 So, good morning and welcome back to the classics in total synthesis NPTEL lecture series. In the last lecture we talked about the application of photochemical reaction in the total synthesis of trichonanes. So, we will continue our discussion on synthesis of few more trichonanes using different types of photochemical reaction and how they have successfully used this photochemical reaction in synthesis of trichonanes. So, first we will start with two total synthesis reported from Oda's group, one on Hissutane other one on Capnallene. So this is a structure of Hissutane and E again as I said E has used photochemical reaction as well as a trimethylsilate iodide mediated rearrangement of a bicyclic system as key reactions in the synthesis of Hissutane. So, let us see how he has thought about it and according to him this molecule can be easily obtained as you can see obtained from this enone, you do a reductive alkylation at this carbon and followed by Wittig reaction one can convert this into the natural product and this can be obtained from this tricyclic compound using trimethylsilate iodide mediated rearrangement of this bicyclic compound, the six-umber and four-umber it undergoes a rearrangement I will come back how this rearrangement takes place in a while and of course this can be easily obtained by 2 plus 2 cycloaddition reaction. What is the trimethylsilate iodide mediated rearrangement and how does it work? So, if you have a bicyclic system particularly a six-umber ring fused with a four-umber ring and if you treat with trimethylsilate iodide one of the carbonyl group will attack trimethylsilate group and then you form the corresponding axonium ion. Immediately the bond which is fusing the six-umber and four-umber ring so will migrate as shown here to form a bicyclic compound where both the rings are five-umber ring. Once you have this carbocation iodide will attack and you will get the corresponding iodide. This undergoes further cleavage to introduce the double bond, both iodide and OTMS will eliminate to generate the double bond and the double bond under the same condition will isomerize to get the conjugated. So, basically if you look at this reaction is done in 2 steps. First the photochemical reaction 2 plus 2 to get this compound then you treat with trimethylsilate iodide that rearranges to the bicyclic compound where both the rings are five-umber rings. Let us see how he has developed this for the synthesis of et cetera. So, he took cyclohexene dion and then did 2 plus 2 cycloaddition with the cyclopentene having a gem dimethyl group to get this tricyclic compound then treat with trimethylsilate iodide. So, which forms this intermediate followed by migration of this bond you get this tricyclic compound. And as I discussed in the previous slide this will be attacked by iodide followed by elimination you get the corresponding enone that undergoes isomerization to give that tricyclic compound. So, this tricyclic compound you could easily get in 2 steps very interesting 2 steps. Then reductive alkylation was done with lithium in liquid ammonia. So, lithium in liquid ammonia reduces and then you basically it reduces the double bond and generates manion here that can be quenched with methyl iodide and followed by nitric reaction on the ketone gives natural product. So, if you look at this synthesis in 4 steps Oda's group could successfully achieve the total synthesis of et cetera. And overall yield is also very high and 36% overall yield for a natural product total synthesis is considered as an excellent outcome and that is mainly because you could do it in 4 steps and one of them is photochemical reaction other one is rearrangement. So, that is how you could successfully do this. Then he extended the same methodology to its isomer capnally if you look at Hirsutine and capnally this I already discussed when I talked about initial introduction to tricunanes. So, there is some minor modification or adjustment of alkyl groups between Hirsutine to capnally. So, he thought he could extend the same method to the total synthesis or capnally and here he used one more key reaction that is titanium mediated ester ketone reductive coupling which later people call it as Shapiro reaction which later people call it as McMory coupling. So, how he did this let us see his retro synthesis if you look at it. This portion as you know it comes from the TMS iodine mediated rearrangement. So, once you have that this 3 carbon unit can be easily introduced by Michael reaction with ethyl acrylate and one can also cyclize this to get the corresponding ketone and then followed by VT reaction you can introduce a double bond. This as I said one can use a Michael reaction to introduce the CH2CH2CO2ET and this is obtained by TMS iodide rearrangement and which in turn can be easily made from cyclohexene dia and isobutylene. And this McMory coupling you know if you have a di ketone and if you treat with titanium 0 it can form either a ring with a double bond or it can form a diol. But if you have a ketone ester same thing if you do first it will form the diol which is almost like Penochol type coupling then this will undergo elimination to get the enol ether which upon hydrolysis will give you the corresponding ketone. So, this is what McMory has reported if you have a ketone and enester you will get the ketone. If you have 2 ketones you will get either diol or the diol will be further converted into the double bond. And the other starting material that is cyclohexene 1,4 diome. So, that was not easy to prepare but there are reports how one can make this in good quantity. So, this was done using a combination of diol salt reaction followed by reduction and pyrolysis. In 3 steps one can get or one can reduce one of the double bonds of