Asymetric Synthesis.pptx

This PPT consists of types of asymmetric synthesis with examples. It consists of absolute asymmetric synthesis and partial asymmetric synthesis. The partial absolute synthesis consists of chiral pool, chiral catalyst, chiral reagent.

1. METHODS OF ASYMMETRIC SYNTHESIS PRESENTED BY A.S Madhu Prasanth M. Pharmacy, 1 st Year Pharmaceutical Chemistry JSS College Of Pharmacy, Mysore

2. CONTENTS Introduction Stereoselectivity and Stereospecificity Mechanism of asymmetric synthesis Generations Approaches Advantages and disadvantages

3. INTRODUCTION Asymmetric synthesis 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 (CHIRAL) 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.

4. Asymmetric synthesis refers to the selective synthesis of one of the isomer of the chiral product. The enantiomers can be separated by the methods includes -Chiral chromatography -Enzymes -Asymmetric synthesis. The asymmetric synthesis is also called as enantioselective synthesis. A B + B I B Asymmetric synthesis

5. STEREOSPECIFIC REACTIONS STEREOSELECTIVE REACTIONS A stereospecific reaction is a rection in which the stereochemistry of the reactant completely determines the stereochemistry of the product without any other option. A stereoselective reaction is a rection in which there is a choice of pathway, but the product stereoisomer is formed due to its reaction pathway being more favorable than the others available. Gives a specific product from a certain reactant. Can result in multiple products. Final product depends on the stereochemistry of the reactant Selectivity of the reaction pathway depends on differences in steric effects an electronic effects S N 2 reaction is an example for the stereospecific reaction . Dehydrohalogenation of 2-iodo butane which yields 60% trans and 20% cis

6. MECHANISM The aim is to make enantiomers into diastereomers . To make this possible ,we need to incorporate reagents or catalysts having chirality. The reaction will now proceed differently for different enantiomers because of the difference in energy of transition state. In the absence of chiral influence, reaction producing enantiomers in equal amounts via transition states of identical energies (enantiomeric transition state) . These reactions therefore takes place at identical rates to give equal amounts of enantiomers If we are using chiral components , then we could make the possible enantiomeric transition state, diastereomeric transition state with different activation energy which results in unequal amounts of isomers

7. GENERATIONS There are total four generations of asymmetric synthesis, those are 1 st Generation – Substrate controlled asymmetric synthesis Diastereoselective reactions where the formation of chiral centre is controlled by another chiral centre already present in the substrate. 2 nd Generation – Auxiliary controlled asymmetric synthesis In this method a chiral auxiliary is covalently attached to the substrate and, through that controls the asymmetric synthesis 3 rd Generation – Reagent controlled asymmetric synthesis The formation of a new chiral centre is induced by a chiral reagent, intramolecularly. 4 th Generation – Catalyst controlled asymmetric synthesis One general procedure involves a reaction of a chiral substrate with a chiral reagent, and is especially useful in reactions where two new stereogenic units are formed stereo selectively in one step.

8. 1 st Generation Substrate * Product * 2 nd Generation Substrate + Auxiliary S-A P-A * Product * 3 rd Generation Substrate Product * 4 th Generation Substrate * Product * Reagent Reagent Reagent * Catalyst * Auxiliary *

9. APPROACHES Asymmetric synthesis are of 2 types 1.Partial asymmetric synthesis 2.Absolute asymmetric synthesis Partial Asymmetric Synthesis- Synthesis of new chiral center from an achiral center by using optically active reagents. 1. Use of chiral substrate- It uses natures ready-made chiral centers as starting materials It is more economical way of making compounds in enantiopure form. Eg . – Conversion L-tyrosine into L-DOPA. In this conversion starting material L-tyrosine is a naturally occurring chiral molecule. This conversion doesn’t affect the existing stereocenter.

10. This method is also known as “ CHIRAL POOL” strategy. Pure natural products, usually amino acids or sugars, from which pieces containing the required chiral centres can be taken and incorporated into product. It is an internal asymmetric induction – refers to the control of stereoselectivity exerted by an existing chiral centre on the formation of new chiral centre. Chiral pool is the collection of cheap , readily available natural products . Eg :(+)nicotine, (+)tartaric acid, D-glyceraldehyde etc .

11. II Use of chiral auxiliary In this approach a prochiral substrate attach with a chiral auxiliary to give a chiral intermediate. During which auxiliary directs the preferred stereochemistry. Finally we can remove the auxiliary from product to use it again. It is an relayed asymmetric induction – refers to the control of stereoselectivity exerted by chiral auxiliary on the formation of new chiral center Eg - Asymmetric alkylation of cyclohexanone using SAMP

12. III Use of chiral reagents In this method an inactive substrate converted selectively into one of the enantiomer (enantiospecific). In this type of synthesis chiral reagent turns achiral by transforming an achiral substrate to chiral. Thus the reagent is “self- immolative ”

13. IV Use of chiral catalyst In this 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. Ru-catalysed asymmetric hydrogenation of unsaturated carboxylic acids

14. Ru-catalysed asymmetric hydrogenation of allylic alcohols The industrial application for the catalytic asymmetric synthesis is the production of the painkiller (S)-naproxen

15. METHODS ADVANTAGES DISADVANTAGES Chiral Pool 100% ee is guaranteed Often only 1 enantiomer available Chiral Auxiliary Often excellent ee & can recrystallize to purify to high ee Extra steps to introduce and remove auxiliary Chiral Reagent Often excellent ee & can recrystallize to purify to high ee Only few reagents are successful and often for few substrates Chiral Catalyst Economical, only small amounts are recyclable material used Only few reactions are really successful

16. Absolute Asymmetric Synthesis It is the synthesis of optically active products from achiral substrate without the use of optically active reagents. In this type of synthesis a physical presence of chirality is necessary. Eg : Addition of bromine to 2,4,6-trinitrostilbene give a dextrorotatory product. Here we are using circularly polarized light for the induction of chirality. The role of circularly polarized light is reminiscent of an optically active compound in conventional resolution.

17. REFERENCES Stereochemistry CONFORMATION AND MECHANISM – P S Kalsi BASIC ORGANIC CHEMISTRY : Ernest L Eliel   Clayden , Jonathan, Nick Greeves and Stuart Warren. Organic Chemistry, 2nd Edition. Oxford. 2012. 

18. Thank you Any Questions?