Self explanatory really, this lecture looks at chiral auxiliaries. We will concentrate on oxazolidinones in alkylations, aldol reaction and the Diels-Alder reaction. There will be a couple examples of other auxiliaries.

1. 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.
1

2. 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 …
2

3. The last lecture looked at substrate control.
This involves an existing stereocentre within
our substrate influencing the
diastereoselectivity. The obvious limitation of
this methodology is that the substrate must
contain a stereocentre and it must influence
the reaction to give the desired diastereomer.
One solution to this is to add a stereocentre
to control the diastereoselectivity … this is
auxiliary control.
Macbecin I is a marine natural product that
has anti-carcinogenic properties.
Funnily enough the synthesis on the next
slides is going to involve the use of a chiral
auxiliary …
3

4. In this reaction the the isopropyl
stereocentre on the oxazolidinone (the 5-
membered ring containing both and oxygen
and a nitrogen) is used to control the
configuration of the hydroxyl functionality.
This example may look like an example of
substrate control and in many respects it
is. The reason it is given a different
classification is due to the fact the
controlling stereocentre is not an inherent
part of the substrate; it is incorporated
into the substrate earlier in the synthesis
and, perhaps more importantly, it can be
removed after it has influenced the
diastereoselectivity of the key reaction …
4

5. … here is a cartoon trying to shown this.
In this idealised example we are converting
an achiral substrate into a pure
enantiomer.
We do this by:
1) adding a new stereocentre.
2) using this to control the
diastereoselectivity of the reaction.
3) removing the original stereocentre to
leave the pure enantiomer.
Ultimately, the chiral auxiliary does not
have to control the diastereoselectivity. It
can just act as a resolving agent.
As the auxiliary allows the creation of a
diastereomer we should be able to separate
the two molecules before removing the
auxiliary and leaving the pure enantiomer.
5

6. This is an early example (which I appear to
have forgotten to reference but I guess that
is what SciFinder or Reaxys) is from the
synthesis of a beatle pheromone.
The chiral auxiliary is 8-phenylmenthol and
this example demonstrates that it can
control the facial selectivity of the addition
of the Grignard reagent to a ketone.
The original stereocentre is then removed
by reducing the ester to an alcohol.
Ozonolysis then gives a ketone that
undergoes ketal formation … you should
know the mechanism for each of these
reactions.
6

7. The control of diastereoselectivity relies on
a number of criteria being met.
• The magnesium coordinates to both
carbonyl groups and this prevents rotation
around the central C–C bond.
• The carbonyl of the ester eclipses the C–
H of the ring to minimise interactions.
• A 𝛑–𝛑 interaction (𝛑 stacking) helps the
phenyl ring to block on face of the
substrate.
Probably the most common family of chiral
auxiliaries are the oxazolidinones. These
have been used in a huge range of
reactions and many different syntheses.
Their popularity arises from their reliable
diastereoselectivity, versatility in wide range
of reactions and …
7

8. … their ease of synthesis. They are readily
prepared by the reaction of an amino
alcohol with phosgene (or a synthetic
equivalent). The amino alcohols themselves
can be prepared from amino acids (as the
slide indicates). Obviously, there are a large
number of readily (cheap) available amino
acids.
Oxazolidinones permit highly diastereoselective
electrophilic reactions of enolates. The imide
precursors are readily prepared by reaction with the
appropriate acyl chloride (the propionate (above) is
very common).
Deprotonation with a strong metal base results in
the formation of an enolate. The bulk of the
oxazolidinone results in the formation of the Z-
enolate. Coordination of the metal with the
oxazolidinone carbonyl fixes the conformation of the
molecule, preventing rotation around the C–N bond.
This ensures only one face of the enolate is
blocked.
8

9. Treatment of the enolate with the
appropriate electrophile (this is an example
of an alkylation) normally results in a
highly diastereoselective reaction.
The isopropyl group of the auxiliary blocks
the bottom face of the enolate so the
benzyl iodide must approach from the top
(Si) face.
Here is an example of an allylation reaction
using a phenylalanine derivative.
Again, deprotonation results in the Z-
enolate. Coordination of the lithium
between the two oxygen atoms fixes the
conformation of the substrate. The
electrophile then approaches from the top
face.
9

10. A huge number of electrophiles can be
used in this reaction.
This example uses an electrophilic source
of oxygen to perform a diastereoselective
hydroxylation reaction. The reagent is
called an oxaziridine.
While this example is a diastereoselective
azidation.
All these examples display very high
diastereoselectivity … all of them >90% de,
which would suggest I cut-and-paste …
10

11. For the oxazolidinone to be a chiral
auxiliary it must be easily removed from
the substrate after the diastereoselective
reaction.
There are a number different methods to
do this …
It can be removed by transesterifaction to
give an ester …
… or it can be hydrolysed to give an acid.
Note that instead the standard alkaline
hydrolysis the optimum results are often
achieve with the lithium peroxide. This
basic reagent leads to preferential
hydrolysis of the correct carbonyl
functionality of the imide. Lithium
hydroxide can be plagued by ring-opening
of the oxazolidinone instead of cleavage of
the Csubstrate–N bond.
11

