 So, good morning everyone and welcome back to the NPTEL lecture on classics in total synthesis part 1. So, let us continue our discussion on total synthesis of natural products and today we will talk about a very interesting but small alkaloid called epibattery. As you can see here it is a bicyclic compound having a substituted pyridine attached to the asobicyclic compound. This compound was isolated from a poisonous frog in equator ok. And earlier we all know that strychnine was the most poisonous compound isolated in nature but epibattery is more poisonous than strychnine and also it shows analgesic activity at 1 200 dose of morphine as a morphine has been used as a analgesic for long time and this is much more active than morphine. And from synthetic point of view when you look at this molecule it has 7 asobicyclo 221 heptane system ok. So, this is the 7 asobicyclo 221 heptane system with a chloropyridine ok with a chloropyridine attached at the side side ok. So obviously when this molecule was isolated because of its biological activity people are interested in total synthesis of this particular natural product and in this lecture we will talk about 3 different strategies to synthesize this molecule. The first one which we will talk is about Reagan's total synthesis and what he did was he used 2 key reactions one Diels-Aul reaction, second a reductive palladium catalyzed head type coupling reaction to synthesize AP palladium ok and this synthesis is highly stereo selective and they could get only the x-y somewhere in the end. Of course this is a racemic synthesis and not a chiral one. So from the retrospective point of view as you can see this NH should be protected first. Which was protected as a carbomede so that was the first retrosynthesis where you add a functional group in the form of a protecting group. Then this can be obtained by a key reaction which I mentioned that reductive head coupling. So that means you have a double bond here and a palladium catalyzed reductive head coupling on this should give you are the key intermediate which can be converted into AP palladium in one step. Now the starting materials the ASSA bicycle 2-2-1 system is prepared from pyrrole. So the pyrrole if you treat with chloromethyl format you get the diene which on treatment with tosyl acetylene here the triple bond acts as the dienophile. You heat these two and it undergoes a Tilsol reaction to form this ASSA bicycle 2-2-1 system. So now it has two double bonds one is electron deficient that is on the right side and other one is electron rich. So selectively one can reduce the electron rich double bond under standard hydrogenation condition. Now you do not need this Tilsol group is not it? You do not need this Tilsol group. So this Tilsol group can be easily cleaved under sodium amalgam condition. Still you need the double bond intact because that is required for the reductive head coupling reaction. So without touching the double bond the Tilsol group was reductively removed under sodium amalgam condition. So that way the Bicyclo 2-2-1 ASSA bicycle system was prepared in 3 steps from substituted pyrrole. Next starting material is the pyridine that is 2 chloro 4 iodide pyridine. So for that we started with 2 amino pyridine as you know 2 amino pyridine is very easy to make. If you have pyridine using Sitchibab in reaction you can easily get 2 amino pyridine in large quantity. So this upon treatment with iodine and acetic acid you can introduce the iodine at 3 position with respect to the nitrogen in the pyridine. Then you can do diacetation and Sanmay reaction to convert this amino group, convert the amino group at 2 position to chlorine. So now this fragment is also ready already we have prepared the ASSA bicycle 2-2-1 system what we need to do is only the head coupling reaction. So the head coupling that is reductive head coupling worked very well. So for reductive head coupling as you know you have to use the formic acid. So that is the proton source and that reaction worked very well and it gave exclusively the XO isomer as you know in the natural product this 2 chloropyridine is in XO position. So that is one key transformation which is very much required for making the XO isomer. Then what is left is just to remove the protecting group. The protecting group was easily removed by treating with HBr and acetic acid to get the natural product and this natural product be battered in was synthesized in resemic form. If you look at this synthesis this synthesis was reported in 1993 and there are 2 key reactions. One is intermolecular Diels-Aub reaction and then second one is the palladium catalyzed reductive head coupling reaction okay and this reaction this whole synthesis is convergent because you prepared 2 different starting materials and then coupled and highly stereo selective where you have seen the formation of only XO isomer during the head coupling and overall if you look at the yield it is 25.9% in 2 steps. This is significantly very high any total synthesis which gives 25.9 overall yield should be considered as you know excellent synthesis okay. So now we will move to the second total synthesis of epipatterdine reported by Olivo. Here what is important was a very clever use of biocatalyst to introduce a hydroxyl group okay. So nowadays there are many CH activation method to introduce hydroxyl group but those days a bio catalytic approach to introduce a hydroxyl group and followed by attack of 2 chloropyridine was the key step okay. So that was one of the key reactions in the synthesis of epipatterdine. So from retrosynthetic point of view it was divided into 2 fragments again it is a convergent strategy. So this is the asopbicycler 2 to 1 heptonone system and this is the lithiospecies