Chiral resolution, orenantiomeric resolution,[1] is a process instereochemistry for the separation ofracemic mixture into theirenantiomers.[2] It is an important tool in the production ofoptically active compounds, includingdrugs.[3] Another term with the same meaning isoptical resolution.
The use ofchiral 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 ofdiastereomeric derivatives by reacting them withchiral derivatizing agents, also known aschiral 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 orracemized for reuse. It is common to test several resolving agents. Typical derivatization involves salt formation between anamine and acarboxylic acid. Simple deprotonation then yields back the pure enantiomer. Examples of chiral derivatizing agents aretartaric acid and the aminebrucine. The method was introduced (again) byLouis Pasteur in 1853 by resolving racemictartaric acid with optically active (+)-cinchotoxine.
One modern-day method of chiral resolution is used in theorganic synthesis of the drugduloxetine:[4]
In one of its steps theracemicalcohol1 is dissolved in a mixture oftoluene andmethanol to which solution is added optically active (S)-mandelic acid3. The alcohol (S)-enantiomer forms an insoluble diastereomeric salt with the mandelic acid and can be filtered from the solution. Simple deprotonation withsodium hydroxide liberates free (S)-alcohol. In the meanwhile the (R)-alcohol remains in solution unaffected and is recycled back to the racemic mixture byepimerization withhydrochloric acid in toluene. This process is known asRRR synthesis in which the R's stand forResolution-Racemization-Recycle.
Thechiral pool consists of many widely available resolving agents.[8]
Via the process known asspontaneous resolution, 5-10% of allracemates crystallize as mixtures of enantiopure crystals.[9] This phenomenon allowedLouis Pasteur to separate left-handed and right-handedsodium ammonium tartrate crystals. These experiments underpinned his discovery ofoptical activity. In 1882 he went on to demonstrate that byseeding asupersaturated solution of sodium ammonium tartrate with a d-crystal on one side of the reactor and a l-crystal on the opposite side, crystals of opposite handedness will form on the opposite sides of the reactor.
Spontaneous resolution has also been demonstrated with racemicmethadone.[10] In a typical setup 50 grams dl-methadone is dissolved inpetroleum ether and concentrated. Two millimeter-sized d- and l-crystals are added and after stirring for 125 hours at 40 °C two large d- and l-crystals are recovered in 50% yield.
Another form of direct crystallization is preferential crystallization also calledresolution by entrainment of one of the enantiomers. For example, seed crystals of (−)-hydrobenzoin induce crystallization of this enantiomer from anethanol solution of (±)-hydrobenzoin.
Inchiral column chromatography the stationary phase is made chiral with similar resolving agents as described above.
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