 So good morning everyone, welcome back to the course on classics in total synthesis. As you know, we have been discussing about total synthesis of many alkaloids and today we will talk about total synthesis of one more alkaloid. In fact, we will talk about three total synthesis of this alkaloid by name Galanthamine. So this is the structure of Galanthamine and if you look at this structure, you can see some similarity with another famous alkaloid called morphine. Already we discussed total synthesis of morphine earlier, so it is easy to compare and then see how this new natural product that is Galanthamine differs from the earlier natural product morphine which we discussed. So both have the same aromatic ring with a hydroxyl group and you can also see the 5 membered ring that is also there in Galanthamine and next the cyclohexenol is also there in Galanthamine. Only difference is here instead of first three carbon atoms, the same allylic alcohol is there in the next three carbon atoms. So there is a CH2 here in Galanthamine and the next major difference is this particular bond is not there. This particular bond is not there and also if you look at the two bonds which are connecting the aromatic ring with nitrogen. So there are two CH2 CH2's between the aromatic carbon and NME in morphine whereas in the case of Galanthamine there is only one CH2. So these are the major differences between morphine and Galanthamine structure wise. So this Galanthamine was isolated from Amarylita C alkaloids and it showed potential clinical application in the treatment of Alzheimer disease due to its selective acetylcholine esterase inhibitor activity. So that is why many groups were interested in the total synthesis of Galanthamine and also as I said it is closely related to the structure of morphine. So morphine you know there are many total synthesis of morphine and because of that you know you can see a similar number of people who were interested in the total synthesis of Galanthamine. The first total synthesis was reported by Barton's group and he used a very interesting biomimetic oxidative phenol coupling as the key reaction to form a bond between the two aromatic rings okay and how he has done is very interesting way and for that you can see this is the bond I am just talking about this is the bond he was trying to make using a biomimetic approach involving phenolic oxidative phenolic coupling reaction. The first retro synthesis is the reduction of ketone. So once you have this enone one can reduce it selectively to get the Galanthamine. So that also leads to another alkaloid called Narviti okay then comes the key step. So the key step involves actually first you remove this benzyl protecting group selectively so you get the phenolic hydroxyl then under you know conditions where you can generate radical. So you generate radical here you generate radical here so they come all the way okay and then cyclise. So once it cyclises you get a enone double bond here and double bond here like this enone. So then this phenolic hydroxyl group will undergo intramolecular oxamical addition to give Narviti. So that was the idea that was that idea was based on biomimetic strategy and this can be obtained from so these two you know simple starting materials aldehyde and corresponding para hydroxy phenyl acetic acid. Now let us see how Barton's group synthesized Galanthamine starting from commercially available isopanil. So isovaniline is nothing but we have already discussed when we talked about morphine synthesis. So this is isovaniline okay you can benzylate the free hydroxyl group the phenolic hydroxyl group was benzylated under basic condition then in C2 you form an imine by treating with methyl amine okay. So this imine can be immediately reduced with potassium borohydrate to get the corresponding CH2 NHMU okay. The for the other fragment you start from the para hydroxy phenyl acetic acid para hydroxy phenyl acetic acid. Then you protect the phenolic hydroxyl group as benzyl ether then convert the acid into acid chloride okay. So these two fragments are you know very easily made from commercially available starting materials once you have acid chloride and then amine just combine these two you know under mild base you get the corresponding amide okay. This amide now it can be reduced with LIH to get the corresponding amine here comes the key step. Now the first step is you have to remove the protecting group. So that was done under hydrogenalysis condition to get the two phenolic hydroxyl groups okay. Once you have this phenolic hydroxyl groups then you treat with potassium ferricinide okay. So potassium ferricinide as I said first it forms the free radical so O radical and that goes all the way to here okay. So then it couples that way this is the first CC bond formation okay as a result of oxidative phenolic coupling. Once this is formed now you can see this ketone can enolize once it enolizes it becomes phenol that phenol can immediately undergo an oxa-mical addition okay. If that happens this is what you get that is a natural product Narvedin is not it. Now this Narvedin if you reduce it with LIH you get a mixture of galanthamine and as well as epi-galanthamine where this particular stereocenter is opposite. So this is how he completed E and his bottom and his group completed the total synthesis of racemic galanthamine and this was the first total synthesis and the starting materials are isovanaline and parahydroxy phenylacetic acid and the key reaction I already mentioned the key reaction was the oxidative phenolic coupling. Overall the whole sequence took about 7 steps but yield was not that high overall yield was only 0.53 percent nevertheless this involved a very very important oxidative phenolic coupling as the key reaction that actually paved way for many people to synthesize galanthamine via this method as well as improve the whole process. So the next method which I am going to talk about was reported from industry and how they synthesize this compound in multi gram quantity multi kilogram quantity using one of the key reaction is again the phenol oxidative phenolic coupling reaction. This was reported by Jody's and Kovalkers in 1999 