 So, good morning and welcome back to NPTEL lecture series on classics in total synthesis. We have been talking about quite a few total synthesis of triquinones and today also we will continue and complete discussion on more total synthesis of triquinones. Today we will start with our home grown total synthesis where we discuss total synthesis of 3 triquinones, actually 2 triquinones and one having a diquinone moiety reported by none other than Prof. Gowadhan Mehta and first let us start with known molecule Hirsuteen and how his group has synthesized this molecule. He has used a unique reaction, now we all know what is metathesis, ring closing metathesis, enamel metathesis, ring opening ring closing metathesis is all. But in 80s, but that to early 80s he is the one who introduced the term thermal metathesis, so where you know it undergoes a retro 2 plus 2 under very high temperature, one can even call it as flash vacuum pyrolysis to get triquinones, so that is a key reaction in many of his total synthesis of triquinones and related natural products. So, let us see how he did a retro synthesis of this Hirsuteen molecule as you know when you have a double bond and the double bond can be obtained from alcohol via oxidation and vitic reaction and this can be obtained from this keto intermediate, this keto intermediate is required which we will come to know when we talk about the synthesis, so you can remove the carbonyl group in 2-3 steps and at the same time after doing that you can remove the mom group to get the hydroxyl and this can be obtained from the diketone, so you can see there are 2 carbonyl groups and one is you know highly sterically hindered position, so one can easily manipulate the other ketone, so that is what you have seen in this retrosynthetic disconnection and this can be obtained from cyclopentadiene, so this is a well known but I will come to that how he has done, so it involves 5 steps to come to the triquinone moiety, first step is 4 plus 2 cycloaddition between cyclopentadiene and 1, 4 benzoquinone to get this tricyclic compound and this tricyclic compound if you redraw like this, now you can see this double bond and this double bond they are close to each other and this upon photochemical reaction can undergo an intramolecular 2 plus 2 photocycloaddition to give this highly strained compound, okay basically if you look at this in 2 steps one can get this highly strained compound, so this was reported by Cookson, so it is called Cookson's Dione but what is important was Metha's group used this Cookson Dione for a very important transformation as I already mentioned called thermal metathesis, this upon flash vacuum pyrolysis if you heat it at 600 degrees this undergoes a retro 2 plus 2, so if you do like this you will get this tricyclic diene diome, tricyclic diene diome, this you can also write for better understanding, better visualization you can write like this, clearly from cyclopentadiene and benzoquinone one can get this linear triquinone, okay linear triquinone core structure basically in 3 steps, so what are the key reactions and what are the key take away from this whole sequence, one as I said so first time the thermal metathesis was used to get this tricyclic compound, two people often talk about atom economy okay this is a buzz word in the last 2 decades, if you look at the whole transformation you started with 5 plus 6, 6 carbons and you can see in the product you have this same 5 plus 6, 11 carbon atoms all the hydrogen atoms, all the oxygen atoms all are retained, so it is a 100% atom economy reaction over 3 steps, so this is a second beauty of this whole sequence which is group exploited in the total synthesis of many natural products, now let us see how this core structure was taken further for the completion of total synthesis of Hirsutine, okay, so that was the key step, so instead of benzoquinone if you use 2, 5, okay 2, 5 dimethylbenzoquinone you will get this tricyclic intermediate, this upon intramolecular 2 plus 2 cycloaddition with under photochemical condition will give you this trained compound, okay, then you do the flash vacuum pyrolysis, you get this tricyclic compound where compared to the triquinone which we discussed in the previous slide, we have 2 methyl groups in addition, one is angular methyl group, other one is attached to an sp2 carbons, okay, so how we took this intermediate to the final compound Hirsutine, okay, so you take this diene-dione and heat it, okay, basically what he wants was these 2 hydrogens should be alpha, okay, so he could do this using thermal condition when you heat it the double bond migrates, okay and further heating it isomerizes to this more stable triquinone because this is what he wants, so by heating it for long time he could convert this into this tricyclic compound, okay, this tricyclic compound he took it and then reduce both the double bonds, okay, you have 2 double bonds and both the double bonds are reduced to get the corresponding di ketone. Next, he wanted to introduce one more methyl group here, if you look at Hirsutine, you have a dimethyl group at that carbon, so he wanted to introduce one more methyl group, obviously if you see there is another ketone and then next to that is CH2, there also one can do the deprotonation, so what he did, he treated with potassium tertiary peroxide, okay, and quench with methyl iodide, so he could introduce the one more methyl to get the gem dimethyl group but he got only 50% yield which is understandable because one can also methylate at this carbon, nevertheless you could successfully isolate 50% of the required product where you have the gem dimethyl group, after having this di ketone next as you know you need to remove this carbonyl group but