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Enantioselective separation of Racemates by extraction using Chiral Metal Complexes based on modular Chiral Ligands obtained by parallel synthesis

Final Activity Report Summary - ENANTIOSEPARATIONS (Enantioselective Separation of Racemates by Extraction using Chiral Metal Complexes Based on Modular Chiral Ligands Obtained by Parallel Synthesis)

Chiral is a word obtained from the Greek 'keir', which means hand, and this word is used in chemistry to describe a molecule which cannot overlap with its mirror image, like one's left hand with his right hand. These two images are called enantiomers. In the world of pharmaceuticals, it is often important to use only one enantiomer of a compound since the other may be useless or even harmful. It is therefore important to have available methods to prepare drugs as only the 'left hand' or the 'right hand' molecules, i.e. pure enantiomers, and not both together as a mixture, i.e. racemate.

Nature is able to do this quite easily, however chemists are still learning. In 1849 Louis Pasteur, upon examination of the minuscule crystals of sodium ammonium tartrate, noticed that the crystals came in two asymmetric forms that were mirror images of one another, i.e. enantiomers. Tediously sorting the crystals by hand gave two forms of the compound. Solutions of one form rotated polarised light clockwise, while the other form rotated light counter-clockwise. An equal mix of the two, i.e. a racemate, had no polarising effect on light. Pasteur correctly deduced that the molecule in question was asymmetric and could exist in two different forms, enantiomers, which resembled one another as would left-hand and right-hand gloves. This was the first time anyone had demonstrated chiral molecules.

Since then, traditional methods for the separation of racemates included crystallisation of diastereomeric salts, chiral chromatography and enzymatic resolution. Each of these methods might have certain advantages over the other, such as efficiency, practicality, economy, etc., for a particular chiral compound. However, the selection and optimisation of the method could require considerable time and effort for each separate case and the optimised procedure might not always be general for a certain class of chiral compounds. Therefore, there is a continuous need for alternative general strategies, able to resolve racemic mixtures in a cost, time and waste saving manner. A promising methodology relies on the ability of a chiral selector to discriminate between the two enantiomers of a racemate, thus making the enantiomeric separation of racemic mixtures possible, for example, by transport across a chiral membrane, or by liquid-liquid extraction with a chiral host in the case of hydrophilic substrates. This latter protocol involves the extraction of one enantiomer into an organic phase by selective coordination to a hydrophobic selector, in order to leave the uncomplexed enantiomer in an aqueous phase. The advantage of this method is that it circumvents the use of excessive handling of solids, which is associated with classical resolution by crystallisation of diastereomeric salts and which is often, on a production scale, the slowest step in the process.

In this project, the efficient resolution of racemic N-benzyl alpha-amino acids was achieved by a liquid-liquid extraction process using a lipophilic chiral salen-cobalt(III) complex. As a result of the resolution by extraction, one enantiomer (S) of the N-benzyl alpha-amino acid predominated in the aqueous phase, while the other enantiomer (R) was driven into the organic phase by complexation to cobalt. The complexed amino acid (R) was then quantitatively released by a reductive, i.e. CoIII/CoII, counter-extraction. The reductive cleavage allowed for the recovery of the chiral salen-cobalt(II) complex in good yield, which could be easily re-oxidised to cobalt(III) with air/AcOH and reused with no loss of reactivity and selectivity. This methodology was also extended to the resolution of racemic N-benzyl beta3-amino acids, which were precursors of biologically important molecules including peptide mimetics and beta-lactam antibiotics.