 Good morning and welcome back to the NPTEL course on Classics in Total Synthesis. So we have been discussing total synthesis of several natural products and the last class we talked in details about K. C. Nikolaus' Total Synthesis of Taxol using Dealsol reaction as the key reaction. So today so we will move ahead and then we will talk about one more total synthesis which was reported by Danie Scherzky's group. As you know in the 20th century there were 6 total synthesis and the first one was reported by Robert Halton and almost at the same time Nikolaus also reported the total synthesis of Taxol and 2 years later Danie Scherzky reported the total synthesis and a year later Paul Wender reported the total synthesis from the chiral terpid called Verbino. And in 1998 Kovacima reported the total synthesis of Taxol and Mukayama reported the total synthesis of Taxol from an Amino acid. So today when we talk about total synthesis of Taxol by Danie Scherzky so what he did was he made first the backatein. So the backatein means so this is the backatein structure okay. First he made the total synthesis of backatein then followed by attaching the side chain thus he completed the total synthesis of Taxol. It was reported in 1996 and he started with a very well known starting material called Weyland-Mesher ketone. So Weyland-Mesher ketone is commercially available as well as one can prepare in optically active form from 2-methyl cyclohexane 1-3-dione using L-proline as the chiral promoter in the Robinson annihilation sequence okay. So his scheme was started with as I said Weyland-Mesher ketone and if you look at the Weyland-Mesher ketone and then Taxol you can see here this X-mombard ring has the carbonyl function which later will be converted into the hydroxyl group here and then you have the angular methyl group already fixed. So this forms the C-ring of Taxol okay. So he thought of making the C-ring of Taxol this is A-ring, this is B-ring, this is C-ring and then you have D-ring also okay. So the C-ring of Taxol came from this cyclohexane and later he cleaved the other 6-mombard ring which later become the 8-mombard ring of Taxol okay. So let us see how he worked on the total synthesis. So first let us start with the construction or synthesis of C-ring because I said he started with Weyland-Mesher ketone with the intention of making the C-ring from the cyclohexane one ring okay. So this was made from the cyclohexane 1,3-dione 2 methyl cyclohexane 1,3-dione using asymmetric Robinson annihilation to get the Weyland-Mesher ketone okay in optical active form. Then you have 2 carbonyl groups one is alpha, beta unsaturated ketone other one is a normal carbonyl group okay. One can selectively reduce the carbonyl group of C-ring using sodium borohydrate and ethanol. You can take 0.25 equivalents of sodium borohydrate and do it at sub 0 you can get this alcohol. Once you have this alcohol you can protect the alcohol as acetate by treating with acetic anated and D-map. Now when you protect the carbonyl group of the alpha, beta unsaturated ketone under acidic condition what happens invariably the double bond migrates to the other ring okay. So this well known in the literature when you protect the ketone of alpha, beta unsaturated ketone the double bond migrates to the other ring okay. Now as you know for the C-ring you need to functionalize these 2 carbon atoms because that is where you have the oxidant ring. So the pushing of the double bond to the other ring actually helps. So how it helps now the double bond if you do hydroboration and oxidation you will get the hydroxyl group at this carbon okay. So before that you have to remove the acetate okay so that could be easily done by treatment with sodium ethoxide methanol then protect the alcohol okay, re-protect the alcohol as TBS ether okay, protect this as TBS ether. Then as I said you do the hydroboration oxidation and you introduce the hydroxyl group. Now using this hydroxyl group you have to introduce the oxidant okay. The first step is obviously the oxidation of the secondary alcohol to the ketone okay. So now you have the ketone from this ketone he got the oxidant by 2 different roots okay. The first root where he has used trimethylsulfonium elide okay when you have this trimethylsulfonium iodide treatment with potassium exomethyl disoloside it forms trimethylsulfonium elide okay. That elide attacks this carbonate group and it forms the epoxide okay. Now if you treat with a Lewis acid aluminum triisopropoxide that opens the epoxide and it generates a positive charge followed by loss of proton you get the allylic alcohol. So now what you have done you have introduced another functional group. So using this double bond one can get the oxytane which is required in the CDV. Another method to get this allylic alcohol he started with the same ketone but what he did was he treated with a base potassium exomethyl disoloside generates anion and he quenched that enolate with pH NTF2 to form the enol triflate. Once you have enol triflate then palladium catalyzed carbonyl insertion okay palladium catalyzed carbonyl insertion followed by attack of the intermediate with methanol one can convert the enol triflate to alpha beta unsaturated ester okay. Once you have alpha beta unsaturated ester simple reduction with the