This document provides an overview of asymmetric synthesis. It discusses how asymmetric synthesis produces unequal amounts of stereoisomers from achiral precursors under chiral influence. The key methods covered are:
1. Chiral pool synthesis which uses readily available chiral natural products as starting materials.
2. Use of chiral auxiliaries, such as oxazolidinones, which provide temporary chirality and are later removed.
3. Catalytic asymmetric synthesis where a chiral catalyst directs formation of one stereoisomer over another.
It also discusses enantiopure separation techniques like preferential crystallization, biochemical separation using microorganisms, and chromatographic separation to obtain single enantiomers from a race
Top Rated Hyderabad Call Girls Erragadda ⟟ 6297143586 ⟟ Call Me For Genuine ...
Asymmetric Synthesis and Methods of Preparing Enantiopure Compounds
1. Department of Pharmaceutical Sciences
Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur 440033
Presented by:
Dhanashree N. Sarwan
M. Pharm. First Year (Pharmaceutical chemistry)
Asymmetric synthesis
1
4. The direct synthesis of optically active substance from optically inactive compound with or without
use optically active reagent called as Enantioselective synthesis or asymmetric synthesis.
It is a reaction in which an achiral unit in a substrate molecule is converted into a chiral unit in such a
manner that unequal amounts of stereoisomers (enantiomers or diastereomers) are produced.
When a compound containing an asymmetric carbon is synthesized by conventional laboratory
methods from an achiral compound the product is a racemic mixture.
If such a synthesis carried out under chiral influence, only one of optically active isomer will form
preferentially over the other.
Asymmetric synthesis
4
5. Importance of Asymmetric Synthesis
D-dopa is toxic
L-dopa treatment for
Parkinson's disease
(S)-citalopram
antidepressant
Enantioselective synthesis is a key process in modern chemistry and is particularly important in the
field of pharmaceuticals, as the different enantiomers or diastereomers of a molecule often have
different biological activity.
(R)-citalopram
inactive
5
6. Methods of preparation of asymmetric compounds
1. Chiral pool method
2. Chiral auxiliaries method
3. Catalytic method
6
7. Chiral pool synthesis or chiron approach
Is one of the simplest and oldest approaches for enantioselective synthesis.
Chiral pool refers to - Pool of chiral compounds, collection of cheap, readily available and
enantiomerically pure natural product as a starting material.
Usually amino acids or sugars, from which pieces containing the required chiral centers can be
taken and incorporated into the product.
Eg. Conversion of L-tyrosine into L-DOPA
7
8. In stereochemistry, a chiral auxiliary is a chiral molecular unit that can be temporarily incorporated
or attached chemically to achiral substrate to give a chiral intermediate.
At the end of synthesis chiral auxiliary can then be typically recovered for future use or removed.
Achiral substrate + Chiral Auxiliary S-A Product-A Product
Auxiliary
Reagent
Chiral Auxiliary Approach
8
9. Oxazolidinone auxiliaries, applied to many stereoselective transformations, including aldol reaction,
alkylation reactions, and Diels-Alder reaction.
The auxiliary is subsequently removed e.g. through hydrolysis.
Preparation: Oxazolidinones can be prepared from amino acids or amino alcohols.
Eg. Acylation of the oxazolidinone is achieved by deprotonation with n-butyllithium and quench with
an acyl chloride (Propanoyl chloride)
Oxazolidinones 9
10. Catalytic asymmetric synthesis
In this synthesis the chiral catalyst directs the formation of a chiral compound such that formation
of one stereoisomer is favored.
Effective optically pure catalysts are much more promising, because reagents are required in
stoichiometric amounts while catalysts are required only in very small amounts.
Eg. : Catalytic asymmetric reduction of ketones.
Catalytic asymmetric hydrogenation of alkenes.
Asymmetric epoxidation.
10
11. An enantiopure drug is a pharmaceutical that is available in one specific enantiomeric form.
Most biological molecules (proteins, sugars, etc.) are present in only one of many chiral
forms.
Enantiopure separation is a process of separating isomers in a racemic mixture into their
individual enantiomer.
Enantiopure separation
11
12. Method of separation of enantiopure
Mechanical separation
Preferential crystallization
Biochemical separation
Chromatographic separation
Kinetic method
Precipitation
Diastereomers
12
13. This involved mechanical separation of the crystal of one enantiomers from the other in racemic
mixture based on difference in their shapes.
Crystal of two forms have different shapes separated by magnifying lens and forceps.
First used by Pasteur, sodium ammonium tartarate which crystallise out in the form of racemic
mixture.
1. Mechanical separation
13
14. 2. Preferential crystallization
This method involve seeding of a saturated solution of the racemic mixture with a pure crystal
of one the two enantiomers. The solution now become supersaturated with respect to the added
enantiomers. It begins to crystallise out.
Eg. Harda obtained free from amino acid by adding corresponding d/l isomers of amino acid.
14
15. 3. Biochemical separation
Introduced by Pasteur in 1858.
This method is based on fact that when certain micro organisms like bacteria, fungi, yeast, etc are
grown in dilute solution of racemic mixture, they eat up one enantiomer rapidly than other.
Eg. The mould Penicillium glaucum preferentially destroys the (+) isomer of racemic ammonium
tartarate leaving (-) ammonium tartarate in solution.
4. Chromatographic separation
The racemic mixture can be separated by chromatography on an optically active support
15
16. 5. Kinetic method
This method is based on the fact that one of the enantiomer of racemic mixture reacts faster than
other with optically active compound.
Eg. Menthol reacts faster with(+) mandelic acid than with (-) mandelic acid.
6. Precipitation
Formation of precipitate by reaction between any reagent and racemic mixture.
Eg. (+)&(-) narcotine when dissolved in HCL, precipitates (+) narcotine.
16
17. 7. Diastereomers
When racemic mixture is allowed to interact with optically active material, it give a diastereomeric
derivatives.
Diastereomer have different physical properties and hence can easily separated into two component
by fractional crystallisation.
17
18. Many reactions can produce two or more stereoisomeric products.
If a reaction shows a preference for one of the stereoisomers, it is stereoselective reaction.
If the products are enantiomers, the reaction is Enantioselective.
If the product are diastereoisomer, the reaction is Diastereoselective.
Stereo selective synthesis
Eg. Dehydrohalogenation of 2-iodo-butane which yields 60% trans-2-butene and 20%
cis-2-butene
18
19. References
1. Stereochemistry Conformation and Mechanism- P S Kalsi.
2. Basic Organic Chemistry: Ernest L Eliel.
3. Finar, L.L. Organic Chemistry: Stereo Chemistry and Chemistry of Natural Products
(Vol:2) 5th Edition Dorling Kindersley Pvt. Ltd., Noida, India 1975.
4. Organic Chemistry 2nd Edition Jonathan Clayden, Nick Greeves and Stuart Warren.
19