Chiral resolution

Source: Wikipedia, the free encyclopedia.

Chiral resolution, or enantiomeric resolution,

optically active compounds, including drugs.[3]
Another term with the same meaning is optical resolution.

The use of

Asymmetric synthesis
of one of the enantiomers is one means of avoiding this waste.

Crystallization of diastereomeric salts

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
.

Case study

One modern-day method of chiral resolution is used in the organic synthesis of the drug duloxetine:[4]

RRR synthesis
RRR synthesis

In one of its steps the

epimerization with hydrochloric acid
in toluene. This process is known as RRR synthesis in which the R's stand for Resolution-Racemization-Recycle.

Common resolving agents

Main article: Chiral derivatizing agent

The chiral pool consists of many widely available resolving agents.[8]

Spontaneous resolution and related specialized techniques

Via the process known as spontaneous resolution, 5-10% of all

optical activity. In 1882 he went on to demonstrate that by seeding a supersaturated 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 racemic methadone.[10] In a typical setup 50 grams dl-methadone is dissolved in petroleum 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 called resolution by entrainment of one of the enantiomers. For example, seed crystals of (−)-hydrobenzoin induce crystallization of this enantiomer from an ethanol solution of (±)-hydrobenzoin.

Chiral column chromatography

In chiral column chromatography the stationary phase is made chiral with similar resolving agents as described above.

Further reading

ISBN 978-0-8247-9143-8
.

References

  1. doi:10.1021/ac00046a026
    .
  2. ISBN 978-0-471-72091-1
  3. S2CID 35860450
    .
  4. doi:10.1021/op060118l
    .
  5. ISBN 978-0-470-13237-1
    .
  6. doi:10.15227/orgsyn.017.0080
    .
  7. doi:10.15227/orgsyn.055.0080
    .
  8. doi:10.15227/orgsyn.067.0001
    .
  9. ISBN 0-471-08058-6.{{cite book}}: CS1 maint: multiple names: authors list (link
    )
  10. doi:10.1021/ja01615a084
    .
Retrieved from "https://en.wikipedia.org/w/index.php?title=Chiral_resolution&oldid=1217310927"