 Yeah, good afternoon and welcome back to NPTEL lecture series on Classics in Total Synthesis Part 1 and we have been discussing about total synthesis of many alkaloids and today we also continue to discuss one more complex alkaloid called manzamine. So manzamine as you can see from here it is quite a complex molecule and it was isolated 1986 from marine sponge called Okinawan sponge and from the structure one can easily make out how many rings are there and how many chiral centers are there. It is a quite challenging molecule and because of its complex molecular architecture several groups were interested in the total synthesis and the first person to complete the total synthesis was Geoffrey Winkler and today we will talk about the total synthesis of manzamine by Winkler's group. After the isolation of manzamine there were 100 manzamine alkaloids which were isolated from various species belonging to 8 different families and they generally show a very good activity against malaria and as I mentioned Winkler was the first one to report the total synthesis in 1998 and there are other synthesis afterwards but today we will talk only about the total synthesis of manzamine by Winkler's group. So his group the retro synthesis of manzamine was based on 3 or 4 key reactions, 3 or 4 key reactions. The first key reaction was the pitted sprinkler reaction to construct this ring pitted sprinkler reaction. So we will come to that what is pitted sprinkler reaction and then the second key reaction was you know the cyclization and to form the macro cycle that is also very important from the size of the ring which is being formed during the synthesis and the third key reaction which is of course you know combination of 3, 4 reaction is an intramolecular managed reaction you can see you have an imenium ion here okay and anion generates here and then attacks and then utilize the positive charge on the nitrogen which as you know it is a managed reaction. This is an intramolecular managed reaction and this is obtained this imenium ion is obtained by series of rearrangement and that started from this cyclobutane okay. So here it undergoes a retro managed reaction and followed by managed reaction okay. So when I discuss the total synthesis you will know what exactly I mean okay. So once you can see the cyclobutane the simplest reaction one can use to make cyclobutanes is a photochemical reaction. So this can be disconnected into this compound where you have 2 double bonds and under suitable photochemical condition it should be possible to make the cyclobutane using intramolecular 2 plus 2 cycloaddition reaction and this can be obtained from this enone okay and if you look at this carefully this can be obtained from this bicyclic compound okay. So these are the key fragments this is a fragment 1 or starting material I would say starting material 1 and starting material 2 in the synthesis of manzamine by Jeffrey Winkler okay. Now as I said there are 3, 4 key reactions which Winkler has used in the total synthesis of manzamine. The one key reaction is the intramolecular 2 plus 2 cycloaddition which is also called demyoreaction. One of the oldest reaction known in the literature photochemical reaction known in the literature is this demyoreaction. Carvone a commercially available monotirpene can undergo an intramolecular 2 plus 2 cycloaddition reaction between these alkene and other alkene. One is electron rich other one is electron deficient and in fact under sunlight also this can undergo if you keep it for long time to see these 2 plus 2 cycloaddition to take place okay. And the pigtail sprinkler reaction is if you have phenyl ethyl amine okay. Then this one treatment with aldehyde or protected aldehyde in the presence of acid it can undergo cyclization basically what you are doing is you are introducing the CH2 or CH if you are using aldehyde okay. So this is how one can cyclize okay cyclize to form a 6-membered brain okay. Now let us see how the starting materials are prepared before we actually go into the complex total synthesis how the starting materials are prepared for the complete synthesis. The first the pyridine nitrogen was benzylated okay. When pyridine nitrogen was benzylated it becomes quaternary ammonium salt okay. Then one can reduce this imenium with sodium borohydrate. So 2 such successive reaction one can remove 2 double bonds of pyridine okay. So that leads to the formation of this allylic alcohol okay. So very simple reaction first you have to benzylate followed by reduction of the successive imenium ions with sodium borohydrate you get the corresponding alkene okay. Only 1 double bond is there. Now he wanted to remove the benzyl and then protect it as bog for that he has to do a 2 step process first he treated with chloromethyl for meat. So what happens the lone pair on the nitrogen attacks the carbonyl and then chlorate comes out first. So this is the intermediate this is the first intermediate nitrogen attacking the carbonyl and chlorine coming out. Now the chloride which comes out attacks the benzylic carbon attacks the benzylic carbon and breaks the Cn bonds so that nitrogen will be now neutralized. So in the process what happens the chloromethyl formate removes the benzyl group okay removes the benzyl group has benzyl chloride. So now you have removed the benzyl at COTME but as I said he wanted to protect the nitrogen as bog protecting group. So again he treated with potassium hydroxide methanol and followed by a treatment with bog anhydride he could get N-mog okay. So the next step is to make this as a good leaving group as you know which should be converted into bromide or mesylate or tosylate or triplet so that an SN2 reaction can take place at that carbon. So here the hydroxyl was converted into bromine using a standard triphenolpastamine bromine immunosol treatment so to get the corresponding allylic bromide okay. So now one small fragment of manzamine is ready. Next how you can introduce the chiral center okay how you can introduce the chiral center. So for that he started with soda feed ring okay. So now this carbon has two acidic protons okay one can treat with LDA of course you need excess LDA because you have free hydroxyl group then quench with this allylic bromine okay. So that is how you introduce this chiral center okay. So now you could