 Good morning, welcome back to the NPTEL lecture series on Classics in Total Synthesis Part 1. Today what we will do, we will move to a new class of natural products called triquinanes. And after a brief introduction, we will talk about total synthesis of at least one such triquinane. And the next few lectures, we will discuss more about various total synthesis of several triquinanes. So what are these triquinanes? As you know, we have seen many natural products having five-ambered as one of the key rings in the natural product. And this five-ambered ring can be called as quinane. There are five carbon atoms, so you can call that as quinane. If two five-ambered rings are fused, then you can call that as diquinane. Two five-ambered rings are fused, so you can call them as diquinane. And if three five-ambered rings are fused, then there are three possibilities. One, they are fused in a linear fashion. If they are fused in linear fashion, then they are called linear triquinane. And on the diquinane, if you add one more five-ambered ring in an angular fashion, you can see this is the diquinane and you are adding one more five-ambered ring in an angular fashion, then they are called angular triquinanes. Then the third ring, third five-ambered ring, if you attach in such a way that if they look like propellant, so then that is the third category propellant type triquinanes. And when you talk about linear triquinanes, then there are two types, one cis-anti-cis. If you look at the relationship between these two rings, they are cis. However, the relationship between the first and third ring that is anti. However, the relationship between the second and third ring is cis. So that is why this is called cis-anti-cis. And then you also have cis-sin-cis system. So when you look at many natural products belonging to linear triquinanes, you will see both skeleton present. Likewise, you can see if you look at the linear triquinanes closely, the core structure has 11 carbon atoms. This is a five-ambered ring. This is a five-ambered ring and there is one extra carbon atom which is also part of the five-ambered ring. So there are 11 carbons which forms the core structure of any triquinane. So the remaining four carbon atoms because they are sesquiterpenes, so the remaining four carbon atoms are distributed across this 11 carbon atoms. The way they are distributed, the way you have oxygen functionalities, you can see several linear triquinanes. See if you look at the difference between hisutine and capnoline, okay. The hisutine has exocytol double bond here whereas capnoline has here. And then hisutine has a dimethyl group here whereas it has dimethyl group here. So like this subtle changes will lead to different natural products. This is based on their way they cyclize during the biosynthesis and accordingly, you know, you see different natural products. And quite a few are highly oxygenated as you can see in hisutic acid, coriolin. There are 3 to 4 oxygen atoms present in such natural products. Coming to angular triquinanes, again angular triquinanes of skeleton wise, they are of 4 types. One, for example, if you look at this isochromane angular triquinanes, there are 4 methyl groups in that 2 are angular methyl group, okay. 2 are angular methyl groups. The remaining 2, they are attached to a tertiary carbon atom. They are attached to tertiary carbon atom. And in the case of sylphenine, we have 1 angular methyl group. One methyl group which is attached to tertiary carbon atom. And then you have 2 methyl groups. They are gem dimethyl and they are quaternary, okay. Same way pentalining, you can see 2 quaternary methyl groups and 2 methyl groups which are attached to tertiary carbon atom. 2 methyl groups which are attached to tertiary carbon atoms. And sylphyperfolane type angular triquinanes, it has only 1 angular methyl group. The remaining 3 methyl groups are attached to tertiary carbon atoms, okay. And there are many angular triquinanes. Here are some alpha isochromene, beta isochromene, sylphenine and so on, okay. We will try to cover total synthesis of some of them. And as you know, each group would have used different key reactions to make these natural products. So over a period while talking about various total synthesis of triquinanes, you also will know or you also will get an idea how such molecules can be synthesized using different key reactions and different key strategies. Coming to the third one that is propellant type triquinanes, the third ring, okay, you can see first the basic triquinanes almost same. Only the third one is different and some of them are oxygenated, okay. So for example this one, a modified epoxide and polycarol. So these 3 are oxygenated. The basic one which is just modifying having only a double bond, okay. Now what we will do, we will talk about the total synthesis of alpha and beta isochromenes today. And these isochromenes were isolated from isochroma righty. And a closer look at these molecules, you can see that there are 3 contiguous quaternary