Asymmetric synthesis
From Wikipedia, the free encyclopedia
Chiral synthesis also called asymmetric synthesis or enantioselective synthesis is organic synthesis which preserves or introduces a desired chirality.
Living beings do produce chiral molecules that can be used for chiral separation, but to separate a racemic mixture is to effectively throw out half of it. Therefore, especially with complicated and expensive substances, it is cost-efficient to get the synthesis itself to give the correct chirality in the first place.
The obvious approach would be to find a chiral starting material, such as a natural amino acid. However, this restricts the number of possible syntheses and requires a stoichiometric amount of the starting material, which may be poorly available and expensive. The more efficient approach is chiral catalysis, as only catalytic amounts are needed.
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 SN1 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 SN2 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.)
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 a 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 ligand. The ligand complexes to the starting materials and physically blocks the other trajectory for attack, leaving only the desired trajectory open. If the ligand is enantiopure, the different trajectories are not equivalent, but diastereomeric. Several examples:
- One chiral substance that is widely used for introducing chirality is 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
Other strategies in chiral synthesis are the use of chiral auxiliaries, chiral pool synthesis or biocatalysis.
