Enantiomer separation Flashcards
How do we approach the issue of separating chiral molecules and where does the issue stem from?
Issue stems from the identical energies and physiochemical properties of enantiomers. Approach by separating via diastereoisomers (different in energies and properties) and reforming enantiomers - this may be in the transition state or through an intermediate product.
What is the chiral pool approach?
Using a member of the chiral pool as a starting material in the synthesis of a target molecule
What are the pros and cons of the chiral pool approach?
Advantages: cheap and abundant starting material, wide variety of structures available and high level of diastereocontrol can be achieved by leveraging existing stereocentres
Disadvantages: often only one enantiomer naturally occuring, multi-step synthesis may be required
What are ideal features of chiral auxiliaries?
Readily available compounds, cheap and easily prepared, easily coupled to SM, available as both pure enantiomers, induce high stereoselectivity, easily removable
What are chiral auxiliaries and how do we use them?
Species that are covalently coupled to the substrate, control the stereochemical outcome of the subsequent reaction and are then cleaved. Basically a protecting group for a specific chirality.
What are the advantages and drawbacks to chiral auxiliaries?
Advantages: produce high selectivities in a predictable manner, minor undesired product can be easily separated as diastereoisomers
Disadvantages: Requirement for additional steps, poor atom economy
How does classical resolution work?
Combining the racemic mixture with an enantiomerically pure compound, a resolving agent. Generation of a pair of diastereomeric compounds that are separable. Afterwards, regeneration of resolving agent and two physically separated enantiopure products.
What is resolution by molecular recognition?
Design of a macrocycle that will selectively sequester only one enantiomer of the racemic mixture.
What are some examples of hosts for resolution by molecular recognition?
Chiral crown ethers and cyclodextrines
How does chromatography on CSP work and what does CSP stand for?
Chromatography on chiral stationary phase. Enantiomers in mobile phase interact different with the CSP, resulting in different retention times.
How can chromatography on achiral SP be used to separate enantiomers?
Can only work with scalemic mixtures, where self-disproportionation of enantiomers on silica can occur. Formation of SR compounds leaves excess of major enantiomer, which can be separated from each other as diastereomeric entities.
How does crystallisation work as a resolution method?
Limited scope. Seeding of a saturated racemic or scalemic mixture can result in homochiral crystal formation. Or changing conditions to encourage homochiral crystals to form.
What are the properties of an ideal resolving agent?
Readily available, cheap, stable in use and storage, low toxicity, easily recovered or recycled, low molecular weight, available in both isomeric forms with high ee, suitable physical properties (e.g. salt formation)
What are the principles of kinetic resolution?
Diastereoisomers can be formed at different rates, so resolution of a racemic mixture can be achieved through kinetic grounds. Selectivity arises from difference in activation energies, quantified by Arrhenius/Eyring equation.
What types of interactions can be used to influence kinetic resolution rates?
Interaction with chiral species (e.g. mold with Louis Pasteur), chiral ligands + metals to induce chirality, avoidance of steric clash