centers, okay. 1, 2, 3. There are 3 contiguous quaternary carbons, okay. So always construction of quaternary carbons is not easy, okay. And particularly if you have to construct stereo selectively, it is really a tough job. And in addition, you have one chiral center. The difference between alpha and beta isochromene is the position of the double bond. In the case of alpha isochromene, you have internal double bond whereas in the case of beta isochromene, you have external double bond. So first let us start with synthesis of isochromene by Michael Pirang. And Michael Pirang used a intramolecular 2 plus 2 photocyclic addition as the key step. And this is the structure of isochromene. He also used one more key reaction that is ring expansion under acidic condition. The first key reaction is intramolecular 2 plus 2 photocyclic addition. And the second one is acid catalyst ring expansion of 4 ombre ring to 5 ombre. So according to Pirang, isochromene can be easily obtained from this carbocation. So if you can generate, this is an intermediate, okay. It is not a precursor. This is an intermediate. This carbocation, if you can generate, that should lead to isochromene, okay. He thought this carbocation, normally what you would have thought this carbocation can be obtained from a tertiary alcohol or a double bond, exocyclic double bond, okay. Simply, you know, from synthetic point of view, it is easy to think that this carbocation can be generated from the corresponding alcohol. But what he thought was that is a key thing that if you have like this system, then you know Wagner-Mirwin type rearrangement can occur. This bond can migrate. If this can migrate, that will lead to this angular trichunate with a carbocation. Once you have this carbocation, obviously, loss of proton will give the natural product. Then how do you generate this carbocation? Suppose if you have a ketone, then the ketone, you can add either methylgrignal or you can do a VT followed by protonation should generate that tertiary carbocation, isn't it? And how do you get this tricyclic compound? So, when you look at this 4-membered ring, immediately you should think about 2 plus 2 photo cycloaddition. Again, there are two possibilities. One, you can break this way, okay. That is, if you call this breaking A bonds, the other one, you can break the vertical one, so vertically. So, that you can call it as breaking B bonds. So, what he did was he broke the bonds B to form the 4-membered ring. So that way, this became the precursor. Now, if you look at this, this can be easily made by simple acid-catalyzed rearrangement again. So, if you have this enone, okay, if you have this enone, then you add this gyrignard. So, this gyrignard will add 1, 2 and then you will get an alcohol here. Then simple acid-catalyzed hydrolysis will transposition the oxygen, okay. So, that way you can easily get this product in 2 steps from this, okay. So, this was the, you know, simple retro synthesis planned by Pyrene and let us see how this synthesis worked out. He started with commercially available 2-methyl cyclohexane-1, 3-dion. He started with 2-methyl cyclohexane-1, 3-dion. This on treatment with para-toluene-sulphonic acid and methanol, it will give enol ether. So, as you know, when you have 1, 3 diketone, 1, 3 diketone also can exist in corresponding enol form. So, that is basically emethylated, okay. The enol is methylated under acidic condition. Now, if you do LDA methylated treatment, you can introduce a methyl group here, because that is the only place it can generate anion and then quench with the methylated, okay. So, the fragment A is ready. Now, what you need is, you need to make the bromide and then add that trigonade to this enol. So, for that, you started from this gamma-keto ester, then you do the Wittig. So, Wittig will go selectively to the ketone to get the double bond and reduction of ester with LAH, you get the corresponding alcohol. Now, convert that into bromide and then make trigonade of that bromide and add to this enol. So, that will give you that tertiary alcohol. So, now simple acid treatment, first it will make this as a good leaving group, then this lone pair will come and the water molecule will go, that will lead to the key precursor, which is required for the intramolecular 2 plus 2 photo cycloaddition, okay. So, now once you made this key precursor, what he did, he tried the key photochemical 2 plus 2 cycloaddition reaction and this molecule also one should draw in such a way that one can easily explain the stereochemical outcome of the 2 plus 2 photo cycloaddition. So, you draw the cyclohexenone in such a way that put the methyl group in pseudo equatorial position, okay. Now, when you bring this, when you bring this appended side chain for 2 plus 2 photo cycloaddition, this methyl group should point upwards, okay. That way, if you keep this properly, then you will get this stereochemistry, okay. If you look at this compound, this methyl group is in equatorial position and when this double bond comes, this