 Yeah, good morning and welcome to the NPTEL lecture series on Classics in Total Synthesis part 1. And today we will continue our discussion on total synthesis of taxol. In the last lecture we talked about total synthesis of taxol by K. C. Nikolaou's group and today we will talk about total synthesis of taxol by Halton. In fact, Halton claims that he was the first one to report the total synthesis and let us see how he and his group achieved the total synthesis of taxol. And it was reported in 1994 and the key reaction according to Halton is the fragmentation of an epoxy alcohol derived from another natural product to get the key 531 skeleton. He got it through fragmentation of an epoxide which I will discuss in the next slide. And of course there are other key reaction, one more key reaction is the Chan rearrangement which also I will discuss briefly and then a Deakman cyclization which you all know what is Deakman cyclization. The epoxy alcohol fragmentation which was really a very, very clever reaction to be utilized by Halton in the total synthesis of taxol. So he started with an epoxide which is commercially available called Pacino or Patcholin epoxide. This idea is when you treat this epoxide with BF3 ethylate, so BF3 ethylate it can coordinate this, oxygen coordinate with Lewis acid. Then that epoxide will break, then this bond will migrate, this bond will migrate which is anti to that, anti to the leaving group that epoxide. Now you will get a paucity charge here, you will get a paucity charge here then a loss of proton will give you this compound. So this is a very, very important fragmentation reaction because his total synthesis involved two epoxy alcohol fragmentation. One is this, subsequently what he does using this hydroxyl group, he epoxylizes the double bond from the same side. So now when he makes the epoxide, automatically the epoxide, this epoxy alcohol undergoes fragmentation to give this by Bicyclo 531 system. So this is the A and B ring of taxol. This is the A and B ring of taxol. I will leave it for a few seconds so that you will be able to understand after this hydroxyl group breaks, this bond is broken. That is how it becomes A pump burrowing, a 5 and 5, 5 and 5 becomes A pump burrowing that leads to the B ring of taxol. Now let us see the retro synthesis, how overall for the total synthesis of taxol using this particular rearrangement as a key reaction, how Holton has cleverly made a retro synthesis. And as I said he also used another rearrangement called Chan rearrangement to obtain 2 keto, 2 hydroxy, 3 keto esters to obtain 2 hydroxy, 3 keto esters from alpha acyl oxyacetates. See what happens when you have alpha acyl oxyacetates, alpha acyl oxyacetates, this on treatment with base, it can generate an anion and immediately it will attack the carbonyl group. So it forms an epoxide, now the O minus will come, the O minus when it comes the 3 membered epoxide will open. So that will give you alpha hydroxy keto esters. So this is another key reaction which is used cleverly in the synthesis of taxol. So from retro synthetic point of view, the first and easiest way to disconnect is to remove the ester. So if you have the hydroxyl group, always one can attach the side chain esters. That is the normal and easiest retro synthetic disconnection. The next disconnection which he has done was if you have a ketone here, if you have ketone here, then this 4 membered ring can be easily attached. So the first step should be to make this 6 membered ring. Once you have the 6 membered ring, the oxidant ring can be easily attached. Now how this 6 membered ring can be used? So this is where he used a Deekman condensation. So Deekman condensation, if you look at this double bond, if the double bond is for example cleaved and then converted into ester, cleaved and converted into ester, then one can generate anion here. One can generate anion here and attack intramolecularly and if you open this, what you will get is this compound. The double bond should be converted into ester followed by treatment with base. It will intramolecular undergo Deekman cyclization to give cyclohexanone. So that was his plan and this compound can be obtained by aldol reaction. If you have a ketone, then you can generate anion that enolate can add to the whole aldehyde. Now if you look at this, this remains you of the rearranged product that is epoxy-alcohol fragmented product. So that means this could be obtained from this epoxy, this substituted epoxy. Now if you look at this, this can be obtained from the rearranged product. Again another rearrangement. So now this epoxy opens, this bond migrates and this hydrogen is eliminated, you get a double bond and that double bond is epoxylized. So this epoxy can be obtained from another epoxy. Again what will happen when you treat with strong base, this will open up and you will get an allylic alcohol, then that allylic alcohol double bond can be epoxylized. So this was a simple retrosynthesis which he thought based on the epoxy-alcohol fragmentation. So he started with the commercially available natural product. It was a natural product available in large quantity called petrolinoxide and this petrolinoxide on treatment with butyl lithium. When you have an oxygen particularly epoxide and then treat with LDA or strong base, then it can open the epoxide to give the corresponding allylic alcohol. The epoxides can be opened with LDA to give corresponding allylic alcohol. This has been successfully used in many synthesis that epoxides are converted into allylic alcohol. Sometimes de-symmetrization also has been done to give corresponding chiral allylic alcohols. So once you have this then when you epoxidize the alpha hydroxyl group will direct the epoxide from the same side. So you get alpha epoxide. So first you open the epoxide, now the epoxide will open at the same time rearrangement also will take place. So if you treat with PF3 ethyl, along with trifluoramethan sulfonic acid, as I said first it will coordinate with Lewis acid, then this bond will migrate and followed by loss of proton, you will get the corresponding alkene. At the same time the epoxide is open, is it easy