Here we continue our brief overview of some of the factors effecting substrate control.

Again I must emphasise that there are only 6 lectures on stereoselectivity so they are necessarily brief and only give a taste of this intriguing area.

This lecture moves away from addition to the carbonyl group to look at other forms of substrate control but the key concept is still the conformation of the substrate.

Here we see the diastereoselective epoxidation of two closely related alkenes.

Hopefully you remember what m-CPBA is? It is meta-chloroperoxybenzoic acid. You might have forgotten the mechanism of epoxidation … look it up).

The real question is …

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… why does one give a highly diastereoselective reaction and the other not even though the stereocentre does not change?

The answer is to do with the stereochemistry as the two molecules are diastereomers, one is an E and the other a Z-alkene.

Again the conformation of the substrate is key to understanding the preference …

Let us look at a simpler system first …

This is Z-4-methylpent-2-ene. There are four extreme conformations, the two shown and two in which either the hydrogen of a methyl group is coplanar with the alkene but pointing away (antiperiplanar). All are disfavoured (8-15 kJmol–1) except the one on the left where the hydrogen is synperiplanar with the alkene.

Why is this one more favoured?

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The difference in the energy of the two conformations is caused by non-bonding (or steric) interactions between the methyl group on the alkene and either the methyl or hydrogen atoms.

The interaction between Me & Me is bigger than Me & H.

This is called allylic 1,3-strain or A1,3 strain (the interacting groups are on atoms 1 & 3)

If we have a non-substituted alkene or the E (trans) alkene then there is less energetic difference between the two conformations as there is reduced A1,3 strain. There is little interaction between a hydrogen atom and either a second hydrogen atom or a methyl group as shown in the next cartoon …

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… the small hydrogen atom causes little steric interaction with the allylic substituent.

If we return to the original example we can now use this new knowledge to explain the differences in diastereoselectivity …

The epoxidation of the E-alkene occurs with good diastereoselectivity as one conformation of substrate is greatly favoured (the one shown above). This has the hydrogen atom of the allylic stereocentre synperiplanar to the alkene to minimise A1,3 strain.

As a result the bulky dimethylphenylsilane blocks approach to the top (Re) face of the alkene …

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… the bulk of the silyl group hinders the approach of the reagent as two bulky objects do not like to pass each other if they can help it.

As a result …

(the mechanism can be found in 123.312 and other undergraduate papers … start practicing ‘arrow pushing’ you are going to need every reaction you have covered …)

… the m-CPBA approaches from the less streakily demanding bottom (Si) face to give the observed diastereoisomer.

(yes diastereomer and diastereoisomer are both correct spellings. I guess one is for the lazy … or space conscious).

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If we look at the E-alkene we get reduced diastereoselectivity during the epoxidation.

The epoxidation still occurs anti (from the opposite face) to the silane but now there is less A1,3 strain so both conformations are possible. As a result we observe a mixture of epoxides.

Generally speaking the cartoon above can be used to explain the substrate control of the reaction of an alkene with an allylic stereocentre.

The favoured conformation of the molecule has the smallest substituent (in this case a hydrogen atom) synperiplanar to the alkene.

The reagent then approaches the substrate anti to the bulkiest (L) substituent.

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Of course, this is a vast over simplification and should be thought of more as a useful model than a rule.

Other factors, such as electronics, will influence the selectivity. To be honest, in this example the silane is probably perpendicular to the alkene as this would increase the alkenes nucleophilicity and hence reactivity … we then have to worry about which substituent would prefer to be ‘inside’ (the hydrogen) and which would be on the ‘outside’ …

But as models go it is very useful …

Here we are going to apply it to the alkylation of an enolate. Enolates are amongst the most useful and important nucleophiles in organic chemistry (think aldol reaction).

In this example we see that the existing stereocentre can control the alkylation through A1,3 strain …

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The first step of the reaction creates the lithium enolate.

Once the double bond is formed we then have to look at the most stable conformation of the enolate. Once again, this places the smallest substituent (H) synperiplanar to the C=C bond.

The electrophile will then approach from the least sterically demanding face.

This slide shows the same thing in cartoon form.

Note that there is no need to control the geometry of enolate formation. Both geometries have a cis-substituent so will demonstrate A1,3 strain.

The favoured conformation has the hydrogen synperiplanar and the electrophile then approaches from the side with the small substituent.

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Yet another example of A1,3 strain controlling the diastereoselectivity of electrophilic addition to an alkene is demonstrated in an early synthesis of monensin, a molecule with antibacterial activity. This synthesis involves a number of substrate controlled hydroboration reactions.

If you cannot remember the factors that control regio- and stereoselectivity of the hydroboration reaction (along with its mechanism) then read a textbook … please.

This slide shows two hydroboration reactions followed by oxidation. Remember that the oxidation of an organoborane occurs with retention of stereochemistry (look up mechanism if you do not remember this).

In both reactions an allylic stereocentre controls the diastereoselectivity. We can look at this in more detail …

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Again, we need to predict the favoured conformation of the substrate. The smallest group is synperiplanar to the alkene, this minimises interaction with the methyl. The reagent, borane, will then approach the alkene from the least sterically demanding face.