methyl group goes to beta because that side only hydrogen is there, is not it? That side only hydrogen is there. So, methyl group will try to go to axial or beta, okay and during the 2 plus 2 cycloaddition, this methyl group will go to alpha and this molecule can be redrawn like this, okay. I will leave it for few seconds for you to visualize how I have drawn this structure into this. Is it easy to visualize? So, this 5 membered ring is alpha, this methyl group is beta and this methyl group is alpha, okay. So, the first key reaction you could do successfully that is the intramolecular 2 plus 2 photo cycloaddition worked very well to give that tricyclic compound. Now, what we need to do is you have to add a methyl grignard or methyl lithium to get the tertiary alcohol followed by acid treatment should generate the carbocation, then the carbocation will undergo Wagner variant type rearrangement to give isocomium. So, he took this ketone and treated with methyl magnesium bromide and also methyl lithium. Unfortunately, these 2 did not give the corresponding tertiary alcohol. What happened? Methyl magnesium bromide and methyl lithium, they both acted as base and they did not act as a nucleophile, only enolate was formed in while treating with methyl magnesium bromide and methyl lithium. So, alternatively, it is very easy, you can do abitic reaction. So, simple methyl abitic gave the precursor to Wagner-Mirvin rearrangement. So, once you had the double bond, treat with para toluene sulphonic acid that gave straight away isocomium. Now, let us see the mechanism, how this was rearranged to isocomium. First, the protonation of this double bond took place to give the tertiary carbocation. Now, you have 2 bonds which can migrate. One is bond A, the other one is bond B. If bond A migrates, that will lead to isocomium. If bond B migrates, that will lead to some other natural product. Assume that bond B migrates, then you will get this skeleton. You can see this bond migrates here and that will lead to positive charge here. Now, if bond A migrates, it is very simple that will straight away give the isocomium skeleton and simple loss of proton will give you isocomium. However, if you look at this intermediate, which is obtained by the migration of bond B. Now, again this particular bond, this particular bond, if it migrates, what will you get is, you will get the same intermediate. So, essentially, it does not matter whether bond A migrates or bond B migrates. What you get is the same intermediate which upon loss of proton will give the natural product which is isocomium. So, this is one of the real classical total synthesis and it is a single author paper by Michael Pirin on the total synthesis of isocomium. So, in the total synthesis which was reported in 1979, he started with commercially available 2-methyl cyclohexane 1, 3-dione and the key reactions involved are 2 plus 2 photocyclic and Wagner-Mirwin rearrangement. Overall, the total synthesis involved 6 longest linear steps, 6 longest linear step and the yield was 42 percent which is quite quite high considering this angular trichonates. The second synthesis which was reported by Fiddler and here again the key reaction was ring enlargement and also Wagner-Mirwin type rearrangement. This is the key reaction. So, if you look at this molecule, you can see two 4-membered rings, isn't it? Two 4-membered rings, spirofused and one of the 4-membered rings is spirofused with a 5-membered ring. This upon treatment with acid, this upon treatment with acid gives isocomium. This is a very, very interesting sequence of reaction involving Wagner-Mirwin type rearrangement. Let us see how he achieved this. The retrosynthesis wise isocomium can be obtained in one step from this tertiary alcohol and this as you know, if you have a ketone, you can introduce one methyl group here by treating with LDA methyl iodide and if you add a methylgrignard to this ketone, you get the corresponding tertiary alcohol. So, in two steps you can get the precursor for the acid catalyzed rearrangement. Now, how you get this? Cyclopentamol. As you know, if you have an epoxide, if you have an epoxide, epoxides are known to undergo ring enlargement or ring enlargement rearrangement. So, a 4-membered ring with an XO epoxide can undergo rearrangement under acidic condition to give 5-membered ring. See for example, if you use a Lewis acid here, so what will happen? This can open up and this bond can migrate to get the corresponding 5-membered ketone. And epoxides can be easily made from the corresponding double bond and the double bond can be made from the ketone using Wittig reaction. And finally, the starting material for the whole scheme on total synthesis isochromene biphidair is cyclobutane having an XO cyclic double bond with two methyl groups. So, this is a starting material. Let us see how he successfully achieved the total synthesis of isochromene using this acid catalyzed ring rearrangement. First he started with acetone. You can imagine for the synthesis of isochromene