12. Alternatively, reduction will remove (and
destroy) the auxiliary giving you an alcohol.
An example of the use of a chiral auxiliary
in total synthesis comes from a synthesis
of bistramide A …
12

13. This example uses an auxiliary derived from
valine. Hopefully, you can rationalise the
selectivity of the allylation. Deprotonation gives
the Z(O)-enolate with the isopropyl group
blocking approach of the electrophile from the
bottom face. As a result the top (Si) face of the
enolate attacks the allyl iodide.
The auxiliary is removed by reduction and the
resulting alcohol is subjected to Swern oxidation
(temperature must be kept below –35°C to avoid
epimerisation) … of course, you all known the
mechanism for the Swern oxidation?
The next reaction is the ‘king’ of chemical
reactions (see what I did there) … the aldol
reaction.
This reaction permits the formation of a C–
C bond and potentially two stereocentres.
The resulting β-hydroxyketone contains
functionality for further elaboration and is a
common motif in many natural products.
13

14. The aldol reaction is a classic organic
reaction involving the movement of 6
electrons around a 6-membered ring … a
motif that reoccurs throughout organic
chemistry.
You should see that the reaction is almost
identical to the crotylation reaction and so
virtually everything we have learnt about
crotylation can be applied to the aldol
reaction …
The aldol reaction normally proceeds through
a Zimmerman-Traxler chair-like transition
state.
The relative stereochemistry is controlled by
the geometry of the enolate (cis gives the syn
aldol).
The position of everything is fixed except the
orientation of the aldehyde; it will be in the
pseudo-equatorial position to minimise 1,3-
diaxial interactions.
14

15. The trans enolate [E(O)-enolate] gives the
anti aldol product.
Changing the geometry of the enolate
changes the position of the methyl group
(so that it is equatorial) and this effects the
relative stereochemistry.
As before, the position of all the atoms is
fixed except the aldehyde (which again
prefers to be equatorial).
We have seen how we can control the
relative stereochemistry now we just need
a method to control which face of the
enolate reacts.
This can be achieved with a chiral auxiliary
with the isopropyl group blocking approach
to one face of the enolate.
Invariably these reactions involve a boron
enolate …
15

16. … but be careful.
Initially, you may think the boron is going
to coordinate to the two oxygen atoms of
the substrate and this fixes the
conformation of the nucleophile as in the
previous examples …
… but this is chemistry so of course this
does not happen.
The initial step is formation of the enolate;
coordination of the boron and the carbonyl
group activates the 𝛂-proton.
Deprotonation forms the Z(O)-enolate. The
bulk of the auxiliary aids control of the
enolate geometry.
For the aldol reaction to occur the aldehyde
must coordinate to the Lewis acidic boron
and this prevents internal coordination …
16

17. … the conformation of the substrate is no
longer fixed and the auxiliary can rotate
around the C–N bond.
Fortunately, one conformation is favoured.
The favoured conformation has the imide
carbonyl orientated in the opposite direction
to the enolate oxygen. This minimises dipole-
dipole interactions (like magnets, dipoles like
to oppose one-another).
Once we know the conformation of the
substrate we have to rationalise the
approach of the aldehyde.
The aldehyde is coordinated to the boron
atom. If the aldehyde approaches from the
Si face (right hand picture) then there is an
unfavourable interaction between the
isopropyl group and the substituents of the
boron.
17

18. The alternative is that the aldehyde
approaches to the Re face of the enolate
(left hand side). This has the isopropyl
group and the butyl substituents separated
so is favoured.
So the reaction proceeds through the right
hand side transition state.
And this explains the observed results.
The geometry of the enolate controls the
syn selectivity.
The auxiliary controls the facial selectivity.
As you can see the reaction is incredibly
diastereoselective.
18

19. If you want to find an example of an
oxazolidinone being employed in total
synthesis then you should probably read
the work of Dave Evans … this example is
from a beautiful synthesis of cytovaricin.
On this slide the two opposing dipoles are
marked (crossed arrow notation) on the
transition state. Hopefully, this shows the
two substituents blocking one face of the
enolate so the aldehyde (and the boron
ligands) must approach from the bottom
(Re at C2) face.
19

20. A second example uses a different aldehyde
and sets up another two stereocentres of
the molecule.
Another fantastic reaction is the Diels-Alder
reaction.
This reaction allows the formation of two
C–C bonds and up to four contiguous
stereocentres.
If you see a non-aromatic six membered
ring in a target you almost always can
consider using the Diels-Alder reaction to
prepare it.
20

21. The Diels-Alder involves the reaction of a
diene and a dienophile.
It is a [4+2]-cycloaddition, so is an
example of a concerted pericyclic reaction
(this means that all bonds are made and
broken at the same time).
The electronics of the two reactants are
very important. Normally the diene is
electron rich and the dienophile is electron
deficient (has an EWG attached).
This slide shows the two bonds that are
formed.
The regiochemistry of the addition is
controlled by the electronics of the
substituents (or more correctly the orbital
coefficients/frontier molecular orbitals).
For more information look at some of my
other lectures:
http://www.massey.ac.nz/~gjrowlan/stereo.html - lecture 8
http://www.massey.ac.nz/~gjrowlan/adv.html - lecture 5
21

