 So good morning and welcome back to the NPTEL lecture series on classics in total synthesis part 1. So in the last lecture we talked about total synthesis of prostaglandins by Professor Coray and today we will talk about two more total synthesis of prostaglandins one by Professor Gilbert Stott the other by Professor Carl Johnson. So first let us start with Stott's synthesis of Pgf2Alpha as you know this is the structure of Pgf2Alpha. The key reactions which Professor Stott has used in the synthesis of prostaglandin Pgf2Alpha is radical cyclization to form the F5 membered ring and followed by trapping that radical at 5xO radical, 5xO radical cyclization followed by formation of another radical which is trapped by their acceptor. So this is the key reaction in the synthesis of Pgf by Stott and also you could do this reaction on a 1 gram scale and the next one is intramolecular thermal rearrangement which later called as Brooks rearrangement also was used as the key reaction. How he has done the retro synthesis, his idea was if you break this double bond, if you break this double bond on the left hand side you will get aldehyde and the right hand side you will get the corresponding triphenylposponium bromide. So that you can do a wittic reaction to get the cis double bond. Now once you have this aldehyde, aldehyde and alcohol if you combine the alcohol will attack the aldehyde to form a lactol and the lactol if you can protect. So that is the precursor for Pgf2Alpha. At the same time you can also keep this as carbonide and later one can reduce it to get the corresponding allylic alcohol as required in the natural product. Now the next step is the real key reaction as I said the radical cyclization followed by trapping of the resultant radical. So what he did was he prepared this halo compound. Now this can undergo a 5-exo radical cyclization on to this double bond that will generate a radical at this color okay. Now if you add an acceptor like this okay so that can add to this triple bond. So that will straight away give you this alpha beta unsaturated keto okay that was the original plan but let us see how he has achieved this particular transformation and this can be you know this five member ring can be obtained from this diol and this can be obtained from cyclopentadiene okay if you look at the earlier synthesis of Pgf2Alpha by EJ Quorae they are also the starting material was cyclopentadiene okay. Now let us see how he got this diol from cyclopentadiene. So take cyclopentadiene and this is a known transformation and do a 4 plus 2 cycloaddition with oxygen okay so why photochemical conditions are required is normally oxygen is in triplet state is not it. So it has to come to ground state so that is why photochemistry is used and since you use thiorea after this the OO bond also gets cleaved under the same condition to get this corresponding diol okay but this is you know mesocompone one can easily resolve and for that you first protect this diol as diacetate. This diacetate enzymatically can be selectively hydrolyzed one of the acetates can be selectively hydrolyzed to get energiomerically enriched one alcohol other one acetate. So this was done successfully with peak liver esterase to get this corresponding you can see one of the hydroxyl group one of the acetate is hydrolyzed to hydroxyl group the other one is acetate. Now this is an octaglyclic compound okay. So he took this compound then treated with TBS chloride so that you can protect this free hydroxyl group followed by hydrolysis of the acetate with catalytic compound of potassium cyanide and ethanol at room temperature now you get the corresponding allylic alcohol. Next step is treatment of this allylic alcohol with ethyl vinyl ether in the presence of N iodo succinamide see what happens when you treat with ethyl vinyl ether and N iodo succinamide you get this compound okay. So you can see I do not need my arm okay. Now this will open this so what you get is corresponding OET plus now the lone pair on the oxygen will attack and utilize the positive charge so that will give you this compound. So that is the precursor required for the key radical cyclization that is phi XO radical cyclization followed by trapping the resultant radical. So what happens you do this reaction with catalytic compound of Azaz, this isobutonitrile and tributyltin chloride and stoichiometric compound of sodium cyanoboride. So it forms as I said the radical attacks here and it forms a radical at this carbon. Now you do the trapping with tertiary butyl isocyanide that means this radical which is formed here attacks the carbon and this C N bond breaks. So what you get is the corresponding cyanide okay. So now you can see you have made a 5 ombre ring and also you have introduced a cyanoclub. Once you have the cyanide then as you know you can reduce it with the dye ball to get that aldehyde at low temperature you know minus 78 you can reduce the cyanide to aldehyde then carry out Wadsworth Imans modification of Wittig reaction to get the trans double bond or E double bond. So this is what you get. So what is left now you have to reduce this to alcohol, idolize this lactol ethyl ether to lactol and do the Wittig reaction and followed by removal of this TBS group will give Pgf to alpha. So you also attempted this same thing by a second method where the acceptor is different okay. It took the radical precursor and did the same condition except that acceptor was this alpha beta unsaturated keto. Earlier what he did he wanted to check how it works. So he tried with tertiary butyl isocyanide. So he could introduce the cyanide and then reduction of cyanide you got aldehyde. Once you have aldehyde of