There are two lectures on chiral catalysis and this highlights the potential importance of this field (and the amount of research that has been undertaken in this area in the last 20-30 years).

In many respects, chiral catalysis is the ultimate goal of most research in asymmetric synthesis but it should be noted that its use in industry is still dwarfed by more ‘traditional’ techniques such as resolution of racemates and use of the ‘chiral pool’.

There are a number of reviews on this topic (industrial chiral catalysis) by H.-U. Blaser.

Regardless of the advances made (and some even covered in these lectures) much is still not understood about asymmetric catalysis.

It is a challenging area as differences in activation energies of a few kcal mol–1 can make a huge difference in enantiomeric excess (differences in the same scale as the energy required to rotate a C–C bond).

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... so what is happening?

Well as always we will start with a cartoon ...

This is the classic example that kickstarted the chiral catalysis revolution and helped Knowles snag a share of the 2001 Nobel Prize for chemistry.

The Monsanto synthesis of L-DOPA is achieved by the asymmetric rhodium-catalysed hydrogenation of an enamide.

Only 0.05 mol% (0.0005 equiv.) of catalyst is required ...

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... the idea is that a small, sub-stoichiometric quantity of reagent can interact with the substrate. This interaction causes the formation of diastereomeric intermediates, complexes or transition states. One of these diastereomeric interactions is more favoured and reaction proceeds selectively. The catalyst is either not consumed or is regenerated in the reaction so that one molecule of catalyst can selectively transform many molecules of substrate.

Effectively, the substrate is activated towards reaction in a chiral environment. So an achiral material may be converted to a chiral product.

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In this course I do not discuss the elegant asymmetric hydrogenation chemistry that has been developed even though it is probably the most commonly used catalytic asymmetric technology.

For those that are interested there are many reviews (and even my own lectures on ‘oxidation and reduction’).

Good starting places would be the Nobel lectures of Knowles and Noyori.

We will start our brief look at chiral catalysis with chiral Lewis acid catalysis.

As always here is a simplistic introduction ...

Hopefully you are all happy that a nucleophile can attack a carbonyl group? Depending on the nucleophile this can be a slow process (e.g. organozincs & allylsilanes).

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A Lewis acid is a molecule that will accept electrons.

The classic examples come from Group 13 with reagents such as boron trifluoride.

The empty p orbital accepts 2 electrons to gain a full Octet.

This can be used to activate electrophiles ...

... BF3 can coordinate to the lone pair of electrons on a carbonyl.

This results in a formal charge on the oxygen, which in turn increases the polarity of the bond. The carbon is now considerably more electrophilic and the rate of addition of a nucleophile is increased.

This is the basis of Lewis acid catalysis.

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A Lewis acid can be made chiral by the addition of a chiral ligand (of course, it should be noted that this often reduces the efficiency of the catalyst as we are donating electrons to the Lewis acid and decreasing its electrophilicity).

One of the most common and useful set of ligands are the bis(oxazolines) or box ligands.

The advantage of these is that they are readily prepared by the condensation of an amino alcohol with the appropriate acid or nitrile.

The amino alcohols can be derived from amino acids.

Furthermore ...

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... box ligands are C2 symmetric. This effectively halves the number of possible transition states available on coordination with a substrate (it halves most variables in the reaction).

C2 symmetry is a 180° rotational axis. Thus, as this cartoon tries to show, it does not matter which way the substrate interacts with the chiral catalyst the same chiral environment is created ...

... so there are a reduced number of substrate-catalyst arrangements in C2 ligands than non-C2 systems.

Exactly the same shape complex, which reveals exactly the same face of the substrate regardless of whether the substrate coordinates to the bottom or ...

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... the top of the molecule.

The advantages of C2 symmetric ligands have been outlined in a review:Chem. Rev. 1989, 89, 1581

While box ligands are reviewed in:Chem. Rev. 2006, 106, 3561

Of course, there is no reason why ligands need to be C2 symmetric.

