This document discusses organocatalysis, which uses small organic molecules rather than metals to catalyze chemical reactions. It notes the benefits of organocatalysis such as robust catalysts, new reaction types, and cleaner chemistry. Specific examples are provided of reactions catalyzed by proline, imidazolidinones, thioureas, and phosphoric acids. These catalysts form reactive intermediates like enamines and iminium ions to activate substrates for nucleophilic attack. Overall, organocatalysis is presented as a useful tool for synthetic chemists to address issues like solvent use, purification, and atom economy.

1. The last of the lectures devoted to
asymmetric synthesis will look at
organocatalysis.
This was the big growth area in asymmetric
catalysis over the last 10 years but has now
settle down to be another valuable tool in
the synthetic chemists arsenal ...
There have been a number of different
‘sales pitches’ for organocatalysis but I
believe there are three benefits arising from
organocatalysis:
1) the catalyst are robust (unlike many
metal complexes)
2) new/unorthodox transformations have
become viable
3) cleaner chemistry
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2. ... to become more environmentally benign
chemists must think about how we do
chemistry. The big problems are:
• solvents
• purification
• atom economy
Organocatalysis is just another (useful) tool
to address these problems.
By cleaner the normal ‘sales pitch’ is that
organocatalysis avoids the use of toxic and
expensive metals that need to be removed
from the reaction mixture at the end of the
process.
This is only half the story ...
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3. Nature has understood the principle of
organocatalysis for a long time.
Many enzymes do not require the presence
of a metal to catalyse reactions ...
... for example certain aldolases use
enamine (condensation of an amine and
carbonyl followed by tautomerisation)
chemistry to catalyse the aldol reaction.
Taking this (and other reactions) as
inspiration, organic chemists have
developed a toolbox of simple organic
molecules that can catalyse a host of
different transformations.
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4. There have been many monographs written
about organocatalysis and I thoroughly
recommend you read some.
Good starting points are:
http://pubs.rsc.org/en/content/articlelanding/2009/cs/b903816g#!
divAbstract
http://pubs.rsc.org/en/content/articlelanding/2013/cs/c2cs35380f#!
divAbstract
http://onlinelibrary.wiley.com/enhanced/doi/10.1002/chem.201301996/
The reaction the probably kickstarted the
organocatalysis field was the proline-
catalysed aldol reaction.
Here the simple amino acid catalyses the
direct aldol reaction of non-activated
aldehydes (unlike the Mukaiyama aldol
reaction we saw earlier that requires
formation of the silyl ketene acetal).
As you can see the reaction is highly
diastereo- and enantioselective.
4

5. O H
N
O
H
H
O
H
There is debate as to the transition state for
the proline catalysed aldol reaction but this
simplified mechanism will do for now ...
The first step is condensation of the proline
with the less sterically demanding aldehyde.
This initially gives the iminium ion.
‘Tautomerisation’ generates the nucleophilic
enamine.
Addition to the aldehyde reforms the iminium
cation. Hydrolysis regenerates the catalyst
and releases the product.
The transition state is probably similar to the
one shown above, with a proton tethering and
activating the incoming aldehyde. It is
possible that the proton is also interacting
with the lone pair of the nitrogen to give a
more rigid structure.
This is a little bit stylised to allow the
transition state to be drawn based on the
chair but is close to the predicted structure
(and highlights the value of being able to
draw that 6-membered ring).
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6. The proline-catalysed direct aldol reaction
effectively started what has been termed
the organocatalyst ‘gold rush’. Literally
hundreds, if not thousands, of papers
using various amines to catalyse a host of
reactions.
Some of those papers are excellent but
there is a bit of ‘bandwagon’ jumping going
on as well so you will need to filter the
papers ...
Here are some examples of the power of this
reaction manifold and the classic catalyst
structures ...
A number of attempts have been made to
improve the structure of the catalyst (proline
is not soluble in many organic solvents).
Prolinol derivatives have a wide variety of
uses. Here is an α-fluorination. The aldehyde
is reduced before isolation to prevent
racemisation of the highly acidic α-position.
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7. The mechanism is very similar to before;
amine condensation to give the iminium
species. Deprotonation gives the enamine.
