Chemo-enzymatic synthesis of new chiral C2-symmetric bipyridyls and bipyridyls N,N'-dioxide alcohols

Optically active C2-symmetric 2,2'-bipyridines and their related N,N'-dioxides bearing stereogenic carbons in the side chains have recently attracted great interest in organic and coordination chemistry.1 The access to such derivatives in optically active form has been mostly achieved by "chiral pool" approach or asymmetric synthesis, but a valuable alternative route could rely on kinetic resolution of racemic bipyridine frameworks. In this context, lipase catalysed acylation could provide useful tool for the preparation of enantiopure bipyridine alcohols, as an extension of well-known biocatalysed resolution of phenyl substituted alkanols. However, few data are available on resolution or desymmetrization processes applied to racemic or meso- bipyridine having secondary hydroxy groups in side chain. As part of our continuous interest in the study of lipase behaviour concerning the stereo-recognition of bipyridines and phenanthroline derivatives with central and/or axial chirality,2 we have focused our attention on the lipase catalysed kinetic resolution of racemic C2-symmetric 6,6'-bis(2-hydroxypropyl)-2,2'-bipyridine 2, obtained as an inseparable 1:1 mixture of dl- and meso-forms by metallation and treatment with acetaldehyde of commercially available 3,3'-dimethyl-2,2'-bipyridine. The esterification of the whole stereoisomeric mixture with vinyl acetate as acyl donor in presence of immobilised Mucor Miehei lipase (Lipozyme IM) has resulted in the selective transformation of the alcoholic functions on the stereogenic carbon having R configuration. This selective chiral recognition gave the simultaneous resolution of (±)-2 and the desymmetrization of meso isomer, allowing the recovery of the diacetate (R,R)-4, monoacetyl derivative (R,S)-3 and unreacted alcohol (S,S)-2a, in high optical purities. The absolute configuration was confirmed by NMR spectroscopy. The enantiopure products obtained were then converted into the corresponding N,N'-dioxide derivatives, whose stereochemistry and axial stability were investigated by dynamic circular dichroism spectroscopy.