between these 2 carbonyl groups, this carbonyl group is more reactive because that is less sterically hindered compared to the other ketone, so what one can do, you can protect that, so protection is done through reduction, so first you reduce the carbonyl, the left hand side 5 ombitoring carbonyl to alcohol, then protect that alcohol, as ma-meter using q-nicks base, you get the corresponding ma-meter, now you have to remove the carbonyl group, how do you remove the carbonyl group, there are many methods but he chose a 3 step protocol where you reduce the ketone with LAH to get the alcohol, then that alcohol was converted into zandate, you treat with sodium hydride and conch with carbon disulfide and methyl hydride, you get the corresponding zandate, that zandate you treat with tributyltin hydride AABN, you remove the oxygen, so the right hand side 5 ombitoring is fine, the middle 5 ombitoring is fine, now what he has to do is to remove the protecting group, oxidize the alcohol and do the wittig to complete the total synthesis of Hirsutin, so the mahm group was removed under acidic condition to get the corresponding secondary alcohol, the secondary alcohol was oxidized with PCC to get the ketone, then simple methyl wittig gave that final natural product that is Hirsutin, so if you look at this synthesis, overall the key step was the photothermal metathetic sequence, so this sequence also as I mentioned is one of the earliest 100% atom economy reaction and the starting material of course the tricyclic compound was prepared from cyclopentadiene and 2-5-dimethylparabensoquinone using Diels-Alder cycloaddition reaction, overall this group took 12 longest linear steps to complete the total synthesis of Hirsutin and the yield was about 13%, so 13% yield for this molecule is quite competitive and that is mainly because of the 100% atom economy reaction. So now we will move to another natural product which is not a tricunin but it has a di-cunin substructure plus one 6-ohm-bird ring and another 6-ohm-bird ring having a heteroatom, so this molecule is called deoxy-magalininone, you can see there are 2 5-ohm-bird rings and one 6-ohm-bird ring and another 6-ohm-bird ring which you can call it as n-methylpiperadiene. So since we are talking about tricunins, I just want to extend that method which Professor Mehta has used, I want to discuss the extension of Professor Mehta's methodology to synthesize such molecules. So this was the first total synthesis reported by Professor Mehta and in addition to the standard metathesis, thermal metathesis reaction, he has also used an intramolecular micro addition reaction as the key reaction to construct this 6-ohm-bird ring. Let us see how he has done this, first let us look at the tetrosynthetic analysis. So this molecule as you know you can easily obtain from this diketone. So if you look at the diketone between 5-ohm-bird and 6-ohm-bird, 6-ohm-bird is little bit more reactive, so you can do a vitic on this ketone followed by isomerization, you will get a natural product. And this diketone if you look at carefully it is 1, 2, 3, 4, 5, it is a 1-5 diketone. So whenever you see a 1-5 diketone in a natural product immediately the Michael reaction should come to your mind. So obviously the precursor for this could be the corresponding diketone. So if you remove this and if you have double bond then it can generate anion and it can undergo Michael addition. And the same time the other side 6-ohm-bird ring if you see that is n-methyl piperidine if you osanolize this double bond, if you cleave that double bond and if you get a dialdihyde then one can think about reductive methylation on this dialdihyde or you can reduce that aldihyde to alcohol convert that into leaving group then treatment with methyl amine one can get this compound. And this compound can be obtained from here if you convert this into a methyl ketone normally this is then using Wacker process. So the terminal double bond can be selectively oxidized under Wacker process to get the corresponding methyl ketone and that methyl ketone can undergo intramolecular Michael addition reaction. And this of course can be obtained from this tricyclic compound where you have an enone and one can think about using another Michael addition to introduce this pore carbon unit. And this of course can be obtained from cyclopentadiene and benzoquinone. So that is why I thought I should discuss this if you look at this whole synthesis it also goes through the trikonic point okay. So this compound we already discussed this is obtained from cyclopentadiene, parabenzoquinone 4 plus 2 cycloaddition followed by 2 plus 2 cycloaddition you get this compound. Now you do pyrolysis you will get the tricycline but you if you look at the previous example one side you do not have the ketone so you have to remove one of the carbonyl groups and that is best achieved at this stage. So this is symmetrical diketone so one of the carbonyl groups is protected as ketone then the other carbonyl is reduced to get the corresponding alcohol and basically you have to deoxygenate okay the carbonyl ketone group should be removed. So it went through 3 steps reduction followed by conversion of the hydroxyl group into bromide and that bromide during the conversion of hydroxyl group into bromide under HBR condition not only the hydroxyl group was converted into bromide by using a SN2 reaction the ketol also got cleaned because you are using acidic condition okay. So again he has to protect the ketone as ketol then remove the bromide under reductive condition that is metal ammonia condition to remove the bromide so now you have this remove the ketol to get the ketone then flash vacuum pyrolysis at high temperature you get this compound and if