Gives an introduction to total synthesis and why we do it (which reminds me, I must add a picture of Everest, as I think the fact that 'it is there' is the main reason for most syntheses). Then to introduce the topic with a reasonably simple synthesis, we will look at an example of the synthesis of Tamiflu.

1. The last four lectures will look at a number
of total syntheses. Hopefully these will
demonstrate how we link the last three
years’ worth of organic chemistry together
with asymmetric synthesis to start making
our target molecules.
So why do we need Total Synthesis.
Well I gave you a number of reasons at the
start of lecture 1 but lets recap …
This molecule is spongistatin 1 (or
altohyrtin A). It is one the most potent anti-
carcinogens tested. As a result it might
make a good lead for the development of a
new cancer treatment. But there is one big
problem …
1

2. … it took 400 kg of sponge to isolate just
13 mg of spongistatin.
This means nature is not a viable source of
this material.
The only way around this problem …
… is to devise a synthesis of spongistatin
(it turns out that there are 7 syntheses at
the moment only one has produced over 1
gram and even that is not sufficiently
economical or viable for screening).
So we need to be able to design an efficient
synthesis …
2

3. How do we design a synthesis? Well there are many ways!
Chemistry is the only truly creative science.
Not only to we have the ability to study the
fundamental properties and reactivity of
molecules but we have the possibility of
applying this knowledge in any way we feel.
We can create a myriad of routes to one
molecule or we can create something that
has never be synthesised before …
3

4. … but how? The most reliable method to plan a total
synthesis is the system known as
retrosynthesis.
(I’m not convinced it is the only method and I confess I believe many
practising chemists probably use a mixture of retrosynthesis and intuition/
experience).
Retrosynthesis is the idea of thinking
backwards. Of starting with the target and
breaking it apart to a simpler starting
material.
4

5. Retrosynthesis is a thought process that
formalises how we look at a molecule so
that we can identify bonds that can readily
be disconnected (in the backward sense)
or readily formed (in the forward sense).
A disconnection leads us to …
… new targets and the process starts
again.
Here we see that we can make an alkene by
a Wittig reaction, alkene metathesis,
selective reduction or a McMurry coupling
(amongst other reactions). Each possible
disconnection takes us to a different target
(aldehyde, phosphorane, alkene, alkyne
etc.) and so each disconnection may
simplify our synthesis.
5

6. Hopefully, it is obvious that the more
organic chemistry you know, the more
reactions that you can call upon, the more
possible disconnections you can see.
The more organic chemistry you know the
easier the analysis of each disconnection
and the quicker you should be able to
dismantle a molecule.
So please go back and read your notes from
123.202 & 123.312.
Find a good textbook and skim through it. If you like
or are interested in synthesis read:
‘Organic Synthesis: The Disconnection Approach’ by
S. Warren & P. Wyatt
‘Classics in Total Synthesis I, II & III’ by KC Nicolaou
& others
Look at my notes for:
Retrosynthesis: 123.312
Retrosynthesis: Interactive pdf
Retrosynthesis: UoS PG course
6

7. So lets look at some examples of the
synthesis of useful molecules and we will
start with Tamiflu the anti-flu medication.
There are a large number of the syntheses
of this molecule in the literature …
… how were they planned? Lets look at
potential retrosynthetic analyses of Tamiflu
and show how a knowledge of reactions
can lead to different routes to the same
target.
Note: in each case I’m just showing the
broad outline and not the details (limited
lectures etc.)
7

8. In this first disconnection we have a C–N
disconnection or a functional group
interconversion (FGI). The diamine can be
prepared from an aziridine. Ring-opening
will be stereospecific with inversion of
stereochemistry (as it is an SN2 reaction).
Regiocontrol is based on steric hindrance
with the large ether blocking approach to
one carbon atom.
The aziridine itself can be prepared from
either a diol or an epoxide (which in turn
can be prepared from a diol).
These disconnections lead back to shikimic
acid. How do we know this? Well that
comes from experience, a knowledge of the
‘chiral pool’ and being able to search
databases effectively.
8

