 So, good morning and I will come back to NPTEL course on Classics in Total Synthesis Part 1. In the last lecture, we talked about the Total Synthesis of Strychnine by Viresh Rawal and Larry Overman's group. So, today we will talk about another Total Synthesis of Strychnine reported by Martin Kunis group, okay. So, here in this Total Synthesis, again they used iso-strychnine root that means the synthesizer via iso-strychnine and the key reactions which they used was a tandem manik, co-prearrangement and manik reaction, okay. So, that is a key reaction used to construct the five umber ring. So, this is this five umber ring they constructed using this key reaction, five umber as well as the six umber ring, okay, together they constructed using this three reactions in one step. First they reported resemic synthesis, then they used chiral version starting with corresponding chiral amino acid. So, overall it took about 14 steps to complete this synthesis of Strychnine. So, their synthetic strategy as I said depended on three reactions in one pot, they are manich reaction followed by co-prearrangement followed by another manik reaction. So, they did a model study where they started with this alpha, beta and saturated aldehyde derived from pure and 3-carb aldehyde. So, they treated this with this corresponding amino ester in the presence of Lewis acid at high temperature. The first the aldehyde forms iminium ion with this amine, aldehyde forms iminium ion and the manich reaction takes place. Once the manich reaction takes place, this is the intermediate you get, that is a first intermediate. Now, you can see this can undergo a co-prearrangement, so 1, 5 diene, okay, this 1, 5 diene can undergo co-prearrangement. So, once it undergoes co-prearrangement, you get this intermediate. So, now you have a 9-membered ring, okay, so what you have is a 9-membered ring because of the co-prearrangement. Then as I said it undergoes the second manich reaction. So, the second manich reaction cyclizes again back to the 6-pi system, okay, so that is how in one part he could successfully make this tetracyclic compound, basically he made 2 rings in one part. So, that is the key reaction which he later used for the synthesis of strychnine. So, for the synthesis of strychnine, he does not need this furan, okay, he wants an aldehyde, he wants an aldehyde. So, what he did, he started with the corresponding protected aldehyde, it is a furan, he got this compound and the next slide we also will see how this starting material was made from commercially available starting material. So, he started with this tryptophan, tryptophan is NH2, then he treated with tertiary butyl oxychloride. So, tertiary butyl oxychloride is known to introduce chlorine here, okay, so that way you get the chlorine here. Now, you treat with dimethyl marionide and sodium methoxide, okay, so that will give you the CH, COTME, COTME. What you do not need here is one COTME you do not need, okay and one benzyl group you do not need. So, it is easy, one of the esters can be easily removed by crapto condition, you heat it at high temperature lithium chloride and dimethyl acetone, then dimethyl acetamide, so you treat this with lithium chloride and dimethyl acetamide, it undergoes decarboxylation, so you get only one ester, now as I said you do not need one more benzyl group, so you can easily selectively remove by doing hydrogen aliases. So, that is how this starting material was prepared in 4 steps, okay, starting material was prepared in 4 steps, but I should say 5 steps from triptophan, okay, so once this was prepared then this was treated with this alpha beta and saturated aldehyde, so as I said in one pot 3 reactions taking place, a managed reaction 3-3, sigmatropic rearrangement that is copery arrangement followed by another managed reaction, okay, so then a copery arrangement followed by another managed, you get the corresponding tetracyclic compound, so earlier we had a furan, now you have the dimethoxy, okay, once you have this, next what you should do is you have to hydrolyse the acetal to aldehyde, hydrolyse the acetal to aldehyde, so you do that, now the aldehyde can be homologated, so how do you connect this, now you have to connect these 2, is not it, now you have to connect these 2 and you need one more carbon atom, basically you need one more carbon atom and connect this, so that can be done, now if you take this and then treat with trimethylsulfonium elide, the trimethylsulfonium elide as you know when it treats with aldehyde it will form an epoxide, is not it, so that is what you get, you get an epoxide, now this epoxide, okay, if you remove the benzyl group, if you remove the benzyl group hydrolysis, then what will happen it will open the epoxide, so when it opens the epoxide from the less in that side if it attacks you get the thermodynamic products, okay or it can also attack this carbon, okay, one will give 5 umber ring, other will give a 6 umber ring, okay, correct, one will give, this is 5 umber, this is 6 umber, so you take the thermodynamic product that is the 6 umber which is required, then that can be controlled to get only one as the major product, now if you remove the benzyl group, okay, benzyl