okay. So obviously addition of this lithium to this 2 asopbicycler 2 to 1 system will give the alcohol then if you do dehydration followed by hydrogenation you will get epipatterdine. So now this ketone was obtained from alcohol by simple oxidation and the key step as I said is the bio catalytic hydroxylation here. If you look at this system this is asopbicycler 2 to 1 heptane system okay. Introducing a hydroxyl group by simple chemical transformation is not that easy whereas here olivo cleverly used bio catalytic method to introduce the hydroxyl group. So the starting material was you know well known hydroxyaminocyclohexane and they are 1, 4 related okay and a modified Scottenbaum reaction one can easily you know benzoylate the amino group okay. After benzoylation then you need to convert this hydroxyl group into your leaving group. So it was mesylated to get the corresponding mesylate then intramolecular acento displacement reaction was done with potassium tertiary butoxide to get the bicyclo 2 to 1 system okay. Here comes the key bio catalytic reaction and this was responsible for the introduction of hydroxyl group. Here the hydroxyl group as you can see you got was endo alcohol okay. Now once you introduce the hydroxyl group what you need to do is you have to add the lithiocluoropyridine. So for that simple oxidation with the tip up that is tetra n-propyl ammonium perruthenate as a catalyst and the co-oxidant is n-methylmorphylene n-oxide gave the ketone then you take this iodocluoropyridine and treat with butyl lithium to give a corresponding tertiary alcohol. So once you have the tertiary alcohol there are 2 possibilities one you can do the dehydration okay you can do the dehydration and then hydrogenate or you can do the deoxygenation okay you can do the deoxygenation. So olivore opted for the second option that is the deoxygenation so this is derived from oxalic acid oxalic acid of ester okay. So once you got this ester then tributyl thin hydrate mediated deoxygenation work very well so overall from here you can see you could deoxygenate using this 2 step process but unfortunately during this 2 step process you got maximum of endo isomer okay but what you need is x-y isomer is the natural point so you took this mixture and then treated with potassium tertiary butanol in tertiary butanol so you could get exclusively the x-y isomer. Now once you have this x-y isomer what you need to do is to remove this benzyl group so that was very simple straight forward you it is an amide so you simply treat with x-y isomer HCl and heat it at 100 degrees so the benzyl group was cleaved and it gave the natural product again this natural product if the synthesis led to the resemic epipattery and here if you look at this synthesis this synthesis was done in 10 steps and from commercially available trans 4-amino cyclohexanol and the overall yield of this total synthesis is about 8% still 8% is quite good considering the starting materials are commercially available and they are not that expensive. The third synthesis is about steve-lase a steve-lay what he has used in this total synthesis was mostly polymer supported reagents in the whole synthetic scheme so that is something which is unique except a few reactions most of the reactions you use polymer supported reagents why polymer supported reagents? So when you use polymer supported reagents the purification becomes very simple okay so then one polymer supported reagent to another polymer supported reagent one can do it now people talk about flow chemistry this was pre-flow chemistry time where polymer supported reagents played a very important role in synthesis of natural products and this is one classical example how polymer supported reagents were used in the synthesis epipattery and the main advantage is you do not have to purify through chromatography okay just to do the reaction filter it remove the solvent go to the next step just to filter and then remove the solvent go to the next step. So it is very easy if you use polymer supported reagent and because of this purification less synthetic route polymer supported reagents are well known. So this total synthesis was based on again the intramolecular SN2 reaction as the key step. You can see here so this is a nucleophile and this is the leaving group so intramolecular SN2 reaction will give the bicyclo 2 to 1 system okay. Now the difference between this SN2 reaction based total synthesis epipattery and olivos total synthesis is here Steve Lee used a Diels-Ald reaction between a diene and a diene of oil that way he constructed this cyclohexane ring. Let us see how we did that okay first he started with the 2 chloro nicotinic acid chloride and as you can see here this is the polymer support. The acid chloride was reduced with this polymer supported trimethyl ammonium borohydride region okay so that reduce the acid chloride to primary alcohol okay. So once this reaction was done it is very easy to purify then oxidize again here he used another polymer supported reagent and if you look at this this is polymer supported perruthenate reagent okay we know what is tip up tetra in propyl ammonium perruthenate. So here so another ruthenate reagent which is attached to polymer okay so one can easily oxidize the primary alcohol to aldehyde using this reagent. Now you carry out a henry reaction with nitromethane so nitro you take nitromethane and use this base and you do the henry reaction to get the nitro aldol products. Now you need a double bond that means you have to dehydrate this nitro aldol and for that first you treat with trifluoroacetic anhydride to make it as a trifluoroacetate because that is a good leaving group okay. So then you treat with base okay again you could have treated