9. An alternative retrosynthetic analysis is given
here. Again we are looking at the chemistry of
aziridines but this time we have a C–O
disconnection and remove the ether.
Again, aziridine ring opening is normally
stereospecific as it is an SN2 reaction.
Regioselectivity arises from both steric
arguments (the protected nitrogen blocks
approach to one carbon) and electronic
factors (the allylic C–N bond is going to be
more reactive due to orbital overlap).
There are many routes to this aziridine (we will
look at 2).
If you ever see a 6-membered ring with a double
bond in it you should consider the Diels-Alder
reaction as a potential route (top right).
Alternatively, we could remove the aziridine to
give an alkene (nitrene chemistry in the forward
sense or oxidation and FGI). The resulting alkene
could then be made in enantiomerically enriched
form through palladium chemistry (bottom
right).
9

10. Which is the right route?
It depends on your criteria: number of
steps? Yield? Stereochemistry? Availability
of starting materials? Cost? Scalability?
Showing off your latest methodology?
Different routes have different purposes
and teach us different things.
The first route we will look at is from the
original Gilead/Roche publications and was
probably one of their early routes to large
quantities of Tamiflu but not necessarily
their final industrial route (as we shall see
there are a couple of less than desirable
steps).
10

11. So lets look at the retrosynthesis is a little
bit more detail.
The diamine can be formed from an
aziridine (C–N disconnection) as stated
before.
C–N disconnections (or aziridine-epoxide
FGI).
Epoxides can relish be converted to
aziridines (in several steps). Note how the
stereochemistry is inverted (this due to the
first step in the forward sense being ring-
opening of the epoxide by an SN2 reaction).
11

12. The epoxide can be disconnected by C–O
disconnection (or epoxide–diol FGI).
This requires selective protection of the
three hydroxyl groups of shikimic acid so
that we can chemoselectively react each
one in turn.
At first glance this may appear hard (and
bits of it are!) but we can rely on
stereochemistry to allow protection of the
syn-diol. Formation of the 5-ring acetal will
selectively occur on the syn diol as a trans-
fused 5,6-bicyclic ring system is highly
strained. This leaves the hydroxyl group at
C5 (bottom) free to be activated as a good
leaving group by conversion to the mesylate
(Ms = SO2CH3).
The only difficult step is the selective
cleavage of the acetal …
12

13. So lets look at the actual synthesis:
1. Esterification via the acid chloride
2. Ketal formation - selective for the syn
diol to minimise strain
3. Mesylation of the free alcohol converts it
into a good leaving group.
Then comes a clever step. This is the
selective reduction of the ketal. TMSOTf
[(CH3)3SiOSO2CF3] is a strong Lewis acid
and will activate one of the ketal oxygen
atoms making it into a good leaving group.
The lone pair on the other ketal oxygen
feeds in to form an oxonium ion (of the
carbocation), which is reduced by the
borane.
Why does one oxygen react and not the
other?
13

14. My guess (and it is only a guess) is that the
C–O bond interacts with the electron
deficient enoate (C–O σ bonding orbital
overlaps C=C π* antibonding orbital) and
this reduces the Lewis basicity of the
oxygen. Thus the C4 (lower) oxygen is
silylated and the C2 oxygen participates in
oxonium ion formation.
Reduction gives the desired ether.
Once the ketal has been cleaved, base-
mediate cyclisation with substitution of the
mesylate forms the epoxide (must be
antiperiplanar and thus diaxial).
14

15. Epoxide ring-opening with sodium azide
must occur from the top face (SN2
substitution).
It does not matter if we achieve
regiocontrol of the ring opening as both
azides give the same aziridine on treatment
with a phosphine.
The mechanism for the aziridine formation
is given here. As is so often the case it
relies on the strength of the P=O bond to
drive it forwards.
15

16. 1. Regioselective ring opening of the
aziridine occurs at the least sterically
demanding carbon. Surprisingly, the
aziridine did not require activation, which is
unusual.
2. Acylation of the free amine is followed
by …
3. Reduction of the azide to give the
second amine. This order of reactions
permits the amines to be differentiated.
4. Salt formation gives Tamiflu.
The problem with this route is that two
steps use sodium azide.
This compound is very toxic and is
explosive (it used to be used in car safety
airbags).
As a result a route that avoided its used
was developed (and is probably the
industrial route to Tamiflu).
16