group can be easily removed under hydrogenalysis condition, then the double bond, you know I mean the push pull double bond can be reduced with sodium cyanoborohyd, but you get a mixture at this carbon, you get a mixture at this carbon, no problem, the free hydroxyl, now you have a free hydroxyl that should be acetylated, okay, so when you acetylate at that stage you should be able to separate these 2, okay, so you have this beta ester and alpha ester in the ratio 3 is to 1, okay, you can take both beta and alpha, you can take both beta and alpha ester and treat with 2 reagents successfully, one is lithium-examethyl disoloside, say what is lithium-examethyl disoloside or what will you do, it is a base, hindered base, so you have n acetate that n acetate, what it does here, you can see, okay, I have written only this portion, LIHMDS, lithium-examethyl disoloside will generate anion here and it can attack this and your OEM will come out, so that way you will get a 60013 dicarbonyl compound, 60013 dicarbonyl compound and followed by treatment with sodium ethoxyl methanol, the sodium ethoxyl methanol will hydrolyze the acetate and you get this, okay, so both will give, but the second one that is this, the first step it does not work, so it hydrolyzes only the acetate and in the second step you treat with lithium-examethyl disoloside and you can get this, okay. Once you have this, now you can see how many rings you have made, 1, 2, 3, 4, 5, 6, okay, what is missing? You have to connect the seventh ring, that is the seventh number ring, you have to connect, how do you do it? You reduce the ketone, you produce the ketone to alcohol, basically you have to introduce a double bond, you have to introduce a double bond. Now you treat with acetic anhydride, you get a beta-alpha acetate, okay, does not matter, then you treat with DBU, okay, when you treat with DBU you get this intermediate, okay, so if you look at other synthesis, you will see this intermediate you would have seen. What you need is you have to homologate this, you have to oxidize this hydroxyl and do the homologation. So how will you do? First you oxidize with swan, swan condition to get the ketone, then you do the Wittig reaction. So when you do the Wittig reaction, the destabilized Wittig, you get the corresponding alpha, beta and acetate ester, both E and Z in 1 is to 1 ratio, okay and you know you need this isomer, you need this isomer for the cyclization to get the 7-membered ring, no problem. So this can be isomerized, so 1 isomer can be isomerized to required one through a photochemical condition. So photochemical is you know very well, the double bond can be isomerized, cis trans isomerization or trans cis isomerization can be done under photochemical condition. So once you have this alpha, beta and acetate with the right regiochemistry, then reduce it with di-ball. So once you reduce with di-ball that will give you the iso-stichnid. As you know iso-stichnid has been converted into stichnid in one step by treatment with base, okay. The base first it will isomerize the double bond here, then followed by oxamical addition you will get stichnid, okay. So this was a very simple straightforward synthesis, however the key step was one part manage 3-3 sigma tropic rearrangement and another managed reaction. Then he also used another route instead of homologating using Wittig reagent, he used a vinyl Grignard addition. So on this ketone they added vinyl Grignard to get the tertiary allylic alcohol. Then he did the palladium catalyst rearrangement, so after making the tertiary alcohol as acetate he treated with palladium catalyst to get the allylic rearrangement, allylic rearrangement to get this protected allylic alcohol, okay. So once you have that if you treat with potassium hydroxide THF that the acetate is hydrolyzed then you oxidize you get the corresponding aldehyde, okay. That aldehyde can be isomerized to get this isoparticular isomer. Then sodium borohydride cerium chloride, sodium borohydride cerium chloride reduces the aldehyde to corresponding alcohol that was acetylated and that is called isostichnid acetate and that alcohol itself if you treat with base that will convert the isostichnid into stichnid. So these are the two strategies he used to make isostichnid and stichnid, okay. But if you look at these two approaches by reported by Q and A both are resimic synthesis. He also tried and reported an asymmetric synthesis and in this asymmetric synthesis he started with drift of an derivative, okay chiral one and he also took about 14 steps the same number of steps which he took for the synthesis of resimic stichnid, okay. So now the difference between the earlier one and now is this chiral center, okay. Everything else is same except this additional chiral center. Then he treated with this alpha beta unsaturated aldehyde and R being CH, OME and OME, okay. So you do the same reaction and you get the same product and here this is CH OME, CH OME the main difference is this compound is chiral. So because of one chiral center present you can make now three chiral centers, okay. Once you have that then you do not want this ester, is not it? You do not want this ester, okay ester