Here is an example of a Mukaiyama aldol reaction catalysed by a copper(II) salt.

As you can see the reaction occurs with remarkable regio- and enantioselectivity and reasonable diastereoselectivity.

Can we start to rationalise the outcome?

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The diketone acts a bidentate ligand, coordinating to the Cu(II) centre. All evidence suggests that the Cu is square planar or distorted square planar [Cu(II) normally octahedral].

Coordination fixes the conformation of the substrate; the C(O)–C(O) bond cannot rotate.

The regioselectivity is the result of sterics. The ethyl group blocks approach of the nucleophile to ethylketone.

Facial selectivity for the addition of the nucleophile to the methylketone is controlled by the bulky tert-butyl group. This blocks the bottom (re) face.

Hopefully, you can see the role of C2 symmetry; if the substrate had the methyl group on the left (but the ligand has not changed) then the tert-butyl group would block approach from above and this is still blocking the re face.

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The Mukaiyama aldol occurs though an open transition state and not a closed transition state. This is due to the fact the nucleophile cannot coordinate to the substrate or Lewis acid.

There is some debate as to whether the nucleophile is antiperiplanar to the carbonyl (as shown) or synclinal. Ultimately, we want to minimise interactions between substrate and nucleophile.

This cartoon shows that the ligand blocks approach to the re face of the carbonyl and that the nucleophile tries to minimise interactions so has the bulky groups away from the ligand and the methyl dissects the O=C-CH3 segment (flipping the nucleophile so that the methyl dissected the C=O–C=O segment would cause increased non-bonding interactions between the methyl and the substrate.

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An example of this kind of chemistry in synthesis is taken from a synthesis of phoboxazole B.

Here we have a phenylglycine-derived box ligand with a tin Lewis acid.

Again, it is assumed that the tin coordinates to the carbonyl and the nitrogen of the oxazole ring, locking the conformation of the substrate. The phenyl group then blocks approach to the re face of the carbonyl. The nucleophile must attack the si face (and we are not worried about diastereoselectivity).

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This reaction is a rare example of chiral catalysis in a radical addition (although it uses 1 equivalent of Lewis acid-box complex).

The first step is preparation of the radical reagent. This is achieved by the reaction of triethylborane and oxygen, which results in the formation of an ethyl radical. This system forms radicals at lower temperatures than the more traditional reagent AIBN. Primary radicals are not very stable so the ethyl radical abstracts iodine from 2-iodopropane

to give a more stable secondary radical. This will be the nucleophile.

The Lewis acid interacts with the carbonyl groups of the bidentate substrate. The magnesium complex probably has a tetrahedral geometry. The indane group blocks approach from the top (re) face.

The indane-derived amino alcohol may look esoteric but it is a common ‘chiral pool’ material as it is a by-product of the synthesis of indinavir.

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Box ligands have been used in a vast range of reactions. Another excellent example of their use is the Diels-Alder reaction. This reaction permits the creation of two new C–C bonds and up to four new stereocentres with both good stereospecificity and stereoselectivity (if you don’t know the difference look it up!).

The reaction employs a Cu(II) catalyst and achieves excellent enantioselectivity (98.5 : 1.5 er) at low catalyst loadings.

It should be noted that this is a standard test reaction ... cyclopentadiene will undergo Diels-Alder reaction with nearly any alkene (including itself).

Rationalisation of the stereochemistry is similar to before ...

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The tetrahedral Cu(II) coordinates both substrate carbonyl groups. This rigid chelate blocks approach of the diene from the bottom face so it must approach from above (re at C2).

Note the endo transition state common in Diels-Alder reactions. This gives the sterically more demanding product as a result of an electronic effect called secondary orbital overlap.http://www.massey.ac.nz/~gjrowlan/stereo.html - lecture 8http://www.massey.ac.nz/~gjrowlan/adv.html - lecture 5

This is an example of a hetero-Diels-Alder reaction, where one of the carbon atoms has been replaced by a heteroatom (in this case oxygen).