Once the organoborane has been formed, oxidation with basic hydrogen peroxide occurs with retention of stereochemistry (the reaction involves a 1,2-shift/alkyl migration)).

While the simplistic model we have covered works it may not be that accurate. It is highly likely that the aromatic furan ring will be perpendicular to the alkene. This maximises orbital overlap and makes the alkene more nucleophilic.

The hydrogen will still be close to the alkene in what is called the ‘inside’ position to minimise allylic strain and so the bulk of the electrophilic reagent passes close to the smallest substituent.

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So far the diastereoselectivity has been controlled by non-bonding or steric interactions … basically the reagent has approached the carbonyl or the alkene from the least sterically hindered face.

An alternative method of control involves an interaction between the substrate and reagent (hydrogen-bonding, covalent attachment, ionic interaction etc) and this leads to what are known as directed reactions.

Epoxidation of this simple cyclic alkene occurs from the less sterically demanding bottom face with reasonable (but not stunning) diastereoselectivity …

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This means the epoxide is formed on the opposite face to the large protecting group. The bulk of the ester hinders the approach of the mCPBA.

If we remove the protecting group (the acetate), the epoxidation occurs from the opposite face with even higher diastereoselectivity …

… suddenly the epoxide is on the bottom face and the diastereoselectivity is much higher.

This occurs because …

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… a hydrogen bond is formed between the alcohol and the peracid. This delivers the epoxide to the same face as the alcohol.

The diastereoselectivity is higher as we are not relying on repulsive interactions but attractive interactions. Additionally, the hydrogen-bonding increases the reactivity of the peracid, thus favouring the reaction to occur only with the H-bonded reagent.

It is relatively simple to picture directed reactions with small and medium ring substrates.

It is harder to see the effect in acyclic substrates but it is still a very powerful method for controlling diastereoselectivity.

The above example shows an alcohol directing epoxidation. Hopefully you are already looking to use A1,3 strain to explain this result.

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The favoured conformation of the substrate minimises A1,3 strain, with the smallest substituent synperiplanar to the alkene.

The alcohol is now on the top face and delivers the peracid accordingly (to the top (Re) face).

Calculations have shown that an torsional angle of approximately 120° is optimum for delivery of a peracid by hydrogen bonding. This in turn means the A1,3 strain model works to explain the observed diastereoselectivity.

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The minor diastereomer could be formed by delivery from one of the disfavoured conformations of the substrate or from non-directed epoxidation.

The representation above shows the other reactive conformation of the molecule (torsional angle of 120°). In this we have a destabilising interaction between the two methyl substituents.

This is an example of a metal-catalysed epoxidation. The diastereoselectivity is the same as the previous example (just expressed as a different normalised ratio).

If you do not know how vanadium (and many other transition metals) catalyses this reaction … please find out. The more reactions you are exposed to the easier synthesis is.

A good place to start would be my lectures on oxidation & reduction!

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So why do we observed such high diastereoselectivity even though there is not a cis substituent on the alkene?

The reaction is directed by the alcohol, which displaces one of the ligands on vanadium and covalently binds reagent and substrate together.

The transition state is different to before with the favoured torsional angle between hydroxyl and alkene now 50° (or the hydroxyl favours the ‘inside’ position).

This means the reactive conformation is not controlled by A1,3 strain but rather A1,2 or the substituent on the internal carbon of the alkene.

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So here are the two possible transition states; the favoured transition state has the alkene substituent and the hydrogen synperiplanar while the disfavoured conformation is higher in energy due to the repulsion between the two methyl groups.

The key to the diastereoselectivity is the conformation of the molecule. Hopefully, you now realise that all those times we discussed the conformation of butane were not a complete waste of time!

An example of the directed epoxidation in total synthesis comes from Evans’ synthesis of oleandomycin …

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Treatment of this advanced intermediate with a substoichiometric quantity of VO(acac)2 and the stoichiometric oxidant t-BuOOH (a version of hydrogen peroxide that is soluble in organic solvents, non-explosive and relatively cheap) leads to one epoxide in good yield and remarkable diastereoselectivity.

The reason for the high selectivity is the same as before. The favoured conformation minimises the interaction between the two halves of the molecule (R1 and R2). Both substituents are considerably larger than the methyl group in our original and hence the high (complete) diastereoselectivity.

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The next example shows that we can direct a reaction over a larger distance (not just allylic stereocentres).

The diastereoselectivity of a reaction frequently falls with increasing distance between stereocentre and reactive site.

In this example we still observe reasonable diastereoselectivity as the reaction can proceed through a chair-like transition state.

As we shall increasingly find, being able to draw the chair conformation of cyclohexane and manipulate it is incredibly important in predicting and rationalising diastereoselectivity …

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The large paramethoxyaryl substituent will adopt the pseudoequatorial position while the methyl substituent is pseudoaxial as drawn above. The oxygen is then delivered from the top face.

Presumably if the methyl group had the opposite configuration the diastereoselectivity would be higher.

There are many other directed reactions. Crabtree’s catalyst permits highly diastereoselective hydrogenations to be achieved (including acyclic examples … simply by applying the concept of A1,3 or A1,2 strain).

Evans has devised a directed carbonyl reduction (and a non-directed variant) that permits aldol products to be converted into ether diastereomer of 1,3-diol.

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