dipole gives the same allylic alcohol okay. So the allylic alcohol was prepared by two different routes and this method actually involved four steps whereas the earlier method involved only two steps. So with this allylic alcohol in hand the next task for dinosaurs group is to make the oxytane ring that the four membered oxytane ring. So for that you need to do a dihydroxylation okay so simple osman tetroxide dihydroxylation gave a mixture of the required triol with some amount of the unwanted triol okay. Now if you see so the hydroxyl group here which is should be alpha in the taxol if you see that is OAC then this CH2OH also should be beta and using this you can cyclize here okay. So what you need to do is the primary alcohol you have to protect it then the secondary alcohol you have to make it as a good leaving group then you make the oxytane ring followed by protection of the tertiary alcohol. So the primary alcohol was in C2 in C2 protected as TMS either as you know TMS is a level protecting group and that was protected then the secondary alcohol so the secondary alcohol was protected as triplet okay the secondary alcohol was protected as a triplet. So now you can see the secondary alcohol is made as a good leaving group now if you remove the TMS if you remove the TMS automatically the O- can attack intramolecularly and form the oxytane ring. So this was accidentally observed by treating with ethylene glycol so when they reflex with ethylene glycol so it removed the TMS and then also formed the oxytate. They also got a very interesting product if you look at this product you can easily you know explain how this would have formed when you see a 1-2 diol when you see a 1-2 diol one rearrangement which should come to your mind is pinnacol, pinnacol and rearrangement is not it. So here the secondary alcohol is made as a good leaving group and you have a tertiary alcohol so automatically the reaction which should come to your mind is pinnacol, pinnacol and rearrangement. So this product is obtained by pinnacol, pinnacol and rearrangement okay the expected product the required product was converted into the corresponding benzylate that is the tertiary alcohol the tertiary alcohol was protected as benzyl ether though if you look at the natural product the tertiary alcohol should be protected as acetate but acetate is a level protecting group and this has to undergo so many functional group transformation this particular intermediate has to undergo so many functional group transformation. So it is better to keep a more stable protecting group than what is really required at the end so with that idea Dianichel's group protected the tertiary alcohol as benzyl ether okay. Then you have to remove the ketal as you know this 6 membered ring now it should be converted into 8 membered ring is not it. So for that you have to remove the ketal to ketone that is easily achieved by treating with toluene sulphonic acid and acetone in the presence of water. So now you have the ketone and you have to clean this carbon this carbon carbon bond needs to be cleaned. So how this can be done you have to make enol ether is not it. So the enol ether formation is quite simple and straight forward if you take this ketone and then treat with TMS triflate then you get the corresponding enol TMS ether okay. This enol TMS ether if you treat with epoxidizing agents like dimethyl dioxide and DMDO okay then what you get is the corresponding epoxide. Now the epoxide can be opened with camphor sulphonic acid to get alpha hydroxy ketone okay. So this alpha hydroxy ketone means when you have alpha hydroxy ketone if you treat with L-tetra acetate then this C-C bond can be easily cleaned when it cleaves the top portion that is the hydroxy carbon will become aldehyde the carbonyl one if you use methanol then it will become corresponding methyl ester. So now you can see clearly here so you have the CD ring in place and the B ring now earlier it was 6 rumble ring now that has been opened okay. So it has to be converted into 8 rumble ring and at the same time you also have to attach the A ring okay A ring and B ring together it should be attached. So how he did? So if you look at this you have a carbonyl group in the form of aldehyde and another carbonyl group in the form of ester one can easily differentiate these two okay. As you know carbonyl group of aldehyde is more reactive so that aldehyde is protected as acetol with methanol and mylacid so you have protected the aldehyde now. Now what you need is you have to remove one carbon you have to remove one carbon and get aldehyde there okay I will tell you why we need that when I come to the attachment of A ring to this okay. So this is done first you reduce the ester to alcohol with LAH then what you need as I said you need to remove one carbon basically you have to cleave this okay. You have to cleave this to get this aldehyde so this is the intermediate you need because this upon treatment with A ring so you have A ring which is a 6 ombre ring that 6 ombre ring can be easily attached to this aldehyde okay. This has one extra carbon this has one extra carbon that extra carbon should be removed how one can remove if you carefully look at this if you can convert this alcohol into a double bond okay if you can convert this alcohol into a