 So, good morning everyone and welcome back to the NPTEL lecture series on classics in total synthesis part 1. So, we have been discussing about total synthesis of few alkaloids and today we will continue our discussion and also on total synthesis of one of the very important alkaloids called lysergic acid, okay. So, the lysergic acid belongs to a family called ergot alkaloids. So, the ergot alkaloids have this basic skeleton, this is a tetracyclic skeleton if you look at carefully. So, they have the indole as their core structure, okay. They have indole and two more six-pumper ring fused with this indole, okay. In fact, they were the first drugs used or first among the, they were among the first drugs used for the treatment of migraine headache and all, okay. And they believe that the tetracyclic core structure, okay, the tetracyclic core structure is responsible for its biological activity. So, most of the derivatives further derived from this basic skeleton, they made sure that tetracyclic skeleton was kept as such only there was some functional group transformation around the tetracyclic ring. So, these are three ergot alkaloids, you can see this is ergolin, okay, having a double bond here and festuclavin where the double bond is reduced and the ring junction is trans. And pyrochlorine, so here also you can see the ring junction is trans, so whenever the double bond is not there then the ring junction is trans in ergot alkaloids, okay. And if you look at lysergic acid, so double bond is there, okay. You can see in the tetracyclic ring there is a double bond and here instead of methyl group you have carboxylic acid, so that is why it is called lysergic acid and if you reduce the carboxylic acid then it is called lyserjol, okay. And the stereocenter if it is opposite then this is called isolyserjol, there was one semi-synthetic derivative which is called pergolide and the difference between pergolide and lysergic acid is instead of methyl group here, so what you have is a propyl group, N propyl is attached to the nitrogen and in this case on the left hand side instead of carboxylic acid what you have is CH2SMe and this pergolide is used for the treatment of Parkinson's disease as of now, okay. The more important analog of lysergic acid and infamous one is LSD, so LSD is nothing but lysergic acid diethyl amide, so that is this carboxylic acid is converted into the corresponding diethyl amide, okay. So the small change from carboxylic acid to the diethyl amide makes huge, huge difference. In fact, LSD is one of the most potent psychoactive agents known in the literature. If you look at the history of LSD that is lysergic acid diethyl amide, so this was accidentally discovered in 1938 when a scientist called Hoffman when he was synthesizing this molecule that is a derivative of lysergic acid during the purification and crystallization, during the purification and crystallization he felt something unusual, so he had different sensation, so he immediately wanted to go home, so he went home and then he was just lying down on the sofa and then he could imagine so many things, you know many are, you know he had a very nice feeling of imagining so many things. So then immediately he wrote to the other scientist and in Sanders said this compound has some unique type of you know effects, okay, so this molecule should be taken further, so that is how this molecule was developed and in 1970 it was formally announced that LSD is a controlled substance, okay but today we are not going to talk about LSD but what we are going to do is talk about two total synthesis of its precursor that is lysergic acid. The first total synthesis was by as usual Woodward, so Woodward thought this can be easily obtained starting with the basic skeleton, so that means you know you start with indole and try to append the two 6-membered rings over the indole, so his starting material was indole 3 propionic acid and the key reactions which he used for the synthesis of lysergic acid are photocrafts oscillation that is intramolecular photocrafts oscillation to construct the first 6-membered ring and an aldol reaction to construct the second 6-membered, okay, let us see how he originally thought of making lysergic acid, so his initial idea was as I said you can do an aldol here, you can do an aldol to form the second 6-membered ring, okay, then the carboxylic acid can be easily added, okay that was the first major disconnection, then the second disconnection was an ascent to substitution reaction, okay, you have bromide, alpha-bromo ketone, so you can do ascent to reaction to introduce this methyl amino ketone which can be further used for intramolecular alder condensation. The third disconnection was obviously the CCO bond because it is so clear that one can easily use photocrafts oscillation reaction to introduce the second 6-membered ring and this acid chloride of course can be obtained from 3-indole propionic acid, okay, let us see how he has done the synthesis. He started with indole 