see one new chiral center has been introduced once the chiral center is introduced then you have to cleave the chiral oxalary okay. So cleaving the chiral oxalary can be done but before that the free NH2 should be protected. So the NH2 was protected as allyl oxy carbonyl group this is called alloc alloc is allyl oxy carbonyl group. So the corresponding chloride you take and treat with base you get the NH protected as alloc protecting group. So now as I said you remove the chiral oxalary once you remove the chiral oxalary you have the corresponding carboxylic acid. Now if you look at this carefully this is substituted amino acid is not it? This is substituted amino acid but unnatural it is not a naturally occurring compound it is an unnatural amino acid okay. So now one fragment is ready what you do you convert that carboxylic acid convert that carboxylic acid into a vaned up amide. So why vaned up amide is required because once you have vaned up amide if you treat with the Grignard reagent or if you treat with reducing agents like LAH or diabol you will get only corresponding aldehyde. If you treat with Grignard reagent you get corresponding keto. So here what they want was they wanted an aldehyde okay. For that once they made this vaned up amide treatment with either diabol or LAH gave the corresponding aldehyde okay. So I have written this structure you know I rotated this 180 degree so as I leave it for a few seconds just see this carefully okay just I rotated this by 180 degree okay. So here if this is alpha this is beta okay. Then once you have aldehyde then this long chain compound okay a vitic reaction was done on this aldehyde to get the corresponding cis alkyne. So this is vitic reagent can be easily prepared from the corresponding diol. So if you have this diol okay what is this diol 1, 2, 3, 4, 5 pentane diol if you have pentane diol you can selectively protect one of them as TBS ether okay. Then the other alcohol you converted into bromide and then make the vitic salt then you do this vitic reaction okay. So what is left now you have to do this cyclization here you have to do the cyclization here okay. So for that first you have to remove the TBS group okay. The TBS group primary TBS was removed using PPTS methanol then converted that alcohol into a good leaving group that is tosylate okay. Now sodium hydride and THF what happens this NH that is actually proton okay. So sodium hydride will remove that proton so you form N minus that N minus will intramolecularly attack the carbon bearing tosylate so that SN2 reaction will give this ring okay. So now we have made the bicyclic compound okay. You know we have to make 2 more rings okay. Once you made this that alloy group the protecting group should be removed so that is normally done under palladium catalyst so tetrakis palladium removes the allyl oxy carbonyl group so that is how we get the free bicyclic compound which is ready for further transformations okay. Now the other fragment okay which is required for the for making the macro cycle that all kind for that again you started from a diol okay you can see 1, 2, 3, 4 butane diol 1, 4 butane diol and the hydroxyl group one of the hydroxyl group was protected as THP ether and the other hydroxyl group was converted into bromide in 2 steps by treating with mesyl chloride followed by lithium bromide okay. So now this alkylating agent is ready then you have to start with the triple bond okay. So the triple bond and the carboxylic acid this also can be easily made in few steps from known starting material. Now if you treat with butyl lithium so more than 2 equivalents of butyl lithium is required 1 to generate anion here other 2 remove this proton. So once you do that then quench with this halide okay so that will give you this long time okay. Now what you need the ester you have to that carboxylic acid you have to convert into ester so that was done by reflexing with methanol in the presence of acid. So now as I said the second fragment which you need is this alcohol so use the ester you treat with windrup amine in the presence of trimethylaminium so this OME will be replaced with this compound okay. So now you have got the windrup amine okay. So if you see here the required compound has said triple bond and here you have the windrup amine. So basically what you need is you need to add a triple bond to that. So the simplest one is the corresponding acetylene grignard okay acetylene grignard in THF directly will give you the second fragment which is required for the total synthesis of Mansor. So now we have these 2 fragments the next step is to carry out the intermolecular Michael addition reaction. So you have the Michael acceptor and here you have the nucleophile. So intermolecular Michael reaction takes place first and that gives you this product that is the one which is ready for intramolecular DMAO reaction that is 2 plus 2 cycloaddition reaction. So you can see when you looked at manzamine the molecule was looking very very complex isn't it. So you disconnect the molecule in such a way that you got into 2 simple fragments. Once you have these 2 simple fragments what you have done you are doing now an intramolecular intermolecular Michael reaction. Intermolecular Michael addition gives you the precursor for the photochemical reaction. Once you have that carry out the intramolecular 2 plus 2 cycloaddition reaction that gives this intermediate and this intermediate actually it does not stop there you do not get this intermediate you do not isolate what happens as I mentioned when I talked about retro synthesis it undergoes a retro managed fragmentation. So that means you can see this lone pair comes here and opens up the opens the cyclobutane to give this product the lone pair opens the lone pair on the nitrogen opens the cyclobutane to give this intermediate. Now what will happen the O minus O minus can directly neutralize the iminium ion the enolate can neutralize the iminium ion if that takes place what you will get is this tetracyclic compound but what you want is not this what you want is cyclization at this between this carbon and this carbon. So how to do again you have to open up again you have to open up this amino how do you do you treat with pyridine and acetic acid when you do that again it opens up okay when it opens up this becomes the