The last lecture will detail one of the many syntheses of epothilone A & C. This is almost one of my favourite syntheses (but due to one step hasn’t made the list) due to the fact it demonstrates many of the principles of asymmetric synthesis such as substrate control, auxiliary control, reagent control and asymmetric catalysis.

The epothilones were originally isolated from a gram-negative bacteria, Sorangium cellulosum found in a river delta (but I have forgotten which river).

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TMSOO Li

OHTMSO

O OHTMSO

O

73 27

OCy Cy Cy

H

OO

LiH

H

H Cy

TMSO

Felkin-Anhdisfavoured syn-

pentane interaction

OO

Li

H

H

CyTMSO

anti Felkin-Anhfavoured

HOH

O

H

H

CyTMSO

≡ OHTMSO

OCy

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As always the goal of the retrosynthesis is to sequentially simplify the target.

The first disconnection is epoxide. This removes reactive functionality from the molecule (good) and takes us back to another natural product, epothilone C (good).

Chemoselective epoxidation of the electron rich alkene should be possible (forwards).

They show great potential as cancer drugs. They prevent cell division by interacting with the microtubules in an analogous fashion to the taxanes.

They have a number of advantages over the taxanes including better efficacy, greater solubility, less side effects and simpler synthesis.

I do not believe any have made it out of clinical trials yet.

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Next we want to cleave the ring as this:

1) simplifies the synthesis2) begins the task of fragmenting epothilone to permit convergent synthesis

The obvious disconnection is the lactone group (and there are examples of syntheses of epothilone that take this route).

In this case the C=C disconnection was chosen. The forward synthetic reaction ,ring-closing metathesis is a reliable reaction (see later).

Epothilone was then divided into three roughly equal sized fragments.

The C–O disconnection (esterification) is an obvious place to split the molecule as this is a standard transformation.

The 1,3-diX disconnection of the β-hydroxyketone allows two stereocentres to be controlled through the aldol reaction.

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The first fragment is readily prepared in enantiomerically enriched form.

The retrosynthesis is:FGI - ketone to alcohol (forward is oxidation)C–C - forward is addition to a carbonyl groupFGI - forward is oxidation of alkene to carbonylC–C - forward is Brown allylation

The second fragment involves:

FGI - aldehyde to chiral auxiliary (forward is reduction and oxidation)C–C - forward is enolate alkylationFGI - forward is addition of auxiliary and conversion of alcohol to alkene.

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Final fragment:

FGI - alkene to alcoholC=C - split internal alkene (forward is HWE)A resolution step (or step below must be asymmetric)C–C - nucleophilic addition

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1) Mono-protection of the diol. The selectivity in this step is believed to arise from the insolubility of the mono-alkoxide preventing over reaction (J. Org. Chem. 1986, 51, 3388).2) Swern oxidation (if you don’t know this by now ...)3) Brown crotylation

We went through the enantioselectivity of this reaction in lecture 4.

Basically, remember that the Lewis basic boron tethers the substrate and reagent together so that the reaction proceeds through the Zimmerman-Traxler transition state. The crotyl reagent is bulkier than the aldehyde so will minimise non-bonding interactions with the methyl substituents.

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1) Acetal formation - the reaction conditions are sufficiently acidic to promote deprotection of the primary silyl ether (TBS = tert-butyldimethylsilyl).

2) Oxidative cleavage of the alkene. This employs a substoichiometric quantity of OsO4 and stoichiometric NaIO4. The OsO4

mediates dihydroxylation while the NaIO4 re-oxidises the osmium and cleaves the diol. This is analogous to ozonolysis.

1) Addition of a Grignard reagent. We do not care if the reaction is diastereoselective or not because ...

2) Oxidises the alcohol to the ketone. TPAP (tetrapropylammonium perruthenate [Pr4N][RuO4]) is a catalytic oxidant while NMO (N-methylmorpholine N-oxide) is the stoichiometric oxidant (it oxidises the ruthenium).

That finishes the first fragment.

