 So, good morning everyone and welcome back to the NPTEL lecture series on Classics in Total Synthesis Part 1. The last few lectures we have been talking about total synthesis of various alkaloids and today we will continue our discussion on the total synthesis of one more alkaloid called quinine. And the quinine has a very interesting history, the structure of quinine is this one and you can see here there is another epimer, this is called quinidine and these two alkaloids were found in the bark of synchronous and Remigia species. So, these were originally part of the high forest in anti mountains from Venezuela to Bolivia in South America, okay. These two alkaloids were found in the bark of synchronous and Remigia species and the South American natives they used to call this tree synchronous tree as cuina cuina, the bark of barks and as is the case with many natural products, South American natives they have been using this bark for the treatment of high fever and also much before the Spanish people arrived in South America as you know most of the South America was taken over by Spanish people in 16th and 17th, 16th, 17th and 18th century. Interestingly, the discovery of quinine got major focus when one of the Spanish Vizra s wife in Peru was diagnosed with malaria and she was cued by giving extracts of this synchronous tree bark, okay. So, this was a major impact of South America in the treatment of malaria in Europe. Once this news came to Europe what happened automatically the plantation of synchronous trees started in whole Europe particularly in Italy where the Rome was considered as the capital of malaria, okay. So many people were suffering from malaria and this was a big boon that the bark of synchronous tree could be used for the treatment of malaria. So, afterwards as you know people started using this extracts from the bark of synchronous tree for treatment of malaria not only in Rome, but also in other parts of Europe. However, it took 200 years to isolate the pure form of quinine, it took 200 years as I said only in 1820 two French researchers Pierre Palatier and Joseph Covento. So, they isolated the pure form of quinine and afterwards British people they wanted to plant this in their colonies. So, they succeeded in planting this in India and Sri Lanka and then Dutch people also succeeded the same by planting in Java and Indonesia. Incidentally, Java became the major hub for exporting quinine even today and quinine exhibits antipyretic, anti-malarial, analgesic and anti-inflammatory activities. And as I mentioned this is the major exporter of the cultivated bark is from Java and the cultivated bark of synchronous tree has 7 to 10 percent of this alkaloids, okay out of which 70 percent is quinine. That means it has about 5 percent quinine. If you take the bark and then cultivate it from that you can isolate 5 percent pure quinine which was exported. In fact, US imports about 70 tons of quinine every year that is a major import. The cost of quinine and quinidine differs little bit, 1 gram of quinine cost about 3 US dollars whereas 1 gram of quinidine cost about 7 US dollars. However, people were always interested in the chemical synthesis of quinine. In fact, if you look at 19th century and 20th century, one natural product which you got maximum attention next to strychnine is quinine. In 1950 French Society of Pharmacy, they announced a cash price of 4000 francs for the group which completes the chemical synthesis of quinine. However, it took much more time to come up with the synthesis of quinine in fact I would say it took about 100 more years to come up with the synthesis of quinine. If you look at the structure of quinine now you may feel that it is not structurally as complex as some of the natural products being isolated in recent years. However, one should also remember that when quinine was isolated there was no NMR, no IR, no mass spectrum. So, without all these techniques one has to prove the structure of quinine then go for the total synthesis. Obviously it must have been very, very tough job to assign the correct structure of quinine first. So, those days whenever a natural product is isolated and if they find that natural product is showing exceptional activity then they use lot of degradation studies to assign partial structures first. So, once they assign partial structures then they try to link, connect it to come up with the correct structure and always synthesis is considered as the final proof for confirming the structure of isolated natural products. So, in 1853 Pasteur actually reported that quinine is levorotativic, a year later Stucker establishes correct empirical formula then it took about 50 years in 1907 Paul Rabbe proposed the correct structure of quinine. During this period though the synthesis of quinine was not accomplished lot of efforts were focused on synthesis of pyridines and quinolines. So, much literature has gone into synthesis of pyridines and quinolines. So, there are lot of degradation studies known on quinine but in this particular slide I will talk about 4 or 5 reactions where quinine gave some important clue to assign the structure. When quinine was treated with acid, strong acid it rearranged