with normal trimethylamine but here you use a polymer substituted tertiumene which gives the required dienophile that is alpha beta unsaturated system here it is alpha beta unsaturated nitro cop okay you can call it as nitro alkene once you have this nitro alkene then you do a Diels-All reaction with the diene having an electron donating group that is enol TBDMS and you do this Diels-All reaction in a CL tube you get this tri substituted cyclohexene okay. So here the nitro group and this RL are trans to each other and you have enol TBDMS that can be easily hydrolyzed to get the ketone. To proceed further as you know this ketone should be reduced to get alcohol then that alcohol should be made as good leaving group then followed by reduction of the nitro group. So these are 3 steps before you do the intramolecular acento substitution to get 2 azobicyclo 2 to 1 heptane system okay. You take this ketone and again polymer substituted borohydrate reagent. So this is the same reagent which we have seen used for reduction of acid chloride to primary alcohol okay in the first step the same reagent was used to reduce acid chloride to corresponding primary alcohol. So here again this reagent was used to reduce the ketone to corresponding alcohol and this is again very stereo selective and you get a maximum only this syn alcohol. Now the alcohol should be made as good leaving group that means you have to treat with either mesyl chloride or tosyl chloride or you have to convert into halide. So here mesyl chloride was used and instead of DMAP that is dimethyl amino pyridine you can see a polymer substituted dimethyl amino pyridine was used as a base and the hydroxyl was mesylated. Again the nitro group, nitro group was reduced with the borohydrate reagent here in addition they also used nickel chloride okay. So to selectively reduce the nitro group to get the corresponding amino compound. So once you have this amino compound the next step is to carry out an intramolecular acento reaction. This was done with this sterically crowded base and that worked very well. Then you have to use this polymer supported primary amine to remove all acidic byproducts which are formed during this reaction okay. So that you do not need purification why the second polymer supported primary amine was used that take care of the acidic impurities formed in this reaction okay. So that you will get only the epibatterin but unfortunately when they did this reaction they got endo epibatterin okay but what we want was XO epibatterin. So it was easy so again it was treated with potassium tertiary butoxide under microwave condition. So the ephemerization took place to the XO and once it was formed again it should be treated with polymer supported sulfonic acid to take care of some basic impurities and followed by treatment with ammonia methanol it gave exclusively the natural product which is XO epibatterin. And if you look at this whole synthetic sequence it involved 10 steps and started with you know known pyridine nicotinic acid chloride and the key step in this whole synthesis was intermolecular Dielsall reaction, intermolecular Dielsall reaction between nitroalkene and two substituted butadiene. Overall the synthesis was achieved with a yield of 32.45% and this is really significant considering that 10 steps synthesis with 32.45% yield is really commendable. More importantly since this is the whole sequence involved many polymer supported reagent the number of chromatography purification was very, very, very less. So with this I will stop here. So about the racemic total synthesis of epibatterin and now we will move to two asymmetric total synthesis of epibatterin in the next few minutes. The first asymmetric total synthesis of epibatterin was reported by barium truss group in 1996. So what he has used was he has used a palladium catalyst cross coupling as well as de-symmetrization as the key reactions to synthesize epibatterin. Let us see how he has done the retrosynthesis and how he finally accomplished the total synthesis of epibatterin. So first retrosynthesis was it is a very simple one that is you know you do in a intramolecular S2 reaction. So you make this hydroxyl as a good leaving group followed by intramolecular S2 reaction and remove the bar group will give the corresponding epibatterin in optically pure form. And this can be obtained from this enone by reducing the double bond first and followed by reducing the ketone to corresponding alcohol. And this is where the first key step comes where he has used a still coupling between this alfabromo substituted cyclohexenone with the corresponding stand-in from the pyridine unit. And this alfabromo substituted cyclohexenone was made from this azide as you know azide can be easily reduced and then protected as NH barc. The next key reaction was the de-symmetrization of this particular compound using a chiral palladium catalyst. So this truss group has been using in the synthesis of many other natural products. So they just extended that methodology to synthesize epibatterin in optically pure form. The starting material for this reaction that is this dibenzoate was prepared from cyclohexadiene using a photochemical 4 plus 2 cycloaddition reaction with oxygen followed by treatment with thiorea cleaves the OO bond to get this cis diol with a double bond. And both hydroxyl groups were benzoylated using benzyl chloride and base. Then he did this de-symmetrization with this palladium catalyst and this ligand followed by attacking with nucleophile TMS azide to introduce the azide as well as the chirality. So once we have the azide as you know azide can be easily hydrolyzed using starting a reaction condition and followed by protection as Bok derivative by treating with