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123713AB lecture09


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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).

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123713AB lecture09

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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