Group 5 Organic Chem 2 of chiral centers and racemization

Describes synthesis of new chiral centers and resolution of racemic mixtures

1. Organic chemistry 2 Group 5

2. Group members KABUUKA RICHARD VU-BPC-2307-0724-DAY NOURELDEIN ABDALLAH VU-BPC-2307-0889-DAY KAGOYA AGNESS VU-BPC-2307-0313-DAY KOBUSINGYE PHIONA VU-BPC-2307-1114-DAY

3. CONTENTS ASYMETRIC CENTRES RACEMIC MIXTURES ROLE OF RACEMIZATION QUESTIONS

4. Asymmetric synthesis Asymmetric synthesis is a reaction in which an achiral unit in a substrate a 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.

5. EXAMPLE :reduction of pyruvic acid. Chiral environment is the necessary condition for asymmetric synthesis.

6. DEPENDING ON THE RELATIONSHIP BETWEEN PRODUCTS FORMED DURING ASYMMETRIC SYNTHESIS ,REACTION MAY BE ENANTIOSELECTIVE OR DIASTEREOSELECTIVE . A+B C + D STEREOISOMERS C and D formed in unequal amounts STEREOSELECTIVE C and D are diastereomers C and D are enantiomers DIASTEREOSELECTIVE ENANTIOSELECTIVE

7. FUNDAMENTALS One of the two conditions need to be met for successful asymmetric synthesis. PROCHIRALITY A tetrahedrally bonded achiral atom have general formula Cabc2 will become a chiral center Cabcd on replacement of one of the identical ligand c with a different ligand d is called a prochiral centre and the molecule is said to be prochiral .

8. DEPENDING ON THE PRODUCT FORMED FROM A PROCHIRAL CENTRE, THE MOLECULE WILL BE ENANTIOTOPIC OR DIASTEREOTOPIC . Eg:Enantiotopic Eg:Diastereotopic

9. B) ASYMMETRIC INDUCTION The second condition of asymmetric synthesis is brought about in the reaction pathway by the presence of an element of chirality, which plays an active role in the reaction. Property of chirality is induced by chiral reagent,solvent,catalyst or circularly polarized light

10. Importance of synthesis of new chiral centers Before 1940 optically pure compound is obtained by isolation from natural products, resolution of racemic mixture and by laboratory controlled enzymatic reactions, but the yield of optically pure compound was very less. All natural or biologically occurring molecules are chiral . Because nature uses enzymes ,these are biological catalysts. Synthesis of optically pure substance are important because different enantiomers or diasteroemers of a compound have different biological activity. Eg :+ and – thalidomide have different action with biological receptors.

11. MECHANISM OF ASYMMETRIC SYNTHESIS 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

12. If we are using chiral components , then we could make the possible enantomeric transition state , diastereomeric transition state with different activation energy which results in unequal amounts of isomers. We have to go through a diastereomeric transition state to achieve asymmetric synthesis.

13. MAJOR APPROACHES IN ASYMMETRIC SYNTHESIS Asymmetric synthesis are of two types PARTIAL ASYMMETRIC SYNTHESIS synthesis of a new chiral center from an achiral center by using optically active reagents . Different methods of partial asymmetric synthesis are: 1) Use of chiral substrate (first generation method) It uses natures ready-made chiral centers as starting materials . More economical way of making compounds in enantiopure form.

14. Eg : Conversion of 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 .

15. This method is also known as “ CHIRAL POOL” STRATEGY. Chiral pool is the collection of cheap , readily available natural products . Eg :(+)nicotine, (+)tartaric acid, D-glyceraldehyde etc . Nucleophilic attack on acyclic carbonyl compounds : For certain additions to c=o groups of chiral aldehyde or ketones CRAM’S RULE is useful to predict which diastereomer will predominate .

16. 2) Use of chiral auxiliary (second generation method) In this approach a prochiral substrate attach with a chiral auxiliary to give a chiral intermediate. During which auxiliary dictates the preferred stereochemistry. Finally we can remove the auxiliary from product to use it again . Eg : asymmetric alkylation of cyclohexanone using SAMP .

17. Eg : Asymmetric halolactonization – Synthesis of α -hydroxyl acid

18. 3)Use of chiral reagents (third generation methods) 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 ” eg :

19. Eg : Reduction of a prochiral carbonyl group enantioselectively by a chiral reducing agent

20. 4)Use of chiral catalyst 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 : Sharpless asymmetric epoxidation- It is an enantioselective reaction that oxidises alkenes to epoxides.

21. The mechanism of Sharpless asymmetric epoxidation involves following steps .

22. B) 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.

23. Eg : Light induced cyclisation of 1,2 – diarylethylenes to dihydrophenanthrene derivatives The role of circularly polarized light is reminiscent of an optically active compound in conventional resolution. It combines with individual enantiomers of diarylethylene , forming a pair of excited states which are diastereomerically related and thus formed and decomposed at different rates .

24. Advantages and disadvantages of different methods METHODS ADVANTAGES DISADVANTAGES RESOLUTION Both enantiomers are available Maximum 50% yield 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 of recyclable material used Only few reactions are really successful.

