1) The document discusses various methods of substrate control in organic reactions, focusing on how substrate conformation can influence diastereoselectivity. Allylic 1,3-strain (A1,3 strain), where substituents on the first and third carbons interact sterically, is a key concept. 2) Reactions like epoxidation and hydroboration are often highly diastereoselective when the substrate adopts a conformation that positions the smallest substituent syn to the reactive double bond to minimize A1,3 strain. The reagent then approaches from the least hindered face. 3) Directed reactions use hydrogen bonding or coordination to deliver the reagent to one

1. 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 …
1

2. … 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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3. 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
…
3

4. … 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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5. … 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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6. 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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7. 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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8. 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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9. 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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10. 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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11. 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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12. 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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13. … 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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14. 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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15. 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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16. 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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17. 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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18. 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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19. 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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20. 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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