The reaction occurs with excellent diastereoselectivity (endo product) and enantioselectivity.

Hydrolysis gives an acid that cyclises onto the alkene in an SN’-like reaction kicking out the alcohol as a leaving group.

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I have marked one of the carbon atoms so that you can visualise this rearrangement more readily.

Rationalisation of the enantioselectivity is identical to before. The box ligand blocks approach to the re face of the aldehyde as shown.

Secondary orbital overlap between the diene and the ester functionality ensure the endo product is formed.

On the next slide I have tried to depict this product in different ways ...

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... just in case you are having problems visualising the reaction.

As always time for an example of the catalytic asymmetric hetereo-Diels-Alder reaction in synthesis.

This example is from a synthesis of ambruticin ...

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... a molecule that has the potential to treat coccidioidomycosis a disease almost as nasty as its spelling ...

This reaction demonstrates that non-symmetric catalysts can also give excellent results.

The hetero-Diels-Alder reaction occurs with reasonable yield but excellent enantioselectivity under ‘green’ chemistry conditions (no solvent).

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The aldehyde is activated by the chromium complex. It coordinates to the top face of the catalyst to avoid the indane moiety. The bulk of the aldehyde is orientated away from the massive adamantyl group (which obviously has nothing to do with adamantium, a made up element).

The diene then approaches from above.

A second example of this reaction is found in the same synthesis.

This time the enantiomer of the catalyst is used to create the opposite stereochemistry on the dihydropyran ring.

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The CBS (Corey-Bakshi-Shibata) reduction is a powerful catalytic asymmetric reduction of ketones. It has good generality, working for a range of ketones.

It involves a oxazaborolidine catalyst derived from proline and a stoichiometric reductant in the form of a borane complex.

The mechanism is beautiful ...

The first step of the reaction involves coordination of the borane and the lone pair on the amine. This has two effects; it activates the borane as a borohydride reductant and it increases the Lewis acidity of the endo-cyclic boron.

The ketone then coordinates to the Lewis acid. It binds to the bottom face to avoid destabilising interactions with the proline ring. This places it adjacent to the ...

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... borohydride.

At this point the catalyst has activated both the nucleophile and the electrophile. It has organised the substrate and reagent into a chair-like transition state. The enantioselectivity is determined by the smallest substituent of the ketone adopting the pseudo-axial orientation to minimise 1,3-diaxial interactions. Finally, dissociation of the product and spent borane regenerates the catalyst.

An example of the CBS reduction in synthesis is found in the preparation of a cholesterol lowering agent ...

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The CBS catalyst controls (reagent control) this reduction and the existing stereocentre within the substrate plays no role.

As you can see the results are impressive; good yield and very highly diastereoselectivity.

In 2001 Noyori and Knowles were awarded a share of the Nobel prize for chemistry for their research on catalytic enantioselective hydrogenation.

We have already seen an example of Knowles contribution. Here we see one of Noyori’s contributions ... the use of BINAP in hydrogenation reactions.

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Levofloxacin is an antibacterial agent. It used to be sold as a racemate but it is this enantiomer that is active. It is now sold as a single enantiomer allowing the dosage to be halved.

It has one stereogenic centre and this can be prepared by catalytic asymmetric hydrogenation …

A combination of BINAP and ruthenium mediates a high yielding and highly selective hydrogenation.

The three most common metals for catalytic asymmetric hydrogenations are rhodium, ruthenium and iridium. They all promote hydrogenation in different ways.

The enantioselectivity of the rhodium system we met earlier (DOPA) is often said to be ‘anti-lock and key’, with the least stable complex giving the major product …

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… ruthenium-catalysed hydrogenations tend to proceed so that the most stable complex leads to the major product.