I should say it opened this bond was cleaved to give a very interesting compound called quinotoxy. Then the same compound when it was oxidized it gave Miroquinine, Miroquinine if you look at this does not have the quinoline part. The same Miroquinine was observed when quinine was treated with dilute HCl for long time continuous exposure of quinine to dilute acid for long time converted quinine into Miroquinine. When quinine was treated with fused potassium hydroxide they could get methoxy quinoline that means this whole portion disappeared and when it was treated with nitric acid and chromic acid they could get this quinoline with a carboxylic acid here. Then they took quinine reflects with water. So they could get this methyl methoxy methyl quinoline. So these are the important degradation studies which actually gave an idea about what would be the correct structure of quinine. However, you know as you know you have to make this compound then only you can propose the correct structure. So Paul Rabi was the one who proposed the correct structure of quinine in 1907 and 11 years later he reported partial synthesis of quinine from quinotoxin. We will come to that little later and 25 years later another partial synthesis was reported by Vladimir Perlov but in 1944 was the year where Woodward reported the first formal total synthesis of quinine. This was a big news among all synthetic chemists as well as for the world. So the synthesis of quinine was considered as a major breakthrough in chemical synthesis and it took almost 70 years for the first enantioselective total synthesis of quinine which was reported by Gilbert Stock in 2001 and another 10 years it took for Jacobson to complete the total synthesis of quinine and quinidine using asymmetric catalytic reaction. However, there was some controversy about the total synthesis of quinine reported by Woodward. So there were few papers questioning the authenticity of the total synthesis of quinine reported by Woodward. So Robert Williams from Colorado University and his team they completely they just followed the same route reported by Paul Rabi and completed the total synthesis of quinine thus confirm that Woodward indeed completed the formal total synthesis of quinine. So I will come to that when I talk about total synthesis of quinine by Woodward. So the first partial synthesis of quinine as I said was reported by Paul Rabi and Kainler and how they reported was that degraded product quinotoxin they took and then treated with sodium hypopromide. So that gave that N-bromocompone okay this N-bromocompone on treatment with sodium ethoxide niethanol. So they could get this keto okay it is a you know just you generate anion and then attack here goes and here they got a mixture of two compounds okay based on you know you can see that this particular serial center they had two isomers. This upon treatment with aluminum powder okay this upon treatment with aluminum powder they could get about 18% of quinine which was recushed lice and then they could see you know complete you know all the data are matching with their natural quinine. So that is how in 1918 this one can call it as relay approach relay approach that means you know you start with a compound which was originally from the same natural product degraded compound then convert the same into the natural product which we already discussed when we talked about totals and substrignine by Woodward okay and this quinine not only quinine is used as anti-malarial drug afterwards there are many drugs which were which came to the market based on the quinine structure for lot of structural activity studies led to the synthesis of meffloquin, primacoin, chloracoin. Now all these drugs you can see quinoline part is same okay only this region is different okay. Then this is quinidine and this is amodioquin, this is chloracoin and this is called HCQ. So HCQ as you know it was given for the treatment of COVID recently and off late a completely new set of drugs are being used for the treatment of malaria based on this peroxy natural product called RT-mesinine. So RT-mesinine, dihydro-RT-mesinine, RT-meter, RT-sunate that is RT-mesin if you treat with succinic anhydride you get this RT-sunate then this can be given along with amodioquin for the treatment of malaria okay. Now let us see how Woodward reported the synthesis of quinine. So as I said in 19th century as well as early 20th century so people spend lot of time on the chemical synthesis of quinine and during the second world war so many soldiers died because of their non-availability of quinine okay. And that time the Polaroid company very well known and very famous company so they were using quinine for a different reason. So they were using quinine as a light sensitizer okay that is a photo company okay as a light sensitizer and Woodward has been consultant to this Polaroid company. So the Polaroid company asked him whether he can develop a good method for the synthesis of quinine so that is how the Polaroid company funded the project on the synthesis of quinine okay. So according to Woodward quinine can be made from the quinotoxin because the quinotoxin has been already converted into quinine by Paul Rebey