 So, good morning and welcome back to NPTEL lecture series on Classics in Total Synthesis. I think we have discussed about 100 total synthesis in this lecture series and today the last lecture is going to be about Total Synthesis of a complex natural product called Zerogocic acid C. So, Zerogocic acid and squalistatins ok, so both belong to the same family of naturally occurring fungal metabolites where independently isolated and characterized by Merck groups and from also from Glaxo. So, these Zerogocic acids and squalistins where independently isolated by researchers at Merck and Glaxo. So, they are potential inhibitors of squalins synthesis ok. So, that means you know this could be used for the treatment of hypercholesterolemia ok. So, those are cholesterol problem could be potentially be treated by this naturally occurring compounds ok. So, there are many Zerogocic acids and that depends on the substituents at these 2, 1 oxygen that is R2 attached to oxygen, other one that is the side chain R1 ok. And if you look at this natural products carefully you can easily find out 1, 2, 3, 4, 5, 6, 6 stereogenic centers ok and in that how many quaternary centers are there at least 4, 4 quaternary centers. So, it is not that easy to synthesize such complex molecule having 6 stereogenic centers and also having quaternary carbon atoms ok. So, these are some of the squalistatin Zerogocic acids isolated from the nature and today what we will do we will talk about the total synthesis of Zerogocic acid C reported by Eric Carrera's group ok. So, this was the first total synthesis reported in 1995 and his idea was to use commercially available D-ethrolactone as a starting material and build upon the chiral centers present in ethrolactone. So, this chiral approach based on the retro synthesis as you can see here. So, this is the chiral starting material ok. This can be made in few steps from commercially available compound. So, this upon treatment with dimethylamine and methanol one could open this 5 ombre lactone to get the corresponding triole and amine. Now, the triole upon treatment with the protected 3-pendanone protected 3-pendanone and acidic condition. So, you can see this 1, 2 diol was protected as ketone ok. Then, sodium hydride benzyl bromide you could remove this proton and benzylate the remaining secondary hydroxyl group followed by treatment with 2-lithio, 2-lithio vinyl ether ok. This is a vinyl ether and at alpha position you can generate lithium by treating with n-butyl lithium or tert-butyl lithium. So, that will add to this wind-up like amine and you will get corresponding enone ok. Then treatment of this enone with TMS acylene trigonaut. So, that will undergo highly stereo selective 1, 2 addition to this enone to give the quaternize center. So, now if you look at there are 3 quaternize centers, 2 are carbon based quaternize center. So, that 1 is achieved using this addition of TMS acylene ok. Then, one can was analyze the double bond to get the ester that is enol ether is was analyzed to get the ester followed by reduction with sodium borohydride in methanol the ester group is fully reduced to corresponding alcohol. So, now 1, 2 diol and the TMS group which is attached to the acylene. So, these are you know this TMS group can be easily removed by treating with potassium carbonate methanol. Then, the primary alcohol was protected as TBS ether then the secondary alcohol was in situ protected as TMS ether as you know between TBS and TMS. TMS is labile. So, that is how you could prepare the intermediate A required for the total synthesis of Zyracosic acid C. Now, for the synthesis of the other fragment aldehyde, E started with Yvonne's chirol auxiliary and then attached the propionic acid anhydride. So, then boron enolate followed by aldol reaction with this aldehyde ok. It is a classical Yvonne's asymmetric aldol reaction gave this syn aldol ok. Now, once this aldol is there then the chirol auxiliary can be removed by treating with lithium hydroxide and hydrogen peroxide to get carboxylic acid ok. What is the next step? Detection of the carboxylic acid with LAH gave the 1-3 diol. So, the 1-3 diol one is primary alcohol, other one is secondary alcohol ok. Then, take this primary alcohol tosylate you get the primary tosylate. Now, if you treat with phenyl lithium ok. So, the phenyl lithium what it can do? It can remove this proton and then intramolecularly attack to form oxitane ring followed by addition of another equivalent of phenyl lithium that can attack the oxitane and open the oxitane to get or introduce the phenyl group. So, basically what has been done is to remove this hydroxyl group with a phenyl phenyl group. So, you convert that hydroxyl group into a good leaving group followed by treatment with phenyl lithium in the presence of Lewis acid you can replace the hydroxyl group by phenyl ok. Then, protect the hydroxyl group as pyrolyte ester then remove the benzyl group ok. Remove the benzyl group and hydroxyl analysis to release the primary alcohol. This upon Swern oxidation gives the primary aldehyde ok. This upon Swern oxidation gives the side chain aldehyde B ok. So, now we have seen the synthesis of fragment A and fragment B. Let us see the synthesis of the other O acyl side chain. So, for that we started with this terminal alkyne. So, this is easy to prepare in 3 steps from TMS