benzoquinone. See that is what you need isn't it? You take benzoquinone and reduce one of the double bonds. So, how it was done? First you do a diol salt reaction with cyclopentadiene and you get this tricyclic adduct. Then you have to selectively reduce the double bond which is in conjugation with 2 ketones that is very easily done by treating with zinc and acetic acid. So, now if you do a pyrolysis, if you heat it, if you heat it, it will undergo a retro diol salt reaction and this also can be done and if you heat it and then distill. So, while distillation under reduced pressure also one can do the same thing that is pyrolysis that is retro 2 plus 2. Retro 2 plus 2 will give you the cyclohexene 1,4-dione plus cyclopentadiene. So, this cyclohexene 1,4-dione upon photochemical reaction with butylene will give you the bicyclic compound. This bicyclic compound upon treatment with trimethylsilal iodide as I mentioned earlier for the irsutine synthesis it undergoes rearrangement to give the corresponding bicyclic compound. This undergoes further elimination to get the bicyclic enone. Once you have this bicyclic enone then one can do the Michael addition product. For that first introduce a C-H-O that is normally done by treating with sodium iodide and quenching with ethyl formate you introduce the aldehyde. Then you do the Michael addition. So, Michael addition is done with triethylamine and ethyl acrylate and after the Michael addition this aldehyde also undergoes a sort of retrochlycine to give only the Michael addition product. Aldehyde is easily removed. Once you have that then you do the 1,4 addition with lithium dimethylcuprate. You could introduce a methyl group then you carry out the McMurray coupling reaction. You have a ketone, you have an ester then the McMurray coupling gives the five umbered ketone. It forms the enolether hydrolyzed to give the five umbered ketone. In the example where I have shown we formed six umbered ketone. Here it is five umbered ketone. Once you have a ketone next step is just to form the double bond using Wittig reaction to get the corresponding natural product that is capnoline. So, to summarize Oda group could synthesize this capnoline in 1987 and the starting material was same for capnoline as well as Hirsutin that is cyclohexene 1,4-dione which is made from parabenzoquinone by reducing the double bond. The double bond was reduced selectively but through three step sequence first dalesal reaction followed by reduction of the double bond and retro dalesal reaction. And the second key reaction was the McMurray coupling of ester and ketone to get the ketone and overall the whole synthesis was accomplished in six longest linear steps with an overall yield of 28%. So, 28% overall yield for any natural product synthesis is quite high and it was very successful. So, now we will move to another very interesting photochemical reaction which has been successfully used by Paul Wenders group and also others. So, here what he has used is a meta photocycloid reaction of an aromatic compound with a double bond as a key reaction to make many natural product belonging to triquinones. One such natural product which we will discuss is isochromine and his idea is this is a first retro synthesis you can see you introduce a double bond and the double bond if you reduce you get isochromine and this can be obtained by this particular cyclic intermediate where you can see a cyclopropane. Now, let us see how he makes this cyclopropane. He used a very clever are in meta photocycloid reaction as the key reaction. So, you can see a aromatic ring and a double bond this under photochemical condition undergoes this are in meta photocycloid reaction to give this tricyclic compound. I will come to that how this is done and this can be obtained easily in few steps starting with two bromotolivine and methyl vanyl ketone and another bromoputy. So, before going into the details I will discuss about this are in meta photocycloid reaction and before that the starting material that is aromatic compound how they made it. You take this two bromotans butane and treat with lithium. So, you will exchange the bromine with lithium then exchange with copper and that undergoes one for addition with methyl vinyl ketone to get this intermediate. This intermediate then you add to a lithioderivative of two bromotolivine and coprosiodate. So, that will give you this alcohol. This lithium if you add to this ketone you will get this compound. Now, again if you treat with lithium in liquid ammonia, so this benzylic alcohol will be clear and you get the starting material which is required for the photocycloid reaction. So, this photocycloid reaction gives you this intermediate as well as B. So, A and B they are obtained in almost equal amount and if you take A and again heat it. So, after protocol reaction you isolate that and then heat it this will undergo. So, opening of the cyclopropane to give this diet and that if you reduce selectively only this double bond you will get isochrome. And this method was extended for the total synthesis of ceratopicenol. Again same arene olefin metaspotocycloid reaction was used following what Wendrey has reported. As you can see here this can be obtained from the corresponding enone by simple reduction and this can be obtained again from this cyclopropane and which in turn can be obtained from this aromatic substituted compound. How is synthesized? So, you took this aldehyde. So, this aldehyde can be obtained in two steps from isobutronitrile. You take isobutronitrile and treat with base like LDA and quench with allyl bromide and you will get corresponding the allyl group. This upon reduction with dibol you get the corresponding aldehyde and this aldehyde on treatment with this lithium you will get the alcohol