 So, good morning and welcome back to NPTEL lecture series on Classics in Total Synthesis. So, today we will talk about another very interesting and complex natural product called discordermalide. It is a marine natural product and it shows really excellent biological activity particularly it is an anti-cancer agent and also it could be used as immunosuppressant. So, that is why since its isolation many groups were interested in the total synthesis of this particular complex natural product. The first total synthesis was reported by none other than Stuart Stryber. So, who reported this synthesis? Three years after the molecule was isolated when you look at this molecule you can see there are many chiral centers first of all ok. And you have a six-bumper ring on the left hand side and you have five chiral centers on the right hand side ok. So, in between you have three chiral centers here ok and all these are connected by a double bond ok. So, you can easily disconnect this molecule into at least three fragments. So, that is what Stryber at his group did. So, they disconnected this molecule into three fragments, fragment A, fragment B and fragment C. Let us see how they have done that. So, first disconnection on the left hand side was to break this bond. So, the idea is to use Nossochi-Kishi coupling reaction ok. So, here if you have a triple bond and you can add to this aldehyde so you can get this propagalic alcohol that can be reduced to the corresponding pallelic alcohol ok. So, that was the first key disconnection. The second key disconnection was here. The idea was to have a carbonyl group here instead of alcohol ok. If you have a carbonyl group then you should be able to generate an anion here and if this is a leaving group then it is easy to do an alkylation. Later the ketone can be reduced to get the alcohol. So, the second disconnection was on that so you can see. So, this pallel group can be removed and then converted into a good leaving group followed by alkylation you can make this bond. So, the first disconnection led to three fragments, fragment A, fragment B and fragment C. And these three fragments can be obtained for example, first to start with fragment A and that can be obtained from this compound which has already three chiral centers ok. These three chiral centers were established or built upon one chiral center. This molecule is called rochester ok and it has one chiral center and from using this chiral center so you could build two more chiral centers. And for the fragment B again if you look at it was made from almost similar starting material. If you have closer look at this molecule then you will see only it differs at this chiral center ok and again the same starting material that is rochester. And the third fragment incidentally again comes from the same intermediate which was the intermediate for making fragment B and the starting material is same. That means he has designed this synthesis in such a way that all the three fragments can be made from one starting material that is rochester ok. Let us see how he has synthesized all the fragments and then combined to form the square thermolyte. So the first step obviously is to protect the primary alcohol and reduce the ester ok. So the primary alcohol was protected as TBS ether and then Dybal reduction gave the aldehyde. Then came the first key reaction. The first key reaction was to use William Roche Crotyle boration. So what he has done was he has taken this chiral Crotyle borane derived from diisopropyl tautorates ok. So it is known and was reported by William Roche that if you start with trans 1 you will get this anti aldehyde. And if you start with cis 1 if you start with the cis double bond then you will get here syn aldehyde product ok. This is a very established aldehyde reaction ok. So he could now based on one chiral center as well as using this chiral auxiliary he could establish three chiral centers ok. Next the double bond was osomalized to get the aldehyde. Then stabilized vitic gave the alpha, beta and saturated ester. The second key reaction was when you have this alcohol and also the alpha, beta and saturated ester if you treat this alcohol with potassium hexamethyl disolocyte. So what will happen? It will become O minus it will pick up this proton. Then when you add benzaldehyde so the benzaldehyde is like this. So it will add to benzaldehyde and then the benzaldehyde carbonyl oxygen will attack the alpha, beta and saturated ester. And the whole process we can call it as oxamycal addition ok. So what you get is now you introduce the fourth chiral center and also the two secondary alcohols are now protected as benzaldehyde derivative. So this is a very interesting reaction developed by David Evans group ok. So now you can remove the TBS group with HF pyridine and once you have that you need aldehyde. So that was done with Desmartine pyridine to get the primary aldehyde. The idea to form the six-phombered ring is to first cleave this benzaldehyde derivative then this hydroxyl group should attack the aldehyde to form the six-phombered ring ok. So that was done in one step by treating with camphor sulfonic acid and methanol. So camphor sulfonic acid and methanol first removes the benzaldehyde derivative that so the two hydroxyl groups are released. Once these two hydroxyl groups are released one of the hydroxyl groups will immediately attack the aldehyde to form the six-phombered ring ok. And since you use methanol then in the presence of acid it will become the corresponding lactol methyl ether ok. Then you protect the secondary alcohol here with the other secondary alcohol which did not react to form the corresponding TBS ether ok. Now the ester should be converted into aldehyde ok. So that was first hydrolyzed with lithium hydroxide to form the carboxylic acid then the carboxylic acid was coupled with Weindrup amine to form Weindrup amine. So this is called Weindrup amide as you know when you have Weindrup amide if you treat this Weindrup amide with Grignard reagent or organolithium reagent you will get the corresponding keto. But if you treat this with reducing agents like dibol, redol or lithium aluminium hydride you will get the corresponding aldehyde. So that was the idea he wants to get the aldehyde or before that this OME group which is slightly labile. So he wanted to convert that into SPH that was done under Lewis acid condition by treating with zinc iodide and pH STMS. Then lithium aluminium hydride reduce the Weindrup amide to get aldehyde which is fragment A ok. So now the next step is to make fragments B and C for the fragment B again as I said he started with the same rose ester in two steps you could get the aldehyde in good yield and now instead of trans what he has used is cis-crotyl boration ok. So that he could get the synaldol products ok. Now once you have the synaldol protect the secondary alcohol as corresponding TBS ether