you look at this this is dienone okay normally you get a ketone one more ketone here that ketone was selectively removed using this process. So once you have that then the double bond should be migrated see basically what you need this double bond has to come here. So that was best achieved by reflexing heating in benzyl benzoate at 300 degrees the double bond could be successfully migrated to another alpha beta unsaturated ketone but this time the double bond is tetrasubstituted this double bond if you look at this tetrasubstituted whereas here it is disubstituted. Next step is the key 1, 4 addition so that was done using 4-butanol magnesium bromide and copress bromide dimethyl sulfide complex so that added this 4-carbon unit and as I said this once you do this next step is the conversion of the terminal olefin to methyl ketone which is normally done using Wacker process but before doing that you have to introduce a double bond here then only the Wacker process will give methyl ketone and that methyl ketone can undergo intramolecular Michael reaction. So the double bond was introduced in the following standard protocol first LDA phenyl celluline chloride you introduce as phenyl selenol group at this carbon and then oxidation to phenyl selenol oxide and elimination of phenyl selenol oxide gives that double bond then you carry out the Wacker process to get the corresponding methyl ketone this on treatment with sodium hydride it generates anion and then undergoes Michael reaction to give this tricyclic compound okay. Having got that next this 5-amper ring should be converted into the 6-amper ring with hetero atom that is the hetero atom is nitrogen and in order to do that you need to host analysis or you need to dihydroxylate and then cleave with sodium peroxide. Before that one has to protect these 2 carbonate groups. So that was the first step protect those 2 ketones as ketol then you do host analysis of the double bond to get aldehyde in situ you reduce that aldehyde you get the diol the diol was treated with methyl chloride to get the dimesolate so basically what you are doing is you are converting the hydroxyl group into better leaving group this upon treatment with methyl amine if you reflect with methyl amine it will undergo 2 Sn2 displacement to get okay. So now what is required you have to remove both the ketol you have to remove both the ketol to get the di ketone yes that was done under acidic condition then selectively you have to do vitic reaction on the 6-amper ring in the presence of 5-amper ring yes you can do that and basically the exocyclic double bond has to be isomerized and that was done by treating with para toluene sulfonic acid. So though this is not a trichunane but if you look at the total synthesis it went through trichunane and though that trichunane also was obtained through a thermal metathesis which was developed by Prasad Mehta's group. So this synthesis was reported in 1990 and the starting material as you know is a cyclopentadiene and benzoquinone and the key step is also intramolecular micro addition to get this deoxy majelinole. Overall it took 11 longest linear steps and yield was little lower but considering the complexity of the molecule 2% overall yield is really good and this way he could successfully extend the methodology developed in his laboratory to extend his methodology not only to trichunane but also to other natural products having a diquinane as a substructure okay. The 2 natural products which we discussed reported by Prasad Mehta's group they are recipe. The third synthesis which is about total synthesis of another trichunane is a Kairan approach where he started with the Kairan starting material called limoni and the natural product which he synthesized is ceratopic now okay. This was isolated in 1988 and it has 5 contiguous stereo centers as usual for a typical trichunane framework. So it has cis ante, cis configuration and for him the key step is as I said not like the earlier 2 synthesis where he has used thermal metathesis here it is a Kairan approach and in the Kairan approach he started with limoni as a Kairan starting material and he also used 2 key reactions. One is Johnson's ortho ester glycine rearrangement the other one is acid mediated or catalyzed diaso ketone olefin cyclization to get a cyclopropane followed by opening up the cyclopropane to get the fibromedric okay. Let us see how we did and this natural product first he wanted to introduce a double bond and a carbonyl group here so that he wanted to use as a handle for further disconnection and this molecule can be obtained from acid catalyzed intramolecular fredelcups like cyclization okay. So I will come to that when I talk about this how this reaction took place and this can be obtained from this diol okay. So if you look at this diol one can selectively oxidize the primary alcohol once you oxidize this alcohol will attack and then it will form a lactol that lactol will be oxidized to the corresponding lactol and this can be obtained from the corresponding ketone okay and this is where the first key step that is intramolecular diaso ketone addition to the double bond to get a cyclopropane and opening up cyclopropane gives a fibromedric and this can be obtained from the second key reaction that is Johnson's ortho ester glycine rearrangement that can be obtained from this alcohol which in turn can be obtained from limonium and this process is more okay this process is more. Let us see how he accomplished this before that I just briefly describe the mechanism of Johnson ortho ester glycine rearrangement. So you can take trialkyl ortho acetate so for example if you take primethyl ortho acetate if you treat with acid one of the methoxy group will be protonated and