Mastering Asymmetric Catalysis: Enantiomerically Pure Molecules

1. Year 3 CH3E4 notes: Asymmetric Catalysis, Prof Martin Wills 2012-2013 You are aware of the importance of chirality. This course will focus on asymmetric catalysis, i.e. the use of a catalyst to create new enantiomerically pure molecules. This can be achieved in several ways: Introductory, no need to revise, but understand concepts. 1) A metal atom may ‘template’ the reaction in some way e.g. Sharpless epoxidation of alkenes: 2) A covalent intermediate may be formed – a catalytic unit binds in a temporary process to the substrate: M Wills CH3E4 notes

2. understand concepts. 3) The reaction may take place within an asymmetric environment controlled by an external source: The key features of these approaches will be described and examples from the literature will be described. Some examples of enantiomerically pure drugs: M Wills CH3E4 notes

3. For information only. No need to memorise. 9 out of the top ten US prescribed drugs in 2010 are in single enantiomer form http://cbc.arizona.edu/njardarson/group/sites/default/files/Top 200 Brand-name Drugs by Total US Prescriptions in 2010sm_0.pdf M Wills CH3E4 notes

4. Oxidation reactions of alkenes. Understand how each enantiomer of ligand gives a different product enantiomer. The Sharpless dihydroxylation reaction employs ligand-acceleration to turn the known dihydroxyation reaction into an asymmetric version. M Wills CH3E4 notes

5. Understand how each enantiomer of ligand gives a different product enantiomer. Be aware and learn which enantiomer is formed relative to the substituents using each form of ‘ADmix’. M Wills CH3E4 notes 5

6. Oxidation reactions of alkenes. Learn the two possible mechanisms for the oxidation, The means by which chirality transfer is achieved is not fully understood. Evidence favours the [3+2] addition mechanism: K. B. Sharpless et al, J. Am. Chem. Soc. 1997, 119, 9907. 6 M Wills CH3E4 notes

7. Oxidation reactions of alkenes. No need to memorise the examples, but understand what the dihydroxylation achieves, and how versatile it can be. M Wills CH3E4 notes

8. Understand the concepts, no need to memorise examples. M Wills CH3E4 notes

9. Zaragozic acid synthesis – key asymmetric dihydroxylations. Understand the concepts, no need to memorise examples on this slide. K. C. Nicolaou. E. W. Yue, Y. Naniwa, F. DeRiccardis, A. Nadin, J. E. Leresche. S. LaGreca. Z. Yang, Angew. Chem. Int. Ed.1994, 33, 2184

10. Reduction reactions of Double bonds (C=C, C=N, C=O). M Wills CH3E4 notes

11. Reduction reactions of Double bonds (C=C, C=N, C=O). Understand how a chiral environment is created around Rh(I) and how the enamine substrate co-ordinates. Addition of hydrogen to an acylamino acrylate results in formation of an amino acid precursor. The combination of an enantiomerically-pure (homochiral) ligand with rhodium(I) results in formation of a catalyst for asymmetric reactions. M Wills CH3E4 notes 11

12. Rh-diphosphine complexes control asymmetric induction by controlling the face of the alkene which attaches to the Rh. Hydrogen is transferred, in a stepwise manner, from the metal to the alkene. The intermediate complexes are diastereoisomers of different energy. Using Rh(DIPAMP) complexes, asymmetric reductions may be achieved in very high enantioselectivity. Understand how a chiral environment is created around Rh(I) and how the enamine substrate co-ordinates. M Wills CH3E4 notes

13. Other chiral diphosphines are not chiral at P, but contain a chiral backbone which ‘relays’ chirality to conformation of the arene rings. Understand how a chiral environment is created around Rh(I). M Wills CH3E4 notes

14. Reduction reactions of C=C Double bonds using Rh(I) complexes– representative examples. No need to memorise examples but understand that the sense of reduction in each case is relative to the directing group X. M Wills CH3E4 notes

15. Reduction reactions of C=C Double bonds using Rh(I) complexes– representative examples. No need to memorise examples - understand that the sense of reduction in each case is relative to the directing group X – different ligands give different product enantiomers. M Wills CH3E4 notes 15

16. Reduction reactions of Double bonds using catalysts derived from Ru(II) (C=C). Learn that Ru(II) complexes of diphosphine ligands can also direct hydrogenations. No need to memorise examples. M Wills CH3E4 notes

17. Reduction reactions of Double bonds using catalysts derived from Ru(II) (C=C). Learn that Ru(II) complexes of diphosphine ligands can also direct hydrogenations of allylic alcohols. No need to memorise examples. M Wills CH3E4 notes 17

18. Reduction reactions of isolated C=C double bonds can be achieved with variants of Crabtree’s catalyst. No need to memorise examples. M Wills CH3E4 notes

19. Reduction reactions of isolated C=C double bonds can be achieved with variants of Crabtree’s catalyst. Understand that Ir(I) complexes with P and N donors can reduce double bonds without a directing group in the substrate, i.e. sterically-driven. No need to memorise examples. M Wills CH3E4 notes 19

20. Reduction reactions of C=O Double bonds using organometallic complexes. Understand that a C=O group can be reduced by a chiral Ru or Rh complex as well. No need to memorise examples. M Wills CH3E4 notes

21. Reduction reactions of C=O Double bonds using organometallic complexes. Understand that a C=O group can be reduced by a Ru or Rh complex as well. No need to memorise examples. M Wills CH3E4 notes

22. Reduction reactions of C=O Double bonds using organometallic complexes. Dynamic kinetic resolution can result in formation of two chiral centres: Learn that a beta-keto ester can epimerise rapidly and that one enantiomer is more quickly reduced. Be able to draw the mechanism of this. No need to memorise examples. M Wills CH3E4 notes

