These are the old slides that made up the ‘traditional’ version of these two units (asymmetric synthesis & total synthesis).

I will annotate these slides and see if they work as the reading material for the course ... bear with me, it is a bit of an experiment.

These notes are NOT comprehensive but supplement your own reading. It is impossible to cover these two areas in just 10 lectures (the original length of this module).

Some of my colleagues would go as far as saying “we don’t”. They would, of course, be wrong. There are two quick answers:

1) We need organic compounds so we need to learn how to make organic molecules.

2) Research and Education. The problems encountered in total synthesis push forward the development of new methodology and teach us the application of chemistry.

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It is made by Roche and at least one of their published routes is based on the conversion of shikimic acid (isolated from star anise) to the final drug.

The entire pharmaceutical industry and much of the agrichemical industry (and many other industries) is build on the chemists’ ability to synthesize molecules with specific properties.

On this slide we see the molecule oseltamivir or Tamiflu, an antiviral medication used in the prevention and treatment of flu.

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The reported route takes 12 steps to convert shikimic acid to the final product. There are many other reported syntheses in the literature. Some are longer, some are shorter. We need to learn how to compare these routes, to determine the pros and cons of each route and, ultimately, how to design similar syntheses so that we can make our own target molecules.

Atorvastatin or Lipitor was one of the most successful of the statin drugs used to low blood cholesterol. From 1996-2012 it was the world’s best selling pharmaceutical. It is now off patent.

Yet again, it was initially discovered by organic chemists ...

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The original synthesis started from isoascorbic acid, a stereoisomer of vitamin C. It is a cheap ‘chiral pool’ natural product.

Again, we need to be able to deduce how Lipitor can be prepared from this material ...

I could go on and on ... there are many examples of small organic molecules used to treat ailments. This is another bestseller from the pharmaceutical industry and is used to both treat and manage asthma.

The synthesis of the top molecule salmeterol is relatively quick, taking just ...

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... six steps from this salicylic acid derivative.

Of course, not all treatments are small organic molecules. Peptides are becoming popular targets. Fuzeon or enfuvirtide is a biomimetic peptide that confuses the HIV virus. It is hard to make and a tad expensive ($25,000 US per year) so is a last resort medicine.

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But chemists are everywhere. To display my Massey card, the next example is from both the agrichemical sector and companion animal health sector. Imidacloprid is probably the world’s most commonly employed insecticide.

On the downside, it has been linked to colony collapse disorder in bees.

Its synthesis is shockingly simple and it can be prepared in just four steps from 3-methylpyridine.

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Another example from the companion animal health sector is the various components of Drontal ...

... while we use this to keep our pets in good health, one of the major components, praziquantel, is found on the WHO Model List of Essential Medicines needed for basic health care. It used to treat intestinal parasites.

New synthetic methodology is needed to allow a cheaper synthesis to be developed so there is more access to such useful drugs.

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Given enough time and resources (money and students!) it looks like most molecules can be prepared. One of the most ambitious syntheses was the preparation of palytoxin. This is the largest (non-polymeric, non-peptide) compound I could find.

It is not entirely clear how many steps are involved as the synthesis of the starting materials was not reported.

Interestingly, it is often small molecules that are hard to prepare. The problem with such molecules is they lack functionality for us chemists to play with.

This is octanitrocubane. It was predicted to be one of the most potent carbon based explosives but it turns out it is not and that the heptanitrocubane is more explosive. This fact shows the importance of shape and conformation to reactivity (as we shall see later).

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A knowledge of organic chemistry is also required for disciplines such as nanochemistry; making carbon-based materials underpins this area. Here we see a single aromatic belt or a single strip of a nanotube.

This was made in a rational manner (unlike most nanotubes which are effectively purified soot).

So why do we need asymmetric chemistry/synthesis?

Hopefully you are all aware that the shape of a molecule is key to many of its properties. One of the most famous examples is that of thalidomide (shown above). This was sold as a mixture of enantiomers (hands) to treat morning sickness (amongst other ailments) but caused children to be born with malformation of the limbs.

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There are many examples of different enantiomers (hands/mirror images) of molecules having different biological properties.

This example shows a cough-suppressant and a painkiller. As you can see they are mirror images (as are their trade names …)

Stereochemistry also finds its way into nanochemistry. Above is an example of a molecular motor that can only rotate in one direction (and we can control the speed of rotation by varying temperature and light sources).

This remarkable molecule has multiple stereogenic elements including stereogenic centres (chiral tetrahedral carbons) and a chiral helix.