Nucleophilic attack on the source of “F+”
gives the iminium species, which is
hydrolysed to product and catalyst.
The silyl protecting group prevents
formation of a non-active hemiaminal.
One of the most successful classes of
organocatalyst is the imidazolidinones
introduced by MacMillan.
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8. These are readily prepared from amino
acids thus allowing easy access to a
structurally diverse array of chiral
molecules.
Condensation to form the aminal means
more sterics or functionality can be readily
incorporated into the molecule.
The imidazolidinones promote enamine-
based reactions like proline and prolinol
derivatives.
The mechanism is just the same;
condensation, deprotonation, nucleophilic
attack and hydrolysis ...
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9. Just as an example ... here a phenylalanine
and acetone derivative is used in an α-
chlorination reaction.
Hopefully you can see that the reagent in
red is a good source of “Cl+” as this would
result in the formation of an aromatic by-
product.
And now for an example of the MacMillan
chemistry being employed in the synthesis
of a natural product ...
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10. First the hydroxyl stereocentre marked in
red was introduced by a proline-mediated
α-hydroxylation reaction.
This follows the standard enamine
mechanism. There is some debate as to the
nature of the transition state. It could be
identical to the aldol reaction earlier or
might occur through a more pronounced 6-
membered ring with all the major
substituents trying to adopt the pseudo-
equatorial conformation.
An aldol dimerisation catalysed by proline
installs two of the stereocentres found in
the carbohydrate moiety.
The mechanism and transition state were
given earlier.
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11. This example is taken from the synthesis of
a potential pharmaceutical compound ...
It involves the conjugate addition of an
enamine to a nitroalkene.
The catalyst is a proline derivative in which
the carboxylic acid functionality has been
replaced with a highly acidic sulfonamide
fragment.
As you can see the reaction is highly
effective with good yields, diastereo- and
enantioselectivity.
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12. The transition state is believed to be more
complex than those we have looked at
before and might involve water/solvation as
means of organising the two substrates.
Organocatalysis takes many different forms
and is not just about the formation of
nucleophilic enamines.
An incredibly powerful form of
organocatalysis is the use of iminium species
to replace Lewis acid catalysis.
Lewis acid catalysis normally involves the
lowering of the Lowest Unoccupied Molecular
Orbital (coordination increases the
polarisation of the molecule by dragging
electrons towards the Lewis acid).
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13. This can be achieved through the formation
of an iminium ion. The charged
intermediate activates the double bond to
nucleophilic attack or cycloaddition with
the electron rich molecules such as
dienes ...
... here is an example of a secondary
amine promoting the conjugate (1,4- or
Michael) addition of a malonate to an
enone.
This elegant example of ‘green’ chemistry
(no solvent, good atom economy) proceeds
with good yield and excellent
enantioselectivity.
13

14. The reaction proceeds through the
standard formation of the iminium species.
In this case deprotonation to give the
enamine is slower than nucleophilic attack.
The geometry of the iminium species is
thought to arise as a result of π-π
interactions (π stacking). This blocks
approach of the malonate from the top
(Re) face so it must approach from the
bottom (Si) face.
This chemistry has been used in the
synthesis of warfarin, a blood thinner ...
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15. ... as well as a rat poison ... In this reaction the secondary amine
activates the enone, making it more
electrophilic while creating a well-defined
chiral environment. The nucleophile
(tautomeric form of a β-ketoester) then
attacks from the least sterically demanding
face of the iminium species. Hydrolysis
regenerates the catalyst and frees the
product.
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16. Iminium activation has been used to great
success in Diels-Alder reactions.
This example employs an imidazolidinone
formed from pehnyalanine and a furanyl
aldehyde.
It proceeds with the standard exo
diastereoselectivity (secondary orbital
interactions) and excellent
enantioselectivity.
The enantioselectivity can be rationalised
as shown above.
First condensation gives one geometry of
iminium cation. The furanyl moiety can
accommodate the ethyl group more readily
than the benzyl substituent as there are
fewer non-bonding interactions (CH2 vs.
CH2 bad). The benzyl group can adopt a
conformation that allows π-stacking so
favours the alkene.
