 Yeah, good morning. I will come back to the lecture series on classics in total synthesis. So we have been discussing about synthesis of alkaloids and today also we will continue our discussion on the total synthesis of one more alkaloid. And these alkaloid actually is a combination of many alkaloids. They are basically derived from squalling. As you can see here they are quite complex. So this is called a proto-daphnifillane and if you remove this portion, so you can see a methylhomosecodaphnifillate. I will repeat methylhomosecodaphnifillate. And instead of ester, if you have this bicyclic moiety, it is called ccodaphnifilling. So these were isolated in the 70s. Today what we will do, we will talk about the total synthesis of these two natural products. First let us start with methylhomosecodaphnifillate. So this was isolated in 1971-72 and it was isolated from the bark and leaves of Yuzhuriha tree which was found in Plenty in China. Basically the extracts of this bark as well as leaves were used for the treatment of asthma. It is a herbal treatment and this has been going on for centuries in China and the crystal structure of this particular compound as you can see here, it is a quite complex natural product. So you need crystal structure to find out the correct structure. So it was done in 1971. Due to its complex structure, many synthetic groups were interested in the total synthesis of this particular alkaloid and from structural point of view, if you see this molecule, you can find it is a pentacyclic compound. Not only that, it is highly congested. There are five rings in this molecule. Then there are eight contiguous stereocenters. There are eight contiguous stereocenters. You can see 1, 2, 3, 4, 5, 6, 7, 8. Eight contiguous stereogenic centers. In that, if you look at 3 and 8, if you look at 3 and 8, they are contiguous quaternary centers. So presence of eight stereogenic centers in that two contiguous quaternary centers coupled with a complex pentacyclic skeleton really provided enough synthetic challenge for synthetic chemists to attempt the total synthesis of this molecule. The first total synthesis was reported by Clayton Heathcock and he used a combination of two key reactions. One, an intramolecular Diels-Aubre reaction followed by a Soprince reaction. So this is a combination of two reactions in one part and before that, he used a sequential Michael addition followed by alkylation. The first key disconnection was here what he did was cleverly he introduced a double bond here. He cleverly introduced a double bond. So when we talk about retro synthesis, we always look at the functional groups and strategic bonds so that disconnection will be easier. But sometimes what will happen? You may not have functional groups or you may not have a proper strategic bond for further disconnection. In such cases, as I had already mentioned, you need to introduce a functional group. Occasionally, you will also see that you will have functional groups but those functional groups are not sufficient for proper retro synthesis. In such cases also, one can think about introducing a functional group. So that is what he has done. If you look at the natural product, you could see an isopropyl group at equatorial position. So what he did? He did one minor change that is instead of isopropyl group, he put two propenyl group that means he introduced a double bond. Why he introduced the double bond? Because that brings a lot of flexibility and also that brings sea change in the thinking of how to approach this natural product. Let us see how he has done and what he has done and why this double bond was introduced and how it helped in the retro synthesis. What he thought was the moment he introduced a double bond, then he can think about what we call ASA prints or ASA in reaction. What is that? You can see here, if you have an emine, if you have an emine, then you can think about carrying out ASA prints reaction or ASA in reaction. So what will happen? This CH bond will come and this will attack the emine and it will undergo cyclization to form a six ombre ring. Basically what you have done in this retro synthesis, you have removed one ring and this ring is constructed via ASA in or ASA prints reaction. And if you look at this molecule, you can see a cyclohexene but with a heteroate. Normally when you see a cyclohexene, the key reaction which will come to your mind is Diels-Alder reaction. Here instead of cyclohexene, what you have is a heteroatom, nitrogen is present in the double bond. So this also can be obtained by a Diels-Alder reaction. Only thing is you will have a heterodyne. You should start with a heterodyne. So that is what he proposed. So this could be obtained by an intramolecular Diels-Alder reaction. By an intramolecular Diels-Alder reaction, one should be able to obtain this tricyclic compound in one part. And this in principle, so of course it can be redrawn for the sake of better understanding. So this could be redrawn like this. Now if you look at this molecule, this bicyclic compound, this can be obtained from this Diels-Alder reaction. When you treat this with amine, for example ammonia, if you treat with ammonia, first what will happen? It will react with this alderite. It will form amine. Since you are treating with ammonia and it is forming amine, it can undergo isomerization to form enamine. That enamine can react with this alderite and to get this