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A similar motor has been used to rotate a liquid crystal and thus cause …

… a glass rod to be rotated in a specific direction.

Obviously I can’t put the movie into a pdf file but I recommend you look it up (or I might attempt to upload it to Stream but don’t hold your breath).

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I keep all of my lecture notes and course material on my own website. Often you will find different versions of the current material. I rarely remove older versions as some times my attempts at improving material is not successful (I’m an experimentalist after all).

My notes are not comprehensive but for the background to your studies. I recommend that you consult …

… textbooks

I can’t recommend these books enough for those of you that have an interest in organic chemistry, total synthesis and stereochemistry. They are all very well written and all very useful.

… and of course …

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… the original literature.

For the most part I have given the references to the original literature (especially for the examples of and from total syntheses).

Reading the literature is invaluable. All the major organic journals (some shown above) will have very good examples of both Total Synthesis and asymmetric synthesis (especially catalysis).

We will start with Asymmetric Synthesis. The rest of this pdf file will look at introducing some of the basic terminology that surrounds (and mystifies) asymmetric synthesis before looking at substrate control.

I’m going to make the assumption that you have studied some basic organic chemistry and that you have encountered stereochemistry and chirality before …

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Chirality is not a chemical principle or an exclusively chemical property. Any object that cannot be superposed upon its mirror image is called chiral.

Classic examples are shoes and, of course, our hands (chiral comes from the Greek for hand ‘kheir’ and hence pronounce it with a ‘k’ not ‘ch’).Note: it is superpose not superimpose (which means lay one thing over another so that both are still evident)

There are many examples such as corkscrews, propellers and golf clubs …

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Molecules can be chiral. If the mirror image of a molecule cannot be superposed upon the original molecule however many times you twist or rotate it (and its bonds).

Common examples of chiral molecules are the amino acids (with the exception of glycine). The example above is cysteine.

The two non-superposable stereoisomers are known as a pair of enantiomers or an enantiomeric pair. A molecule can only ever have one enantiomer (its mirror image or twin).

Stereoisomers are isomeric molecules that have the same constitution (same atoms) and have the same sequence of bonds but differ by the three-dimensional arrangement of the atoms. The most obvious examples are alkenes.

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If you have a 1:1 mixture of enantiomers it is termed a racemic mixture or you could be said to have a racemate.

Converting one enantiomer into its mirror image (a process that can only occur by breaking and making bonds) is called racemisation.

The opposite of a chiral object or molecule is …

… an achiral object.

The mirror image of a spoon can be superposed upon the original object and so it is an achiral object. The two mirror images are identical (there is no twin).

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This is the same for molecules. If the mirror image of a molecule can be superposed upon the original molecule it is achiral and has no ‘twin’. The two mirror images are the same molecule.

The simplest test for an achiral molecules to see if it has a plane of symmetry (internal mirror plane). Imagine a mirror dissecting the molecule in half, if both sides are identical (one side is reflected on the other) the molecule is achiral. If it does not have a plane of symmetry it is chiral.

This is simplistic but works for the vast majority of molecules.

I think the formal definition is that a molecule is achiral if it has an improper rotation, which might take into account other forms of symmetry.

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We need to be able to communicate the chirality of a molecule with each other. There are many (historical) ways of doing this. The organic naming convention now uses the Cahn-Ingold-Prelogue (CIP) system for stereocentres (and it is often used for axial, planar & helical chirality, even though helical chirality has a different system, which can be employed for axial and planar chirality … it’s confusing). Inorganic chemists use a different system.

This should be revision so I’m not going through it. If you don’t know how to assign R or S look at lecture notes for 123.202.

Basically, to designate a sign to a chiral centre look at its substituents. The higher the atomic number the higher the priority. Keep moving along the substituent until you find a difference.

This done for you with alanine (above).

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Once you have assigned the four priorities place the lowest priority (number 4 (4th) by convention) away from you.

This may involve rotating the molecule. Be careful, this is where most mistakes are made.

The draw an arrow connecting the remaining three substituents, going from highest priority to lowest priority.

If the arrow is clockwise (or to the right) the stereocentre is designated the descriptor R. If it is anticlockwise then it has the descriptor S.

So if we return to alanine …

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… you should see that the arrow is going anticlockwise so this amino acid is given the descriptor S.

Please remember that this designator is not based on any physical property of the molecule (rotation of plane polarised light etc.) and is purely a very useful part of chemical nomenclature.

The CIP rules work for all stereocentres and not just those based on carbon.

So we can use R or S for the sulfoxide (if you do not understand why a sulfoxide is chiral then please draw the Lewis dot & cross structure) and phosphine oxide above (both are S if you interested).

