 So, good morning everyone and welcome back to the lectures on Classics in Total Synthesis. We have been discussing total synthesis of many natural products and the last few lectures we are focusing on synthesis of quite a few alkaloids. So today and tomorrow we will talk about an alkaloid which is also very well known and famous alkaloid which is used as a painkiller is none other than morphine. So, morphine is an interesting alkaloid in fact in 1806 that was a year where the morphine was isolated in pure form, it was isolated in pure form from the puppy seeds. So, that was the beginning of isolation of pure natural products from the natural source. So, it was done by a young pharmacist called Fredridge Satunar and this is the structure of morphine. So, if you look at this molecule it is a pentacyclic structure as an aromatic ring having a phenol and 3 6-cell bud rings 1, 2, 3 and a dihydrofuran ring and you can see 1 chiral center 2, 3, 4, 5. There are 5 contiguous chiral centers in this molecule and since then there are many natural products which were isolated in pure form from the naturally occurring sources. And as you can see the natural product is quite complicated as structurally. So, it took quite some time to elicit its correct structure in fact about 100 years ago Sir Robert Robinson a well known synthetic organic chemist he proposed the correct structure of morphine and it took another 27 years to confirm the structure of morphine as you know those days any new structure was isolated and then the correct structure was proposed by someone but still the final proof came in the form of only total synthesis. So, the first total synthesis of this molecule was reported by Gates in 1952 and 3 years later X-ray also confirmed its structure. So, there are several total synthesis of this molecule considering its complexity it is understandable many synthetic groups jumped on the total synthesis of this molecule more than 30 total and formal synthesis are there in the literature. However, this molecule if it has to be used in you know treatment particularly pain related treatment still people use only the natural sources because it can be obtained in huge quantity from natural sources. So, that is why that is a major supplier for morphine and its analogs. And since morphine is well known pain reliever people started making several analogs one of the infamous analogs is nothing but diacetylmorphine which has a unique name called heroine because of this particular infamous molecule which can be easily obtained by simple oscillation of morphine with acetic anhydride. Acetic anhydride is a controlled substance okay. So, we all know so when you have to use acetic anhydride you have to follow certain guidelines and then you cannot get more amount of acetic anhydride for academic purpose. And simple reason is the conversion of morphine to heroine can be done in single step using acetic anhydride. And there are several analogs some are natural see for example if one of the hydroxyl that is the phenolic hydroxyl group if it is methylated then this is called codeine. So this is also naturally occurring and if both the hydroxyl groups are methylated then that natural product is called pibane. And if the phenolic hydroxyl group is free and the other hydroxyl group that is you have a diene in fact it is you oxidize this the alphabet the allylic alcohol to alphabet answer the ketone then you form the dienol ether so that is called pibane okay. So these are all naturally occurring but there are many semi-synthetic molecules. So one is hydro morphine that means you reduce the double bond and also oxidize the alcohol so that is called hydro morphine and if this hydrogen is replaced by hydroxyl group then it is called oxymorphone okay and this molecule is called hydrocodone where the hydro morphine is just methylated the phenolic hydroxyl group is methylated. And here too the oxymorphone to oxycodone what you have done is the phenolic hydroxyl group is methylated these are all semi-synthetic morphine derivative and instead of n-methyl group okay. So you morphine n is methylated and it is a methyl group if you have allyl group and here if you have a hydroxyl group then this is called naloxo okay and this is diacetyl morphine already I told you its common name that is heroin and if you do not have carbonyl group if you do not have that oxygen if you do not have the double bond and if the phenolic hydroxyl group is acetylated so this is called disomorphine these are all for just information and you do not have to worry too much so why I am saying all this and then showing all these structures is because morphine derivatives are used as analgesic so there are still lot of work going on in making more and more analogs of morphine. So this particular molecule if you look at this is made from tibane so they take tibane and then do a Diels-All reaction okay they do a Diels-All reaction with methyl vinyl ketone and followed by addition of tertiary butyl lithium you introduce this and here instead of methyl group you have cyclopropyl methyl group okay so this is also a very interesting analog of morphine. So now let us see how this molecule was synthesized and reported for the first time as I mentioned gates was the first one to report the total