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Asymmetric Synthesis

We know that the molecules which have one or more asymmetric carbon atoms are called as chiral molecules. Asymmetric carbon atom can be defined as the carbon atom which is bonded with four different atoms or groups of atom. The chiral molecules are non-super imposable mirror images of each other.  The non-super imposable mirror images are known as enantiomers of each other. They show almost same physical and chemical properties but different chemical and optical properties. 

 

Asymmetric Synthesis Definition

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Asymmetric synthesis can be defined as the chemical reaction in which one or more chiral elements are formed in a substrate molecule. Such reactions also produce the stereoisomeric products in unequal amounts. These stereoisomers can be enantiomeric or diastereoisomeric forms. These reactions are also known as enantioselective synthesis or chiral synthesis.

Asymmetric synthesis favors the formation of a specific enantiomer or diastereomer during the reaction. It is key process in the manufacturing of several drugs and very important in pharmaceuticals. Some of the common examples of asymmetric synthesis are asymmetric organo-catalysis, enzymatic asymmetric synthesis and metal-catalyzed asymmetric synthesis.

Asymmetric Synthesis Examples

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Let’s discuss one of the best examples of asymmetric synthesis.  Sharpless asymmetric dihydroxylation is also known as Sharpless bishydroxylation. It involves the conversion of an alkene to vicinal diol in the presence of osmium tetroxide and a chiral quinine ligand. 

Asymmetric Synthesis
 
The catalyst for the reaction that is osmium tetroxide can be regenerated with either potassium ferricyanide or N-methylmorpholine N-oxide. The Ad-mix which contains (DHQ)2-PHAL  helps to regenerate the expensive and toxic osmium tetroxide. The product of Sharpless asymmetric dihydroxylation is chiral diols which are important in organic synthesis as diols are produced from nonchiral reactants with the use of chiral catalysts. It introduces the functional group ( -Oh) to double bonded carbon atoms.

Use of expensive and toxic osmium (VIII) makes it desirable to develop catalytic variants. Some other options of stoichiometric terminal oxidants are potassium chlorate, hydrogen peroxide (Milas hydroxylation), NMO (Upjohn dihydroxylation), tBHP (tert-butyl hydroperoxide), and potassium ferricyanide. K. Barry Sharpless developed Sharpless Asymmetric Dihydroxylation that involves the use of low levels of $OsO_{4}$ with $K_{3}Fe(CN)_{6}$.

Principles of Asymmetric Synthesis

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Asymmetric synthesis is based on the conversion of chiral carbon atoms to other enantiomers. Asymmetric synthesis is a type of chemical reaction which affects the structural symmetry in the molecules and converts compound into unequal proportions of compounds with different symmetry. These reactions involve those organic compounds which contains asymmetric carbon atoms. In the asymmetric synthesis one of the identical groups is modified to form product with a mixture of two dissymmetric compounds.

Asymmetric reactions effects the dissymmetry of reacting system like the presence of a dissymmetric centre, a dissymmetric solvent, catalyst, circularly polarized light etc. That is the reason; asymmetric synthesis is also called as stereoselective but if it forms one of the products exclusively, it is called as stereospecific.

Catalytic Asymmetric Synthesis

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Asymmetric synthesis catalysis is also called as enantioselective catalysis. Enantioselective catalysis involves the use of chiral coordination complexes as catalysts to initiate the reaction. Catalytic asymmetric synthesis is a common approach for a broader range of transformations. The catalysts which are used in such reactions have chiral ligands. These catalysts are effective at low concentrations and good for industrial scale synthesis. They are exotic and expensive therefore can be used affordably. Asymmetric hydrogenation is good example of asymmetric catalysis as given below. 

Catalytic Asymmetric Synthesis

Today we have a wide range of ligands which can be used in asymmetric synthesis such as BINOL, Salen andBOX. Most catalysts require certain functional groups in the substrate to form the transition state complex such as Noyori asymmetric hydrogenation with BINAP/diamine-Ru requires a β-ketone, whereas presence of BINAP/diamine-Ru results the formation of α,β-olefins and aromatics.

Asymmetric Synthesis of Amino Acids

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Amino acids are chiral molecules (excluding glycine) as the center carbon atom is bonded with one amino group, carboxylic group, hydrogen and one alkyl group. Several reactions of the amino acids follow asymmetric synthesis. These reactions produce a new stereogenic centre on an achiral molecule that makes two enantiomeric transition states of equal energy. It results the formation of two enantiomeric products in equal amounts.

If reactant molecule has an existing chiral centre there is probability of the formation of 2 transition states which are diastereomeric with different energy. Hence one isomer with new stereogenic centre will be produced in a larger amount.
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