The CIP rules can be applied to axial and planar stereoelements but rarely helical chirality (or inorganics).

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A molecule is either chiral or it is not. It can either be superposed upon its mirror image or not. But chemists don’t like things so simple. So we class these molecules depending on the motif that breaks the symmetry of the molecule.

The example above is a stereocentre (but often termed an axis of chirality. Please note that the stereocentre is a tetrahedral carbon with only 2 different groups so ignore what you were taught as an undergraduate … again.

Called oleane, the molecule above is the sex pheromone of the olive fly.

The classic example of axial chirality is BINAP.

This does not contain any tetrahedral carbon atoms but is still chiral. Rotation around the bialy C–C bond is restricted (not free to rotate). This results in two non-superposable mirror images (like scissors).

Restricted rotation around a single bond as atropisomerism. There is a good review by Clayden in Angew. Chem. Int. Ed. 2009, 48, 6398-6401.

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Helical chirality is beautiful to look at. Often described as inherent chirality as the molecule is chiral regardless of any substituents (most chiral molecules are only chiral as a result of substituents attached to a central point, inherent molecules are curved).

Interestingly, helicenes often undergo racemisation at a lower temperature than one might imagine due to a cycloaddition-retrocyclisation process.

My personal favourite form of chirality is planar chirality as exhibited by ferrocene derivatives and, of course, [2.2]paracyclophane derivatives.

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A molecule with a single stereogenic element can only exist as two stereoisomers, the enantiomers.

If a molecule has two stereogenic elements then it can have up to four stereoisomers. It will have one mirror image. The mirror image has the same relative stereochemistry (both substituents on the same face) but different absolute stereochemistry (are they up or down).

It will also two diastereoisomers. These are molecules that have a different spatial arrangement of their atoms (stereoisomers) but they are not mirror images.

They have the different relative stereochemistry (the relationship between substituents) and different absolute stereochemistry.

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There are another pair of enantiomers (mirror images or twins).

Enantiomers as mirror images have almost identical properties (as you would expect).

Diastereoisomers are completely different molecules so have completely different properties.

So if a molecule has two stereogenic elements it can have up to four stereoisomers.

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Here we have the stereoisomers of the aldopentoses. These molecules have 3 stereocentres. There are 8 possible stereoisomers. Each molecule has 1 enantiomer and 6 diastereoisomers. Another way of describing this would be four enantiomeric pairs.

It turns out that the maximum number of stereoisomers a molecule can have is given by the formula 2n, where n = the number of stereogenic elements.

But …

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… we have to remember that this is just the maximum possible number of stereoisomers. There might be less …

Here is tartaric acid (or, to give it its old name, racemic acid. And yes, it is important in the history of asymmetric synthesis).

At first glance it might appear that there is four stereoisomers on this page but there isn’t …

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Hopefully, you can see that all of these are diastereomers of each other (both the relative and absolute stereochemistry are different for each molecule).

Hopefully, you can see that these two are enantiomers. They are mirror images of each other and they cannot be superimposed.

It is the other two that we have to inspect in more detail …

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… these two are actually identical.

They may look like enantiomers with each molecule containing two stereoisomers …

… but if we inspect the molecules in more detail we find that they contain a plane of symmetry (which is shown on the next slide). This means they are achiral so will be superposable upon their mirror image. Or, in other words, they are identical.

Molecules that contain multiple stereogenic elements but are still achiral are called mess molecules.

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The internal mirror plane means the molecule is achiral.

Note: it is really important to be able to manipulate our representations of stereocentres.

Remember that an sp3 carbon is tetrahedral. Only two bonds can be in the plane of the paper at one time.

To change which bonds are in plane (but not swapping any groups around) simply remember that if you start with a bond up you will end with a bond up.

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Alternatively, if you fully rotate the C–C bond shown this cause the two groups at the end of the bond to swap places. If you do this then you must also swap a wedge for a dash (or vice-versa).

Please note these are ‘cheats’ or stereochemical hacks; try to picture the molecules in your head (or draw them) and understand the changes during any manipulation.

Enantiomers will have identical properties. They are mirror images so they are energetically identical. As a result all physical properties such as mp, ir and nmr will be identical for a pure sample of each molecule (and yes that word ‘pure’ is very important).

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Diastereoisomers are not related by symmetry. They are not mirror images. They are totally different molecules so they can have completely different properties.

You would not expect structural isomers to have the same properties so you should not expect diastereomers to have the same properties.

Diastereomers are different molecules.

