Synthesis of hirsutene. Here because I love the use of radicals in synthesis (and yes, this lecture includes a quick re-cap of radical chemistry).

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.
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. It is made by Roche and at least one of
their published routes is based on the
conversion of shikimic acid (isolated from
star anise) to the final drug.
The entire pharmaceutical industry and
much of the agrichemical industry (and
many other industries) is build on the
chemists’ ability to synthesize molecules
with specific properties.
On this slide we see the molecule
oseltamivir or Tamiflu, an antiviral
medication used in the prevention and
treatment of flu.
2

3. The reported route takes 12 steps to
convert shikimic acid to the final product.
There are many other reported syntheses in
the literature. Some are longer, some are
shorter. We need to learn how to compare
these routes, to determine the pros and
cons of each route and, ultimately, how to
design similar syntheses so that we can
make our own target molecules.
Atorvastatin or Lipitor was one of the most
successful of the statin drugs used to low
blood cholesterol. From 1996-2012 it was
the world’s best selling pharmaceutical. It
is now off patent.
Yet again, it was initially discovered by
organic chemists ...
3

4. The original synthesis started from
isoascorbic acid, a stereoisomer of vitamin
C. It is a cheap ‘chiral pool’ natural
product.
Again, we need to be able to deduce how
Lipitor can be prepared from this
material ...
I could go on and on ... there are many
examples of small organic molecules used
to treat ailments. This is another bestseller
from the pharmaceutical industry and is
used to both treat and manage asthma.
The synthesis of the top molecule
salmeterol is relatively quick, taking just ...
4

5. ... six steps from this salicylic acid
derivative.
Of course, not all treatments are small
organic molecules. Peptides are becoming
popular targets. Fuzeon or enfuvirtide is a
biomimetic peptide that confuses the HIV
virus. It is hard to make and a tad
expensive ($25,000 US per year) so is a
last resort medicine.
5

6. But chemists are everywhere. To display my
Massey card, the next example is from both
the agrichemical sector and companion
animal health sector. Imidacloprid is
probably the world’s most commonly
employed insecticide.
On the downside, it has been linked to
colony collapse disorder in bees.
Its synthesis is shockingly simple and it
can be prepared in just four steps from 3-
methylpyridine.
6

7. Another example from the companion
animal health sector is the various
components of Drontal ...
... while we use this to keep our pets in
good health, one of the major components,
praziquantel, is found on the WHO Model
List of Essential Medicines needed for
basic health care. It used to treat intestinal
parasites.
New synthetic methodology is needed to
allow a cheaper synthesis to be developed
so there is more access to such useful
drugs.
7

8. Given enough time and resources (money
and students!) it looks like most molecules
can be prepared. One of the most
ambitious syntheses was the preparation of
palytoxin. This is the largest (non-
polymeric, non-peptide) compound I could
find.
It is not entirely clear how many steps are
involved as the synthesis of the starting
materials was not reported.
Interestingly, it is often small molecules
that are hard to prepare. The problem with
such molecules is they lack functionality for
us chemists to play with.
This is octanitrocubane. It was predicted to
be one of the most potent carbon based
explosives but it turns out it is not and that
the heptanitrocubane is more explosive.
This fact shows the importance of shape
and conformation to reactivity (as we shall
see later).
8

9. The next synthesis demonstrates the value
of radical chemistry, an area of chemistry
that is sadly glossed over for the most part
and undergraduate level …
This lecture’s target is hirsutene. It has
some antibacterial activity but nothing
spectacular.
The challenge with this molecule is the
fused tricyclic ring system and lack of
functionality for a chemist to play with
during the synthesis.
But first an (re)introduction to radical
chemistry …
9

10. In this example of a radical reaction three
C–C bonds along with three new rings are
created in a single step. It may not have
been the product the researchers were
looking for (they wanted a different
tetracyclic ring system) but it shows a
remarkable increase in complexity can be
achieved within a single step.
So what happened? I’ll discuss the actual
formation of the radical in a couple of slides
time but here are highlights …
• The iodide is transformed into a highly
reactive primary radical (a carbon with a
radical on it only has 7 valence electrons so is
electron deficient and is stabilised by the
same factors that stabilise a carbocation).
• This reacts with the activated (electron
deficient) alkyne - radicals are both
electrophiles and nucleophiles.
10

11. • After the 13-endo-dig cyclisation the
reactive alkenyl radical attacks the furan
ring in a 6-exo-trig cyclisation.
• One of the resonance forms of the
product has the radical stabilised by two
allylic groups and an oxygen. This acts as
quite a driving force for the cyclisation.
• But the ketyl radical keeps reacting and
formation of a stable ketone with
concomitant ring opening results in the
formation of a tertiary radical that is again
doubly allylic stabilised.
• Finally another cyclisation results in
formation of the tetracyclic product.
11

