1 Year 3 CH3E4 notes: Asymmetric Catalysis, Prof Martin Wills 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: M Wills CH3E4 notes Introductory, no need to revise, but understand concepts. 2) A covalent intermediate may be formed – a catalytic unit binds in a temporary process to the substrate: 1) A metal atom may ‘template’ the reaction in some way e.g. Sharpless epoxidation of alkenes:

2M Wills CH3E4 notes 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: understand concepts.

3 M Wills CH3E4 notes 9 out of the top ten US prescribed drugs in 2010 are in single enantiomer form Brand-name Drugs by Total US Prescriptions in 2010sm_0.pdf For information only. No need to memorise.

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

5M Wills CH3E4 notes 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’.

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

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

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

9 Zaragozic acid synthesis – key asymmetric dihydroxylations. 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 Understand the concepts, no need to memorise examples on this slide.

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

11M Wills CH3E4 notes Reduction reactions of Double bonds (C=C, C=N, C=O). 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. Understand how a chiral environment is created around Rh(I) and how the enamine substrate co-ordinates.

M Wills CH3E4 notes12 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 notes13 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).

14M Wills CH3E4 notes 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.

15M Wills CH3E4 notes 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.

16M Wills CH3E4 notes 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.

17M Wills CH3E4 notes 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.

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

19M Wills CH3E4 notes 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.

20M Wills CH3E4 notes 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.

21M Wills CH3E4 notes 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.

22M Wills CH3E4 notes 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.

23M Wills CH3E4 notes 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.

24 Ketone reduction by pressure hydrogenation (i.e. hydrogen gas) can be achieved using a modified catalyst containing a diamine, which changes the mechanism. M Wills CH3E4 notes 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.

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

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

27M Wills CH3E4 notes 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.

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

29M Wills CH3E4 notes 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.

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

31 More applications of organocatalysis. M Wills CH3E4 notes 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.

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

33M Wills CH3E4 notes 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.

C=C reduction by organocatalysis. 34 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.

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

36 M Wills CH3E4 notes 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.

37 M Wills CH3E4 notes 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.

38M Wills CH3E4 notes 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.

39M Wills CH3E4 notes 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.

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

M Wills CH3E4 notes41 Asymmetric catalysis – Isomerisation Understand that this is an isomerisation.

42M Wills CH3E4 notes 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.

43M Wills CH3E4 notes 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.

44M Wills CH3E4 notes Enzyme catalysis: amine oxidation. Chem. Commun. 2010, Uses of dehydrogenase enzymes in synthesis. 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, These are examples to provide an appreciation of the scope, No need to memorise examples.

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

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

47M Wills CH3E4 notes There are many other reactions which have been converted into asymmetric processes. 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. Concluding material, non examinable.