3-propionic acid and first step was a stratification with ethanol and HCl, gave the ethyl ester, so then this double bond, so this double bond was reduced under rhenical hydrogenation condition, then the ester was hydrolyzed to get the corresponding carboxylic acid, okay. So the acid then the NH was protected as benzoate, then the thionyl chloride converted the carboxylic acid into acid chloride which is the intermediate for the Frelkov's oscillation reaction, the Frelkov's oscillation reaction worked well to get the first 6-membered ring added over the dihydro-indole. So after that alpha bromination was done, okay, with little bit complex region but it is not really complex pyridine HBr and bromine, okay, so under photochemical condition, so he introduced bromine alpha to the carbonyl group, so once the bromine was introduced the next step was to carry out the intermolecular acetyl reaction, so he took the amine and then treated with this alpha promo ketone, reflected benzene, so the acetyl reaction took place, so next step is to remove the ketol, so that you will have the diketone ready for the intramolecular aldol reaction, so it was easily removed under acidic condition to get the 1,5 diketone, 1, 2, 3, 4, 5, so the 1,5 diketone upon treatment with sodium ethoxide methanol and an intramolecular aldol reaction to give this 6-membered ENO, okay. And the free NH was again acetylated using acetic anhydride pyridine, then the alpha beta unsaturated ketone was selectively reduced to get the corresponding allylic alcohol and once you have the allylic alcohol it requires 2 steps to introduce a carboxylic acid synthetic equivalent, the synthetic equivalent for carboxylic acid in this case is cyanide, if you can introduce cyanide then cyanide can be hydrolyzed to carboxylic acid, okay. So the allylic alcohol was treated with first HCl, okay why HCl because this free NH should be protonated, okay. So after protonation then thionyl chloride treatment, thionyl chloride treatment converted the allylic alcohol into the corresponding allylic chloride in this specific case, then treat with sodium cyanide, say it underwent SN2 reaction and this upon treatment with sulfuric acid and methanol, so that means the cyanide you are hydrolyzing to carboxylic acid and in that process since you are using methanol the carboxylic acid which is formed also getting esterified because of the presence of acid and methanol, okay. So the cyanide is directly hydrolyzed and esterified in one step to get the corresponding methyl ester, okay. So once you have this ester then what is next is only to hydrolyze. During the formation of ester from cyanide you one also should know that acetate also was removed, okay under acidic condition one can remove the acetate to get the corresponding free appeal. So then simple hydrolysis was done here as you use potassium hydroxide, rannin nickel to get the corresponding carboxylic acid which is the natural proton, okay. So this lysergic acid synthesis reported by Woodward overall involved about 15 steps and yield was close to 1 person, okay. As I already mentioned the key reactions involved in the synthesis of lysergic acid reported by Woodward or Ptolkovs acylation that is intramolecular Ptolkovs acylation to get the first six-membered ring and again an intramolecular aldol condensation reaction to get the second six-membered ring. Then we will move to the second total synthesis which was reported by Wolfgang-Opulser, okay. So his idea was when you look at this six-membered ring you have a double bond, okay. So he thought if you can migrate this double bond here, okay if you can migrate this double bond here then it should be possible to use an intramolecular Diels-All reaction to form this six-membered ring, okay. The only thing is here the dienophile will be an imine, okay. So then one can call this as intramolecular imino Diels-All reaction, okay that was his original idea and let us see how he has done this. So as you can see here again the starting material is indole and with a substitute here so that he can introduce this diene which is required for the intramolecular Diels-All reaction then you attach the dienophile which is required that is heterodynophile required for the Diels-All reaction then you carry out this intramolecular Diels-All reaction followed by migration of the double bond and hydrolysis will give lysengic acid. So this is the simple strategy planned by Opulser for the total synthesis of resemic lysengic acid, okay. Let us see how he actually carried out the total synthesis for the synthesis of Fragment A he started with this nitrocarboxylic acid, okay. So esterification of carboxylic acid with ethanol and HCl he got the corresponding ethyl ester then this methyl group, okay this methyl group was converted into this enamine that is done with dimethyl formamide dimethyl acetone in DMF, okay. So basically you know you generate an anion, you generate an anion and then attack the DMF, okay to get the double. Then you reduce