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Standard FGI prep the second fragment for the auxiliary controlled alkylation.1) Lactone hydrolysis2) Protection of acid and alcohol to prevent cyclisation back to the lactone3) Hydrolysis of the acid O–Si bond (much weaker bond the alcohol O–Si)4) Acyl chloride formation5) Addition of the valine-derived oxazolidinone.

Auxiliary controlled alkylation.1) enolate formation gives the O(Z)-enolate to prevent interaction of alkyl chain and auxiliary. The metal chelates the two oxygen atoms preventing C–N bond rotation and thus the auxiliary blocks the top (Re) face.2) LiAlH4 - reductively cleaves the auxiliary.3) Swern oxidation (at low temperature to avoid racemisation) forms aldehyde.

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Naughty chemists fail to install the alkene required on the second fragment ...

... and when they came to use this fragment at the end of the synthesis it has magically appeared ...

Synthesis of the third fragment starts from the the same aldehyde as fragment 1 (which is convenient).

Simple Grignard addition results in the formation of a racemic mixture of alcohols.

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The racemic alcohol is resolved by a clever application of the Sharpless Asymmetric Epoxidation.

This is an example of kinetic resolution and relies on the two enantiomers reacting at different rates. Ideally, one enantiomer should react completely before the other reacts and this permit the maximum 50% yield (remember 1/2 the material is the wrong enantiomer) to be achieved.

If you remember the SAE reaction there was a mnemonic that told us which face of the alkene the oxidising reagent would approach.

If we apply this mnemonic to a racemic alcohol you will note that with one enantiomer the reagent must pass the substituent R. This will lead to a slower reaction than the enantiomer that has the R group anti to the reagent.

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This means that we are able to selectively transform one enantiomer into the epoxide leaving the other enantiomer as an enriched sample of alcohol.

Ideally we should have 50% of each enantiomer with 100% purity. This rarely happens and we normally sacrifice yield to insure high enantiomeric enrichment.

A good review on KR: Adv. Syn. Catal. 2001, 343, 5.

The enantiomerically enriched alcohol was converted into the third fragment by the following transformations:

1) TBS protection of secondary alcohol2) Ozonolysis of the alkene with reductive work-up furnishes the ketone3) HWE alkenylation - This favours formation of the E-alkene (equilibration of initial alkoxide)4) HF/glass - selective deprotection of the more reactive primary silyl ether. Glass tempers the reactivity of HF (it contains silicon, which can react with the fluoride)5) Oxidation of the primary alcohol to an aldehyde using Dess-Martin periodinane6) Wittig alkene formation7) Deprotection of the remaining silyl ether.

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With all the pieces made it is time for the ‘end game’ ...

... stringing them all together.

The first two fragments were joined together by a substrate controlled aldol reaction in a highly diastereoselective reaction.

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Deprotonation leads to the formation of the O(Z)-enolate.

The Ireland-model of deprotonation (shown above) rationalises the observation that the methyl group of the enolate would prefer to be trans to the bulky neopentyl-like group.

The relative stereochemistry of the C7 hydroxyl and C6 methyl is controlled by the geometry of the enolate.

The diastereoselectivity of the reaction is hard to visualise.

Both substrates are chiral so will both influence the facial selectivity. The stereocentre on the aldehyde controls the facial selectivity of nucleophilic attack.

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The addition is anti-Felkin-Anh (in other words if you draw the Newman project ... going on draw it) then when the nucleophile attacks along the Bürgi-Dunitz angle it must pass the methyl substituent and not the small hydrogen atom to give the observed diastereoselectivity.

Why does this happen? The reason is the geometry of the enolate and a disfavoured syn-pentane-like interaction if we have ...

... Felkin-Anh selectivity.

This argument is shown in a simplified reaction above.

If we had the opposite geometry of enolate then the standard Felkin-Anh model would predict the product.

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The facial selectivity of the bond formation on the enolate is harder to explain suffice to say that the stereocentre of the acetal control the approach of the aldehyde.

It is highly likely that one of the acetal oxygen atoms is also coordinated to the lithium counterion and that this effects the selectivity (although it is possible that a formyl hydrogen bond from the aldehyde is involved).

