 Yeah, good morning and welcome back to NPTEL lecture series on classics in total synthesis part 1. So, we have been talking about total synthesis of various terpenoids in the last couple of weeks and today we will move to total synthesis of another very interesting natural product called epithelons. So, there are quite a few epithelons for example, epithelon A, epithelon B and epithelon C and of course, epithelon D. So, there are 4 epithelons, epithelon A, epithelon B, epithelon C and epithelon D. So, they were isolated from sand with this unusual source and they were found to be showing exceptional anti-cancer activities ok. And some analogs also were made while synthetic chemists were trying to make this natural products. One of the analogs which is now introduced as a drug is Ixobipelone, you can see the major difference between the natural product that is epithelon B and this analog is instead of a lactone, it is a lactone ok. So, epithelon if you look at carefully it is a macro lactone having an epoxide, an aldol, a ketone you can call it as another aldol ok, both sides you have aldol and a lactone. So, here in this analog it is a lactone ok and the side chain you can see you have a thiosol ok and 2 methyl thiosol and that has been replaced in this analog with 2 amino thiosol ok and here a benzo thiosol also people used instead of the whole side chain that is if you connect these 2 and then put a double bond that is benzo thiosol. So, several analogs were made as epithelon showed exceptional anti cancer activity ok. So, now let us see 2 total synthesis today both reported by K. C. Nicolau. So, K. C. Nicolau what he thought was if you look at the epoxide ok in the case of epithelon you have an epoxide ok. So, he thought that epoxide can be made from a double bond and that double bond can be made through ring closing metathesis. So, directly this molecule can be open to a linear chain through metathesis. So, a metathesis is a well known reaction for the last 3 decades. So, one can make 5 member to 30 member cyclic compounds and simple mechanism you take either Grubbs 1 or Grubbs 2 now there are many catalyst which are come to convert a diene into an alkene ok. So, here are some examples where you can see an 8 membered ring has been formed with the help of Grubbs 1 this is Grubbs 1 catalyst and this is another reaction again a difficult 8 membered ring is formed through the Grubbs 1st generation catalyst. So, there are as I said there are many other catalyst Grubbs Grubbs Covider and so on ok. Coming to the total synthesis of epithelon as I mentioned this epoxide was formed from olefin and that olefin was formed through ring closing metathesis. So, that was a first key retro synthesis of epithelon by K. C. Nikolov then you can see this ester if you can cleave that you will get alcohol on one side and carboxylic acid on another side. And the next cleavage is here. So, you have an ethyl ketone on the southern hemisphere and aldehyde on the northern hemisphere and intramolecular or intermolecular aldol reaction can generate these two stereo centers. So, the first disconnection as I said is the ring closing metathesis and this can be obtained from the corresponding carboxylic acid and alcohol through esterification. So, that means these are the two precursors. So, you have a carboxylic acid and coupled with alcohol you get the ester ok. Now this carboxylic acid can be obtained from this ethyl ketone and aldehyde. So, ethyl ketone you can see this is CH2, CH3 one can generate anion here that anion if it attacks aldehyde you will get this aldol and this allelic alcohol can be obtained from this alpha beta unsaturated aldehyde through chiral allelation ok. Now let us see how Nicholas group made all these precursors. First they started with isobuteroldehyde. Isobuteroldehyde and treatment with morpholine it formed this enamine ok. This enamine upon acylation with propanol chloride which gave this intermediate which upon hydrolysis gave this aldehyde ok. It is a beta keto aldehyde. Now you do chiral allelation using Brown's allyl boron ok. So, this is chiral reagent derived from alpha pining it is a well known reagent for introducing a chiral center upon addition to aldehyde. This allyl source depending on the nature of the pining whether it is alpha or alpha or S alpha you will get the corresponding chiral center here ok. So, now one chiral center is introduced and that alcohol is protected as TBS ether. Then you do the vasoanalysis followed by oxidation of the resultant aldehyde to carboxylic acid. So, this is how you made the fragment A. Now for the synthesis of fragment B he started with propogyl alcohol following Patterson's protocol. First upon treatment with lithium in liquid ammonia followed by quenching with this bromide you could get this trans allelic alcohol where you can see the whole 4 carbon unit of the electrophile is attached. Now sharpness asymmetric epoxidation of this allelic alcohol gave this epoxide. This upon opening with trimental aluminum it can give a syn hydroxy compound ok. Then this was protected as pyrolyte ester both hydroxyls were protected as pyrolyte ester and the THP was removed THP is tetrahydropinally ether that was removed using pyridinium pyridolin sulfonate and oxidation of the primary alcohol with sulfur trioxide with pyridin and DMSO gave aldehyde. This upon mittic reaction gave the double bond. Now reductive removal of the pyrolyte ester with dibol gave the diol and sodium perovidate cleavage gave the aldehyde which is a precursor B. So, you have made A and B for the fragment C he started with the thiosol ester reduction of the thiosol ester with dibol gave the aldehyde and the homologation with this mittic reagent gave this alpha beta and such a tereldehyde then the brown allelation gave fragment C. So, having the fragments A, B, C in place then he attempted the totals in this apothelan A. So, he took the carboxylic acid ok on the left hand side you see it is an ethyl ketone. So, two equivalents of LDA or more first it will generate anion here as well as it will generate the enolate on the ethyl ketone side then you quench