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Asymmetric Synthesis: Partial and Absolute

During chiral substance formation by de novo synthesis from an achiral precursor, one enantiomer predominates over the other.

Asymmetric Synthesis

During chiral substance formation by de novo synthesis from an achiral precursor, one enantiomer predominates over the other. The term 'stereoselective' or 'enantioselective' synthesis, as well as diastereoselective synthesis, is used when molecules already possess chiral elements, with synthesis adding a new chiral element.
  • Ethyl methylmalonic acid can be decarboxylated to produce methyl butyric acid as one of the first asymmetric reactions recorded.

  • Typically, chiral reagents are employed to carry out the reaction, though chelation, solvation, etc. may be used if such reagents aren't available
  • As reactants adhere to chiral surfaces or crystals, they are adsorbed
  • The chiral auxiliary or adjuvant that is temporarily attached to the achiral substrate is hydrolyzed to recycle the adjuvant after the synthesis.
  • Any new stereogenic center in an achiral molecule produces a racemic mixture, but diastereoselective synthesis ensures any of the desired stereoisomers over the other.
Asymmetric synthesis includes -
Partial synthesis was used to indicate the use of optically active compounds as reagent in the preparation of optically active compounds from achiral compounds, in contrast to 'absolute' asymmetric synthesis that used circularly polarised light as reagent.

Asymmetric Hydrogenation

Analgesic drug Naproxen is synthesized asymmetrically using this chemical.

Hydrogenation of a double bond occurs with the assistance of a chiral catalyst. An enantiotopic face of the double bond is selected by the catalyst and hydrogens are added across it.

This chelating diphosphine is BINAP. A chiral compound is caused by the restricted rotation of the bond between two naphthalene ring systems. This metal is a superb hydrogenation catalyst along with Ruthenium.

When double bonds with amino groups are involved, rhodium catalysts are better.

Catalysts are triphosphonate derivatives of DI PAMP with a cationic complex of rhodium.

Asymmetric hydrogenation is an important method for synthesising L-menthol from citronellol (R).

Asymmetric Epoxidations

Alkenes are oxidized by asymmetric epoxidation, one of the Sharpless reactions.

It has tertiary butyl hydroperoxide containing Titanium tetraisopropoxide as a catalyst. Diethyl tartrate is the ligand, a chiral compound that enhances selectivity.

An allylic alcohol can be epoxidized using a metal catalyst. The active complex is made up of two tartrate ligands that link two titanium atoms together. There are two isopropoxide ligands on each titanium atom. In the tartrate ligand, the ligands are coordinated with the carbonyl groups. tBuOOH oxidizes the remaining isopropoxide ligand and isopropoxide carbonyl group, displaces them and reduces their reactivity. Another isopropoxide ligand is displaced by allylic alcohol coordinated with titanium. The hydroperoxide molecule must deliver its reactive oxygen to the lower surface of the alkene due to the shape of the complex, and high enantiomeric excesses of epoxide result.

Epoxides have the capacity to easily react with nucleophiles to give disubstituted 1,2 products, which are then used to synthesize drugs. For instance, propranolol is a β blocker.

Asymmetric Dihydroxylation

Osmium tetroxide is used as a catalyst for dihydroxylation of alkenes.

  • As an oxidizing agent, osmium (VIII) can be reoxidized by K3Fe (CN)6 following each catalytic reaction.
  • A combination of K2CO3 and methanesulfonamide speeds up the reaction.
  • Alkaloids that contain dihydroquinidine and hydroquinone are commonly found as chiral ligands. Phthalazine, for example, serves as one such ligand.
  • Due to the alignment of the ligand and catalyst, trans alkenes dihydroxylate more selectively than other alkenes.
  • Chloramphenicol has been synthesized in a few steps using this reaction.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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