3DfluorCO - Three-dimensional fluorine-based carbonyl bioisosteres: asymmetric synthesis and validation

Bioisosteres provide valuable design elements that medicinal chemists can use to enhance potency or selectivity, reduce methabolic liabilities, modify toxicophores, or gain new intellectual property. It is difficult to overlook a recent trend in drug design: a shift from easily accessible flat molecules of drug candidates to synthetically challenging but clinically more successful three-dimensional molecular architectures with higher fraction of sp3-hibridized carbon atoms. In this context, stereogenic C*–CF3 functional group being isopolar with the C=O group is an appealing option to be implemented as a carbonyl surrogate in molecular motifs such as carboxylic acid, amide, α-amino acid, α-hydroxy acid and peptide. Accessing such fluorinated molecules with multiple chiral centers is a daring task. It is often precluded by the limitations of synthetic chemistry or avoided by medicinal chemists due to requirement of exotic reagents and limited reach of chemical space. The 3DfluorCO project addresses this scientific challenge by developing conceptually new stereoconvergent synthetic methods towards the target CF3-substituted 1,2-diols, aminoalcohols and diamines via dynamic kinetic resolution. Our approach to the challenging class of molecules is based on detailed studies of stereochemical outcome and transition state geometries during the asymmetric transfer hydrogenation of complex ketones using Noyori–Ikariya type ruthenium-based organometallic complexes. This type of catalysis is not sensitive to air and moisture, has a robust temperature and solvent range and is thus highly practical, transferable and scalable. The synthetic method development will be conducted in close synergy with in silico drug design to answer the actual synthetic needs of medicinal chemistry, delivering analogs of bioactive compounds with rational CO–to–C*CF3 replacements. 3DfluorCO encompasses in-house determination of physicochemical properties relevant to drug development, and evaluation of biological activity against two model antimicrobial targets. The project therefore offers an integrated approach to sp3-enriched fluorine-doped bioactive lead compounds and to a validated concept for medicinal chemist’s toolbox.