it did its purpose. It introduced three new chiral centers. So once that is done you have to remove that. So first you convert that ester into amide. So that is normally done by reflecting with ammonia. Then the amide to cyanide was done with trifluoroastic anhydride, a dehydrating agent, amide to cyanide can be done. Basically you are removing water, you are doing with trifluoroastic anhydride. Once you have the cyanide the cyanide group can be removed because you have lone pair here so the lone pair will help. So potassium borohydride you get the corresponding pyrrolidine ring without the cyanide, okay. Next it is straight forward. So what we have done earlier so this is aldehyde, you remember this is aldehyde we had and once you have this aldehyde what he did he treated this with the corresponding tributyltin methanol but that alcohol was protected with ethyl vinyl ether, okay. So now if you treat with butyl lithium, butyl lithium what will happen it will exchange. It will exchange this and then you will get a lithium here. That lithium will add to this aldehyde. So what you get is this compound. You have the CH2 and the alcohol is protected as ethoxyethyl ether, ethyl vinyl ether and ethoxyethyl ether, okay. Then you oxidize the secondary alcohol under swan-like condition to get the ketone. Then remove the protecting group that is ethoxyethyl group under acidic condition you get ethoxyethyl is like THP protection, okay. So you remove that and then you get the corresponding CH2 OH. Once you have the CH2 OH convert that into toacylate, okay, toacylate. Now if you remove this benzyl group automatically it will undergo SN2 reaction and then this toacylate will go and you will get this six-mombot ring, okay. So now you have made pentacyclic core structure of strychnine. So what is required, you have to add the two carbon unit and then cyclise and then you get the isostrychnine structure or the umlic aldehyde. So what you did? You did a VTG reaction, okay. The VTG reaction give a mixture. Then the required one you took and then treat it with di-ball, okay. When you treat with di-ball it forms the oneness. So this is not as reactive as this. So one can selectively reduce that to get the alcohol. Now you reduce this double bond selectively, you see sodium cyanoborohydrate, acetic acid, you get this compound, okay. You can see the double bond is reduced and it gives only 1 isomer. Sodium ethoxide methanol in THF, sodium ethoxide methanol in THF, this compound you can write like this, okay. The compound can be written this way. So what is happening? Sodium ethoxide methanol, look at this chiral center. Hydrogen is beta whereas here alpha. So the epimerization takes place. The epimerization takes place to give alpha hydrogen. So once you have that then di-ball will give, this ester will be converted into aldehyde. As soon as the aldehyde is formed, this alcohol will attack the aldehyde to give Vlan-Gumlich-Aldehyde. As you know when you talk about totals in this of strychnine, there are 2 key intermediates. One is Vlan-Gumlich-Aldehyde, other one is isostrychnine. So you can make either isostrychnine or Vlan-Gumlich-Aldehyde. If you make isostrychnine which he made, okay. That is in the racemic synthesis of strychnine, Martin Kuhl made isostrychnine, okay via Wittig reaction. He did the Wittig reaction, he also did vinyl grid not followed by palladium catalyst rearrangement. Then he made the corresponding isostrychnine. Here in this case, what he made was Vlan-Gumlich-Aldehyde, what he made was Vlan-Gumlich-Aldehyde. The Vlan-Gumlich-Aldehyde is also known to be converted into strychnine in a single step. You have the lactol, the lactol on treatment with Wittig reaction, okay or you can use Melanic acid, Acetic anhydride and Acetic acid. So, you will get the alpha-beta unsaturated ester, okay, this aldehyde will react, aldehyde and alcohol. The aldehyde will form alpha-beta unsaturated acid and also cyclise with this NH and then same process, the oxa-mical addition also will take place. All will take place in one step, the Vlan-Gumlich-Aldehyde can be converted into strychnine successfully by treating with Melanic acid, Acetic acid, Sodium acetate and Acetic acid, okay. So, this is again another interesting total synthesis, so we talked about 4 total synthesis of strychnine. We started with total synthesis of Woodward, okay, so Woodward used a very nice classical method to synthesize strychnine. Then we talked about Vireshe Ravel, so Vireshe Ravel used a very nice intramolecular Dielsall reaction to construct the six-numbered ring here. Then we talked about Laurie Overman used cleverly a Klaisen rearrangement, okay, Island ester Klaisen rearrangement to get the six-numbered ring and he also used a managed reaction, the combination of managed reaction and Klaisen rearrangement to get the 5 and 6-numbered ring. So, in this case, in Martin Kuhne's total synthesis of strychnine, he used a Domino Managed and 3-3-Sigmatropic rearrangement followed by another Managed, so 3 reactions in one part to construct the C and D ring, okay. So, with this, we will stop and then we will talk about more alkaloids and other natural products in the next few lectures, thank you.