synthesis of morphine and that was in 1952. So you can imagine it took almost 150 years since its isolation and 27 years after its structure was proposed by Robert Robinson to complete the first total synthesis. So this is a structure of morphine so if you do a 180 degree rotation okay you get this structure okay and that can be written like this because this is also important when you think about any molecule in 3 dimensional way so the confirmation is very important. So I leave it for few seconds so that you know you can see how this molecule can be redrawn in this form okay and as I mentioned morphine has 5 contiguous stereocenters okay and the first synthesis was reported by gates and they took about 27 steps to complete this total synthesis. So from the retrosynthetic point of view the first disconnection was the methyl group here if you can demethylate then you will get the morphine and this is also a natural product as I mentioned it is codeine and this codeine can be obtained from this bromocodino. So basically you have to debrominate and then do the reduction of the keto so both can be done in one step if we use LAH so debromination can be done and the keto group can be reduced and this can be obtained from this ketone and if you look at this this is one of the key steps in the synthesis of morphine what they have done they have to introduce a double bond here and they have to form a CO bond at the same time they also have to introduce a bromine okay all these were done in one step I will come to that it is a beautiful step and how it was done I will discuss little later and this compound can be made from this alkene okay so you do either hydroboration oxidation but that time hydroboration oxidation was not known it is just addition of water okay it is a tradition of water introduced the hydroxyl group and when you see this molecule you can see a cyclohexene and you all know the cyclohexene can be obtained by a Dielsall reaction so the precursor for this compound should be the corresponding alkene and the diene okay before that this methylation and reduction of this will lead to the required compound basically what is important is the cyclohexene how you introduce the cyclohexene is introduced using the Dielsall reaction between this dienophile you can see this dienophile and simple butadiene okay then this CH2Cn can be reductively cyclized with this ketone okay we will discuss more in details when we talk about the synthesis so that leads to this particular orthoquinones okay that can be obtained from either the corresponding aminophenol or dihydroxy compound and which in turn can be obtained from the dihydroxy naphthalene so this dihydroxy naphthalene is the starting material which also is a symmetric compound okay now let us see how gates as synthesize this morphine starting from dihydroxy naphthalene so he took this dihydroxy compound as I said this is symmetrical compound so one can selectively protect one of the phenolic hydroxyl group as benzoate then followed by you know nitrosion so treatment with sodium nitrite and acetic acid one can introduce a NO group at this carbon okay so that is what he did and that NO group can be reduced to get the corresponding NH2 so once you have that then you oxidize with ferric chloride so what you get is the orthoquinone and this orthoquinone now can be reduced to get the corresponding dihydroxy compound so this is how the dihydroxy was introduced which as you know one of them should be protected methyl group the other one should cyclize here okay so once you have this dihydroxy compound methylate both of them okay the standard method is use a base mild base like potassium carbonate and dimethyl sulfate to introduce the methyl group. So the next step you have to remove this benzoate so you can remove it with potassium hydroxide and methanol and introduce the NO group here okay so the same thing sodium nitrite acetic acid you introduce the NO and again reduce it to get the corresponding NH2 and oxidize this under the same condition which I had discussed where is ferric chloride you get the corresponding quinone so if you look at this this is a Michael acceptor okay this is a Michael acceptor so that means it can undergo a 1, 4 addition so the next step has been the addition of anion generated from this cyanoythyl ester okay so that will undergo 1, 4 addition followed by introduction of the double bond so that can be done with potassium ferricionate so in this step 1, 4 addition takes place followed by introduction of the double bond you get this compound okay. Then you can do the decarboxylation you do not need this ester once that it served its purpose you have to remove it so that ester could be removed by potassium hydroxide methanol so you get only the CH2CN the CH2CN only is intact okay. So what is the next step you have the digenophile and now you should do the intermolecular dielsal reaction with butadiene okay so that worked well and the cyclohexene is nicely introduced the next step should be to reductive coupling reaction or reductive cyclization the cyanide should be hydrolyzed to CONH2 and the CONH2 to cyclize with one of the ketones of the orthoquinone. So that is you know safely done with hydrogen and this copper chromium reagent so that reduce the cyanide to