Year 3 CH3E4 notes: Asymmetric Catalysis, Prof Martin Wills Reorganised to highlight key areas to learn and understand

Year 3 CH3E4 notes: Asymmetric Catalysis, Prof Martin WillsReorganised 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: Introductory, no need to revise, but understand concepts. 2) A covalent intermediate may be formed: M Wills CH3E4 notes

Introductory, no need to revise, but 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

Oxidation reactions of alkenes. Understand how each enantiomer of ligand gives a different product enantiomer. No need to memorise which way round it goes. The Sharpless dihydroxylation reaction employs ligand-acceleration to turn the known dihydroxyation reaction into an asymmetric version. M Wills CH3E4 notes

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

Oxidation reactions of alkenes. Learn the two possible mechanisms. No need to memorise examples. Most recent evidence favours the [3+2] addition mechanism: K. B. Sharpless et al, J. Am. Chem. Soc. 1997, 119, 9907. 5 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. M Wills CH3E4 notes

Understand the concepts, no need to memorise examples on this slide. Sharpless aminodihydroxylation is a closely-related process 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 M 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. M 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. The difference in reactivity may be due to extra stability of one diastereoisomer or increased activity of one of them. This isomer leads to product, with hydrogen transferred to back face as drawn. M Wills CH3E4 notes 9

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

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 11

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

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 13

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

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. M Wills CH3E4 notes 15

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

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. M 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. M Wills CH3E4 notes

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

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

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. M Wills CH3E4 notes

The use of hydride type reagents. 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. More contemporary focus is on asymmetric transfer hydrogenation and on organocatalysis. Transfer hydrogenation – Ru catalysts. M 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. M Wills CH3E4 notes

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

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

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

Formation of chiral centres by nucleophilic additions to unsaturated bonds. This slide is for information only and does not need to be memorised for the exam. Diethylzinc additions H Ph H H 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 Ph M Wills CH3E4 notes

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

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

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. 20

C=C reduction by organocatalysis. No need to memorise examples. 20

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. M 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. M Wills CH3E4 notes

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.

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. M 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. M Wills CH3E4 notes

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

There are many other similar catalysts for Lewis-acid catalysed Diels-Alder reactions. 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. 24

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

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 43

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 44

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

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). M 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. M Wills CH3E4 notes

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

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

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

Year 3 CH3E4 notes: Asymmetric Catalysis, Prof Martin Wills Reorganised to highlight key areas to learn and understand