bottom portion becomes iminium ion and the top is keto okay just I will leave this for few seconds because it is important for you to visualize what happened this become ketone okay this become ketone and the whole side chain the whole side chain I have brought it down okay whole side chain I have brought it down okay you can see whole side chain I have brought it down. Now once the iminium ion is formed then you can see it can generate enolate on this side as well as the other side okay. If it generates on the top that will give you a 4-membered ring if it undergoes intramolecular managed reaction understand if this undergoes intramolecular managed reaction it will give back the original 2 plus 2 cycloaddition product. But if this undergoes intramolecular managed reaction that will give you 6-membered ring which is actually required for man's element. So between 4-membered and 6-membered which one will be favored the 6-membered will be favored so that is what happens and that managed reaction gives rise to the required 6-membered ring. So now if you look at this intermediate carefully so what we have done so we have used say 2 plus 2 cycloaddition retro managed reaction followed by managed reaction to construct the 6-membered ring. So 4 rings are made now what is left is we have to connect these 2 this nitrogen and this carbon we have to connect then we have to introduce the heterocycle here okay let us see one by one how we introduce or how we form this macro cycle. So the primary alcohol you can protect it as TBS and before that what is important is you also have to introduce a hydroxyl group you need to introduce a hydroxyl group here okay how will you introduce a hydroxyl group okay one you can straight away treat with base you can straight away you treat with base and then treat with you know MCPBA there are many methods to introduce hydroxyl group but at the same time you also have to introduce an aldehyde here when only you can introduce the heterocycle on the top okay. So what you did so you treated with lithium hexamethyl disolacea which will generate enolate here okay it will generate enolate here and then quench with Mander's reagent Mander's reagent is a reagent which is used for introducing ester group the ester group next to ketone so the ester was stereo selectively introduced okay then as I said you also have to introduce a hydroxyl group here you have ketone and you have an ester and then ketone group can be easily reduced in the presence of ester sodium oregano will reduce ketone to alcohol that alcohol can be converted to mesalate and mesalate you know is a good living group that can be on treatment with base can be converted into that double bond. So now when you do that obviously you will get a mixture of alkenes one is the alpha beta and saturated ester which is obvious the other one the beta gamma and saturated ester okay both eliminations are possible okay but what is required is this one because you need to introduce a hydroxyl group here that means you should try to explore the functionalization of this double bond how do you do now you isomerize the alpha beta and saturated ester to the beta gamma and saturated ester then treat with MCBB that MCBVA will give the corresponding alpha epoxide now it is very easy the ester you can generate enolate here isn't it then the enolate can open the epoxide so what you will get is a double bond as well as a hydroxyl group at gamma position yeah so sodium ethoxide here acts as a base and then opens the epoxide and that is how you introduce the hydroxyl group okay then as I said now it is time to construct the macrophage so first you have to remove the TBS group the TBS group can be removed with any fluoride source so Tbuff removes the TBS group to get the corresponding alcohol then the alcohol can be converted into good leaving group okay so you treat with tosyl chloride so alcohol is converted into a corresponding tosylate okay then what needs to be done is to remove the BOC so BOC can be easily removed if you use a trifluoroacetic acid and you get the corresponding amine then treatment with base okay like hewnick's base that is a propyl ethylamine will facilitate the hydro molecular cyclization so now if you look at this compound we have made pentacyclic compound okay so now if you look at this compound they have made the pentacyclic compound so what is now required is to attach the indole and form the required six fombered ring before that you have a triple bond okay the triple bond in manzamine is a double bond so one can easily reduce the triple bond in the presence of double bond using Lindler catalyst condition okay Lindler's catalyst reduces the triple bond to cis double bond then you treat this ester with di-ball to get the primary alcohol and then oxidize with DMP to get corresponding aldehyde now you know you can recall why we need aldehyde was as I mentioned one of the key reactions in the total synthesis of manzamine is pigted sprinkler reaction is not it so you have for that you need aldehyde and then what you need for manzamine synthesis is this amine so you have indole you have CH2, CH2, NH2 okay so now with this if you do the pigted sprinkler reaction by treating with type loracetic acid what happen you will get the corresponding six fombered ring okay now what needs to be done in the total synthesis of manzamine now everything is there everything is there you have the core 5 rings then you also introduce the heterocycle but this particular ring is also aromatic this particular ring also aromatic that means you have to oxidize or you have to aromatize this compound so the best way to do is take this compound and then treat with DDQ okay so DDQ will aromatize that particular ring to get the pyridine ring okay what you need is a pyridine ring here so that is how the total synthesis of manzamine was complete so if you look at this total synthesis of manzamine reported by Winkler there are few key reactions one the 2 plus 2 cycloaddition second sequential retro managed followed by managed reaction sequential retro managed followed by managed reaction the retro managed actually opened the cyclobutane ring and the next managed reaction converted that into SX fombered ring then we had the spigtet spingler reaction to construct the pyridine ring from indole ethyl amine okay so thank you