and let us see how they have used oxidative phenolic coupling as well as other reactions as key reaction to make this. So their retrosynthetic analysis of galanthamine again goes through the same intermediate that is Narvedine then this was made from this aldehyde this N-formyl piperidine that can be easily reduced to give methyl group at the same time this bromine also can be reductively cleaved. This as I said can be obtained from this diol through oxidative phenolic coupling reaction which was already established by Barton's group. Then as you know this is very easy this intermediate is very easy to make that in the case of Barton's synthesis they started with acid chloride here they started with aldehyde and amine so you make skip base and then reduce it. So reductive amination will give this key intermediate which can undergo oxidative phenolic coupling. Now let us see how this synthesis was done. So this synthesis was done starting from commercially available dimethoxybenzoldehyde so this is available in large quantity one can start with 100 grams, 200 grams and here they started with the kilograms several kilograms scale then do the bromine and methanol later they also found better method was bromine and acetic acid to introduce a bromine at this carbon. Then selectively this methoxy group the methyl of that methoxy group was cleaved by treating with sulphuric acid actually this was required the introduction of bromine was required for the selective removal of this methyl group. So when you treat with sulphuric acid the demethylation takes place and you get the corresponding phenol. So now you treat with tyramine so tyramine is nothing but this particular amine is called tyramine so which is also commercially available you take the tyramine and treat with this aldehyde you form this imine and this imine can be in situ reduce with sodium borohydride to form the corresponding amine. So once you have this amine you have to protect that amine so the amine can be protected as N-formyl derivative so that is normally done by treating with ethyl formate and formic acid. Here comes the key reaction so that is the oxidative coupling of phenols so that reaction worked very well and you can see the oxidative coupling followed by oxamical addition gives this very advanced intermediate. Now what is required from here you should remove this bromine which is not required now then this N-formyl group should be converted into the methyl group then finally the alpha beta and saturated ketone should be reduced to corresponding allylic alcohol. So how it was done so to first to convert this N-formyl into N-methyl group you have to protect the ketone here so it was done by treating with propylene glycol and that gave this ketol. Next if you reduce with LAH LAH will convert this N-formyl into methyl group at the same time that also will remove the bromine which is attached to the aromatic reductive rumole of bromine as well as conversion of the N-formyl to N-methyl group takes place when you treat this compound with LH. So once that purpose is solved then the ketol you do not want the ketol so it can be removed using dilute HCl and THF to get the alpha beta unsaturated ketone so that is nothing but the Narvedin which is a natural product. Here comes very important reaction which normally it is done in industry in large scale that is called seeding of crystals what they do they took this resemic compound added ethanol and triethylamine and reflex so that it dissolve it is a crystal so they dissolve it in ethanol and triethylamine while reflexing then they slowly added seeds of minus Narvedin okay they added the chiral one the minus isomer which they have already so that they added seeding so normally when you want to crystallize you do the seeding so they use this seeding technique with the naturally occurring isomer so once you do that the resemic one you know it can be it is possible to convert the resemic one into the same isomer okay. So this is a very interesting process and they have done this on 70 kilo scale to get naturally occurring galladamine okay once they form this Narvedin in 70 kg scale they have to reduce only the alpha beta unsaturated ketone so that was done with L-selectride to get galladamine hydro bromide okay so after reduction they use HBr so that it is good to isolate the galladamine as its HBr salt okay. So overall if you look at this they started with simple commercially available starting material called 3, 4 dimethoxybenzolyride and like Barton's group they also use the oxidative phenol coupling as the key reaction and the most important one was they have used the seeding technique started with you know the chiral Narvedin so they added to the resemic Narvedin they prepared using their method and using this seeding technique so they could convert the resemic into the expected naturally occurring minus Narvedin. So overall this process was done in large quantity and it took about 9 steps and you can see the yield is 12.4% why I have written 6.7 to 19.1 because when they did on several batches the lowest one was 6.7 and then you know went up to 19.1. So then I will move to the third total synthesis which was reported in 2000 reported by Barry Prost here he has used asymmetric allylic alkylation as well as HEC reaction as the key reaction to synthesize galladamine. His total synthesis was the first total synthesis where the oxidative phenol coupling was not used before that most of the synthesis you know involved oxidative phenolic coupling to get galladamine and his synthesis came out of that and then started with the HEC reaction to construct that bond. So galladamine here their first retrosynthesis is you know you oxidize this allylic carbon to introduce the hydroxyl group and this can be obtained by you know from this enol ether and if you have enol ether and n-box both can be hydrolyzed. So enol ether hydrolysis will give aldehyde so if you remove n-box you will get n-h. So then this can undergo addictive amination to give these products and this enol ether as well as n-box can be obtained from this diol. See this though it looks you know almost same these two primary alcohols but one is benzylic alcohol so that