acetylene. Then, n-butyl lithium followed by quenching with formaldehyde one can introduce this CH2OH. So, first you remove this proton and then quench with formaldehyde. So, that gives the CH2OH. Now, LIH reduction proportionally alcohol upon reduction with LIH give trans allylic alcohol. So, that was done easily and this trans allylic alcohol once you have this can undergo sharp less asymmetric epoxidation ok. So, the sharp less asymmetric epoxidation with L plus niacinopropyl tartarate gives this epoxide ok. So, once you have this epoxide that epoxide can be opened particularly the epoxides derived from sharp less condition or allylic alcohol this can be easily opened with trimethyl aluminium. So, now the aluminium will open opposite to this epoxide. So, thereby one can easily get that anti aldol products if you look at this it is like anti aldol product. Now, you have 1 2 diol the 1 2 diol can be cleaved with sodium peroxide to get the corresponding aldehyde. This aldehyde upon treatment with vinyl magnesium bromide. So, you got the corresponding vinyl allylic alcohol ok. So, this vinyl allylic alcohol upon treatment with triethyl ortho acetate ok triethyl ortho acetate with a catalytic amount of acid is well known to undergo glycine reactant ok. So, if that happens you get this gamma delta unsaturated ester gamma delta unsaturated ester whenever you see or wherever you see one reaction we should come to your mind is glycine reactant. So, this is what the product this is nothing but gamma delta unsaturated ester. Then simply you do the hydrolysis you get the carboxylic acid. So, now you can see the 3 fragments A B and C are ready. How these 3 fragments are combined to complete the totals in the synthesis of the ergosic acid C. So, you start from the intermediate or the fragment A and this fragment A upon treatment with butyllithium obviously this is the most acidic proton you remove that proton and then form the corresponding lithioderivative then add the fragment B. So, fragment B has aldehyde. So, that undergoes intermolecular nucleophilic addition reaction to get this propogelic alcohol ok. Once you have this propogelic alcohol one can easily oxidize that alcohol selectively using Des Martins where I would have reagent to get this alkynyl ketone alpha beta unsaturated alkynyl ketone. And this can be reduced the triple bond can be reduced under this condition where the triple bond is reduced to trans double bond ok. If the triple bond is reduced to the trans double bond. Now treatment with tetramutyl ammonium fluoride removes both TMS and TBS to give dialogue ok. And you have this enone, enone can be subjected to Sharpless Asymmetric Diatroxylation. So, the Sharpless Asymmetric Diatroxylation gave this as the major product where the two hydroxyl groups are coming from beta side and also some amount of alpha which is favoring the desired beta diol was obtained the desired compound was taken and moved forward. So, if you treat with HCl and methanol HCl and methanol what will happen this whole group will go this whole group will go. So, that will form a diol ok that will form a diol and this hydroxyl ok this hydroxyl and this hydroxyl will form ketol with this carbonyl group to give this product. Now you can see the core stretcher the core stretcher of Zerogousic acid is formed ok. So, what needs to be done you have to attach the side chain at this carbon and also selectively you have to remove this and then functionalize. These are two additional things to be done. So, the free hydroxyls that is the primary hydroxyl this one and this one were protected as TBS ether by treating with TBS chloride and then base is Lactoethylamine and form NL dimethylamino pyridine. Now the secondary hydroxyl groups here secondary hydroxyl groups here were protected as pivalite ester by treating with pivalite chloride and dima. Then the benzyl group should be removed so that one can think about homologating at this carb. So, the benzyl group upon hydrogenolysis was removed to get the alcohol. So, an oxidation gave the ketone. Now addition of trimethyl silyl methyl lithium gave this product. Normally when you talk about trimethyl silyl methyl lithium or corresponding magnesium salt that is meant for Peterson olefination ok you will get a double bond. So, now so the product has trimethyl silyl ethanol as the subunit. So, that compound upon treatment with 18 crown 6 and potassium examinethyl disilicide that underwent elimination to give that double bond. Basically the whole thing is Peterson olefination ok. Then protect this hydroxyl group during this Peterson olefination one of the pivalite ester also got hydrolyzed. So, you have this free secondary hydroxyl group which was re-protected as TBS eter ok. Then he needs to functionalize this exocyclic double bond ok, but all the time what he got was this undecided diol and not the decide diol. So, basically one has to do the diandroxylation. So, when you talk about diandroxylation the simplest method which will come to your mind is osmintotoxide. When he tried with osmintotoxide only the two hydroxyl groups came from the convex side ok. So, that is not the record one. So, finally what he did he went back to the ketone ok he went back to the ketone. So, instead of doing a Peterson olefination he added lithium trimethyl silyl acetylene to get this as the major product. Now