the starting material is acetone, simple acetone which is solvent. Now you do a Wittig reaction with cyclobutane derived Ely you get the first starting material. Next you have to do another 2 plus 2 cycloaddition reaction. This time you do 2 plus 2 cycloaddition with dichlorochetine. So, if you look at Pyranx total synthesis also, there was a 2 plus 2 cycloaddition reaction. Here also 2 plus 2 cycloaddition reaction. In Pyranx isochromene synthesis he has used intermolecular 2 plus 2 cycloaddition reaction. Here it is intermolecular 2 plus 2 cycloaddition reaction with dichlorochetine. As you know dichlorochetine can be easily generated from either dichloroacetyl chloride by treating with triethylamine or trichloroacetyl chloride. If you take trichloroacetyl chloride and treat with zinc that also will give a dichlorochetine. So, this will give you the spirofused bicyclic system. So, now you have 2 4-membered rings, 2 4-membered rings spirofused. Next what you do not want is this 2 chlorine, is not it? The chlorine was used to keep the ketene stable. So, once that served its purpose the chlorine should be removed. So, normally it is done by treating with zinc and acetic acid. So, you have the spirofused bicyclic ring. Next, again do another vitic with the same cyclobutane, vermocyclobutane and treat with triphenylposphine and then butyl lithium. You get the vitic product. This looks very cute. This molecule looks very nice. You can see 3, 4-membered rings, 2 are spirofused and then 2 are interconnected with a double bond. Then what you have to do is just to treat with MCPBA. Just MCPBA will give the corresponding epoxide. This epoxide as I said when you treat with Lewis acid, when you treat with Lewis acid it undergoes. So, first it will coordinate with DF3 when it will open up and this bond migrates. So, that will give you the corresponding 5-membered ring. If you look at this molecule, now there are 3 spirofused rings. 2 are 4-membered rings and here if you see the spiro system as a 4 and 5-membered fuses of very interesting system. Next, you have to introduce a methyl group next to ketone then add either methyl lithium or methylgrigna. So, LDA methyl iodide you can introduce a methyl group then followed by addition of methyl lithium will give the tertiary alcohol. So, this is the key precursor just before the acid catalyzed rearrangement. So, when you did carry out the acid catalyzed rearrangement you got isochromine as well as another product. So, how isochromine was formed? First as you know protonation will take place. When the water goes you get the tertiary carbocation. Once the tertiary carbocation is formed then automatically one of the bonds of the spirofused 4-membered ring should migrate and this migration of this bond will give you another 5-membered ring. So, now what happens earlier this 5-membered ring and this 4-membered ring are spirofused. Now, after this they are linearly fused. So, that leads to another carbocation that also can trigger the migration of the bond from 4-membered ring as you know 4-membered rings are not that stable. So, that is a key thing which trigger the migration of bonds. Once that happens now you can see what you got is angular trichunane system, angular trichunane system. But still it is not leading to isochromine. You are getting an angular trichunane structure but it is not the isochromine. So, once you have a tertiary carbocation here you have a quaternary center adjacent position. From the quaternary center one of the methyl groups can migrate. So, when one of the methyl group migrates what you get is another tertiary carbocation. And if it loses a proto, if it just loses a proto there are 2 possibilities that it can lead to exocyclic double bond or endocyclic double bond. Of course, since it is treated with acid then possibility of getting exocyclic double bond is high. So, that is how he got isochromine as the major products. So, these are very interesting total synthesis starting with acetone and then do Wittig reaction with bromo cyclobutane derived elide. And you get spirofused 3-spirofused ring and then simple acid catalyst rearrangement gives you the natural product. Wagner-Mirwin rearrangement and 2 plus 2 cycloaddition as key reactions. So, in summary, so this total synthesis was reported about 10 years after Michael Prang's total synthesis of isochromine. And it started with acetone and the key reactions involved in this are 2 plus 2 cycloaddition and acid catalyst Wagner-Mirwin type rearrangement. Overall, this whole synthesis took 9 linear steps and overall yield was about 6.6 percent. So, I will stop here and then I will continue our discussion on total synthesis of various trichunanes in the next maybe 7 to 8 lectures because there are many total synthesis of trichunanes and each synthesis use at least 2 key reactions. Some of them are completely different than the other total synthesis. So, this way when we talk about total synthesis of various trichunanes, we will learn lot of new chemistry. So, thank you.