compound. It is a one-part reaction. You treat this Diels-Alderite with ammonia, you will get directly this dihydroperidin, substituted dihydroperidin derivative. And this Diels-Alderite as you know can be obtained from corresponding lactone or diol. But the next key reaction is the Michael edition or the 1,4 edition followed by alkylation with an alkyl halide. So what he proposed was here the anion generated by treatment of this amide with lithium exomethyl diselicide or LDA can undergo a 1,4 addition on to the alpha, beta and saturated esters. Five-membered alpha, beta and saturated esters this upon alkylation with this electrophile. That should give directly the precursor to the Diels-Alderite. Now let us see how he has accomplished the total synthesis of methyl, homo, seco, daffiniflate using these two key reactions. So first he started with this amide. This can be easily obtained from the corresponding diol. You see 1, 2, 3, 4, 5. You can start from 1, 5, pentane diol and selectively protect one of the alcohols as benzyl ether and oxidize the other alcohol, other primary alcohol to carboxylic acid and convert that into amide. In 3 steps one can make this come. Then you treat with LDA. So LDA what it will do? It will generate anion here. Then as depicted in the retro synthesis it will undergo 1, 4 addition and followed by coenching with this iodide you get this compound. Here if you look at this particularly this whole portion and this electrophile they are trans-teachable. However this stereo center they got mixture but does not matter. The reason is anyhow if you look at the intramolecular Diels-Alder reaction precursor you will have a double bond here is not it? That dihydropyridine. So this stereo center is immaterial. So once you have this the next step is you have to reduce the ester. The ester could be easily reduced with the diabol. And when you do that the ester will get converted into the primary alcohol. Now the primary alcohol if you treat with potassium hydroxide and ethanol. So basically hydrolysis and followed by lactonization you get the corresponding 6-membered lactone okay. Now from the 6-membered lactone you have to convert into dialdic acid which is the precursor for making dihydropyridine. This lactone was reduced completely with lithium aluminum hydride to get the diol and the diol was oxidized under sworn condition to get the dialdic. So this is the key precursor for the subsequent random 4 plus 2 as well as asoprince cyclization okay. Now you take this aldehyde and treat with ammonia. And as I said immediately it forms the corresponding substituted dihydropyridine okay. Once you have this dihydropyridine next the key step is the asoprince cyclization. And for that you treat it with acetic acid at ambient temperature. So the first step is the intramolecular dielsal reaction. So acetic acid protonates the imine okay. The protonation takes place here and immediately it undergoes the intramolecular 4 plus 2 cycloaddition reaction okay. Now at that temperature at that temperature the next step that is the asoprince cyclization did not work. So he has to slowly increase the temperature from ambient to 70 degrees. Now the next step the key asoprince cyclization took place to give the pentacyclic skeleton. So basically if you look at the whole synthesis the two key steps one sequential Michael addition followed by alkylation two tandem 4 plus 2 and asoprince cyclization could give straight away the complex pentacyclic skeleton of methyl HOMO secret definite. Now what needs to be done you have to reduce the double bond and convert this CH2OBN into ester okay. So it was simply reduced while reducing under hydrogenalysis condition the double bond also got hydrogenated and debenzylation also took place to give the corresponding primary alcohol. Then the primary alcohol was completely oxidized fully oxidized to carboxylic acid and esterified to get the natural products which is methyl HOMO seco definite. To summarize if you see the whole sequence of reactions where very straightforward if you look at the whole synthesis the key reactions are tandem 4 plus 2 and asoprince cyclization and the first key reaction is the Michael addition followed by alkylation. He also later reported asymmetric synthesis of this compound. Now if you look at this this is chalamic synthesis, resemic synthesis. So for asymmetric synthesis what he did he started with a chiral starting material he attached a chiral auxiliary. So this chiral auxiliary helped introduce the chiral centers in the next step. So you can you can see in this product okay 1, 2, 3, 3 chiral centers were established by the use of this chiral auxiliary. Same set of reactions okay, same set of reactions instead of simple pyrolidonone he used the 2 pi dimethyl pyrolid. So that is all. So that took care of you know the synthesis of the same molecule but chiral 1 okay. So and he followed the same strategy, same route and he could achieve the asymmetric synthesis of methyl HOMO seco definite and it was almost showing 90% EE the final natural product. The synthetic natural product showed 90% EE compared to the naturally isolated methyl HOMO seco definite plane okay. Having succeeded in that he wanted to use a similar strategy for the synthesis of the related natural product seco Daphne plane. For seco Daphne plane what is additional is this particular pycyclic compound okay. So according to the retrosynthesis