe)(S)-TetraMeBITIANP] as catalyst [3] reaching up to 80% e.e. and quantitative conversion, a prerequisite to perform in the same reactor the second step, i.e. the asymmetric reduction of the prochiral keto group. In the case of propanones 1a and 2a the enantioselective reduction was realized by a ruthenium diamine complex under ATH (Asymmetric Transfer Hydrogenation) conditions in aqueous media, affording the anti-diasteromers in up to 90% e.e. Meanwhile, a biocatalytic approach for the reduction of carbonyl group of the products 3a-4a in R configuration was realized screening different yeasts. In this case, Torulopsis molischiana CBS 837 provided the products in anti-configuration with a molar conversion up to 95% and excellent enantiopurity (up to 99% e.e.) in 24h [4].