22. This shows the 4 contiguous stereocentres
that are formed during the reaction.
The reaction occurs with stereospecificity
and normally very good diastereoselectivity.
The stereospecificity means that the
geometry of the diene and dienophile is
conserved in the product (so a trans
dienophile gives the anti product while the
cis gives the syn product).
The diastereoselectivity is quite surprising.
Normally the sterically more demanding
product (the thermodynamically
disfavoured product) is formed.
This suggests that most Diels-Alder
reactions are under kinetic control. The
reason for this selectivity (often called endo
selectivity) is often rationalised by an effect
called secondary orbital interactions
(although some people argue against this).
22

23. In an achiral reaction a racemic mixture of
the two endo products is formed.
The endo product has the electron
withdrawing ester group ‘under’ the diene.
If you do not know the basics of the Diels-
Alder reaction you really need to read up on
it … it is a really important reaction.
Addition of a chiral auxiliary allows the
reaction to occur to give a single enantiomer
of the endo product.
The Lewis acid is very important to the
success of this reaction. It serves a number of
functions:
• It coordinates both carbonyl groups locking
the conformation of the substrate
• It activates the dienophile by making it
more electrophilic and this allows the reaction
to occur at a much lower temperature.
23

24. As with all our reactions, we can rationalise
the stereoselectivity by inspecting the
favoured conformation of the substrate.
The Lewis acid coordinates both carbonyl
groups. This requires dissociation of a
chloride. We then have 2 x formal +ve
charge on O and –ve formal charge on Al.
This means the dienophile is formally
cationic so highly electrophilic.
The alkene is s-trans to the nitrogen to
minimise the interactions between the
alkene and the auxiliary.
The isopropyl group of the auxiliary blocks
approach from the bottom face so the
diene (cyclopentadiene) approaches the Si
(C2) face of the dienophile.
24

25. This example is from the synthesis of a
Chinese herbal remedy.
It includes an example of an auxiliary
controlled intramolecular Diels-Alder
reaction, which sets up the core six-
membered ring.
An intramolecular Diels-Alder reaction
permits the formation of a bicyclic system
with control of 4 new stereocentres.
The reaction occurs identically to the
worked example; the Lewis acid ties the
two carbonyls together and prevents the
auxiliary from rotating around the C–N
bond. The auxiliary then shields one face
and the diene approaches through the endo
transition state.
25

26. Please excuse me as I plagiarise myself …
This rationalisation comes from the first
ever lecture course I delivered way back in
1999.
It shows (badly) the endo selectivity and
how the auxiliary controls the approach of
the diene.
And as a little light relief the wonderful
Sean Connery …
Of course, this is to introduce an example
of radical chemistry.
For a long time people though asymmetric
synthesis with radicals would be impossible
as they are too reactive but this is not the
case as we shall see …
26

27. This example employs an unnatural amino
acid derivative (diphenylalanine) to form
the auxiliary.
The radical chain reaction is initiated by
Et3B/O2, which allows the use of low
temperature. The Bu3SnH is the radical
chain carrier. (if you don’t know about
radical chain reactions look ahead to
lecture 9).
R–X is a secondary or tertiary halide.
The ytterbium is a Lewis acid, which
functions as normal … it coordinates to
both the carbonyl groups fixing the
conformation of the substrate. It also
activates the enoate making it more
electrophilic.
The diphenyl moiety blocks approach of
the radical from the bottom fact so it must
approach from the top (Si) face.
27

28. There are many other chiral auxiliaries
other than the oxazolidinones. Here is the
8-phenylmenthol auxiliary being used in
the Diels-Alder reaction.
Unusually, the enoate is reacting through
the s-cis conformation, presumably due to
pi-pi interactions between the dienophile
and the phenyl group.
The reaction proceeds through endo
transition state as normal.
This auxiliary is the Oppolzer
camphorsultam. It is an incredibly robust
auxiliary.
This is another example of a Lewis acid
promoted Diels-Alder reaction.
It is very hard to visualise the
diastereoselectivity in this reaction. It is
caused by a mixture of electronics (anti to
the nitrogen lone pair) and sterics.
28

29. N
S
O
O
O
M
H
attack Re
face
H
H
S O
N
O
O
M
H
L
L
approach
Re face
H
H
S O
N
O
O H
≡
aux O
If you are interested … this is my
explanation …
Like the oxazolidinones the camphorsultam
has been used in many different reactions.
Here is an example of it being used in a
conjugate (Michael) 1,4-addition.
The rationalisation of stereocontrol is the
same as with the Diels-Alder reaction.
29

30. This is my favourite auxiliary, the sulfoxide.
Sulfoxides not only control the facial
selectivity but they also give an excellent
handle for further functionalisation (or can
be simply reductively removed).
There are many auxiliaries … there are
plenty of reviews in the literature.
30