and osanolize the double bond to get aldehyde. Then the next step if you look at the structure of disco d'Arnaud carefully the methyl group as well as this the double bond the double bond which is actually connecting fragments A B and C ok here it is you know 1, 2, 1, 2 it is Z isomer ok. So if you want Z isomer then you have to use still a generic volumetization. Here instead of normal alkyl ester the phosphonate ester if you use trifluoroethanol ester then that gives Z isomer as the major product. So that is what he has used to get the Z isomer as the major product then reduce the ester with lithium aluminium hydride to get the corresponding alcohol and that alcohol was protected as pivalite ester ok. Now remove the primary alcohol protected as TBS ether so you remove that TBS selectively with HF pridine to get the primary alcohol which was oxidized under swan condition to get the aldehyde. Now the aldehyde is homologated using best manoeura reagent so you got the triple bond and the triple bond upon treatment with iodine in the presence of morpholine gave fragment B. So the fragment A and the fragment B both are ready the next thing is to make fragment C but the fragment C is we already discussed ok when I when we saw the retrosynthesis fragment B and when fragment C were made from the same intermediate ok this is the intermediate which is common to fragment B and fragment C. So he took this intermediate and then protected the secondary alcohol as PMB ether because at some point of time you have to differentially remove the protecting group. So it is better to protected with a different protecting group ok so that was protected as PMB ether by treating with sodium iodide and PMB bromide, paramethoxybenzyl bromide then you do the ozanalysis you get the aldehyde and treat with methylgrignard to get the secondary alcohol ok. This also now the primary alcohol which is protected as TBS can be cleaved by trifluoracetic acid to release the primary alcohol. Now you can see if you can rotate it by 180 degree along this axis you will get this if you rotate it by 180 degree you will get this ok. So you have this diol then oxalyl chloride will oxidize that is one condition will oxidize both primary alcohol and secondary alcohol to get the corresponding keto aldehyde and the aldehyde was selectively treated with vitic reagent derived from CH2I2 ok to get the cis vinyl iodide ok. Now the cis vinyl iodide was homologated or olefinated with CH2 double bond CH zinc bromide. So this is nothing but legacy coupling ok. So a legacy coupling helped to introduce the next double bond. So you have a diene at the right hand portion of discordarmolyte. So this is how Schreiber introduced the diene in fragment C. So all the three fragments are made now fragment A fragment B fragment C. Now how you combine all the three fragments to make or to synthesize discordarmolyte. So it took the fragment B and combined with fragment A under this Nosaki-Hiyama-Kishi conditions ok. So this is well known reaction which gives the corresponding alcohol. So you got mainly this enantiomer and next you need a double bond. So that can be easily reduced if you have triple bond and the triple bond can be selectively reduced in the presence of other double bonds ok. So once you have this propogelic alcohol reduce the triple bond to get the cis double bond then protect the newly formed hydroxyl group ok. Protect the newly formed hydroxyl group as TBS ether by treating with TBS triflate and base like 2-6-leutidine then you reduce with di-ball ok. So when you reduce with di-ball the pyrolyte ester will be reductively cleaved ok. So that will give you the corresponding primary alcohol. Then this primary alcohol was converted into corresponding bromide in 2 steps via mesolate followed by treatment with lithium bromide you can call it as Fingalstein reaction. So using this Fingalstein reaction you could convert the primary alcohol to corresponding primary bromide in 2 steps. Then you have the fragment C take the fragment C and then treat with LDA so or lithium-examethyl disoloside. So you can generate anion selectively at this carbon then quench with this bromide ok. So it is simple alkylation the centrifugal reaction. So now if you look at this carefully you have the complete structure ok. You have the complete structure of disco-dermalide except that you need to introduce one methyl group here and you have to reduce the carbonyl group and of course you have to remove the protective groups and convert this into corresponding laptop. So these are the steps remain to complete the total synthesis of disco-dermalide. So he treated with lithium-examethyl disoloside and quench with methyl iodide so that he could introduce a methyl group here so he could successfully introduce a methyl group. Then you need a lactone here so the sulfur was removed with mercury chloride and oxidized with chromium trioxide to get the corresponding lactone. So the left hand side is fine the right hand side is fine the methyl group also introduce now only one more functional group remains to be introduced is to get the alcohol that means you have to reduce the ketone. So before reducing the ketone PMB was first removed to get the alcohol the secondary alcohol then the secondary alcohol was treated with chloroisocyanate. So here it forms an ester so it forms an ester here OCO NCO and what you need is OCO NH2. So that can be easily done by simple hydrolysis so neutral alumina just hydrolyze the NCO2 corresponding NH2 then sodium boron reduction gave or reduce the ketone to corresponding alcohol okay. So now only one step is remaining that is removal of all the TBS group so that was successfully done with para toluene sulfonic acid. So that is how he could complete the total synthesis of discordermalide and if you look at the total synthesis of discordermalide reported by Schreiber so what are the key reactions he has done? See first key reaction as you know is the Crotyl boration the rose Crotyl boration established two new chiral centers here it is synaldol or antialdol okay he has established two new chiral centers using rose Crotyl boration one. If you look at he has used Kishi coupling reaction of the Iodol alkene with aldehyde to introduce one more chiral center and later the triple bond was reduced to get the corresponding cis double bond okay. Overall he took about 24 steps and the yield is quite impressive so 3.2% overall yield for such a complex natural product is really commendable okay. After this total synthesis there are many total synthesis of discordermalide reported in literature even Novartis made 60 grams of this discordermalide following different procedures reported in the literature and it is a first time such a high quantity of natural product was made in an industry following literature procedure and then they use this for several studies biological studies okay so I will stop here thank you.