can be selectively you know oxidized. So that way you can easily differentiate these two primary alcohols and this diol was obtained using HEC reaction. So you can see you have a double bond and you have promo-RL compound this can undergo HEC reaction and while doing that this double bond will migrate then followed by allylic oxidation you will get the calendar and this can be easily obtained from these two using asymmetric allylic alkylation. So that is the key step in baritrust total synthesis of gallantan. Now of course if you look at this this can be easily made from isovaniline and that can be made from the corresponding 1, 2, 3, 4, 5 pentane dial. Let us see how it was done started with isovaniline. So isovaniline is one of the commercially available starting materials used in many synthesis of alkaloids. So bromine and acetic acid. So introduce a bromine here. So now you the other fragment you start from this dioldehyde and in one part you treat with this phosphonate okay. One part you treat with phosphonate you get this allylic alcohol and also esters. So this is a very interesting mechanism try to write a mechanism for this and you will get an idea about how such allylic alcohol with an ester can be made in one step. So once you have that so you have to make you know you have to form the allylic carbonate. So that was done with trachloride. So now so this is ready for the palladium catalyzed reaction okay. So what you should do you have to combine these two and so once you have these two fragments the next step is the asymmetric allylic calculation. So for the asymmetric allylic calculation Trost group used they are well established procedure. So they use normally the PN ligands derived from diamines the chiral diamines either they use this chiral diamine or they use the diamine derived from cyclo 1 to diamino cyclohexene okay. So this is what they use and this reaction was well exploited by Trost group to get such allylic ethers and once you have this ether and you can see so you are set for the key heck reaction okay. So now let us see how this was converted into the key heck precursor. So once you have this then you reduce the ester as well as aldehyde in one part to get the corresponding diol. The diol was then protected as TBS ether by treating with TBS triphylate and 2,6-lutidine then comes the next key reaction. So that is the heck coupling. Now this asymmetric heck reaction was done with palladium acetate the phosphine ligand like di cyclohexyl phosphinoethane and in the presence of proton sponge. So this heck reaction took place and here you know during the heck reaction one of the TBDMS also got cleaved does not matter remove both with Tbuff you get the diol okay. As I said this benzylic alcohol can be selectively oxidized so that was done with manganese dioxide to get the aldehyde. Now you treat with methylamine hydrochloride and sodium cyanoborohydrate so that undergoes a reductive amination with methylamine to get CH2NHCH3. So you have an aldehyde and then treat with this so that will give directly the corresponding CH2NHCH3. Then you can protect this NH as Bocchamide and Desmartine pariodinane reagent oxidizes this primary alcohol to corresponding aldehyde. Now you do this enol ether vitic okay enol ether vitic to generate the corresponding enol ether. The next step as I said you have to remove the Bocch group as well as hydrolyze the enol ether to get aldehyde okay. That was done using triploracetic acid and that aldehyde as soon as the aldehyde is formed the NH which is formed in CH2 will attack the aldehyde and then you will get the aminol okay. So that aminol again you can use sodium cyanoborohydrate to reductively cleave that. So that will give you 3D oxycanol. This is how trust group prepared the 3D oxygalanthamine. If you look at this structure and compare it with galanthamine so what is missing is the extra oxygen here. What is missing is the extra oxygen here. So that can be easily done by epoxidation of this double bond and migration okay. So before that the tertiary amine was protected by treating with toluene sulfonic acid okay. Then dimethyl dioxidane treatment with dimethyl dioxidane gives a mixture of the epoxide plus opening of the epoxide by the tosyl group okay that the tosyl group is coming from here okay. Then this can be easily converted back to the epoxide if you treat with DBU okay. Once you have this epoxide you have to open the epoxide okay. So that was done by treating with diphenyl disiline in the presence of sodium borohydrate. So sodium borohydrate cleaves the selenium selenium bond okay. So that you get pH SH that opens up the epoxide to get the transidesomer okay. So normally once you introduce phenyl selenium compound what you can do? You can easily oxidize and then eliminate. So that was done using sodium parohydrate. So sodium parohydrate oxidizes this to selenoxide and the selenoxide picks up this hydrogen and removes phenyl selenic acid okay. So if you look at this you got allelic alcohol but that was not the one which he wanted. Basically the alcohol should be here and then double bond should be here. So that is calendar B is not it? So that transposition should take place. How the transposition takes place? So there is a reagent where you can use this type of the radium trioxide substituted compound that is known to rearrange such things. How does it do? See for example if you have like this system then it forms like this then these attacks followed by hydrolysis you will get the transposition okay. So that is how Galandamine synthesis was successfully accomplished by Trost group. Though it took a little bit longer steps the key steps involved are their own laboratories, palladium catalyzed, asymmetric allelic calculation and also intramolecular head coupling okay. And as I already mentioned so this is the first total synthesis where they have not used the oxidative phenolic coupling reaction. So the number of steps is reasonably high it is about 17 steps and overall yield is close to 1%. With this we will complete total synthesis of Galandamine and now we will move to few more natural products belonging to alkaloids before we move to total synthesis of steelites.