and kindler. So he thought if he makes this then that should constitute what we call it as a formal synthesis of quinine. And this quinotoxin can be obtained from this as well as the corresponding ester okay via a Claisen reaction okay. So you can see you can generate anion and attack here and you will get a beta keto ester and then beta keto ester decarboxylation will give quinotoxin. So now he has to make these two starting materials or key intermediates. So the first one you can draw like this okay can be made from this hydroxy pyridine okay and this for the hydroxy pyridine he started from the metahydroxybenzaldehyde. So you take metahydroxybenzaldehyde and treat with this amine okay. So this first undergoes the imine formation on the aldehyde okay. Then it undergoes an intramolecular cyclization on treatment with acid to give hydroxy isochronally. Then you do a managed reaction. So you introduce the CH2 pyridyl group at alpha to the hydroxyl group then you treat with sodium ethoxide and methanol you get this and that was converted into the corresponding methyl hydroxy isochronally okay. This on treatment with barium salt okay. So basically you deprotonate the acidic phenolic proton then you do the hydrogenation okay. When you do the hydrogenation the hydrogenation takes place at the pyridine aromatic ring okay. Then you do the next step that is high pressure hydrogenation of the phenolic aromatic ring followed by oxidation of the hydroxyl group to corresponding ketone using chromium trioxide and acidic acid. So he got a mixture of these two where this is the major product because since you are using high pressure hydrogenation and when you use hydrogenation cis product should be the major product. So that was a major product. So once you have the major product and that also was crystalline. So once it is crystalline it is easy to isolate and proceed further. So he took the crystalline compound okay and treated with sodium ethoxide and this particular reagent. So this reagent is known to introduce NO group okay known to introduce nitroso group next to the ketone. So when he did that what he got was this compound. I will come to the mechanism of this little later. Basically the idea is to convert this into a double bond okay. You need a double bond binary group is not it? Basically that idea is to get or convert this oxime into double bond. So you can see that you know see this whole thing should be a vinyl group okay. Then you reduce oxime to NH2 okay you can do with LAH or you can also do it with hydrogenation condition. Now if you treat with excess methyl iodide what will happen? It will form the corresponding quaternary salt okay. It will form the corresponding quaternary salt and this on treatment with potassium ethoxide will undergo half bond elimination to give the less substituted alkene okay. So once you have that then you treat with potassium cyanate and before that I will just give the mechanism of the introduction of the nitroso group. So you have this and treat with sodium ethoxide and NO OET you get this compound is not it? So the mechanism is first it generates enolate okay. Then upon treatment with nitroso compound the enolate that is the carbonyl attacks the nitrogen of NO to give this particular intermediate. Now what will happen? This O minus will come back and eliminate the OET. So basically as I said it is a good region to introduce the NO group okay. However next when you use sodium ethoxide because sodium ethoxide is a base which you have to use to introduce the NO group. Now the sodium ethoxide will attack the carbonyl group and this bond will break okay. This bond will break and that will give you the corresponding oxide okay. So then let us see and with this key intermediate in hand the next is you have to make this carboxylic acid as ester because for the glycine reaction you need this ester. Then treat with ethanol and HCl. So ethanol and HCl not only converted the carboxylic acid into ester but also hydrolyzed this urea derivative to corresponding NH. Now on treatment with benzyl chloride okay it is like a Scotland Bobman reaction. You benzylate the secondary amine. Then you have this ester okay this is a known compound okay. Then you do the glycine reaction. So the glycine reaction gives the beta keto ester okay. This beta keto ester can be decarboxylated with 6 normal HCl. So if you reflex it for some time you get quinotoxin okay. So this is how Woodward completed the formal synthesis of quinine because he synthesized only quinotoxin and quinotoxin has been already converted into quinine by Robbie. So this constitutes a formal total synthesis of quinine however there was some controversy. So what happened Paul Robbie when he reported the synthesis of quinine from quinotoxin he did not publish the complete experimental details. Later he published several other papers related to the synthesis of many closely related synchronous alkaloids but he never published the full experimental details of quinotoxin to quinine. So Gilbert Stark who completed the first asymmetric synthesis of quinine he had his own reservation. When this full experimental details were not known for the conversion of quinotoxin to quinine then the