double bond then simple was analysis you can get this aldehyde is not it you can remove one carbon. So how do you introduce a double bond okay that is a very interesting method where you can treat this with this corresponding selenocyanide, autonitrofinite selenocyanide in the presence of tributylposphine so what happens the O H is replaced with this corresponding selenium okay when we introduce selenium you know in the literature it is well known for example if you have a ketone if you want to introduce a double bond next to the ketone normally what you do you treat with a base and then treat with phenyl selenyl chloride so that you can introduce a CPH at the alpha carbon. Now mild treatment with you know parasites like MCPVA hydrogen peroxide it will oxidize the selenium to selenoxide and then automatically selenoxide elimination will take place to introduce the double bond. So once you have done this now you introduce the selenogru just treat with hydrogen peroxide so as I said it will oxidize the selenium to corresponding selenoxide followed by elimination of corresponding autonitro selenic acid you get the double bond. So once you have the double bond it is very simple and straight forward you do the was analysis okay was analysis will give the already. So now you have the real CD ring with two substitutions at C ring which can be attached to A ring to form the B ring okay. So with this now you will see how they made the A ring okay they started with very very simple compound so one is methyl acrylate other one is 3 pentalobe these two are commercially available okay methyl acrylate and 3 pentalobe. Now if you treat with sodium ethoxide methanol okay very interesting see you can see first the enolate that is carbon ion is formed here and it undergoes 1, 4 addition and another enolate forming on the other carbon the carbon ion can attack this and it gives a very good yield decent yield of this cyclohexane okay cyclohexane 1, 3 diodes okay 1, 3 diodes okay and then two position you have methyl group and two and four position you have methyl group 2, 4 dimethyl now what you need is you need if you look at taxol at this carbon you need one more methyl group so that is very simple you treat with sodium hydride and then methyl iodide look at this compound okay. So now it has all the function groups present in A ring you treat with hydrazine okay why hydrazine because later he wanted to introduce a vinyl iodide he wanted to introduce a vinyl iodide so it is well known if you have hydrazine and then treat with bases like DBU or DBN and iodine it will form the corresponding vinyl iodide so that is what he did okay but what happened when he treated with excess iodine and DBN excess iodine and DBN okay so one more iodine was introduced at this carbon okay and followed by elimination we got another double bond okay two double bonds were formed it is okay good so now what we need is as I said this iodine should be exchanged with lithium and added to the aldehyde okay so before that this carbonate group should be protected isn't it if you have to treat with the tertiary butyl lithium to exchange the carbonyl group should be protected okay so how to protect the carbonyl group you can in situ protect with TMS cyanide and catalytic amount of potassium cyanide so basically it is a cyanohydrin formation okay the cyanohydrin formation and the cyanohydrin hydroxyl group is protected as TMS ether okay then if you treat with tertiary butyl lithium the iodine will be exchanged with lithium so this is the A ring once you have this A ring already we have made the C ring with the aldehyde okay straight away you can add this vinyl lithium which is prepared in situ and added to this aldehyde okay now we can see you have coupled the A ring and C D ring A ring and C D ring okay now what you should do you should get back you should get back the ketone here. So if you take one equivalent of T BAP okay you have TBS as well as O TMS but O TMS is very labile so you can easily cleave the O TMS so that means it becomes O minus as you know cyanohydrin are unstable that is because cyanohydrin if we have base then it will form O minus when O minus is there O minus will come back and then eliminate cyanide so here that is the same principle once you treat with T BAP immediately TMS group goes and then you form O minus that O minus O minus here comes and then cyanide comes out and you get the ketone okay. So what is to be done if you look at taxol at this position you have a hydroxyl group is not it at this position you have a hydroxyl group so now you have a double bond so that double bond should be converted into a hydroxyl group. So if you treat with MCPBA if you treat this compound with MCPBA there are 2 double bonds okay one is electron rich other one is electron deficient because this double bond you can say it is allylic alcohol okay. So now if you treat with MCPBA only this double bond will be epoxidized only this double bond will be epoxidized okay. Then you have to open the epoxide you have to open the epoxide as you know if you have allylic ether benzylic ether allylic epoxide then under hydrogenalysis condition one can cleave this type of CO okay it is like hydrogenalysis of allylic ethers benzyl ethers and this also an allylic ether is not it. So if you treat with