Asymmetric synthesis

Retro and Asymmetric synthesis of organic compounds.

1. Asymmetric Synthesis Presented BY : Faizan Ahmed m.Sc(F) presented to : Dr. Imran Ali Hashmi

2. Introduction to Organic Synthesis. Retro and asymmetric synthesis. Why asymmetric Synthesis? Overviews. Contents

3. Introduction of organic synthesis Organic compounds and many other compounds that are physiologically active are synthesized in past century. A number of compounds synthesized like Vitamins, artificial flavors and many pharmaceuticals drugs. Small amounts of many drugs can be isolated from plants or marine animals; much greater quantities are made by chemists in laboratories. A proposal for the synthesis of the target molecule, irrespective of its complexity , can be elaborated by retrosynthetic analysis based on the disconnection approach.

4. Retro Synthesis

5. Guide lines for Organic Synthesis Disconnections must correspond to known, reliable reactions . Synthons are idealized reagents. For compounds consisting of two parts joined by a heteroatom, disconnect next to the heteroatom. Multiple step syntheses, avoid Chemoselectivity problems. Consider alternative disconnections and choose routes that avoid Chemoselectivity problems—often this means disconnecting reactive groups first . Functional Group Interconversion Two-group disconnections are better than one-group disconnections

6. Disconnections must correspond to known, reliable reactions Paracetamol , for example, is an amide that can be disconnected either To amine + acyl chloride Synthon = OR To amine + anhydride Equivelents

7. Synthons are idealized reagents . Synthons are fragments of molecules, that can be used in the forward synthesis. It has an associated polarity (represented by a ‘ + ‘ or ‘–’) which stand for the reagents. Example: The herbicide 2,4-D ( 2,4-dichlorophenoxyacetic acid ).

8. Synthons are idealized reagents.

9. For compounds consisting of two parts joined by a heteroatom, disconnect next to the heteroatom.

10. Multiple step syntheses, avoid Chemoselectivity problems —often this means disconnecting reactive groups first . The next compound was an intermediate in the synthesis of the potential anti-obesity drug ICI-D7114. It has two ethers and an amine functional group. it requires several disconnections to take it back to simple compounds.

11. Both ( a ) and ( b ) pose problems of chemoselectivity as it would be hard to alkylate the phenol in the presence of the basic nitrogen atom. Between ( c ) and ( d ), ( c ) appears to be the better choice because the next disconnection after ( d ) will have to be an alkylation of O in the presence of an NH 2 group. To avoid chemoselectivity problems like this, we want to try to introduce reactive groups late in the synthesis.

12. Consider alternative disconnections and choose routes that avoid Chemoselectivity . This guideline helps us in the next retrosynthetic step for the ICI-D7114 intermediate. Disconnection ( c ) gave us a compound with two ethers that might be disconnected further by disconnection ( e ) or ( f ).

13. Functional Group Interconversion Chemoselectivity problems are also avoided by FGI. As the two different Functional group effect different during the reaction. Drug ofornine contains an amide and an amine functional group.

14. ( a ) seems to pose a problem because we now have to construct an amine in the presence of an acyl chloride. Using FGI the acyl chloride from the carboxylic acid, which can then easily be disconnected to 2-aminobenzoic acid ( anthranilic acid) and 4-chloropyridine. If disconnect the secondary amine first ( b ), we have chemoselectivity problem constructing the amide in the presence of the resulting NH 2 group.

15. Functional Group Interconversion

16. Functional Group Interconversion The synthesis of amines poses a special problem. The problem is that the product is usually more reactive than the starting material and multiple alkylation will take place . Further alkylation is made unfavourable by a) Increased Steric hindrance b) Functional group interconversion .

17. Functional Group Interconversion Further alkylation is made unfavourable by a) Increased Steric hindrance b) Functional group interconversion .

18. Two-group disconnections are better than one-group disconnections it might be hard to control selective alkylation of the primary hydroxyl group in the presence of the secondary one . We have used one functional group to help disconnect another —in other words, we noticed the alcohol adjacent to the ether we wanted to disconnect and managed to involve them both in the disconnection. Such disconnections are known as two-group disconnections.

19. Two-group disconnections are better than one-group disconnections

20. Why asymmetric Synthesis ? In a chiral molecule, From diastereomers , the preparation of one enantiomer is called asymmetric synthesis or enantioselective . Asymmetric synthesis is synthesis of an enantiomerically pure compound . When more stereogenic centers are present , asymmetric synthesis of an optically pure compound is preferred . The painkiller naproxen marketed only as their S- enantiomer because the R- enantiomer is essentially inactive.