25. RESOLUTION OF RACEMIC MIXTURE 26

26. ENANTIOMERS: Isomers which are nonsuperimposable mirror images of each other are called enantiomers . These are distinguished by 1)+/- 2)D/L 27 (l/-)- enantiomer (anticlockwise rotation) (dl/±)- racemate (no overall effect) (d/+)- enantiomer (clockwise rotation)

27. RACEMIC MIXTURE: A equimolar (50/50) mixture of the two enantiomers is called a racemic mixture or a racemate . Enantiomers have identical chemical and physical properties, except:Their effect on plane polarised light. RESOLUTION: the process of seperation of pure enantiomer from their racemic modification is called resolution. 28

28. NEED FOR RESOLUTION OF RACEMIC MIXTURE: CETRIZINE 29   levocetirizine has been found to be less sedating than cetirizine

29. Levodopa 30 levodopa (L-dopa) is used in treatment of Parkinson’s disease, its D-form causes serious side effects,such as granulocytopenia

30. 31

31. 1.MECHANICAL SEPARATION OR SPONTANEOUS RESOLUTION: This invoved mechanical separation of the crystal of one enantiomers from the other in racemic mixture based on difference in their shapes Crystal of the two forms have different shapes separated by magnifying lens and forceps This method first used by pasteur for he resolutiuon of sodium ammonium tartarate which crystallise out in the form of racemic mixture below 27 degree This methods is time consuming and every compound can not be crystallized at room temperature 32

32. 2.PREFERENTIAL CRYSTALIZATION BY INOCULATION: This method involve seeding of a saturated solution of the racemic mixture with a pure crystal of one the two enantiomers . The soluition now become suppersaturated 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 33

33. 3.BIOCHEMICAL SEPARATION: It was introduced by PASTEUR in 1858. This method is based on fact that when certain micro organisms like bacteria,fungi,yeast,moulds,etc are grown in dilute solution of racemic mixture,they eat up one enantiomer rapidly than other. Example: the mould penicillium glaucum preferentially destroys the (+) isomer of racemic ammonium tartarate leaving (-) ammonium tartarate in solution . 34

34. 4.CHROMATOGRAPHIC SEPERATION: The racemic mixture can be separated by chromatography on an optically active support. The diastereomeric adsorbates which are formed have different stabilities. Thus one enantiomer will be held more tightly than the other and would be eluted first. 35

35. 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. menthol reacts faster with (+) mandelic acid than with (-) mandelic acid. Thus with difference in kinetics of reaction,racemic mixture can be seperated . 36

36. 6.PRECIPITATION: This method is based on formation of precipitate by reaction between any reagent and racemic mixture. Example: (+) & (-) narcotine when dissolved in HCL ,precipitates (+) narcotine . 37

37. 7.BY 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 38

38. Factors affecting racemization Racemization is the chemical process where an optically active chiral compound is converted into a racemic mixture of its enantiomers. Temperature ;higher temp generally increases the rate of racemization because thermal energy facilitates the molecular motions by overcoming activation barriers thus increasing action to equilibrium of both forms. Concentration ; higher concentration lead to frequent collision between molecules thus high rates of racemization 39

39. CONTN Catalyst ; these provide an alternative reaction pathway with lower activation energy thus accelerating racemization eg metal ions. Solvent effects ; polar solvents such as water can stabilize intermediates that favor racemization .and also its ability to form hydrogen bonds influence the rate . PH ; Strong acids and bases catalyze racemization by creating intermediates that alter protonation reactions thus increasing chances of reactions into products . 40

40. Applications of Resolution Of Racemic Mixture:- To reduce the adverse drug reaction by making optically inactive form of racemates . To improve the Therapeutic effect of drug. Some enantiomers have side effects (thalidomide) Minimising dosage but increasing efficacy. To improve the chemical stability of a compound; so it can not change its chemical properties when come in contact with the atmosphere or humidity. 41

41. RECENT OPTICALLY ACTIVE DRUGS: Amlodipine Metoprolol Atenolol Omeprazole (OME) Cetirizine Pentoprazole Ketamine Salbutamol Ketoprofen Propranolol Ibuprofen 42

42. questions 1.A patient requires treatment with a chiral compound known for its enantiomeric specificity in pharmacological action.discuss how understanding chirality and resolution techniques can impact personalized medicine approaches for this patient? 2. Dr. Smith is leading a team at a pharmaceutical company developing a new drug that exhibits different therapeutic effects based on its stereochemistry. He seeks advice from Sarah, the regulatory affairs specialist, regarding potential racemization issues and how to ensure the safety and efficacy of their product .   43

43. qtns 3.Investigator Amarra leads an inquiry into adverse effects observed due to unintended species resulting from racemization during patients’ medication usage while Regulatory Officer Agness proposes strategies focusing improved quality control measures preventing such occurrences through enhanced oversight procedures.suggest the strategies.   4.Chemical Engineer Richard faces challenges optimizing production processes creating asymmetric centers essential producing key intermediates used in synthesizing high-value pharmaceuticals ; together with Quality Control Manager Phionah they strategize modifications existing procedures enhance yield purity desired products while minimizing formation unwanted by-products . 44

44. references The organic chemistry of drug synthesis Essentials of organic chemistry Wilson and Gisvold’s textbook of organic medicinal and pharmaceutical chemistry. 45

45. THANK YOU