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17. This arrangement blocks the top (Re at α-
iminium) face.
The diene must approach from the bottom
(Si) face. The charged iminium species is
over the diene (endo) to maximise
secondary orbital interactions.
Concerted cycloaddition then occurs.
There are other forms of organocatalysis
that do not involve the formation of a
reactive intermediate (enamine or iminium)
but involve an adduct/complex.
In Nature, hydrogen bonding is important
for the formation of secondary structure in
proteins but also for molecular recognition
and activation ... chemists have mimicked
this ...
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18. ... to activate aldehydes and ketones in an
analogous manner to Lewis acids.
Hydrogen bonding results in weaker activation
than traditional Lewis acids but has the
advantage that the catalysts are more stable
and are rarely irreversibly deactivated.
Ureas and thioureas are commonly employed
in this role. Thioureas are preferred as they do
not self-associate as strongly.
This is an example of cyanohydrin formation.
The thiourea activates the ketone to
nucleophilic attack. Trimethylsilyl cyanide is a
slightly more user friendly alternative to
hydrogen cyanide and protects the
cyanohydrin.
The story of the discovery of this catalyst is a
testament to good science and it is well worth
reading the original Jacobsen papers.
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19. The next example utilises a thiourea in a
related form of catalysis.
This is taken from the synthesis of
yohimbine, which is used for the treatment
of erectile dysfunction.
The catalyst controls the enantioselectivity
of the wonderfully named ...
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20. ... Pictet-Spengler reaction ... ... which is formally a cyclisation reaction
(although it actually involves cyclisation to
form a 5-ring followed by migration to give
the 6-ring).
This is an example asymmetric counter-
anion catalysis. Effectively an electrostatic
attraction between the iminium species
and a hydrogen bonded chloride creates a
chiral environment of the cyclisation.
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21. Question time ...
What is the smallest catalyst?
It is, of course, a single proton ... or acid
catalysis or Brønsted acid catalysis.
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22. But how do you make a proton, which in
organic terms is an empty 1s orbital,
chiral? Its a spherical entity and a sphere
cannot be chiral ...
Well you attach it to a chiral molecule and rely
on the electrostatic attraction between the
protonated substrate and the conjugate base
to create the necessary chiral environment (or
you hope it does not dissociate and that you
have a hydrogen bond catalyst).
Chiral phosphoric acids and their derivatives
have become very useful catalyst in
organocatalysis and metal catalysis (where
they can be the counter ion).
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23. Here is an example of an aza-ene reaction (I
guess you can think of this as an enamine
version of the Mannich reaction).
In this reaction the phosphoric acid acts as a
manifold to position and activate the
substrates. The acid functionality protonates
the imine while the P=O probably hydrogen
bonds to the N–H of the enamide. With both
the nucleophile and electrophile activated
within a chiral pocket good yields and
enantioselectivities are observed.
Alternatively, in this example the
phosphoric acid simply protonates the
imine and makes it more electrophilic. The
resulting iminium cation is electrostatically
attracted to the conjugate base so when
the indole attacks in a Friedel-Crafts
reaction the bond forming event occurs
within a chiral environment.
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24. And here is yet another example.
This time it is a hetero-Diels-Alder reaction.
Once again the imine is protonated to
make it more electrophilic and it reacts
with the electron rich diene.
Not the phenol substituent on the imine.
This probably permits to points of
interaction between the substrate and
catalyst (bifunctional hydrogen bonding).
These next two slides reveal how
desperately I need to update this section ...
when I wrote these slides this was cutting
edge with less than a handful of papers ...
... now it is an established area of
chemistry that permits some truly
remarkable tranformations to be performed
(so at least I was right in suggesting this
was an area to watch!)
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25. Combing organocatalysis with photoredox
chemistry permits an exciting method to
not only generate radicals under
remarkably mild and clean conditions
(freeing radical chemistry from the tyranny
of organotin compounds) but perform
some highly enantioselective reactions.
If you like organic chemistry and
enantioselective synthesis this is really
exciting and I would thoroughly ...
... recommend that you read the work of
MacMillan and Corey Stephenson (amongst
others).
Next lecture ... Synthesis
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