The mechanism of the hydrogenation can be found in my ‘oxidation & reduction’ lectures.

The rationalisation of the complex stability is hard to see but is based on the X-ray crystal structure of BINAP.

This shows that the phosphine substituents are either pseudo-axial (minimal steric interaction with the substrate) or pseudo-equatorial (face forwards and cause non-bonding interactions with the substrate).

This is shown in the diagram above taken from Noyori’s Nobel lecture.

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The left hand structure is favoured as the largest group on the substrate (R) is orientated towards an axial substituent (this can be visualised in what is known as ‘quadrant model’; the space around the octahedral ruthenium is divided into 4 quadrants, 2 blocked (equatorial) and 2 vacant (axial)). The hydride is then transferred from the ruthenium to the substrate (on the Si face) to give the major enantiomer.

Noyori’s original system required the substrate to be functionalised (it must have a second Lewis basic substituent as well as the carbonyl in order to permit coordination of substrate and catalyst). He also developed a hydrogenation system that allowed non-functionalised ketones to be reduced with high enantioselectivity.

This system is demonstrated in a synthesis of Prozac (sorry for the error in my drawing, I’m missing an H off the nitrogen).

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The combination of a bisphosphine and a diamine allows highly enantioselective hydrogenations to be achieved with remarkably low catalyst loadings (0.0001 equivalents).

The diamine is key to the high reactivity and enantioselectivity; one of the N–H groups hydrogen bonds to the carbonyl group to position the substrate in the correct place.

Next we will turn our attention to catalytic asymmetric oxidation and the two methodologies that landed Prof Sharpless the other 1/2 of the 2001 Nobel prize …

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The Sharpless Asymmetric Epoxidation (SAE) was the first general catalytic asymmetric methodology and it is quite amazing. It is highly unlikely that you can pick up an organic journal that does not either contain an example of the SAE or a starting material that was prepared from by the SAE (or one of its variants).

These examples show the power of the SAE. It oxidises a range of allylic alcohols with high enantioselectivity and incredible chemoselectivity (it preferentially reacts with allylic alcohols).

There are few limitations to this methodology (cis alkenes are often poor substrates but as the top example shows, not always).

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So what is going on?

In the SAE a chiral titanium reagent is formed from Ti(OiPr)4 and a tartrate derivative, either diisopropyl tartrate (DIPT) or diethyl tartrate (DET).

In the presence of a stoichiometric oxidant, normally tert-butylhydroperoxide (TBHP) this selectively epoxidises …

… allylic alcohols

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It is essential to mix the reagents together before adding the substrate in a process known as ‘ageing’ the catalyst.

This permits the active species to be formed. Extensive studies reveal that there are 8 titanium species present in the reaction with the one above believed to be the active species responsible for the oxidation.

The best substrates for the SAE reaction are trans allylic alcohols and the E-trisubstituted alkenes.

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Z-Allylic alcohols and tetrasubstituted allylic alcohols are ok but there are only limited numbers of examples …

… while cis-alcohols are often bad substrates.

But it should be noted that there are always examples of substrates that should give good results failing and substrates which are classed as ‘poor’ giving excellent results … nothing is perfect.

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Normally the selectivity can be predicted by this mnemonic.

Draw the allylic alcohol so that the alcohol is in the bottom right corner and the alkene vertically upwards. The (–)-enantiomer delivers the oxygen to the top (si at C2) face of the alkene while the (+)-tartrate delivers the oxygen to the bottom (re) face.

Today’s mistake is the (+)-enantiomer should be L-tartrate.

There is another aide memoire and that is the left hand guide. Your thumb is the alcohol and your fore finger is the alkene.

The (–)-tartrate (negative) delivers oxygen to your knuckles. The (+)-tartrate (positive) delivers it to your palm.

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There are many examples of this reaction being employed in synthesis (and that is before we even discuss the use of the SAE in kinetic resolution (which we will not do until a different lecture)).