21. Why asymmetric Synthesis? A s you read the book you are probably turning the pages with your right hand and processing the information with the left side of your brain . The smells of orange and lemon differ in being the left- and right-handed versions of the same molecule, L imonene . ( R )-(+)-Limonene smells rounded and orangey whereas ( S )-(–)-limonene is sharp and lemony. Similarly, spearmint and caraway seeds smell quite different,again this pair of aromas differs only in being the enantiomeric forms of the ketone carvone .

22. Some Asymmetric Compounds

23. asymmetric Synthesis A laboratory synthesis of a chiral compound from achiral or racemic starting materials alone always gives a racemic mixture of enantiomers. If you want to make just one enantiomer, you have to use a starting material or reagent which is also just one enantiomer . Chiral Pool: Nature provides a collection of enantiomerically pure compounds that we can exploit in various ways. The collection of natural, enantiomerically pure compounds is called the chiral pool .

24. Examples of chiral pools The amino acids . Simple derivatives of the amino acids: amino alcohols and hydroxy acids . Carbohydrates and their derivatives .

25. Resolution can be used to separate enantiomers Resolution as a means of separating enantiomers. Resolution requires an enantiomerically pure resolving agent, which must be a compound from the chiral pool or a simple derivative of that compound . It give maximum 50% yield as 50% wasted.

26. Chiral Auxiliaries Diastereoselective reactions work just as well whether the starting material is racemic or enantiomerically pure. Chiral Auxiliary assists the substrate to react in a diastereoselective way such that only one of the two possible products is allowed to form. The chiral auxiliary is enantiomerically pure to start with, so the product must be diastereoisomerically and enantiomerically pure. Start with enantiomerically pure material you get enantiomerically pure product.

27. Common Chiral Auxiliary Valine is the chiral auxiliary. It is a member of the oxazolidinone (the name of the heterocyclic ring ) family of auxiliaries developed by David Evans at Harvard University. It is easily and cheaply made from the amino acid ( S )- valine . It can be recycled. The last step of the route, regenerates the auxiliary ready for re-use.

28. chiral auxiliary strategy An enantiomerically pure compound (usually derived from a simple natural product like an amino acid), called a chiral auxiliary, is attached to the starting material. A diastereoselective reaction is carried out, which, because of the enantiomeric purity of the chiral auxiliary, gives only one enantiomer of the product. The chiral auxiliary is removed by hydrolysis , leaving the product of the reaction as a single enantiomer. The best chiral auxiliaries (of which the example above is one ) can be recycled, so although stoichiometric quantities are needed, there is no waste.

29. Asymmetric synthesis using chiral auxiliary The product of a Diels–Alder reaction between cyclopentadiene and benzyl acrylate must racemic as both reagents are achiral. one diastereoisomer —the endo product—is formed, with an exactly 50:50 mixture of enantiomers .

30. using chiral auxiliary Finally comes the step which shows the power of chiral auxiliary strategy. Remove the chiral auxiliary from the product by treating with a nucleophile.

31. using chiral auxiliary

32. chiral auxiliary (Alkylation of enolates ) Treatment with base (usually LDA) at low temperature produces an enolate . The bulky auxiliary means that only the cis enolate forms and the trans enolate is too hindered.

33. chiral auxiliary (Alkylation of enolates ) Electrophiles have little choice but to attack the enolate from the front. The table shows the ratio of diastereoisomers (the diastereoisomeric ratio, abbreviated to d.r .) produced for a selection of alkylating agents .

34. Retro and Asymmetric Synthesis of (S)-1-(Pyridine-3-yl) propan-1-ol

35. Asymmetric Synthesis of (S)-1-(Pyridine-3-yl) propan-1-ol we completely neglected the stereochemistry. This is chiral molecule, and in praxis usually preparation of one enantiomer. The asymmetric synthesis of an optically pure compound is preferred. Let as now assume that our target is (S)-TM . When performed in the presence of a chiral catalyst with a defined absolute configuration. The catalyst induces an S-configuration in the enantiomer of TM.

36. Asymmetric Synthesis of (S)-1-(Pyridine-3-yl) propan-1-ol

37. Mechanism

38. References Organic Chemistry 2 nd edition Jonathan Clayden , Nick Greeves , and Stuart Warren Organic Chemistry from Retrosynthesis to Asymmetric Synthesis Author: Vitomir Šunjić • Vesna Petrović Peroković Springer. Organic Synthesis 2 nd edition Stuart Warren.