12. The advantages of radica reactions are listed
above.
• They occur under very mild reactions so are
tolerant of a host of functional groups (ionic
reagents are either strong acids or strong
bases).
• They are highly reactive so can perform
many valuable transformations.
Ignore the comment about salvation it is very
wrong.
The disadvantages are getting fewer
everyday.
with the only ones remaining from the list
above being:
• They are highly reactive (good and bad)
• People are scared/don’t understand them
12

13. Above is a simple radical conjugate addition. The
classic reagents for this are:
Tributyltin hydride
AIBN - azobisisobutyronitrile
substrate
radical precursor (bromide)
heat
The real disadvantage of this chemistry is that
tin reagent, which while perfect for radical
reactions is highly toxic and very hard to remove
from the product.
So a classical radical chain reaction occurs
in three stages:
1) initiation
2) propagation
3) termination
lets look at each in turn …
13

14. Initiation forms the first radical.
AIBN is the radical initiator. It is a
thermally unstable molecule that readily
decomposes on heating to give nitrogen
gas and 2 alkyl radicals.
These react with the tributyltin hydride to
form a tin radical. This relies on the Sn–H
bond being readily cleaved.
Note: there are two conventions for depicting
the same thing. In the first (previous slide) we
show the movement of every electron. Each
braking bond will require two fishhooks and
every new bond will be formed from two
fishhooks.
Alternatively, chemists being lazy (and
wanting neat drawings) sometimes draw the
fishhooks like curly arrows just showing the
overall flow of electrons … this is cleaner but
not very accurate or helpful.
14

15. In the propagation step the tin radical
reacts with an alkyl bromide, breaking the
weak C–Br to selectively form the
secondary alkyl radical.
The alkyl radical then adds to the alkene to
give the more stable α-keto radical
(resonance stabilisation like an enolate).
This reacts with tributyltin hydride to give
the product and the tin radical.
And here is the alternative representation.
I prefer the first representation with all
fishhooks. It shows what is happening and
does not rely on readers remembering what
is being represented. I confess I am guilty
of frequently drawing the second version
(as shown on this slide).
Just remember every bond is two electrons
so there needs to be two electrons moving.
15

16. You will notice that the tin radical is at the
start and finish of this slide. It is known as
the radical chain carrier as it propagates
the chain reaction.
In theory we only need one molecule of
initiator to form one molecule of tin radical
and then this will be continuously
regenerated until all the substrate has
reacted.
Of course, chemistry is not that simple …
… and we have the termination steps that
kill the chain reaction. These occur
whenever any two radicals meet.
Ideally we want to avoid any terminations.
To do this the concentration of the radical
needs to be kept low.
This can be achieved by using a very small
amount of initiator and more importantly
adding the tributyltin hydride very slowly
(which is a pain in the neck).
16

17. The big problem with classic radical
reactions is the use of the tin reagent.
There has been considerable research
trying to circumvent the use of these
reagents. There are many good reviews
(including two by me) on radical reagents.
The real break through was mentioned in
lecture 6; photoredox chemistry has the
potential to revolutionise radical chemistry.
The retrosynthesis of hirsutene starts by
two C–C disconnections removing two 5-
membered rings.
Radical reactions tend to favour 5-exo
cyclisations over 6-endo cyclisations so this
is a quite reasonable disconnection.
Removing two rings rapidly simplifies the
synthesis. It leaves an iodide as the radical
precursor, an alkene and an alkyne as
radical acceptors.
17

18. A C–C disconnection then removes the
alkyne.
At first glance this may look like a stupid
disconnection as it leaves two iodides and
the issue of chemoselectivity raises its
ugly head.
Fortunately …
… one of the alkyl iodides is next to a
geminal dimethyl group (or is effectively a
pseudo-neopentyl iodide).
The neopentyl group is very bulky and
prevents SN2 reactions (it blocks approach
of the nucleophile to the σ* anti-bonding
orbital so stops backside attack).
18

19. One iodide is going to be derived from a
carboxylic acid (we shall see later why this
is a good idea).
The other will be derived from an alcohol.
We need to remove the iodides early in a
retrosynthesis (or introduce them late in
the forward synthesis) as they are very
reactive/unstable and can cause
chemoselectivity issues.
All these FGI have been useful (as we shall
see) but they have not simplified the
molecule or got us back towards a simple
starting material.
So the next step is to remove one of the
branches off the ring.
Here we show a possible pair of synthons
for a C–C disconnection. We have decided
to make the carbon chain nucleophilic and
the ring electrophilic.
19