CONH2 and then cyclized and this was the final product. So now you have introduced 4 rings one aromatic and 3 6 membered rings so what should be done to complete the total synthesis one one has to methylate here because N-methyl is required for the synthesis of morphine then you have to cyclize or the oxygen should form a bond with this and also the double bond should be isomerized at the same time you also should introduce an oxygen at this corner okay. So these are the few things to do to complete the total synthesis of morphine. So the easiest one and obviously the logically the first one to do is to methylate here okay but before doing methylation you do not need this ketone is not it. If you look at the structure of morphine that carbonyl group is not required. So you remove the carbonyl group using modified version of Wolf-Kristener reduction okay. So now you remove the ketone then obviously the next step is the methylation of this lactum. So methylation was done. So the next step is the removal of the carbonyl group. So that can be easily done by reducing with LAH to get the corresponding amine then dilute sulphuric acid treatment is nothing but addition of water. So the addition of water takes place across a double bond and you get this regioisomer as a major product. So once you have that now what you need to do between these two methoxy groups this particular methoxy group should be demethylate so that you can get the corresponding hydroxyl group then you try to cyclise here. So this was done almost under the same conditions as Wolf-Kristener reduction okay. So when they carried out the Wolf-Kristener reduction you know as you can see in the earlier slide they also I got some demethylated products. So that is why they tried to repeat the same thing after other functional group transformations were done. So now they could get the corresponding phenol. Then you oxidise the secondary alcohol. So this was done using Woodward opener oxidation condition to get this ketone. See until here this was a resimic synthesis until here it was a resimic synthesis and at this point they resolved with dibenzyl tartaric acid to get the naturally occurring skeleton okay. So the dibenzyl tartaric acid was used as a resolving agent. Then comes the key step. See in this one step many reactions were done. What is that? You add bromine and 2, 4 di nitro phenyl hydrazine and acetic acid. Look at the product how many reactions were done in one step okay. One this bromine was introduced. Just obviously if you have a phenol and if you treat with bromine bromination will take place fine. Then what happened? You introduce a bromine here. You introduce a bromine here. So basically 3 bromines were introduced okay. That is the first step. Second step this one cyclised. This one cyclised to form the dihydrofurendering and third one the elimination of HBr. Elimination of HBr to introduce this double bond and the fourth step the ketone and 2, 4 di nitro benzylamine it form an imine okay. So 4 steps took place in this one step. 4 reactions took place in this one step. So once you have that next you have to hydrolyze this imine to get back your ketone. So that was done with HCl and water. And the next step just before completing the total synthesis is to remove or reduce the ketone okay. Reduce the enone 2 corresponding allylic alcohol and remove the bromine. So both were done in one step by treating with LAH and this is nothing but another natural product called codeine and from codeine what you need to do is just to do the demethylation. So that was done with pyridine HCl at 200 degrees to get the corresponding demethylated compound which is nothing but morphine. So overall if you look at that synthesis it was started from an Aphthalene 2, 6 diol and the key reactions were Dilsal reaction and one part tribromination, elimination, cyclization and imine formation. So this is the second key step and it took about 27 longest linear steps and the yield was poor but considering the conditions in the year in which it was reported and that was the first total synthesis as well it was one of the classical synthesis of morphine reported until now okay. So now we will move to the second total synthesis actually this was the first I would say asymmetric total synthesis and was reported by Overman and he has used an intramolecular HEK reaction intramolecular HEK reaction as the key reaction to synthesized morphine. Let us see how he has done the retro synthesis because when you write confirmationally it is easy to visualize and this can be obtained from this enone. A simple reduction of this enone you will get this axial alcohol. Now you reduce the double bond because the double bond can be reduced when you go for the forward reaction. So this will lead to this compound called dihydrocodino okay and that can be obtained from this alcohol. So basically if you treat with MCPBA so it will form epoxide and then immediately this can cyclize isn't it and this double bond can be obtained through intramolecular HEK cyclization and that can be obtained from these two compounds okay. So you have aldehyde and this amine and it can cyclize to give this compound and this particular compound that silyl one can be obtained from this aldehyde. So that aldehyde can be obtained