Asymmetric Synthesis: How Enantioselectivity Is Actually Achieved

The symmetry argument that governs everything

Suppose an achiral starting material reacts with an achiral reagent to form a stereocentre. The two pathways leading to the two enantiomeric products pass through transition states that are themselves mirror images. Mirror-image structures in an achiral environment have exactly equal energies, so the two pathways have exactly equal rates, and the product is a 50:50 racemic mixture.

This is not a practical limitation that better technique could overcome. It follows from symmetry. To obtain one enantiomer preferentially, something chiral must be present, and it must be present at the transition state.

Measuring the outcome

Enantiomeric excess reports how far the product departs from a racemate:

An ee of 90 per cent means 95 parts of one enantiomer and 5 of the other, not 90 and 10. That conversion is a routine calculation and is frequently the numerical part of a question.

Note also how demanding high ee is energetically. At room temperature a difference of roughly 5.5 kJ per mole between the two diastereomeric transition states gives about 90 per cent ee, and around 11 kJ per mole is needed for 99 per cent. These are small energy differences, which is why asymmetric catalyst design is difficult.

The four strategies

The chiral pool

Start from something nature has already made in one enantiomeric form — an amino acid, a sugar, a terpene — and carry its stereochemistry through the synthesis. It is cheap and reliable, but limited to targets whose stereocentres can be traced back to an available natural product.

Chiral auxiliaries

A chiral group is covalently attached to the substrate, the key reaction is run, and the auxiliary is removed afterwards and recovered. Because the auxiliary is bonded to the substrate, the two possible products are genuinely diastereomeric, which brings a practical advantage: they can be separated by ordinary chromatography or crystallisation, unlike enantiomers.

Evans oxazolidinones are the standard example, used for aldol and alkylation reactions. The cost is two extra steps, one to attach and one to remove, and stoichiometric use of the auxiliary.

Chiral reagents

The reagent itself carries the chirality and delivers it in a single step. The CBS reduction, using a chiral oxazaborolidine with borane, reduces prochiral ketones to secondary alcohols with high and predictable selectivity. Diisopinocampheylborane, derived from the natural terpene alpha-pinene, performs asymmetric hydroboration.

Chiral catalysts

The most economical approach, because one chiral molecule generates many chiral product molecules. This makes the chirality catalytic rather than stoichiometric and is the reason the field is dominated by it.

• Noyori asymmetric hydrogenation uses ruthenium with the BINAP ligand. BINAP is axially chiral — it has no stereogenic atom at all, its chirality arising from restricted rotation about the bond joining two naphthalene units. It is the standard example of atropisomerism being put to work.
• Sharpless asymmetric epoxidation converts allylic alcohols to epoxides using titanium isopropoxide, a tartrate ester and an alkyl hydroperoxide. Its reliability comes from a mnemonic: draw the allylic alcohol with the hydroxyl at lower right, and one tartrate delivers oxygen from above while the other delivers from below.
• Sharpless asymmetric dihydroxylation uses osmium with cinchona alkaloid ligands to give a syn diol with defined configuration.
• Organocatalysis uses small chiral organic molecules, proline being the classic, which forms an enamine with a ketone and directs the approach of the electrophile without any metal.

Why it matters beyond the exam

Two enantiomers of a drug interact differently with the chiral binding sites of the body, so one can be active while the other is inactive or harmful. Regulatory authorities therefore expect single-enantiomer drugs to be justified and characterised individually. That commercial reality is what drove the development of catalytic asymmetric methods, and it is why the 2001 Nobel Prize in Chemistry went to Knowles, Noyori and Sharpless for work in this area.

Frequently asked questions

Why can an achiral reagent never give an enantiomerically enriched product?

The transition states leading to the two enantiomers are mirror images of each other. In an achiral environment mirror-image structures have identical energies, so their rates are identical and the product is racemic. Only a chiral influence makes those transition states diastereomeric and therefore unequal in energy.

What is the difference between a chiral auxiliary and a chiral catalyst?

An auxiliary is covalently attached to the substrate, used in stoichiometric quantity, and removed after the key step. A catalyst is used in small amounts, is not attached, and turns over repeatedly. Catalysts are more economical; auxiliaries offer the practical benefit that the intermediates are diastereomers and can be separated conventionally.

What does 90 per cent ee actually mean in composition terms?

It means the mixture is 95 per cent of the major enantiomer and 5 per cent of the minor one. The excess is the difference between the two, which is 95 minus 5, so a 90 per cent excess corresponds to a 95:5 ratio rather than 90:10.

How is BINAP chiral without a stereocentre?

Its chirality is axial. Rotation about the bond linking the two naphthalene units is blocked by steric hindrance, so the molecule is locked in one of two non-superimposable twisted forms. This is atropisomerism, and BINAP is the standard example of it being exploited synthetically.

Why is resolution limited to a 50 per cent yield?

Because a racemate already contains equal amounts of both enantiomers, and resolution only separates what is there. Half the material is the unwanted enantiomer. Asymmetric synthesis avoids the limit by forming the preferred enantiomer in the first place rather than discarding the other.