This is the biggy, the one everyone wants to achieve. Here we will be looking at metal-based chiral catalysis. We will concentrate on bisoxazoline-based Lewis acid catalysis and then look at reductions before finishing with the ubiquitous Sharpless epoxidation and dihydroxylation.

1. 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).
1

2. ... 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 ...
2

3. ... 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.
3

4. 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).
4

5. 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.
5

6. 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 ...
6

7. ... 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 ...
7

8. ... 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?
8

9. 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.
9

10. 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.
10

11. 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).
11

12. 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.
12

13. 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 ...
13

14. 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 8
http://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.
14

15. 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 ...
15

16. ... 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 ...
16

17. ... 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).
17

18. 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.
18

19. 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 ...
19

20. ... 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 ...
20

21. 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.
21

22. 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 …
22

23. … 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.
23

24. 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).
24

25. 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 …
25

26. 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).
26

27. 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
27

28. 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.
28

29. 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.
29

30. 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.
30

31. 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.
31

32. 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.
32

33. 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).
33

34. 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 …
34

35. … 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).
35

36. 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 …
36

37. … 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 …
37

38. 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 …
38

39. 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 …
39