the lone pair on one of the oxygen of methoxy group will push the methanol out. So you generate an axonium ion and the allylic alcohol okay so allylic alcohol normally is required for glycine rearrangement will intermolecularly attack this carbonyl carbon to form this intermediate so this again it will undergo loss of another methanol under acidic condition to give this 1,5 diene and that can be redrawn like this and that will undergo 3,3 sigma tropic rearrangement which is nothing but glycine rearrangement to give this alpha, beta, gamma delta, gamma delta unsaturated ester as you know glycine rearrangement will give gamma delta unsaturated ester, gamma delta unsaturated aldehyde, gamma delta unsaturated carboxylic acid okay so that is the key step and let us see how we prepare the starting material we started with limonene and selective dihydroxylation of this trisubstituted double bond okay so you have 2 double bonds one trisubstituted other one is 1,1 disubstituted so the trisubstituted double bond was epoxidized and then opened with sulfuric acid dilute sulfuric acid to get the corresponding triol and that was cleaved with sodium peroxide to get the keto aldehyde because if you cleave this you get the corresponding keto aldehyde then reduce the double bond so to get isopropyl group and followed by intramolecular aldol reaction will give you the 5 umber ring with aldehyde then simple reduction of the aldehyde with sodium borogate cerium chloride that is called luscious reduction that gives the corresponding allylic alcohol. This allylic alcohol upon glycine rearrangement will give you the corresponding gamma delta unsaturated ester okay this gamma delta unsaturated ester can be hydrolyzed to the corresponding carboxylic acid before that as I said you do not want the double bond here the double bond should go inside so that the diacyl ketone can be added to this double bond so the migration of the double bond to internal double bond was done under acidic condition that is Lewis acidic condition now hydrolyzed the ester to carboxylic acid and that carboxylic acid upon treatment with oxalyl chloride you get the corresponding acid chloride this upon treatment with diacyl methane you get the corresponding diacyl ketone. This diacyl ketone then on treatment with BF3O3 undergoes 3 steps in one part the first step is the formation of cyclopropanation okay it undergoes cyclopropanation okay it undergoes cyclopropanation. Now under this acidic condition the cyclopropane opens so you get this compound okay so in this particular step you can see first the diacyl compound form the cyclopropane and then it opened and in the process your quaternary carbon is fixed stereochemically quaternary carbon is fixed and also formed a 5-unbuttering then this 5-carbon unit was added the bromine lithium exchange was done by treating with lithium and it added to the ketone to get the alcohol now removal of the TBS will give the primary alcohol and the primary alcohol can be oxidized and then cyclized but you do not need this you need a ketone is not it. So do a was analysis you get a ketone then remove the TBS group when you remove the TBS group that for that time one can separate these two okay you can see a beta alcohol and alpha alcohol one can separate these two. Now if you treat with T-POP that is a tetra N-propyl ammonium periutonate NMO NMO is a co-oxidant and you use catalytic amount of T-POP so that will oxidize the primary alcohol to aldehyde and immediately the tertiary alcohol will cyclize to form the lactol and further oxidation gives the corresponding lactone okay. So once you have this lactone this on treatment with methane sulphonic acid and P2O5. So what will happen it will hydrolyze and you will get a corresponding you can see either this double bond or both will undergo intermolecular total gas like cyclization to give these two tricules okay you can the only difference is the location of the carbonyl group okay. Take the required one reduce with sodium boracate methanol so this is enome this is simple cyclopentanone one can reduce the cyclopentanone to get the alcohol and now you treat with lithium and liquid ammonia. So what will happen lithium and liquid ammonia the double bond will be reduced and this carbonyl group also will be reduced. So you get a diol this diol upon treatment with acetic anhydride you get the corresponding diacetate. Then he uses the last key reaction where in one step he removes this acetate completely but hydrolyzes only the acetate to get alcohol. How did he do? He did with sodium in HMP. So this is highly regioselective reductive deacetylation. So the reductive deacetylation takes place here but at the same time this hydrolyzes only the acetate to give the natural product that is serotonin. So to summarize if you look at this total synthesis he started with commercially available R-lemonin a monitor beam and then in few steps you could convert that limonin into 5-hombardering and then he used two key reactions one is aqueous tricenter arrangement then acid catalyzed diacetyl ketone olefin cyclization to form a cyclopropane followed by opening of the cyclopropane to construct the second 5-hombardering and then third 5-hombardering was constructed using acid catalyzed cyclization. Overall he took 14 steps to complete the total synthesis and close to 1% overall yield he could successfully complete the synthesis. So we will have one more lecture on synthesis of trichonin we have already discussed many synthesis of trichonin because if you look at the synthesis of trichonin there are many ways one can make a 5-hombardering. So in the next lecture we will talk about few more methods and then one more total synthesis and complete the total synthesis of trichonin.