from this diprotected aldehyde using a homologation and this particular allyl cyanine can be obtained from two allyl cyclohexene okay. Now let us see how this synthesis was done and this is the you know catalytic cycle for HEK reaction. So I will not go into the details. HEK reaction is one of the well-known reaction and he has cleverly used this tetromolecular HEK reaction in the total synthesis of morphine. So he started with two allyl cyclohexenome and used CBS reagent that is CORE boxy shibata boron reagent oxazoborolidinol to get this allylic alcohol and once you have this then treat with phenyl isocyanate to get the corresponding carbamate. Now the silyl group was introduced and for that before you do that this double bond should be protected. So we did the osmium tetroxide dihydroxylation followed by protection. So you get the corresponding acetonide then you treat with this phenyl dimethyl silyl lithium in the presence of copper. So it undergoes SN2 reaction on this, SN2 reaction on that particular carbon leaving this carbon okay. So once you have that you remove the acetonide and you get the diol and treat with sodium pyruvalide please the diol to get the corresponding aldehyde okay. You have that aldehyde then you treat with dibenzo-suburon amine and that along with sodium cyanoborohydrate it undergoes a reductive amination okay. So the DBS is nothing but dibenzo-suburine okay that NH2 okay this NH2 here if it is NH2 the NH2 will undergo emine formation followed by reduction you get this. This is nothing but a protecting group. This DBS is a protecting group that can be cleaved under hydrogenation condition. So you have this NH so now this aldehyde which is commercially available was protected as dimethoxyacetal. You treat with butyl lithium and quench with iodine followed by removal of the acetal you introduce the iodine here as well as remove this. Not only the acetal will be removed but also mom group also will be removed okay. So first you introduce the iodine the mom group helps to introduce at this carbon and then remove the mom group as well as the acetal using HCl condition. Then protect the hydroxyl group protect the phenolic hydroxyl as the benzyl ether then you homologate the aldehyde to corresponding epoxide with dimethyl sulphonium eryne. Then the epoxide and treatment with BF3th rate it rearranges to give the aldehyde which is now the homologated aldehyde. If you see this is a CHO a protected CHO and you have increased it by one carbon. Take this aldehyde and then treat with this amine which we already discussed and do the reductive cyclization okay. First it forms the iminium ion and that iminium ion undergoes this is a key cyclization you can see this double bond will add and the silicon will come here. So because whenever you generate a positive charge at beta carbon with respect to silicon the silicon will stabilize the positive charge okay. So that is called beta silicon effect and that gives you this particular compound in 91 percent. This also can be written like this okay. So I just leave it for few seconds so that you can understand. So this can be redrawn like this. So this is the A ring this is the B ring so you can see this is A so this is B and the whole unit is here. So now this is set for the intramolecular hex cyclization. So when you do the hex cyclization the double bond also will migrate is not it? So that is how the double bond migrates and then C-C bond formation takes place and now once you have the double bond as I said you can treat with MCPBA okay you can treat with MCPBA to get the epoxide and the epoxide can be opened. But before that you need this benzyl group to be removed. So then only as soon as the epoxide is formed the phenol can open the epoxide. So benzyl group removal was selectively done with BF3 ethyl and ethyl and you get the corresponding phenol. Then you can treat with MCPBA camphor sulfonic acid so as soon as the epoxide is formed intramolecularly the phenol will open the epoxide to give this alcohol okay. So now you can see all the 5 rings are ready okay. Oxidize the secondary alcohol okay to get the ketone then remove the protecting group to get the corresponding secondary amine and what you do when you remove that say in the presence of formaldehyde what happens as soon as the NH is formed the NH reacts with formaldehyde to form the iminium ion okay. That iminium ion again is further reduced and you get the corresponding methyl group. So if you look at this this is dihydrocodionol what needs to be done is you have to introduce a double bond and reduce it. So this is this was already reported so that is how Orman's the formal synthesis of morphine was done where intramolecular HEC reaction was the key step and he started from the commercially available isovaniline and second important key step was sequential iminium ion allylsilane cyclization. Overall he took about 10 steps and yield also was quite high compared to what Gates has reported it is about 1 percent overall yield 10 steps 1 percent overall yield is less but you have to see this is a conceptually a new synthetic root to synthesize morphine in 1993 okay. So I will stop here and then we will continue our discussion on total synthesis of morphine by 2 more groups in the next lecture okay. Thank you.