with this aldehyde and you get the corresponding aldehyde product after acidification. Then you have to attach the alcohol to the carboxylic acid. So, that was done with DCC. So, quickly he could assemble the precursor required for the ring closing metathesis. So, once you have that then Gruff's first generation catalyst gave the ring closing metathesis product since double bond and now if you want to remove you can remove the protecting group here because you do not need OTBS what needs to be done at this stage A is removal of the TBS group followed by epoxidation. So, the TBS group was removed using trifluoracetic acid then epoxidation with MCPBA he could get apothelan A. So, these are first generation synthesis of apothelan A reported by Nicholas group. He also another route and in this route as you know the key steps involved in this total synthesis or olefin metathesis aldol reaction and esterification reaction overall it took about 11 steps and yield close to 7 percent. In the second generation synthesis the major difference was instead of ring closing metathesis he wanted to use a macro lacronization as you can see in apothelan there is a lactone ok it is a macro lactone. So, he wanted to use Yamaguchi's macro lacronization approach to form the macro lactone ok and for that first as you all know what is Yamaguchi's macro lacronization if you have a carboxylic acid and if you treat with 2, 4, 6 trichlorobenzoyl chloride. So, that will form a mixed anhydride this upon treatment with any alcohol that alcohol will attack the less hindered carbonyl group here and then this will come out. So, that is how esters are formed using this Yamaguchi's method. This is particularly very important for making macro lactones ok. For example, here this macro lactone formed by Yamaguchi's method and from the retrosynthetic point of view as I said this particular synthesis used macro lacronization as the key step in the last but one step ok. So, that should give you the corresponding hydroxycarboxylic acid hydroxycarboxylic hydroxy on the right side and carboxylic acid on the southern hemisphere. Then on the left hand side breaking of this bond will give an aldehyde and ethylketone. So, this already we discussed how this carboxylic acid could be formed ok and now this can be made from 2 fragment one side it should be aldehyde other side it should be wittic salt ok. So, these are the 2 fragments already you know in the first synthesis he has made all these fragments but he also followed some modification while making these fragments. For the fragment A he started with propenaldehyde and then he used Indus hydrogen. So, SAM hydrogen to form the corresponding hydrazone. Now, if you alkylate with 4-iodo 1 benzyloxybutane. So, you can introduce the 4 carbon chain. Now, simply hydrolyze you get aldehyde. So, normally hydrazones like Indus or hydrolyzed using ozone analysis just you cleave this you will get aldehyde and on the other side you will get the hydrazine. Reduce the aldehyde and protect it as TBS ether. So, you get the fragment A and of course you also have to remove the benzyl group and convert it into leaving group. Here the OH was converted into iodide by treating with iodine imidazole and triphenyl phosphate. So, now the Wittig salt is made for the fragment B. Already the synthesis of this homoalelic alcohol was discussed during the first generation synthesis of apothelon by Michalow. Just protect the secondary alcohol and then do a 2-step protocol to cleave the double bond to aldehyde. Ask me in the talk side followed by sodium beroidate or lactate tracentate cleave gave the aldehyde. Now fragment A and fragment B can be combined using Wittig reaction ok. So, this Wittig reaction gives you know the cis double bond ok. Next you have the southern hemisphere keto carboxylic acid. You have to remove this make it as aldehyde and then add the methyl ketone through aldol reaction ok. So, for that what is required is removal of this TBS group selectively. So, the left hand side TBS is primary alcohol protected TBS whereas, the right hand side one is secondary alcohol protected TBS. Normally the primary ones can be easily selectively cleaved by treating with campersalphonic acid. So, that is what we did. Then oxidation with SO3 pyridine and DMSO gave the aldehyde ok. The other side that is the southern hemisphere ethyl ketone. It took the ethyl ketone treated with excess LDA and quench with this aldehyde. Now you can see almost all the carbons of apothelone A is ready. So, what needs to be done? Now you have to remove this and then do the macro lactamization. But you have free hydroxyl group here. So, that should be protected otherwise that lactone will be formed. So, that was protected. But when you want to protect that hydroxyl group, carboxylic acid also will be protected. So, both carboxylic acid and the hydroxyl group were protected as TBS ether and ester respectively. Now you have to remove these two TBS ok. So, that was done by potassium carbonate ethanol. First ester TBS was removed subsequently one equivalent of Tbaff. One equivalent of Tbaff removed this TBS ether selectivity followed by Yamaguchi's macro lactamization gave the macro lactone. And now both TBS can be easily cleaved by treating with trifluoroacetic acid. And finally, epoxidation of the double bond with MCBB A gave apothelone A. So, in summary, Nikolaus group synthesized apothelone A in the same year after they reported the first generation total synthesis. Here the key reactions are Yamaguchi macro lactamization and of course on the left hand side highly stereo selective aldol reaction as the key step and the top the double bond was made using metric reaction. Overall the number of steps involved are 18 and yield was 5 percent. Though the yield looks little bit lesser than the first synthesis, the first synthesis we had overall yield of about 7 percent. So, this is completely a new approach to make apothelone A ok. So, I will stop here and then I will continue the discussion on total synthesis apothelone A by 2 more groups, one by Dieter Schinser and the second one by Samuel Nadeczewski. Thank you.