you can see this trimethyl silyl acetylene comes from the equatorial side and this is the major product you can see 6 is to 1 ratio. So, take this compound and then treat with silver nitrate to remove the TMS group attached to the triple bond ok. So, the TMS was cleaved to get the triple bond then di-ball reduction. You have 3 pivalite esters you have 3 pivalite esters all this can be removed by using di-ball. Reductive cleavage of the pivalite esters were done with di-ball to get a trial. Then treatment with acetic anodine pour in a dimethylamino pridine gave the triacetate ok. TBS was removed and then re-protected as triacetate. Now you do not need this TBS group ok you do not need this TBS there are 2 TBS groups ok this particular TBS which is less hindered compared to the other one was removed by treating with dichloroacetic acid ok. So, that primary alcohol as you can see here you have the primary alcohol and the triple bond. So, if you want to reduce the triple bond you can do it under heterogenalist condition. So, that the triple bond is reduced to the double bond. Now Desmartine peregrine oxidation oxidizes the primary alcohol to aldehyde which upon oxidation further under pinnacle oxidation condition gave the carboxylic acid basically the CH2OH is converted into carboxylic acid in 2 steps ok. Then came the esterification this is one of the very rarely used esterification method where the testibutyl esters are made like this from corresponding urea derivative ok. So, once you have this testibutyl ester the next step is to remove this TBS group. So, that was done using HF pridine and next what one has to do is you have to attach the side chain here ok. And before that this primary alcohol was oxidized under Desmartine peregrine condition to get the aldehyde and followed by oxidation and the pinnacle oxidation condition to get carboxylic acid. And that was again protected as testibutyl ester using the substituted urea derivative. Then OS analysis of the vinyl group gave aldehyde. So, that also was oxidized using pinnacle oxidation condition to get the carboxylic acid ok. Now if you look at this carefully the third carboxylic acid also was esterified using the same method to get the testibutyl ester. He also used another method where you could start from here that means he has a triple bond here and then two TBS protected primary alcohol. So, what he did first he reduced the triple bond to double bond. Then the TBS groups were removed using HF pridine to get the primary alcohol. This primary alcohol upon oxidation under Desmartine peregrine condition you could get two primary aldehyde ok, two aldehydes. Then if you do OS analysis you will get one more aldehyde ok. So, you can see there are three aldehydes at the end of this sequence. Now if you oxidize this under pinnacle oxidation condition one could get the corresponding tricarboxylic acid ok. So, now you can also protect all the three carboxylic acids in one step using this testibutyl urea derivative ok. So, then what is required is you have to selectively carry out alkylation at this hydroxyl group ok. So, potassium carbonate methanol will hydrolyze both the acetates to get the diol then this particular alcohol was protected as Boc ether ok. Then the other hydroxyl is free that other hydroxyl group was esterified with this gamma delta unsaturated carboxylic acid. This is esterified with gamma delta unsaturated carboxylic acid which we already discussed how to make this gamma delta unsaturated carboxylic acid. So, you can see this side side chain was established and here also on the right hand side side chain was established. So, what is left is to remove all the protecting groups. What are the protecting groups? There are three tertiary butyl group ok. There are three tertiary butyl groups which should be hydrolyzed to get the corresponding tricarboxylic acid and also there is one tertiary butyloxic carbonyl group ok. So, these two can be easily removed using trifluoroacetic acid condition ok. So, that was done to obtain the natural product called Zerogocic acid C. So, if you look at this synthesis he started with commercially available T-arythro lacto ok and overall he took about 25 steps and yield was very good considering that it is a complex molecule and then he took he and his group took 25 steps 4.1 percent overall yield is a significant method significant total synthesis among many complex natural products. So, what I will do I will stop here and with this we have completed more than 100 total synthesis of really complex natural products starting from you know very small natural product called Illudane and we went all the way to Zerogocic acid and many alkaloids ok. So, with this lecture we completed what the syllabus which I have proposed in the beginning of the course. So, the last two lectures it is basically to summarize what we have discussed ok. I am not going to talk about any more total synthesis in the next two lectures that is the last two lectures I will focus only on the synthesis which we have discussed and that too each synthesis what are the key reactions we have discussed so that you will get an idea of how many reactions which we have discussed throughout this course ok and how these reactions could be successfully used in the total synthesis of complex natural products ok. So, thank you and all the best for your