to visualize? So once you have this alcohol, now you have a secondary alcohol and tertiary alcohol. So the secondary alcohol can be easily protected. So this was protected as TACether by treating with TS chloride and pyridine and the next step as we have seen in the retro synthesis is to epoxidize this double bond. And since you have a hydroxyl group which is in alpha position, automatically that will direct the epoxidization, so you will get the corresponding alpha epoxide. But this reaction is so clean it does not stop there. As expected this undergoes rearrangement and opens the epoxide to get the bicyclo 531 system. The same part that is as soon as the epoxide is formed, it undergoes opening of the epoxide to give bicyclo 531 system. So that is the AB ring. Now if you look at this carefully, the A ring, A ring has all the functional group except at the bridged position you should have OH. Now what you have is H and B ring you need another oxygen functional group and here also you need another oxygen functional group. Let us see how he moves forward and then completes the total synthesis. So instead of LDA it took MDA that is magnesium diisopropyl amide, magnesium diisopropyl amide that is to generate enolate here and then quench with this pentenol. So that will give you the precursor that will give you the precursor which is required for making the C ring. See C ring as you know it is a cyclohexane ring and later you plan for intramolecular decrement cyclization to get the 6-movement. So now the double bond is introduced. Next step is to protect the hydroxyl group. First it was straight, the hydroxyl group was treated as pass gene. So pass gene what will happen that R group will become ROCOCl. Then when you treat with ethanol what will happen it will become ROCO then OET. So that is what you get it is called off ester first you get off ester then the chloride is replaced by ethanol to get OCO2ET. Once you protected the hydroxyl group now as I said you need to have a hydroxyl group here and also you need to have hydroxyl group. So if you treat with LDA the enolate will be generated here then quench with this oxaziridine this is a chiral oxaziridine derived from camphor sulfonic acid. This is called Davis oxaziridine it is used to introduce a hydroxyl group selectively and introduce chirality. So selectively one can introduce a hydroxyl group which is required at this carbon. Now if you look at this conformation again I leave this structure for a minute. You will see that this has a boat chair conformation that 8 membered ring has a boat chair conformation I leave it like this because it takes some time to understand how this was drawn and when you look at this compound carefully now any attack on this carbonyl group any attack on the carbonyl group should take place from the front side that means that should give alpha hydroxyl group. So this boat chair conformation was cleverly used for further steps. So now you treat with red all as I said the hydride will come from the front side so you will get alpha alcohol. You have 3 secondary alcohol 1, 2, 3 and when you treat with pass gene so when you treat with pass gene it can form cyclic carbonate so it can form with 1, 2 diol or it can form between 2 and 3 there are 2 possibilities but what he got was 6 membered cyclic carbonate. It formed a 6 membered cyclic carbonate. Then you can easily oxidize the other secondary alcohol under swan condition once you have the ketone. Now you treat with tetramethyl piperidine okay tetramethyl piperidine and butyl lithium there are 2 possibilities 1 it can generate anion here or it can generate anion here okay. So it generates anion here then it undergoes chant rearrangement then it undergoes chant rearrangement which I already explained what is chant rearrangement. So after the chant rearrangement what you have got is a hydroxyl group okay hydroxy ester is the one which you get isn't it hydroxy ketoyester is the one which you get and that is what you got here. So now the hydroxyl group is it required? No you do not require so how do you remove the hydroxyl group? You can easily remove the hydroxyl group with samarium iodide okay samarium iodide one electron donor so that way you can easily remove halo or hydroxyl group which is next to carb melko and then one why you can ask why it is enol the once the hydroxyl group is removed then it will be in keto enol form which seems to be more stable okay. Now you treat with silica gel so that no you can get back your ketone and when you do that this particular carbon the hydrogen can be beta or alpha but you get a mixture you get beta which is the unwanted one for taxol you need alpha hydrogen but what you get is beta as the major product nevertheless with that again it treated that beta ketoyester with lithium tetramethylpiprodide and followed by treatment with Davis oxaziridine so the idea is to introduce a hydroxyl group so it was easy you can introduce hydroxyl group still what happened during the process the 3 beta 3 beta is becoming more okay so no problem so one can easily solve that so now if you reduce the ketone okay if you reduce the ketone as I mentioned it is in boat chair conformation so that means when you add any reagent to this ketone it will come from the front side okay that means you will get alpha alcohol. So red doll you get alpha alcohol then what you do you do a base treatment basic workup so that basic workup actually is used for epimerization so this way now they could get that trans stevescent okay now what you have to do somehow you have to connect this to get a six number ring so before that you need to protect this dial so that is easily done by treating with pass gene to get the cyclic carbonate then followed by ozone analysis of the double bond you get the aldehyde as I said that double bond should be converted into ester so that was done in 2 steps first oxidize the aldehyde to carboxylic acid then treat with diazomethane you get the corresponding ester then the intramolecular deakmon cyclization takes place by treating with LDA, LDA generates anion that attacks this lactone and opens up and that is what you get okay so what you have to