17. Along with the problem of using sodium
azide the other disadvantage of this
synthesis is that there is a limited supply of
shikimic acid (which is isolated from star
anise, which in turn is only grown in a part
of China … and is damn tasty in sweets
and cooking).
As a result many other routes to Tamiflu
have been developed that try to mitigate
these short comings.
The second synthesis we will look at uses
an elegant asymmetric catalysis to instal
the one stereocentre, which is then used in
substrate control to set up the others.
The retrosynthesis starts with removal of
the ether (C–O disconnection) to give an
aziridine. We can expect good
regioselectivity during the ring opening one
steric and electronic grounds.
17

18. Next the reactive aziridine is removed from
the molecule (it is always useful to remove
reactive functionality early in a
retrosynthesis to avoid any potential
chemoselectivity issues).
The aziridine will be installed by nitrene
chemistry involving the more electron rich
alkene.
The final part of the restrosynthesis
involves the removal of an alkene (the
forward version, adding an alkene, can be
achieved by elimination or palladium
chemistry).
Finally the amine is removed. The forward
version of the reaction will be a palladium-
mediated allylic substitution and this
permits a racemic starting material to be
converted into a single enantiomer …
18

19. So the first step is by the most interesting
and useful.
In this reaction a racemic lactone is
converted into an enantiomerically
enriched amine by treatment with a chiral
palladium complex and a nitrogen
nucleophile.
A brief overview of the mechanism follows.
If you want more information read the work
of Barry Trost or look at my lecture:
Advanced Synthesis - lecture 5
The Pd complex approaches the allylic
ester anti to the leaving group (the
carboxylate). It displaces the leaving group
and forms a π-allyl complex. Both
enantiomers of the racemic starting
material will give the same, symmetric …
19

20. … π-allyl complex. Thus we can convert
both enantiomers into the same product.
The nitrogen nucleophile attacks the
cationic, electron deficient π-allyl complex
from the opposite face to the Pd-complex.
The ligand on the palladium controls which
end of the π-allyl complex is attacked and
thus which enantiomer of product is
favoured.
The reaction occurs in a good yield and a
high enantioselectivity.
Acid catalysed esterification of the
carboxylate furnished the product above.
20

21. 1. Enolate formation by deprotonation of
the α-ester position forms a nucleophile
that reacts with PhSSO2Ph to give a sulfide.
The base, KHMDS = potassium
hexamethyldisilazide or potassium
bis(trimethysilyl)amide or KN(SiMe3)2.
2. Oxidation of the sulfide to a sulfoxide
with meta-chloroperoxybenzoic acid is
followed by a syn-elimination …
… as shown here to give the desired diene.
The regioselectivity of the alkene formation
can be explained in terms of conjugation.
This product as both alkenes in conjugation
with each other and the ester. The other
regioisomer would have the double bonds
isolated from each other.
21

22. Aziridine formation uses rhodium-mediated
nitrene chemistry. The SES-protected
amine (SES = 2-trimethylsilylethanesulfonyl
or Me3SiCH2CH2SO2-) first reacts with the
hypervalent iodine species to give
SESN=IPh (or equivalent), which can then
react with the rhodium to give a nitrenoid
(if such a word exists) that adds to the
alkene in the same manner a carbene
would form a cyclopropane (remember
Vyacheslav’s lectures).
The stereoselectivity of the addition
probably is the result of simple sterics with
the nitrenoid/rhodium complex
approaching from the least sterically
demanding face of the ring (anti to the
protected amine).
22

23. 1. Lewis acid-mediate aziridine ring-
opening with the alcohol occurs by an SN2
reaction at the carbon furthest from the
bulky amine.
2. Acetlyation protects the amine.
Finally two deprotection steps.
1. TBAF (tetrabutylammonium fluoride) a
source of F– removes the SES group
(fluorine and silicon are a match made in
heaven).
2. Hydrazine then removes the phthalamide
(classic Gabriel amine synthesis).
23

24. This is the reference for the Diels-Alder
version of the synthesis of Tamiflu. It is
one of many syntheses reported by
Shibasaki. All have some excellent
examples of asymmetric catalysis and are
becoming increasingly refined.
24