23. Reduction reactions of C=O Double bonds using organometallic complexes. Dynamic kinetic resolution can result in formation of two chiral centres: No need to memorise examples – these illustrate the diversity of the process. M Wills CH3E4 notes

24. Ketone reduction by pressure hydrogenation (i.e. hydrogen gas) can be achieved using a modified catalyst containing a diamine, which changes the mechanism. Understand that the mechanism changes when a diamine is added to a Ru(II)/diphosphine complex, and this allows C=O bonds to be reduced without a nearby directing group present. Be able to draw the mechanism of this. M Wills CH3E4 notes

25. Ketone reduction by pressure hydrogenation (i.e. hydrogen gas) can be achieved using a modified catalyst containing a diamine, which changes the mechanism. No need to memorise the examples. M Wills CH3E4 notes

26. The use of hydride type reagents. Understand that hydride reagents can also be used in reductions. Be able to draw the mechanism of the hydride transfer step. Transfer hydrogenation – Ru catalysts. M Wills CH3E4 notes

27. Examples of reductions using transfer hydrogenation with metal complexes: add C=O and C=N reductions. These are examples to provide an appreciation of the scope, No need to memorise examples. M Wills CH3E4 notes

28. These are examples to provide an appreciation of the scope, No need to memorise examples. M Wills CH3E4 notes 28

29. Asymmetric transfer hydrogenation by organocatalysis. Understand that Hantzsch esters are used as reagents for reduction of C=N bond in organocatalysis reactions. Be able to draw the mechanism of the hydride transfer step and the imine formation. No need to memorise examples. M Wills CH3E4 notes

30. Asymmetric transfer hydrogenation by organocatalysis. No need to memorise examples, but understand the concepts. M Wills CH3E4 notes

31. More applications of organocatalysis. Understand that the combination of a chiral amine and a ketone or aldehyde forms an enamine which directs a subsequent aldol reaction. Be able to draw the mechanism of the enamine formation, the reaction with a ketone or aldehyde and the subsequent hydrolysis step. No need to memorise examples. M Wills CH3E4 notes

32. More applications of organocatalysis. No need to memorise examples – these illustrate the diversity of the process. M Wills CH3E4 notes

33. More applications of organocatalysis which proceed via formation of an enamine – bonds to C atoms. These are examples to provide an appreciation of the scope, No need to memorise examples. M Wills CH3E4 notes

34. C=C reduction by organocatalysis. Understand that a chiral amine can direct a conjugate reduction reaction. Be able to draw the mechanism of the hydride transfer step and the imine formation and hydrolysis. No need to memorise examples. 34

35. C=C reduction by organocatalysis. No need to memorise examples. M Wills CH3E4 notes 35

36. Allylic substitution reactions are powerful methods for forming C-C bonds. Understand that a flat allyl complex is formed and that the ligand directs a nucleophile to one end by a combination of steric and electronic factors. No need to memorise examples. M Wills CH3E4 notes

37. Allylic substitution reactions are powerful methods for forming C-C bonds. Understand that a flat allyl complex is formed and that the ligand directs a nucleophile to one end by a combination of steric and electronic factors. No need to memorise examples. M Wills CH3E4 notes

38. Allylic substitution reactions – examples of ligands and reactions. These are examples to provide an appreciation of the scope, No need to memorise examples. Just understand that a Pd/chiral ligand combination is required. M Wills CH3E4 notes 38

39. Allylic substitution reactions – examples of ligands and reactions. These are examples to provide an appreciation of the scope, No need to memorise examples. Understand that a Pd/chiral ligand combination is required. M Wills CH3E4 notes 39

40. Allylic substitution reactions – examples of ligands and reactions. These are examples to provide an appreciation of the scope, No need to memorise examples.

41. Asymmetric catalysis – Isomerisation Understand that this is an isomerisation. M Wills CH3E4 notes

42. Uses of enzymes in asymmetric synthesis. this can Invert an alcohol overall. Understand that asymmetric reactions can be achieved using an enzyme. By racemising the substrate, the reaction can give 100% of a chiral product. M Wills CH3E4 notes

43. Uses of enzymes in asymmetric synthesis. this can Invert an alcohol overall. Understand that asymmetric reactions can be done by an enzyme. By racemising the substrate, the reaction can give 100% of a chiral product. No need to memorise mechanism of racemisation. M Wills CH3E4 notes

44. Uses of dehydrogenase enzymes in synthesis. These are examples to provide an appreciation of the scope, No need to memorise examples. Enzyme catalysis: amine oxidation. Chem. Commun. 2010, 7918-7920. For a nice example of use of an enzyme in dynamic kinetic resolution to make side chain of taxol see: D. B. Berkowitz et al. Chem. Commun. 2011, 2420-2422. M Wills CH3E4 notes

45. These are examples to provide an appreciation of the scope, No need to memorise examples. Review on directed evolution by Reetz: M. T. Reetz, Angew. Chem. Int. Ed. 2011, 50, 138-174. By undertaking cycles of directed evolution, highly selective enzymes can be prepared, as shown by the example of desymmetrisation (Baeyer-Villiger reaction) shown below: M Wills CH3E4 notes

46. Other asymmetric reactions – for interest. Concluding material, non examinable. M Wills CH3E4 notes

47. There are many other reactions which have been converted into asymmetric processes. Concluding material, non examinable. Other reactions: Hydrosilylation Hydroacylation Hydrocyanation Epoxidation using iminium salts Asymmetric allylation Hetero Diels-Alders 1,3-dipolar cycloadditions. [2+2] cycloadditions Cyclopropanation Cross coupling reactions Conjugate addition reactions Etc. etc. M Wills CH3E4 notes