course you can homologate further. So he wanted to directly trap that radical with this alpha beta unsaturated keto. Did he do? Yes he could successfully do. After that when you heat it what will happen oxygen has got better affinity towards silicon than carbon okay. So when you heat it this oxygen attacks the silicon and followed by breaking of CSI bond gives you the corresponding enol ether. So this is also called Brooks rearrangement. So the migration of silicon from carbon to oxygen is called Brooks rearrangement. So now when you have enol TMS it is very easy to introduce a double bond by treating with palladium acetate is not it? So very famous oxidation reaction. So that gives the corresponding alpha beta unsaturated keto. So now you can see both ways you could get this corresponding enol. Once you have this enol reduce with S by null okay. So that will reduce the carbonyl group and you will get one isomer as a major product. You got the alcohol then treat with Acus HCl. So Acus HCl will hydrolyze the lactol ether to corresponding lactol and at the same time your TBS group also will be cleaved you get the corresponding hydroxide group. Now you do the vitique with the 5 carbon unit having a carboxylic acid at the terminal so you get PGF2 alpha directly. So overall if you look at this synthesis, so this synthesis was done in only 7 steps okay done only in 7 steps starting from the acetoxy or TBS protected cyclopentenol which is a known compound from cyclopentadiene which is a known compound from cyclopentadiene and this was achieved in 7 steps. Then the next key step was the 5xO radical cyclization followed by trapping of the radical with acceptance okay. Now we will move to the third total synthesis of prostaglandins by Carl Janssen's group. So here the key reaction was 1, 4 addition to cyclopentenol followed by quenching the enolate with an electrophile. So the 2 side chains are introduced in one step via 1, 4 addition followed by trapping of the enolate okay basically what they have done is a substituted cyclopentenone was taken and then these 2 side chains were attached okay. Let us see how they have thought about from retrosynthetic point of view. So they thought this can be obtained from the cyclopentenone having these 2 hydroxyl groups which are protected. The idea is this vinyl lithium species or vinyl copper vinyl lithium species followed by converting into copper add to this cyclopentenone in a 1, 4 fashion and quench with this electrophile and this can be obtained from this. I will come to that how it is done and again the starting material looks almost same as what Kelbert Stark has used okay and that can be obtained from cyclopentadiene. So overall if you look at the 3 synthesis which we discussed for the total synthesis of prostaglandins all the synthesis started with the 5 membered that is cyclopentadiene commercially available cyclopentadiene of course cyclopentadiene is not commercially available as such it is available as cyclopentadiene dimer you have to crack it that is you have to make sure that it undergoes a retro 4 plus 2 cycloaddition to get cyclopentadiene. So how we did so there are 2 ways you prepared the chiral starting material. The first method is almost similar to what Gilbert Stark has done a 4 plus 2 cycloaddition of cyclopentadiene with oxygen followed by reduction of OO bond with thioia you get the diol and the diol was protected as the diacetate and from here he changed its route so what he did he did a dihydroxylation. So when the dihydroxylation will happen as you know the dihydroxylation both hydroxyl group will come opposite to these 2 acetates these 2 acetates are beta. So the hydroxyl will come from alpha and the resultant diol was protected as acetonide by treating with acetone with the catalytic amount of para toluene sulphonic acid. Now you hydrolyze so both acetates you get a diol this diol upon oxidation okay one of the hydroxyl gets oxidized and once it is oxidized to get the ketone the other hydroxyl group is nothing but it is an aldol beta hydroxy ketone. So it undergoes elimination under the in the presence of trifluoristic acid. So directly you get the cyclopentadiene but this is racemic in nature okay. This racemic cyclopentenone can be resolved with this sulfoxamine to get the only the required one. You also can get the other one equal amount but what you want is this one with that you can proceed further for the enantiose selective total synthesis of prostaglandic and one can also use the diacetate for preparing the same. So you can use an enzyme to selectively hydrolyze this acetate and oxidize so alcohol will get oxidized to get the ketone and automatically and in the presence of sulphuric acid you undergo elimination to get this cup. So there are two ways one can make this cyclopentenone and this is the way you know normally the optical resolution is done and only problem is the 50% with the other configuration you cannot use it further because that will not give the naturally occurring prostaglandic okay. So you go with what you require. The second method so that is why you know the second method was used in the second method which was developed by Hadley Key. So that involved dihydroxylation of an aromatic compound. So this microbiological process has started with toluene commercially available toluene you can do this soda monosputidop enzyme to do the dihydroxylation. So one of the double bonds of benzene can be selectively dihydroxylated. Now you protect this hydroxyl the two hydroxyl which are cis with acetone so you get the corresponding acetone ion. Then if you cleave these two double bonds under was analysis condition you get the corresponding keto aldehyde