We will start with one of my favourite molecules for demonstrating chemistry … Prozac (and yes I cut and paste the slide so it still has the same error on it).

Starting from cinnamyl alcohol the Sharpless Asymmetric Epoxidation instals the stereochemistry.

Directed reductive ring-opening with REDAL-H then furnishes a chiral benzylic alcohol that is readily converted into Prozac.

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Another example is taken from the synthesis of a natural product with antiviral properties.

Two stereocentres were introduced by the first SAE.

Farnesol (a constituent of many essential oils) contains three alkenes. There is a highly chemo- and enantioselective oxidation under standard SAE conditions.

This sets up the red stereocentre and one of the blue stereocentres.

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The next reaction is one of the many exceptions found in chemistry …

This is the SAE of a non-allylic alcohol. It still occurs with good chemo- and diastereoselectivity.

In this case, only the alkene close to the alcohol is oxidised. This is due to the conformation of the substrate. Coordination of the alcohol and the catalyst position the oxidant close to one of the alkenes (undoubtedly a chair-like transition state is involved).

Yet another stereocentre is installed into the molecule through the SAE reaction.

This one involves the chemo- and enantioselective oxidation of the allylic alcohol found in geraniol (a molecule with a rose-like smell found in many perfumes).

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Sharpless not only developed a method to add one oxygen to double bonds but he also developed what is now called the Sharpless Asymmetric Dihydroxylation (SAD) reaction.

This reaction is not quite as predictable as the SAE but it works for virtually all alkenes. It hasn’t been used as much as the SAE but it is still an incredibly valuable reaction.

So what does the SAD reaction involve? What are all these reagents in this witches brew of a reaction?

The osmium compound is the active oxidant. The iron reagent is the stoichiometric oxidant that regenerates the catalyst. The sulfonamide is present as an accelerant that speeds up the reaction and allows it to be performed at lower temperatures. Finally the ligands …

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… these are dimers of various cinchona alkaloids. The two commonly used are dihydroquinidine (DHQD) and dihydroquinine (DHQ) coupled through a phthalazine motif (other couple motifs have been used and give optimum results for certain classes of alkene … but too much detail for here).

The two things to note about these ligands are:

1) They are monodentate (only one nitrogen coordinates to the osmium).2) They are pseudo-enantiomers (diastereomers that behave as if they were enantiomers).

Bidentate ligands are known for the dihydroxylation reaction. They give better enantioselectivities but kill the catalytic cycle (so have to be used in stoichiometric quantities).

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This slide just shows which stereocentres are retained and which are ‘mirror’ images.

The mechanism of the reaction can be found in my “oxidation and reduction” lectures.

The reaction is very good for a range of alkenes as demonstrated in this simple example.

The stereoselectivity can often be predicted with a simple mnemonic …

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… this mnemonic is not quite as reliable as the SAE version but is at least a useful starting point.

The raised triangles represent sterically demanding areas of the catalyst while the blue box represents an ‘attractive’ area that favours aromatic groups and greasy hydrophobic groups.

Here is an example of its use in a very simple synthesis of a beetle pheromone …

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This one useful transformation permits a simple alkene to be dihydroxylated with high enantioselectivity.

Simple acetal formation then gives the natural product.

Sharpless didn’t stop with the SAE and the SAD reactions. Not only did he go on to propose the concept of ‘click’ chemistry and popularise the cycloaddition of azides and alkynes to give triazoles but he developed another catalytic asymmetric reaction … the asymmetric aminohydroxylation. This can be used to make the side chain of taxol …

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This has not yet been developed as well as the SAD reaction (it doesn’t have the generality or reliability yet) but it can be very effective.

The reaction involves a nitrene (the nitrogen equivalent of a carbene).

Hopefully this gives a very brief overview of some catalytic asymmetric transformations. The next lecture will …

… continue this theme but will briefly introduce organocatalysis …

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