The only difference between enantiomers is their interaction with other chiral objects as the interaction forms a diastereomeric adduct/intermediate/complex whatever.

The difference between diastereomers is key to asymmetric synthesis.

We have form diastereomeric interactions or transition states if we are to measure, separate or synthesise stereoisomers.

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So how do we measure the purity of an enantiomer if its physical properties are the same as its mirror image?

Well before we answer the how we measure the purity just a quick mention how we report the purity …

The most common measure of enantiomer purity is ee or enantiomeric excess. It is an archaic measurement connected to optical purity (measuring the rotation of plane polarised light).

Enantiomeric excess is a measurement of how much more of one enantiomer than the other we have. Basically, its says the minor isomer cancels out 20% of the major isomer (80%) and we measure what is left (60%).

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The same two reporting methods are used to indicate diastereomeric purity.

Diastereomeric excess seems really pointless when talking about the formation of diastereomers as all measurements actually give the ratio. Unfortunately, you will still see it in the original literature.

A more modern variant (that should be used more often) is enantiomeric ratio er.

The version of er normalised to a value out of 100 (e.g. 80:20) can be used in calculations more readily than ee.

Furthermore, the methods of measurement effectively give this value directly.

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So how do we measure enantiomeric ratio or enantiomeric excess?

Measuring the purity of an enantiomer is hard. Remember virtually all physical properties of each enantiomer is identical.

It is like having a mixture of left & right handed gloves. They are identical in every way; they made of the same material, have the same number of fingers and thumbs.

You cannot tell the difference between the two … unless …

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… you add a chiral object such as your left hand.

Now it is clearly obvious if the glove is left or right handed. Only one will fit.

The reason the gloves are now different is that there is a diastereomeric interaction between two chiral objects (glove and hand).

Molecules are just the same. The only way we can measure how much of each enantiomer we have is by studying the interaction of our sample with something chiral thus creating diastereomeric interactions.

The second source of chirality could be a molecule, a machine or special forms of light.

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In cartoon form; we take our mixture of enantiomers (the circles). They are identical so can’t be separated or measured until they interact with an additional source of chirality (the square). This creates diastereomers (circle+square). Diastereomers are different so we can measure or separate these.

The separation of enantiomers is often called resolution.

Over the next slides we will look at different methods of achieving this …

The first method is derivatisation. This is where we form a covalent bond between our substrate and an enantiomerically pure molecule.

The classic example is the addition of the Mosher acid (to make an ester or amide).

The new diastereomers are often separable. They can normally be observed in the 1H & 19F NMR and they can be used to determine the absolute stereochemistry of secondary alcohols of unknown configuration. A possible disadvantage is the addition of extra steps.

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You do not have to form a covalent bond. If the substrate contains an acidic or basic functional group then diastereomeric salt formation can be useful. Resolution is then achieved by selective crystallisation.

This is commonly used in the preparation of pharmaceuticals (as shown above) and many common chiral ligands.

Again it adds additional steps …

It is simpler not to derivatise the substrate but rely on temporary interactions (H-bonding, pi-stacking, van der Waals forces etc) to resolve the enantiomers.

HPLC or GC with a chiral column (stationary phase) is the most common method to measure enantiomeric enrichment.

The problem is cost, finding the correct conditions/column and that it is rarely used on a preparative scale.

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Having recapped the basics lets start looking at the selective synthesis of pure enantiomers and diastereomers or the process normally called asymmetric synthesis (although this is a slight misnomer as a molecule can be symmetric but chiral).

We will start by looking at substrate control; the use of existing stereochemistry within a molecule to control the introduction of a new stereocentre.

The first example is taken from a synthesis of canadensolide … a natural product with anti-fungal properties …

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This is an example of a Mukaiyama aldol reaction (the Lewis acid-mediated addition of a silyl ketene acetal to an aldehyde).

In this reaction an achiral nucleophile is attacking a chiral electrophile. (if you do not know the curly arrow mechanism please start revising your organic chemistry).

We can see the addition gives exclusively one diastereomer.

The question is “why is only one diastereomer formed?”

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This should be revision from undergraduate.

There are a number of models that predict the substrate controlled facial selectivity of the addition of a nucleophile to a carbonyl group. I will not describe all of them.

One of the most useful is the Cram Chelation Control model …

It is assumed that a nucleophile will approach a carbonyl group along the so called Bürgi-Dunitz angle (~107°). This maximises orbital overlap of the HOMO of the nucleophile and the LUMO (𝛑*) of the carbonyl (while avoiding repulsion from the C=O HOMO). (It also relates to the transition state and the fact the carbon will soon be sp3)

This means there is an interaction with the R groups (ignoring the Flippin-Lodge angle).