okay. Keto aldehyde. Now this ketone it can generate anion and attack this aldehyde in an intramolecular aldol reaction followed by elimination of water. You get the same compound which we had discussed earlier start starting from cyclopentadiene. So the second method differs from the other three synthesis where you know cyclopentadiene was used as a key starting material. Here the starting material used is toluene and again they use enzyme to introduce the two hydroxyl groups stereo selectively and followed by intramolecular aldol reaction to get the same starting material. So once you have this substituted cyclopentenone the next key step is the addition of the vinyl copper followed by quenching with the next side chain. So how did they do? Before that the side chain has to be prepared both the side chain one is 8 carbon other one is 7 carbon. The 7 carbon side chain was prepared from propogel alcohol protect the alcohol as THP ether and followed by removing this proton with LDA and quench with this Bromo ester. Then the THP ether could be cleaved with HCl methanol to release the primary alcohol and that can be converted into iodine by treating with PBR3. Then if you use Lindler catalyst this propogel alcohol the substituted propogel alcohol will be reduced to the alkene which is cis. Then you convert the alcohol into corresponding iodine okay same thing you can do with this also no problem. The synthesis of the 8 carbon side chain started with this protected alcohol of course this can be made in two steps from the corresponding aldehyde and add this lithium ethylene diamine you get the alcohol that alcohol you protected as TBMS ether you get the starting material. Now if you treat with tributyltin hydride and the photocomical rendition the tributyltin hydride is known to add to this triple bond to get trans double bond with the tributyltin group at the terminal carbon. Now if you treat with butyl lithium so this can be exchanged with lithium okay. So you get lithium and this upon treatment with copper so the lithium copper exchange will take place so that it can undergo the 1, 4 addition to the cyclopentenone. So that is what happens you take this and then treat with the substituted cyclopentenone followed by quenching with the cis allyl iodine okay which already discussed in the previous slide. So this gives a mixture of three compounds one the required the trans disubstituted cyclopentenone in 64 percent yield then the other two one is the epimer at this carbon the third one is only 1, 4 addition product the alkylation did not take place only 1, 4 addition alkylation did not take place. So what we can do you can convert this into required one by epimerization and this you can convert into the required compound by alkylation. So both were done so epimerization was done with sodium acetate methanol to get the required cyclopentenone then the other one that is the mono alkylated that is only 1, 4 addition product happened not the subsequent alkylation you can treat with LDA and quench with the corresponding iodide you can convert into the required product. So now if you look at this intermediate it has both C7, C8 side chain and what is not required is this oxygen and this three carbon unit okay so that was easily done before that the hydroxyl group was released by removing the TBDMS group by treating with HF pridine and one can also use HF in astronaut rail so that not only TBDMS group will be removed but one can also remove the astronaut okay. So both were done under the same condition but you do not want the extra oxygen is not it that extra oxygen was removed by using aluminium amalgam so basically it gives a radical aluminium and this opens up and you get the acetone and the corresponding beta hydroxy combo okay this is for resemic one how about the chiral one say chiral one already we know how to make this follow the same process that is do 1, 4 addition quench with the corresponding allyl iodide you get 46% yield of the required product of course the other products are mono alkylated product that is the only 1, 4 addition took place the subsequent alkylation did not take place then you got the epimer at this position okay. So no problem as I already discussed the 8 epimer can be further you know treated with base to get the required one and of course this 25% of the product where only 1, 4 addition took place can be converted into this by additional treatment with LDA and quenching with the corresponding allyl iodide okay. From here to PGE to methyl ester we already discussed on the resemic one so HF pridine remove the TBMS group and aluminium amalgam removes the astronaut do so that is how Carl Johnson could complete the total synthesis of PGE2 in a optically active form. So to summarize prostagland in PGE2 both resemic and optically active minus isomer was reported by Carl Johnson and co-workers in 1988 in one synthesis they started with cyclopentadiene as the starting material and in the other synthesis they followed Goodluck's protocol wherein they started with toluene and then do enzymatic dihydroxylation to introduce the 2 chiral centres and these 2 chiral centres were responsible for the introduction of the 2 more chiral centres where you have to introduce the C8 side chain and C7 side chain overall if you look at this whole transformation it is a triply convergent approach that means you have cyclopentenome and you add the C8 side chain and followed by quench with C7 side chain so triple convergent approach and overall this synthesis was achieved in 4 longest linear steps with a yield of 32 point percent and 40.5 percent respectively for resemic and asymmetric synthesis. So thank you I will stop here today.