A set of simple FGI sets up this advanced fragment for coupling to the final third.

1) acetal hydrolysis to give a triol2) Global protection of the three alcohols3) Selective acidic hydrolysis of the more reactive primary silyl ether using the mild acid, CSA (camphorsulfonic acid)4) PDC oxidation of the primary alcohol to a carboxylic acid

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The final fragment is coupled by esterification with DMAP and DCC.DMAP = N,N’-dimethyl-4-aminopyridineDCC = dicyclohexylcarbodiimide

Normally these are peptide coupling reagents but work well with esters. The DCC is a dehydrating reagent while the DMAP forms a highly activated acyl reagent.

To close the ring the researchers used ring-closing alkene metathesis (normally abbreviated to RCM).

This is an incredibly valuable variant of alkene metathesis. Alkene metathesis won Grubbs, Schrock and Chauvin the Nobel Prize in 2005.

Basically, metathesis is the swapping of the components of an alkene ...

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The mechanism for alkene metathesis is given above. It involves the cycloaddition of a metal carbenoid or alkylidene to an alkene to give a metallocyclobutane. Cycloreversion then gives a new alkene and a new alkylidene. A second cycloaddition to a second alkene repeats the process.

In this way the ends of an alkene can be exchanged with the driving force being the release of volatile ethene.

In ring-closing metathesis the two alkenes are joined and so when the ends are exchanged a cyclic alkene is formed.

This reaction has become very popular in organic chemistry as it can be run under mild conditions, shows good functional group tolerance (especially the so-called 2nd generation Grubbs catalysts) and has a wide applicability to a range of ring sizes (5 to 90-membered rings if Wikipedia is to be believed ... ).

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Here are the classic metathesis catalysts but there are large number of variants in which the various metal substituents have been changed.

Of particular interest are the Hoveyda-Grubbs catalysts and the chiral Schrock-Hoveyda catalysts.

Do not be deceived by the way most organic chemists represent the Grubbs ruthenium catalysts ... our drawings invariably make the geometry of the catalysts appear to be trigonal pyramidal. They are not. They are a square based pyramid.

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Here are just some the elegant uses of RCM in total synthesis.

This first slide shows two uses of RCM during the synthesis of manzamine. Especially interesting is the formation of the 13-membered ring in the first step. large rings like this are often hard to form (it is difficult to get the ends to meet!)

This is a particularly elegant use of a combination of ring-opening and ring-closing metathesis. Presumably release of ring strain drives the conversion of the 5-ring into two 6-rings.

Formation of the starting material should be easy with the chemistry we have already covered ... have a go ...

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This example shows just how powerful alkene metathesis can be ...

When both alkenes and alkynes are used we get process called enyne metathesis and this allows the rapid construction of quite complex systems.

But back to epothilone ...

Ring-closing metathesis furnishes the 16-ring in excellent yield.

The desired cis alkene can be converted to epothilone C by simple deprotection of the silyl ethers by treatment with HF.

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The problem with the ring-closing metathesis reaction is that it gives a 1:1 mixture of stereoisomers (a 16-membered ring does not constrain the conformation of the two approaching alkenes).

This means we only have 47% yield of the desired molecule.

Obviously it would be better if you could synthesise a pure stereoisomer.

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This can be achieved by using a related reaction called alkyne metathesis. There are no stereochemical implications in the preparation of alkynes and we can readily control their reduction to give either the cis or the trans alkene selectively.

The trans alkene could be formed by dissolving metal reduction while the desired cis alkene can be formed …

… by a poisoned hydrogenation, the classic conditions using Lindlar’s catalyst (Pd poisoned with various lead and/or sulfur compounds).

The example above comes from Fürstner’s synthesis of epothilone C.

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Anyways, lets finish the original synthesis … Epothilone C can be converted into epothilone A simply by epoxidisation.

DMDO or dimethyldioxirane is an incredibly mild oxidising reaction. It reacts selectively with the more electron rich alkene (well considering the yield it might not be that selective). The other alkene is electron poor due to conjugation with the aromatic ring.

The end …

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