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As the nucleophile approaches from an obtuse angle it passes over the carbonyl substituents and interacts with them.

We need to determine the conformation of the substrate. In the Cram Chelation control model the conformation is locked by a Lewis acid coordinating to the carbonyl and a Lewis basic substituent (L=large, S=small & Z=Lewis base). This prevents free rotation.

The nucleophile then approaches least sterically demanding face of the carbonyl (it moves passed the smallest substituent).

This is shown above as either the skeletal representation or the Newman projection (please practice swapping between the two representations).

This indicates which face of the carbonyl will be preferentially attacked (but not the degree of this preference).

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Lets look at a second example of substrate control.

This is taken from a synthesis of preswinholide (swinholide is a dimer of this molecule).

Massey might not have online access to this journal pre-1996 (but a print version is in the library … that wonderful building full of books where you all check your FaceBook updates … )

Here we observe the Lewis acid-mediated addition of a weak nucleophile (allyl silane) to an aldehyde.

Effectively this is the same addition as before except we have exchanged a methylene group (CH2) for a oxygen atom.

Again we observe good diastereoselectivity.

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Again the question is why?

And, funnily enough, it is not going to be as a result of Cram Chelation control. In this example the bulky silyl ether protecting group on the alcohol prevents the titanium from tying the groups together and fixing the conformation of the substrate. (Funny because I wouldn’t ask the question if the answer was obvious … I’m such a hilarious character).

Key to predicting the outcome is the conformation of the substrate. This is given by the Felkin-Anh model, which is believed to represent the transition state of the addition.

The conformation of the substrate has the largest substituent perpendicular to the carbonyl group. The nucleophile approaches along the Bürgi-Dunitz angle and passes the smallest substituent as shown above.

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This model is very useful at teaching us the basic principles that here is another example.

How would we predict which of the two diastereomers was favoured?

Note: We cannot predict how selective the reaction will be, just which face of the carbonyl will be preferentially attacked (to improve selectivity make nucleophile bigger)

We need to predict the reactive conformation, the conformation the substrate adopts during the reaction.

Felkin-Anh says that this will have the largest group perpendicular to the carbonyl group (minimise non-bonding interactions).

First we convert the skeletal representation into the Newman projection. In this case the phenyl group is in the same plane as the carbonyl. Then …

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… we rotate the back carbon atom so that the phenyl group is perpendicular with the carbonyl group.

There are two conformations that fulfil this criterion.

We are only interested in the one that has the smallest substituent close to the Bürgi-Dunitz angle (close to the substituent of the aldehyde/ketone) …

… the nucleophile will attack the face of the carbonyl opposite large phenyl group and will approach along the Bürgi-Dunitz angle (107°) passed the smallest substituent.

The hardest part is converting the Newman project into a skeletal representation (many people no longer teach the Newman projection). I leave the original stereocentre unchanged and then rotate the front atom so that the longest carbon chain is anti-coplanar (same plane but opposite sides). Then look at the relative stereochemistry.

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The Felkin-Anh model also explains the observed results from molecules that contain a heteroatomic substituent on the 𝛂-carbon.

In this example we see that both diastereomers can be accessed depending on the reagent used.

If we use a Lewis acidic reagent that can coordinate two Lewis bases together …

… then we have an example of Cram Chelation control and we obtain the anti-Felkin-Anh product.

If we use a non-coordinating reducing reagent then we get the opposite result.

At first glance it may not be obvious which group is the bigger, the isopropyl group or the methylsulfide but it turns out it does not matter …

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The Felkin-Anh model also states that if there is an electronegative element on the 𝛂-carbon it will adopt the perpendicular position. This maximises orbital overlap between the carbonyl group and the C–S bond. This in turn reduces the energy of the LUMO and favours nucleophilic attack.

Thus the diastereoselectivity is a balance of steric and electronic factors.

(the old organic catch-all that generally means ‘we’re not sure what is going on’ but for once is actually true)

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So hopefully this has acted as an introduction to substrate control. The idea that an existing stereocentre can control the diastereoselectivity of a reaction.

Basically, the control comes about because the two possible transition states for the addition of a nucleophile to a carbonyl group are diastereomeric and they have different activation energies. The transition state with the lowest activation energy will

be favoured. This invariably means the nucleophile approaches closest to the smallest substituent on an adjacent stereocentre …

Above is a more complex diagram trying to represent this idea (taken from the next version of this course, which unfortunately is not ready for public consumption yet).

Next lecture will look at other substrate controlled reactions.

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