Chiral resolution

Chiral resolution, or enantiomeric resolution, is a process in stereochemistry for the separation of racemic compounds into their enantiomers. It is an important tool in the production of optically active compounds, including drugs. Another term with the same meaning is optical resolution. The use of chiral resolution to obtain enantiomerically pure compounds has the disadvantage of necessarily discarding at least half of the starting racemic mixture. Asymmetric synthesis of one of the enantiomers is one means of avoiding this waste. The most common method for chiral resolution involves conversion of the racemic mixture to a pair of diastereomeric derivatives by reacting them with chiral derivatizing agents, also known as chiral resolving agents. The derivatives which are then separated by conventional crystallization, and converted back to the enantiomers by removal of the resolving agent. The process can be laborious and depends on the divergent solubilities of the diastereomers, which is difficult to predict. Often the less soluble diastereomer is targeted and the other is discarded or racemized for reuse. It is common to test several resolving agents. Typical derivatization involves salt formation between an amine and a carboxylic acid. Simple deprotonation then yields back the pure enantiomer. Examples of chiral derivatizing agents are tartaric acid and the amine brucine. The method was introduced (again) by Louis Pasteur in 1853 by resolving racemic tartaric acid with optically active (+)-cinchotoxine. One modern-day method of chiral resolution is used in the organic synthesis of the drug duloxetine: In one of its steps the racemic alcohol 1 is dissolved in a mixture of toluene and methanol to which solution is added optically active (S)-mandelic acid 3. The alcohol (S)-enantiomer forms an insoluble diastereomeric salt with the mandelic acid and can be filtered from the solution. Simple deprotonation with sodium hydroxide liberates free (S)-alcohol.