Bok and hydrate. Then he has to hydrolyze the benzoate and followed by oxidation gave this force substituted cyclohexenol and what is required is to introduce a bromine at alpha position which is required for the stelaic coupling. So that was done using bromine and triethylamine and this was followed by stelaic coupling with this TANL derivative gave the key precursor. So what is left is to stereo selectively reduce this double bond as well as reduce the ketone. So these two are very critical the double bond which is in conjugation with the ketone so it can be easily reduced with K-selectride and then he got a mixture at this carbon. So treatment with catalytic amount of DBU so epimerized to get only one isomer. Now reduction of this ketone with sodium borohydride gave this alcohol okay. So once you have this alcohol you convert this alcohol into a good living group by treating with mescal chloride this mescalate upon treatment with trifluoroacetic acid first the bark was removed to get the amino alcohol once you have this amino alcohol then triflex with astronitrile it undergoes spontaneous intramolecular acetyl reaction providing minus epibatidine directly. So TAST could accomplish this first asymmetric total synthesis using two key reactions one is paradigm catalyst cross coupling reaction that is stelaic coupling second is the paradigm catalyst de-symmetrization overall it took about 10 steps and the overall yield was about 13 percent the second asymmetric total synthesis which we will discuss was reported by Kibayashi's group in 1998. So what he has used was an asymmetric heterodeal soil reaction as the key reaction to construct a bicycler 2-2-2 system and from there you could go on to make minus epibatidine. So his retro synthesis was if you have this bicycler 2-2-2 system then one can selectively cleave this NO bond ok. Once you cleave this NO bond then followed by converting that OH into a good leaving group then an intramolecular acetyl reaction should give the epibatidine and this can be obtained by reduction of this double bond ok. And obviously once you look at this compound it is a cyclohexene and that can be obtained from this dienophile as well as this diene ok. So that is the idea and let us see how he has done this total synthesis. So he started with this diene and having a grignard at this carbon this grignard was then coupled with this iodide ok. It is like commada coupling to get the substituted diene which is required for the intermolecular dienophile reaction. Then the dienophile the hetrodienophile was in situ generated from this hydroxyl amine ok substituted hydroxyl amine ok. This upon oxidation with oxalyl chloride DMSO that is nothing but swan condition. You oxidize this NHOH to N double bond O ok. Once you have this N double bond O that can undergo intermolecular dienophile reaction to give these two regioisomers in 3 is to 2 ratio ok. So this is racemic one. So once he was successful in getting this bicyclic adducts then he wanted to use a chiral auxiliary to see the asymmetric induction. So the chiral auxiliary which he used was derived from polygone. So 9, 2 naphthyl menthol was used as a chiral auxiliary you can see that. So this is the chiral auxiliary 9, 2 naphthyl menthol ok is the chiral auxiliary. This upon treatment with pass gene followed by treatment with hydroxyl amine you get this product and this upon treatment under swan conditions will generate N double bond O which in C2 will undergo Diels-Aubre reaction with this diene to give 3 compounds ok. One you can see the regiochemistry of this chloropyridine is on the unwanted side. Then the required one where your chloropyridine is on the right side but he got about 42% yield of the required one he also got 5% yield of the other side chiral auxiliary you can see where the chiral auxiliary is. So these are the 3 compounds he got and the major one is the required one. So he took the major isomer proceeded further first he reduced the double bond under hydrogenation condition so that is how he could establish the stereochemistry at this carbon. Next is to cleave the NO bond so there are many methods to cleave the NO bond. So he used molybdenum hexacarbonyl to cleave the NO bond but prior to that he has to cleave or remove the chiral auxiliary ok. So the chiral auxiliary was removed using lithium amine borane and when you remove the chiral auxiliary this carbonyl group also comes out and that free NH was protected as N bond ok. So now the NO bond was cleaved using molybdenum hexacarbonyl to get the corresponding amino alcohol where the amine was protected as bond derivative. Now for the intramolecular acento reaction to take place first of all this stereocenter should get inverted ok the chlorine should be alpha or bromine whatever the leaving group should be alpha then only intramolecular acento reaction will take place. So what he did he converted that alcohol into bromide by treating with triphenol phosphine and CBR4 so which underwent an acento reaction to form bromide at this position ok. Then trifluoracetic acid removed the bog to get the amine alcohol as you know once you have this amine and then bromide you can reflex with acetonitrile or chloroform and which automatically undergoes intramolecular acento reaction to give epipatteria. So to summarize Kibayashi has reported an asymmetric total synthesis involving an intermolecular asymmetric head hold yield cell reaction as the key step. Then the number of steps involved in this total synthesis was 9 and the yield of this whole scheme was about 3.6 percent ok. So with this we completed the total synthesis of epibatterine and now we will move to total synthesis of 2 more alkaloids before we look into total synthesis of steroids ok. Thank you.