this can be obtained by the Claisen type reaction. So already he has successfully made methyl HOMO seco Daphne plane. Now if you can generate anion here and then attack on this acid chloride okay you will get a beta keto ester okay. Then once you have the beta keto ester you can decarboxylate okay. The decarboxylation will give a natural product seco Daphne plane. So for the synthesis of seco Daphne plane what is required is the synthesis of this acid chloride in optically PFO okay. So how did he do? So he started from propanol okay propanoldehyde and then did a canister like reaction okay. So he treated with formaldehyde. So once he treated with formaldehyde it underwent two aldol reaction with formaldehyde to introduce two CH2 OH group and at the same time the aldehyde was oxidized to get the carboxylic acid okay. Then the two primary alcohols were protected as ketol. Now the carboxylic acid was converted into windrup amide okay by treating with windrup amine and DCC. He made the corresponding windrup amide. Now he took this lithiobutine one lithiobutine and added to this windrup amide. As you know when you have windrup amide if you add any argonon lithium species or argonomegnesium reagents you will get corresponding keto. So that was the idea so he could get the corresponding keto. Now to introduce the chiral center he used a combination of lithium aluminum hydride and this amino alcohol it is a chiral one okay. So that helped in getting or introducing the chiral center okay this chiral center was introduced. Now once you have that he used another key reaction okay. So this is called zipper reaction so the zipper reaction is nothing but when you have an internal alkyne. This internal alkyne when you treat with potassium hydride and 1 3 di amino propane okay. If you treat with potassium hydride and 1 3 di amino propane the internal alkyne will move to the terminal alkyne. So that is called zipper reaction as you can see here when you do this reaction this internal alkyne goes all the way to the terminal. How does it do okay. So this is the mechanism okay. So basically as I said it is nothing but if you have an internal alkyne if you treat with potassium hydride and di amino propane it isomerizes the internal alkyne to the terminal alkyne. So first so you have this one of the hydrogen is picked up and then you have the potassium salt. So that will pick up this hydrogen okay and it will form an alene it will form an alene. Then similarly that alene will migrate the same process same way this will migrate to terminal alene. Once the terminal alene is formed then again it will migrate and then you will get okay. So basically it is a series of migration from internal alkyne to the terminal alkyne okay. So one side it will pick up the proton other side it will give the hydrogen okay. So that is how the migration of triple bond goes through alenes okay. This was reported in 1975 by Brown and co-workers. So once you have this terminal alkyne so now you can treat with mercuric sulphate and sulphuric acid okay. So this is again another interesting reaction if we have a triple bond and two alcohols at appropriately placed they can form an intramolecular keto. How it forms the first step is the oxymercuration okay. See under acidic condition this keto is cleaned. So you have primary alcohol. Now this undergoes first oxymercuration followed by just hydration okay, volcanic oxidation of water. So that will give you a mixture of these two alcohols okay. As I said if you can redraw this, if you can redraw this molecule like this then you can see here one oxymercuration followed by this alcohol and this alcohol okay. This alcohol and this alcohol. One will undergo oxymercuration and the other one will undergo simple addition of water okay. First one will undergo oxymercuration to the triple bond. The second one will undergo addition of hydroxyl group to the double bond. So that is how you get this keto okay. This upon oxidation the primary alcohol if you oxidize with ruthenium tetroxide you get the corresponding carboxylic acid and once you have the carboxylic acid convert that into acid chloride using oxalyl chloride. Now you take this methyl homo-seco-definiflate. Already he has made this compound in chiral form. Mix these two okay. You treat with LDA and then quench with the acid chloride you get the corresponding beta keto ester okay. Then this beta keto ester can be decarboxylated by treating with sodium cyanide and DMSO. If you reflect this compound that directly gives seco-definiflate okay. So to summarize Heathcock was the first one to report the total synthesis of methyl homo-seco-definiflate and his synthesis of methyl homo-seco-definiflate involved a sequential 1, 4 addition followed by kunjing of the enolate by an alkyl iodide and the second key reaction was an intramolecular 4 plus 2 cycloaddition between a heterodyne and dienophile followed by Assa Prince reaction to construct the pentacyclic skeleton of this compound okay. Overall the number of steps were very less and the total synthesis of methyl homo-seco-definiflate as well as the seco-definiflate were achieved in very few steps using these two important and key reactions by Heathcock's okay. So with this we have completed the total synthesis of methyl homo-seco-definiflate and seco-definiflate and we will continue our discussion on some more synthesis of alkali in the next few lectures. Thank you.