with 10 chloride so what happens first the nitro group is reduced to get the corresponding amine then this enamine also gets hydrolyzed once the enamine gets hydrolyzed you get the aldehyde, okay. So CH2, CHO you get the CH2, CHO and then NH2 they will form aminol followed by dehydration overall what he got was the corresponding indole with niester here, okay. So what needs to be done for the next few steps you have to attach the dim and also you have to attach the dienophile to this indole, okay. So before that protect the indole nitrogen as N2C8, okay then you reduce the ester with LAH to get the corresponding primary alcohol and this primary alcohol can be further homologated. So here the introduction of diene he followed a unique method what he did was first he took methyl acrylate and then treated with cyclopentadiene to get this bicyclic compound through Diels-All reaction. Then he deprotonated this carbon because that is attached to ester then quenched with methyl forming basically what he had done is he has introduced an aldehyde here, okay. So why he has introduced this aldehyde I will tell you. So once he had this B that is the aldehyde bicyclic adduct then this fragment A that alcohol he converted into the bromide followed by treatment with tributylposphine he made the vitic salt. So then the vitic reaction with this aldehyde was done with dimsil anion, okay. So why this intermediate he wanted to make? So if you look at this intermediate this portion can undergo a retro Diels-All reaction, okay. The retro Diels-All reaction will remove the cyclopentadiene, okay, remove the cyclopentadiene and it will generate the other diene which is required for the Diels-All reaction. So basically one of the double bonds of the diene is protected by cyclopentadiene, okay that will be released when the retro Diels-All reaction takes place. This diene is not reactive, this diene is not reactive so that is why he has to follow this indirect method. Next he took this compound and then treated with aqueous formaldehyde and dimethylamine, okay. That means he is inducing a CH2NN dimethyl, okay this is nothing but managerial reaction is not it. So upon treatment with aqueous formaldehyde and dimethylamine he carried out a marriage reaction at carbon number 3 of indole to introduce this functional problem, okay. What he has to do is he has to introduce one more carbon for that he took nitromethane and dimethyl acetylene dicarboxylate it underwent a sort of SN2 reaction to get this CH2-CH2-NO2, okay. From this CH2-NO2 he needs a double bond N and OR. So he needs an imine, okay. So the imine should be there for an intramolecular imino Diels-All reaction, okay. So what he did, first he treated with sodium ethoxide methanol. So that forms this intermediate, this intermediate when it forms you can immediately recall. So this is nothing but NEPH reaction, okay. If you have a CH2-NO2, okay, NEPH reaction first you have to treat with base then followed by treatment with titanium, titanium trichlorine, okay. So what happens, this will be hydrolyzed to the aldehyde. Then the aldehyde will react with NH2-OME to give this corresponding imine, okay. So now the dienophile is ready. What he needs is the diene should be released through the retro Diels-All reaction then it can undergo spontaneous intramolecular 4 plus 2 cycloaddition reaction. So that was done at high temperature, so 200 degrees so that retro Diels-All reaction took place and followed by intramolecular Diels-All reaction gave this tetracyclic compound, okay. So now you have OME here but in lysogic acid you have methyl group, okay. So just to want oxygen you have to remove. So that was done using fluoromethane sulfonate, it is a good methylating agent, okay. So what happens? So first the nitrogen will be methylated, okay. So then the fluoride can attack and OME bond, NO bond can break to give the corresponding N-methyl, okay. So what needs to be done? Now you have to push the double bond here and hydrolyze the ester to carboxylic acid. If these two are done synthesis of resemic lysogic acid is completed, okay. So the isomerization of the double bond was done with aluminum abalcum to push the alpha beta and saturated ester to beta, gamma and saturated ester. Then simple hydrolysis that is alkaline hydrolysis hydrolyzed the ester to carboxylic acid thus he completed the total synthesis of resemic lysogic acid, okay. So the key reaction as I mentioned was intramolecular immunodeal salt reaction and overall it took 6 steps less than what Woodward has taken, Woodward took about 15 steps whereas Opulsar took only 9 steps to complete the total synthesis as a result. The overall yield also went from 0.78 percent in the case of Woodward to 3.88 percent that is 4 times we got better over yield than Woodward's, okay. So now we have completed the total synthesis of lysogic acid now. Now we will move to total synthesis of 3 or 4 more total synthesis of alkaloids before we move to total synthesis of steroids, okay, thank you.