hydrogenation condition at low temperature very important because otherwise you have benzyl group here O benzyl that also will be removed okay under minus 5 degrees one can selectively open the epoxide to get the hydroxyl group okay. Now once you have these 2 hydroxyl group just reduce the enone reduce the enone with L select right okay. Then you protect this diol protect this diol 1, 2 diol with pass gene okay with pass gene to get the corresponding cyclic carbonate. The southern hemisphere now it is fully functionalized southern hemisphere of taxol is fully functionalized okay. Now what we need to do is you have to connect the northern hemisphere okay. So original plan was to carry out an intramolecular heck reaction okay. So for that what you need you need this to be enol triflate okay. So that is very easy you treat with base and coincide with the corresponding tripletation so you get the enol triflate and for heck reaction other side you need double bond. So you have to remove this acetal and convert into double bond that is also simple. So remove the acetal and then do a vitic reaction you get double bond. So now you see the key intermediate is there and successful intramolecular heck cyclization between this vinyl triflate and the double bond should give 8-mombard ring with exocyclic double bond okay. So that is what happened. So you take the vinyl triflate and then treat with you know tetrakis palladium phosphorus. So as you know this is a very interesting reaction and you got a decent yield of this 8-mombard ring okay. This intramolecular heck cyclization gave this 8-mombard ring okay. So now you remove the TBS with the t-buff and re-protect it as TS because TBS was creating trouble so they change to TS either. So now what you need to do is you need to remove the double bond okay. So the removing the double bond at the same time you have to introduce a hydroxyl group here, carbonyl group here okay. So before removing the double bond first he has to protect this internal double bond okay. So that was done with the MCBBA okay. Then you do the OS analysis and before doing OS analysis you can remove the benzyl group. Now the benzyl group okay it has served its purpose okay. You can remove the benzyl group and get the alcohol then acetylate because in taxol you need the acetate isn't it? Yeah so do the acetate protecting. Now you treat with phenyl lithium as you know in the B ring this is O-benzoate okay. To get O-benzoate if you treat with phenyl lithium it opens region selectively and you get O-benzoate here and at the bridgehead you have hydroxyl group. So this is well established by others so straight away you get this compound. Now if you look at this it has almost all the functional groups except in B ring you need a ketone and acetate and also this epoxide which was originally protected is not required okay. So now what you do you treat with asmin tetroxide followed by cleavage with red tetra acetate it is a standard method to get the ketone okay double bond to ketone. Now if you treat with samarium iodide, samarium iodide your radical anion followed by opening of this epoxide to get alder like product that upon treatment with acetic anion undergoes elimination and you reintroduce the double bond in A ring at the same time what you got is the ketone functional group. But in taxol you have ketone here and you have O acetate here, isn't it? So how will you do that? How you introduce ketone here and acetate? So how it is done you generate enolate okay generate enolate and then treat with you know introduce an oxygen using this particular reagent. So basically what you have done is you enolate and then introduce a hydroxyl group and once again when you treat with potassium tertibutoxide the it rearranges it becomes this side it becomes ketone this side it becomes hydroxyl group okay. Now that compound if you acetate and this is what you need this is what you need for taxol. Now if you see you have everything what is required in the ring except the side chain here okay. So that is simple so you oxidize with PCC and you get the alpha beta and such a ketone that alpha beta and such a ketone if you reduce with sodium borovide you get the allylic alcohol okay. So now the allylic alcohol if you treat with HF pyridine if you treat with HF pyridine then you get a natural compound called bactatein 3 okay. So he synthesized bactatein 3 but instead if he takes this compound if he takes this compound then treat with ogemas lactam okay this we already discussed when we talked about total synthesis of taxol by K. C. Nicolau we discussed this okay. So you take this alcohol and treat with ogemas lactam then you can get or you can easily introduce the side chain. So now what you need is you have to remove this TS group if you remove the TS group that will be the taxol molecule okay HF pyridine you could successfully remove the TS group that gave taxol. So you could successfully synthesize taxol from commercially available Veylon Mischer ketone and also the 2, 4 trimethyl cyclohexane 1, 3-dione which also can be easily prepared from methyl acrylate and 3-pentanol okay. So that is how his synthesis was very simple and straightforward and it is though the number of steps is more but it involved you know very simple and straightforward synthesis okay thank you.