HLDAH enzyme helps cut waste in 'profen synthesis

The enzyme-driven process, described in the journal Chemical Communications​ by Dr Francesca Paradisi, of the Centre for Synthesis and Chemical Biology at University College Dublin in Ireland, and Professor Daria Giacomini and co-workers at the University of Bologna, Italy, involves the use of horse liver alcohol dehydrogenase (HLADH) to achieve dynamic kinetic resolution. In kinetic resolution, a process used for years in the organic synthesis of chiral molecules, the two mirror images or enantiomers of the racemic mixture react at different rates, creating an excess of the less reactive enantiomer. The drawback is that at best only 50 per cent of the racemate can be used, as the catalyst enzyme converts only one of enantiomers. The unwanted enantiomer is therefore wasted, an outcome that is both costly and environmentally unfriendly. With dynamic kinetic resolution it is theoretically possible to achieve 100 per cent conversion to a single enantiomer, as both mirror images of the chiral molecule form a chemical equilibrium and exchange. In this way, the faster-reacting enantiomer is replenished in the course of the reaction at the expense of the slower-reacting form. In the experiment conducted by Dr Paradisi and Professor Giacomini, this technique was applied to the arylpropanol class of molecule, of which ibuprofenol - the precursor to ibuprofen - is a member. These molecules are racemic mixtures, with the biological activity of ibuprofen attributed mainly to the S form. Given that ibuprofen is one of the most commonly used anti-inflammatory agents, the environmental and cost implications of a less wasteful method of synthesis are substantial. The researchers used HLADH in an aqueous organic medium to achieve the asymmetric reduction of racemic 2-phenylpropanol and ibuprofenal to their corresponding (2S​)-2-phenyl-1-propanol and (S​)-ibuprofenol derivatives, thus enabling an efficient biocatalysed process of dynamic kinetic resolution (DKR). With the racemic 2-phenylpropanol, the yield after a five-hour reaction time was more than 80 per cent, with an enantiomeric ratio (S/R) of 82:18. This ratio hardly altered over 24 hours, with little increase in yield. When this process was tested on racemic ibuprofenal in a buffered aqueous solution, with the addition of an organic solvent (CH3CN or THF), "the yields were excellent [81.4 per cent after five hours and 93.0 per cent after 24 hours with CH3CN] and enantiomeric ratios were always in favour of (S)-ibuprofenol"​, the researchers noted. "The oxidation of (S)-ibuprofenol to (S)-ibuprofen has already been reported in the literature, and here we claim to have established a chemoenzymatic process to obtain (S)-ibuprofen via an efficient DKR of the parent aldehyde,"​ Paradisi, Gioacomini et al commented. Work is now underway on optimising the reaction parameters (pH, solvent and temperature) for more efficient scale-up and application to other relevant 'profen derivatives. Two independent research groups have recently reported examples of arylpropanol conversion using dynamic kinetic resolution by means of a hydrogenation reaction catalysed by chiral ruthenium complexes, the researchers note. However, they add, "these methods employ very harsh conditions in comparison to a biocatalytic system"​.