Asymmetric Synthesis: De novo synthesis of a chiral substance from an achiral precursor such that one enantiomer predominates over the other is called asymmetric synthesis. For reactions where molecules already contain a chiral element and synthesis introduces a new chiral element, synthesis is referred to as ‘stereoselective or enantioselective’ synthesis or diastereoselective synthesis.
- Decarboxylation of ethyl methylmalonic acid to give α methyl butyric acid is one of the first recorded asymmetric syntheses.
- Generally, chiral reagents are used to carry out the reaction, if they are not available, chirality is acquired upon chelation, solvation, etc.
- Reactants are adsorbed onto chiral surfaces or within chiral crystals.
- Chiral adjuvant or chiral auxiliary is temporarily attached to the achiral substrate which is cleaved after the synthesis by hydrolysis to recycle the adjuvant.
- When a new stereogenic center is created in an achiral molecule we get a racemic mixture while in diastereoselective synthesis, the formation of any one of the desired diastereomers is preferred over the other.
Typical asymmetric syntheses include
- Asymmetric hydrogenation
- Asymmetric epoxidation
- Asymmetric dihydroxylation
The partial term was used when optically active compounds are prepared from achiral compounds by intermediate use of optically active compounds as reagent without the necessity of resolution, contrary to the ‘absolute’ asymmetric synthesis where physical reagent like circularly polarised light was used.
1. Asymmetric Hydrogenation (Reduction):
It is used for the asymmetric synthesis of the analgesic drug Naproxen.
The reaction is carried out in presence of a chiral catalyst to hydrogenate a double bond. The catalyst selects a single enantiotopic face of the double bond and adds hydrogens across it.
BINAP is a chelating diphosphine. Chirality is due to the restricted rotation of the bond joining two naphthalene ring systems. Along with Ruthenium, it acts as an excellent catalyst for hydrogenation.
For double bonds bearing amino groups, better catalysts are based on rhodium.
The catalyst is a cationic complex of rhodium with another diphosphine DI PAMP.
An important application of asymmetric hydrogenation is in the synthesis of L menthol from (R) citronellal.
2. Asymmetric epoxidation:
Oxidation of alkenes by asymmetric epoxidation is one of the popular Sharpless reactions.
Catalyst is a transition metal, Titanium tetraisopropoxide with tertiary butyl hydroperoxide. The ligand is diethyl tartrate which is chiral and imparts selectivity to the reaction.
Such metal-catalyzed epoxidation works only on allylic alcohols. Initially, the active complex is formed from two titanium atoms bridged by two tartrate ligands. Each titanium atom retains two of its isopropoxide ligands and is co-ordinated to one of the carbonyl groups of the tartrate ligand. When oxidizing agent tBuOOH is added, it displaces one of the remaining isopropoxide ligands and one of the tartrate carbonyl groups. Further allylic alcohol is coordinated with the titanium displacing another isopropoxide ligand.
Because of the shape of the complex of the reactive oxygen atom of the bound hydroperoxide has to be delivered to the lower face of alkene and epoxide is formed in high enantiomeric excess.
Epoxides easily react with many nucleophiles to give 1,2, disubstituted products and thus used in the synthesis of drugs e.g. Propranolol- used as β blocker.
3. Asymmetric dihydroxylation:
Dihydroxylation of alkenes by osmium tetroxide in catalytic amount is carried out.
- Osmium (VIII) acts as an oxidizing agent and K3Fe (CN)6 is commonly used to reoxidize the osmium after each catalytic reaction.
- To increase the rate of reaction K2CO3 and methanesulfonamide are added.
- Chiral ligands are usually alkaloids dihydro quinidine and hydroquinone based which must be attached to aromatic rings e.g. Phthalazine.
- Trans alkenes dihydroxylates more selectively than other alkenes because of the alignment of ligand and catalyst.
- The reaction has been successfully used for the synthesis of antibiotic chloramphenicol in few steps.
Energy Profile diagrams for asymmetric synthesis
Make sure you also check our other amazing Article on : Racemic Modification