total synthesis of quinine reported by Woodward may not be valid is not it. So he has made after all he has made only quinotoxin he has not made quinine. He thought that since quinotoxin has been already converted into quinine by Paul Robbie he did not carry out the conversion of quinotoxin to quinine. So there were many papers and finally Robert Williams and his student from Colorado University they took upon this project repeated the same reactions reported by Paul Robbie in his paper on the conversion of quinotoxin to quinine and they could indeed get quinine in 5% yield. So that confirms the formal total synthesis of Woodward is valid. So what did William do? So William first they made the quinotoxin from quinine so they made about 30 grams of this reasonably large scale from quinine then they treated with sodium bromide followed by treatment with sodium ethoxide. These are the same conditions reported by Paul Robbie and they got the mixture of these 2 ketones. So one is quinidinome other one is quinineome. So the reduction of quinidinome will give quinine the reduction of quinidinome will give quinidin. According to Paul Robbie they used aluminium powder. So aluminium powder and then sodium ethoxide ethanol they could isolate 5% yield of quinine. So they felt that whatever aluminium powder Paul Robbie would have used may be different that is the reason why they were getting 18% yield and in 2010 our Williams they might have got the highest purity aluminium powder sometimes impurity plays a role. So they suggested that impurities present in aluminium powder used by Paul Robbie might have played a role for getting higher yield of quinine from quinineome. So what is important was this actually confirmed that conversion of quinotoxin to quinine as reported by Paul Robbie could be repeated and so the formal synthesis of quinine by Woodward is valid. So now I will quickly talk about Starks first asymmetric total synthesis of quinine and until then there was no report on asymmetric synthesis though there were many resemic synthesis known and the first key step was the SN2 substitution then this can be obtained by the reduction of the corresponding imine. This imine can be obtained from the ketone and azide. So if you do a starting a reaction the N3 you can reduce to NH2 that will automatically form a imine by reacting with the ketone and this can be redrawn like this and this can be obtained by in 2 steps by treating this combo with butylethium and adding to the aldehyde you will get an alcohol that alcohol upon oxidation you will get the ketone. So basically the major focus of this work should be on preparing this compound. So he started with this known compound and with a established chiral center one chiral center is already there. So and then he opened this 5 membered lactone with the thymethyloaluminium and diethylamine and protected the primary alcohol as Tbaseeth. Then you generate the enolate here. So by treating with LDA you generate the enolate and conge with this iodide the 2 carbon alkylation takes place this upon treatment with PPTS. So the Tbase group can be selectively cleaved once it is cleaved then it cyclizes to give the 5 membered lactone. Basically if you see what you have done is you have attached a 2 carbon unit at alpha position of this lactone okay. Then it is an ester it is a cyclic ester lactone. If you reduce with di-ball you will convert this lactone into lactol this upon enolether vitique you will get the corresponding enolether. This upon treatment with triphenylposphine dead and this triphenylposphoryl acide basically mid-snow reaction converts this OH into acide followed by hydrolysis of enolether you get the aldehyde okay. Once you have this aldehyde so this is a known compound treat with LDA. So you generate the corresponding lithium derivative add to this aldehyde you get the corresponding alcohol. So now swenoxidation will give the ketone and treatment with triphenylposphine. So triphenylposphine will form immunoposphoryl that immunoposphoryl intramolecally undergo azobitic like reaction to get the corresponding 6 membered cyclic imine. Once you have this then reduction with sodium borohydride sodium borohydride will reduce the imine to give the corresponding substituted piperdene derivative okay. So what you need to be done this TBDPS group should be removed converted into a leaving group so that the cyclization can take place. So the TBDPS was removed using HF in acetonitrile and followed by treatment with mesyl chloride the SN2 displacement take took place to give the core structure of quinine. So what is left is introduction of the hydroxyl group. So that was done by treating with LDA and in fact it is known in the literature where they have used potassium tercibutoxide followed by oxygen treatment and removal of extra hydrogen of the peroxide with dimethyl sulfide gives quinine okay. Overall if you look at this whole synthesis reported by star it involved 13 longest linear sequence with an overall yield of 18 percent. 18 percent overall yield for 13 step is really a very good very good synthesis and also this is the first asymmetric synthesis of such a complex natural product known in the literature. Thank you.