do you have to protect this hydroxyl group and the whole thing should be converted into oxytane ring. So what you did next you protected the hydroxyl group as with this is not ethyl vinyl ether but a vinyl ether substituted vinyl ether so when you do that you can protect that alcohol as OMOP okay methoxy propyl ether then the this is a beta keto ester this is a beta keto ester you can write like this is not it is a beta keto ester as you know beta keto esters can be easily cleaved under various condition that ester group can be easily removed and one of them is potassium thiophenolate the potassium thiophenolate is known to remove the ester so you get a keto okay. Now if you carefully look at this particular intermediate what you need is a functional group here and then what you need is an oxytane ring okay then you treat with the PPTS because the MAP group should be converted into some other protecting group to make it a better protecting group so that was done with bomb chloride, benzyl oxymetha methyl chloride and that was protected as bomb then you convert this ketone into oxytane for that first treat with the LDA so when you treat with the LDA you can generate anion till form the enolate and coincide with TMS chloride you get corresponding enol TMS ether okay. Once you generate enol TMS ether so you can functionalize here so treat with MCPBA so it opens up and then it form whole TMS you have a ketone and if you do vitic reaction you can get double bond and vitic reaction was not that facile so he treated with methyl magnesium bromide to get corresponding tertiary alcohol. So once you have the tertiary alcohol then he needs a double bond the double bond was easily achieved by dehydration using Burgess reagent so the Burgess reagent is nothing but this reagent so this is used for making or dehydrating an alcohol to get corresponding double bond and usually it goes to less substituted double bond. Once you have the double bond what is left you have to do the oxytane formation and before that you remove the TMS group with HF protein to get the allylic alcohol then azimine tetroxide will give you the triol by dihydroxylation, dihydroxylation on the double bond will give you triol okay. So now almost everything is set for the oxytane formation and selectively protect the primary alcohol in C2 you protect the primary alcohol as TMS ether then make the secondary alcohol as a good leaving group. So you make it as tosyl group then treat with DBU so DBU will give corresponding oxytane so now what needs to be done you have to protect this hydroxyl group and open this cyclic carbonate and introduce another oxygen functionality here. So acetic anhydride pyridine first it will acetylate this hydroxyl group so that is taken care then HF pyridine so you have bulky TBS and then TS group so TS group can be selectively cleaved in the presence of TBS. So once you have the OH then you also can open this the cyclic carbonate to get the corresponding benzoate and bridge head hydroxyl group okay. Now to introduce a functional group here this hydroxyl group should be oxidized so that was done easily with t-bub in the presence of co-oxygen NMO so you get the ketone. Once you have the ketone this is a standard method where hydroxyl group can be introduced next to the ketone here and followed by isomerization with potassium tercibutoxide these 2 gets exchanged so ketone comes here and hydroxyl group goes there okay that is what you need in taxa isn't it that is what you need in taxa keto hydroxy keto what is left now in taxa all this is OAC isn't it that taxa all this is OAC so you have to treat with DMAH pyridine acetic anhydride to get the acetoxic group later if you look at carefully this structure has all the functional groups present in taxa all except the bomb group should be hydrogen and also the tbs group should be cleaved and then attach with the side chain the tbs group should be cleaved and attach with the side chain. So fluoride source removes the tbs group then you attach the side chain with ojima's black term okay now what needs to be done if you look at this particular products you have to remove the bomb group you have to remove the tbs group okay the tbs group can be easily removed with HF pyridine okay this is silyl protecting group so HF is known to remove the silyl protecting group you get the hydroxyl group and now hydrogenation okay benzyl of the methyl chloride hydrogenation can be easily used to cleave the benzyl oxymethyl group benzyl group okay all that can be done and once you remove that you get directly the taxa okay. So the overall if you look at the total sense of taxa reported by Haltern it involve two epoxide rearrangements okay he started with patuline epoxide and then under several acidic condition the epoxides were rearranged to give the bicyclic intermediate bicyclic 531 system okay so once you have the bicyclic 531 system then it was a matter of functional group transformation to achieve the total sense of taxa okay overall if you look at this synthesis the key features are one he started with the chiral naturally occurring compound called Pacino or patuline oxide one second he used two epoxy alcohol fragmentation to epoxy alcohol fragmentation to get the key bicyclic 531 system okay then like others of course since he was the first one to report he used the ojima's protocol to introduce the side chain attached to chiral okay overall he took about 46 linear steps nevertheless as you know this was the first total synthesis of complex natural product having so many functional groups and it was very well thought about you know starting from a natural product to natural product one can easily call this as a nature to natural product you start with a natural product and end with a natural product which is really of very significance okay as you know taxa has been used as anti cancer agent for the treatment of ovarian and breast cancer the methodology developed by Robert Halton is a very interesting and clever methodology though this may not be the method to make taxa in good quantities but it gave excellent scientific training for many co-workers worked on this project okay so thank you.