Asymmetric synthesis

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Asymmetric synthesis, also called chiral synthesis or enantioselective synthesis, is organic synthesis which preserves or introduces a desired chirality. This is important in the field of pharmaceuticals because the different enantiomers or diastereomers of a molecule often have different biological activity.

Contents 1 Approaches 2 Chiral pool synthesis 3 Asymmetric induction 4 Chiral catalysis 5 Biocatalysis 6 Alternatives 7 See also

[edit] Approaches

There are three main approaches to asymmetric synthesis — chiral pool synthesis, chiral reagents and catalysts (asymmetric catalytic reduction and oxidation), and asymmetric induction. In practice, a mixture of all three is often used in order to maximize the advantages of each method.

Chirality must be introduced to the substance first. Then, it must be maintained. Care needs to be taken when planning the synthesis: the chirality might be removed by a chemical change that makes the substance isotropic. This process is called epimerization. For example, a S_N1 substitution reaction converts a molecule that is chiral by merit of non-planarity into a planar molecule, which has no handedness. (To visualise, draw the outlines of both of your hands on paper, and cut the images out. You can now superimpose the images, even if the hands themselves do not superimpose.) In a S_N2 substitution reaction on the other hand the chirality inverts, i.e. when you start with a right-handed mixture, you'll end up with left-handed one. (A visualization could be inverting an umbrella. The mechanism looks just the same.)

[edit] Chiral pool synthesis

This is the easiest approach — a chiral starting material is manipulated through successive reactions using achiral reagents which retain its chirality to obtain the desired target molecule. This is especially attractive for target molecules having the similar chirality to a relatively inexpensive naturally occurring building block such as a sugar or amino acid. However, the number of possible reactions the molecule can undergo are restricted, and tortuous synthetic routes may be required. Also, this approach requires a stoichiometric amount of the enantiopure starting material, which may be rather expensive if not occurring in nature, whereas chiral catalysis requires only a catalytic amount of chiral material.

[edit] Asymmetric induction

What many strategies in chiral synthesis have in common is asymmetric induction. The aim is to make enantiomers into diastereomers, since diastereomers have different reactivity, but enantiomers do not. To make enantiomers into diastereomers, the reagents or the catalyst need to be incorporated with an enantiopure chiral center. The reaction will now proceed differently for different enantiomers, because the transition state of the reaction can exist in two diastereomers with respect to the enantiopure center, and these diastereomers react differently.

Asymmetric induction can also occur intramolecularly when given a chiral starting material. This chirality transfer can be exploited, especially when the goal is to make several consecutive chiral centers to give a specific enantiomer of a specific diastereomer. Aldol reaction, for example, is inherently diastereoselective; if the aldehyde is enantiopure, the resulting aldol adduct is diastereomerically and enantiomerically pure.

One such strategy is the use of a chiral auxiliary which forms an adduct to the starting materials and physically blocks the other trajectory for attack, leaving only the desired trajectory open. Assuming the chiral auxiliary is enantiopure, the different trajectories are not equivalent, but diastereomeric.

[edit] Chiral catalysis

The use of auxiliaries is also used in the use of chiral catalystic oxidation and reduction, where chiral ligands are attached to metal centers which allow selective oxidation and reduction. Examples include:

• BINAP, a chiral phosphine, used in combination with compounds of ruthenium or rhodium. These complexes catalyse the hydrogenation of functionalised alkenes well on only one face of the molecule. Part of the 2001 Nobel Prize in Chemistry was awarded to Ryoji Noyori for this discovery, which is commercialized as the industrial synthesis of menthol using a chiral BINAP-rhodium complex.
• The other part of that Nobel prize concerned the Sharpless bishydroxylation
• Naproxen is synthesized with a chiral phosphine ligand in a Hydrocyanation reaction

[edit] Biocatalysis

Biocatalysis makes use of enzymes to effect chemical reagents stereoselectively. Some small organic molecules can also be used to help accelerate the desired reaction; this method is known as organocatalysis. If the organic molecule is chiral, it may react preferentially with the substrate of a certain chirality.

[edit] Alternatives

Apart from asymmetric synthesis, racemic mixtures of compounds may be separated by various techniques in chiral resolution. Where the cost in time and money of making such racemic mixtures is low, or if both enantiomers may find use, this approach may remain cost-effective.

[edit] See also

• Aza-Baylis-Hillman reaction, for the use of a chiral ionic liquid in asymmetric synthesis.