1 Year 3 CH3E4 notes: Asymmetric Catalysis, Prof Martin Wills Reorganised to highlight key areas to learn and understand. You are aware of the importance of chirality. This section 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:

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: Introductory, no need to revise, but understand concepts.

3M 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. No need to memorise which way round it goes.

4M Wills CH3E4 notes Understand how each enantiomer of ligand gives a different product enantiomer. No need to memorise which way round it goes.

5 M Wills CH3E4 notes Oxidation reactions of alkenes. Most recent evidence favours the [3+2] addition mechanism: K. B. Sharpless et al, J. Am. Chem. Soc. 1997, 119, Learn the two possible mechanisms. No need to memorise examples.

6 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.

7M Wills CH3E4 notes Jacobsen epoxidation of alkenes: The iodine reagent transfers its oxygen atom to Mn, then the Mn tranfers in to the alkene in a second step. The chirality of the catalyst controls the absolute configuration. Advantage? You are not limited to allylic alcohols Sharpless aminodihydroxylation is a closely-related process Understand the concepts, no need to memorise examples on this slide.

8M Wills CH3E4 notes Reduction reactions of Double bonds (C=C, C=N, C=O). Learn how a chiral environment is created around Rh(I) and how the enamine substrate co-ordinates.

9M Wills CH3E4 notes Reduction reactions of Double bonds (C=C, C=N, C=O). Learn how a chiral environment is created around Rh(I) and how the enamine substrate co-ordinates. Understand that there is a difference in energy between the diastereoisomers which leads to enantioselectivity. This isomer leads to product, with hydrogen transferred to back face as drawn. The difference in reactivity may be due to extra stability of one diastereoisomer or increased activity of one of them.

10M 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.

11M 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.

12M 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.

13M 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.

14M 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.

15M 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 substrate. No need to memorise examples.

16M 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.

17M 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.

18M Wills CH3E4 notes Reduction reactions of C=O Double bonds using organometallic complexes. Dynamic kinetic resolution can result in formation of two chiral centres: Understand 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.

19M 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.

20 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.

21 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.

22M Wills CH3E4 notes The use of hydride type reagents. Oxazaborolidines require a relatively high catalyst loading of 10%, But are effective in several applications. Understand that hydride reagents can also be used in reductions. Understand how the mechanism of hydride transfer relates to the previous slide. Be able to draw the mechanism of the hydride transfer step.

23M Wills CH3E4 notes The use of hydride type reagents. More contemporary focus is on asymmetric transfer hydrogenation and on organocatalysis. Transfer hydrogenation – Ru catalysts. Understand that hydride reagents can also be used in reductions. Understand how the mechanism of hydride transfer relates to the previous slide. Be able to draw the mechanism of the hydride transfer step.

24M 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.

25M Wills CH3E4 notes These are examples to provide an appreciation of the scope, No need to memorise examples.

26M 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.

27M Wills CH3E4 notes Asymmetric transfer hydrogenation by organocatalysis. No need to memorise examples, but understand the concept.

28M Wills CH3E4 notes Formation of chiral centres by nucleophilic additions to unsaturated bonds. Diethylzinc additions Another interesting fact: DAIB of 15% ee will give a product of 95% ee! This is because the dimer made from one of each enantiomer is more stable, and does not split up to enter the catalytic cycle. Ph H HH This slide is for information only and does not need to be memorised for the exam.

29 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.

30 More applications of organocatalysis. M Wills CH3E4 notes No need to memorise examples.

31M 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. 20 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. 20 No need to memorise examples.

34M Wills CH3E4 notes Additions to C=O – aldol reactions are a very important class of synthetic reaction. These slides are for information only and do not need to be memorised for the exam. However you should understand that addition of a silyl enol ether to an aldehyde can by catalysed by a Lewis acid.

35M Wills CH3E4 notes Additions to C=O – aldol reactions are a very important class of synthetic reaction. This slide is for information only and do not need to be memorised for the exam. However you should understand that addition of a silyl enol ether to an aldehyde can by catalysed by a Lewis acid.

Other examples of metal/ligand-catalysed asymmetric aldol reactions. This slide is for information only and do not need to be memorised for the exam. However you should understand that addition of a silyl enol ether to an aldehyde can by catalysed by a Lewis acid.

37M Wills CH3E4 notes Cycloaddition reactions can be catalysed by Lewis acid/chiral ligands. The ligand and metal choice can have a dramatic effect: Understand how a copper complex of the bis(oxazolidine) ligand can control the Diels-Alder reaction. Be able to draw the complex of Cu and Mg and illustrate which face the cyclic diene adds from. Be able to draw the product, which is of endo stereochemistry. Do not memorise examples.

38M Wills CH3E4 notes Cycloaddition reactions can be catalysed by Lewis acid/chiral ligands. The ligand and metal choice can have a dramatic effect: No need to memorise examples, but understand how the selectivity is controlled.

There are many other similar catalysts for Lewis-acid catalysed Diels-Alder reactions. Organocatalysts can be applied to Diels-Alder reactions, by forming a cationic intermediate: 24 Be able to draw the Cu complex and how it controls the reaction. No need to memorise examples.

There are many other similar catalysts for Lewis-acid catalysed Diels-Alder reactions. 24 For the organocatalysis part you should be able to draw a mechanism for imine formation, for the cycloaddition (understanding that it is endo and with addition from the unhindered face) and the product, as well as the hydrolysis step. No need to memorise examples.

41 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.

42 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.

43M 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.

44M 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.

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

46M 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 (see analogy with slide 11).

47M 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 (see analogy with slide 11). No need to memorise mechanism of racemisation.

48M 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.

49M 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.

50M Wills CH3E4 notes Other asymmetric reactions – for interest. Asymmetric catalysis – Isomerisation. Concluding material, non examinable.

51M 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.