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 …

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… 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 …

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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 …

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… 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.

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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.

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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: 123.312Retrosynthesis: Interactive pdfRetrosynthesis: UoS PG course

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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.)

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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.

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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).

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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).

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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).

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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 …

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So lets look at the actual synthesis:

1. Esterification via the acid chloride2. Ketal formation - selective for the syn diol to minimise strain3. 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?

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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).

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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.

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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).

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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.

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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 …

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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 …

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… 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.

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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.

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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).

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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).

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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.

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