20. The obvious synthetic equivalent for an
electrophilic carbon atom is an alkyl halide.
We could make the halide above but there
are a number of issues. Firstly, how would
we make it? Secondly, as it would be an
allylic halide would it react by an SN1, SN2
or SN’ mechanism and what would the
consequence be to the stereoselectivity?
Alternatively, we could rely on an SN’
reaction and this would take us back to the
bicyclic lactone above.
This would guarantee the stereochemistry
as the nucleophile would attack anti to the
leaving group and from the outside (convex
face) of a v-shaped molecule.
20

21. Lets now go through this elegant synthesis.
The first stage is to prepare the bicyclic
lactone. This synthesis makes racemic
hirsutene but it would not be hard to
convert it to an enantioselective synthesis.
The starting material is 2-
methylcyclopent-2-enone.
1) A Luche reduction guarantees a 1,2-
reduction that will not be contaminated
with either the 1,4-addition or the over
reduction.
2) Acetylation gives the ester
Finally, silyl ketene acetal formation
furnishes the rearrangement precursor
above.
21

22. There are a number of potential explanations for
the effectiveness of the Luche reduction.
It appears that cerium catalyses the formation of
various alkoxyborohydrides. These reagents are
‘harder’ than NaBH4 so are more selective for
the reaction at the hard 1,2-position rather than
the soft 1,4-position. It is also thought that the
cerium coordinates to methanol making the
protons more acidic and capable of hydrogen
bond activation of the carbonyl (although it is
possible that the cerium does this directly itself).
How might we make the reduction
enantioselective?
Think about some of the earlier lectures
and either the CBS reduction (which would
be perfect for this) or asymmetric
hydrogenation.
22

23. Heating the silly ketene acetal to reflux
initiates an Ireland-Claisen rearrangement.
This is a pericyclic reaction, specifically a
concerted [3,3]-sigmatropic
rearrangement. Such reactions are
stereospecific.
You can recognise the possibility of such
rearrangements just by looking for two
multiple bonds whose terminals are 6
atoms apart.
Normally, such rearrangements occur
through a chair-like transition state and you
can use this to rationalise the
stereochemical communication.
This is shown above.
More information can be found about such
rearrangements here:
Stereoselective Synthesis - lecture 11 or
Advanced Organic Synthesis - lecture 8
23

24. The silyl ester can be cyclised to produce
the lactone by treatment with phenylselenyl
chloride.
This reaction is analogous to bromination
or the reaction of alkenes with ‘bromine
water’. So you know the mechanism …
… if you remember the bromination reaction,
it proceeds through the formation of a
bromonium ion.
This cyclisation occurs through the formation
of a selenonium ion, which is then attacked
by the carboxylic acid. The selenonium ion
forms reversibly but will only be attacked
when it is anti to the acid (SN2-like attack). We
could also argue that as selenium is very big
it forms on the least hindered face.
24

25. To install the required alkene the selenide
is oxidised with hydrogen peroxide to form
the selenoxide.
Such species spontaneously undergo syn-
elimination at room temperature
(analogous to the sulfoxide syn-elimination
we saw in the synthesis of hirsutene).
The SN’ reaction is achieved by forming an
organocuprate. A ‘soft’ nucleophile is
required to insure attack occurs on the ‘soft’
alkene and not at the ‘hard’ carbonyl carbon.
(if you do not know what Pearson’s Hard Soft
Acid Base (HSAB) concept then you should
start reading now … it’s very useful).
The cuprate is formed by reductive halogen-
metal exchange with Li-naphthalenide
followed by transmetallation to the copper
reagent.
25

26. After this, the conversion to the radical precursor, is
straightforward.
1) Acetal hydrolysis cleaves the THP-protecting
group (ppts = pyridinium para-toluenesulfonate)
2) Reduction of the carboxylic acid to an alcohol
gives the diol
3) Treatment with Tf2O forms the triflate. Triflates
are very good leaving groups (consider the pKa of
triflic acid)
4) The iodide displaces the triflate to give the
diiodide
5) Nucleophilic displacement of the accessible
iodide with TMS-acetylene is followed by:
6) Deprotection of the acetylene is achieved with
CsF.
Finally, the radical bicyclisation …
Treatment of the iodide with tributyltin
hydride and AIBN results initiates the
radical chain reaction. First the unstable
primary alkyl radical is formed. This
undergoes 5-exo-trig cyclisation to give the
cis fused 5,5-bicyclic tertiary radical.
Formation of the trans fused bicyclic
compound is disfavoured due the ring
strain.
26

27. The tertiary radical then cyclises onto the
alkyne (5-exo-dig cyclisation) to give an
alkenyl radical.
Reduction with tributyltin hydride gives the
product and regenerates the radical chain
carrier.
As we can see the bicyclisation occurs with
an excellent yield.
Hopefully this synthesis demonstrates the
power of radicals in synthesis and the fact
they can form multiple C–C bonds in one
step.
27