and further reduction gives you precursor for arene metaspotocycloid reaction. So, this undergoes arene metaspotocycloid reaction to give these two products where this is the major product. Take this major product and then treat with benzene thiol in liquid ammonia. So, what happens in the presence of liquid ammonia? Benzene thiol forms pH-S radical. So, that undergoes a 1,4 addition that undergoes a 1,4 addition and pushes the double bond. And followed by lithium and liquid ammonia cleaves the SPH. So, basically this cyclopropane is opened up with benzene thiol and when it opens up the double bond also migrates then the SPH is reductively cleaved with lithium ammonia to get the double bond. Now, you need a functional group here, you need a hydroxyl group there. So, that is done by treating with chromium trioxide dimethyl pyrosol to get the ketone and that was reduced to get alcohol. Before that, you know you need a methyl group here, this place you need a methyl group. So, you treat with LDA and quench with methyl iodine, you can introduce the angular methyl group and followed by reduction with sodium borohyldide you get corresponding serotonin. I will complete the whole process of photochemical reactions being used at the total synthesis of tricunins with one more total synthesis again reported by Wender and that is about total synthesis of subarchlorgic acid. So, this is an angular tricunin having a carboxylic acid. So, now if you look at this particular compound has three functional groups, one you have a ketone then you have a double bond and third one is the carboxylic acid. And Wender could use successfully the arene olefin metaphotocyclic addition reaction to get this compound. How he has device is retrosynthetic analysis. This acid if you have a CH2Cl or CH3 that methyl group attached to the double bond can be converted into carboxylic acid. It can be just simple methyl also, that can be converted into the corresponding carboxylic acid. And the ketone it is better to protect it so that no it will not interfere in other reactions and that can be obtained from this tetracyclic compound using the photocycloaddition reaction. Obviously the precursor for this is this arene substituted compound and that can be obtained from 2 bromo 1,4 dimethylbenzene. So, that is commercially available starting material. So, you take this 2 bromo 1,4 dimethylbenzene and treat with lithium. So, you exchange this with lithium and then add this aldehyde. So, this aldehyde also quite easy to make. You have to think about using glycine rearrangement. This is an exercise, think about it. If you use a glycine rearrangement you will get this aldehyde. Then you will get this menzalic alcohol. Oxidize this menzalic alcohol with PCC to get ketone. Then protect this ketone as the corresponding ketone. Then do the key meta-photocycloaddition reaction that gives a mixture of these 2. One is the linear triconin, other one is the angular triconin 1. So, separate these 2, take the angular one and again use a radical condition. You use a benzyl peroxide and acetonitrile. Benzyl peroxide and acetonitrile it forms a sort of you know benzyl peroxide generates this CH2CN radical and that undergoes a 1,4 addition like it attacks this double bond and the double bond migrates and then breaks this. It is almost like 1,4 addition concurrently breaking the cyclo propane. Now, you do not need the cyanide, okay, you need you know methyl group only there. So, you can use potassium in 18 crown 6, it will reductively cleave the cyanide and you will get the methyl group, okay. Now, what you need? You need to remove this ketone as well as oxidize the methyl group to corresponding carboxylic acid. So, if you treat with the MCPBA, there is only 1 double bond. So, the double bond will become the epoxide. You make this epoxide. Now, if you treat with base, strong base, okay, you can use LDA or you can use isopropyl cycloexyl magnesium bromide. So, that is a base that will act as a base. Basically, what you will get is corresponding allylic alcohol. So, basically, this will open up the epoxide to get corresponding allylic alcohol. So, what you need as I said, this methyl group should be converted into corresponding carboxylic acid, okay. So, it took little bit more steps than what they would have expected. Then, you have to functionalize this here. The double bond should be functionalized at the same time the double bond has to move here. So, this was easily done by treating with tionyl chloride. So, what will happen? The double bond will migrate and you will get a corresponding CH2Cl, allylic chloride. So, once you have this allylic chloride, so you do treat with silver fluoroboride and DMSO, you will get the corresponding aldehyde, okay. It is a DMSO base reagent, okay. So, that is very easy to oxidize the chloride to corresponding aldehyde. Then, vinegar oxidation gives the corresponding carboxylic acid. So, that is the natural product. But what you should remember is during the tionyl chloride reaction, not only the allylic alcohol was converted into the corresponding allylic chloride with the displacement in the form of SN2I reaction, but also the ketol was cleaved because when you use tionyl chloride, HCl also will be formed, okay. Though you use pyridine, the HCl, pyridine HCl also is sufficient to cleave the ketol to give ketol. So, to summarize, Wendell's group reported the total synthesis of subargaergic acid in 1990 using their reaction that is arine, a meta-arine photosychloridic reaction. And they started with bromoparas xylib as the starting material. And as I said, the key reaction is the arine-olefin meta-photocyclic addition. So, this reaction, this particular synthesis took little bit longer steps. So, it took about 11 steps. Still, the overall lead was 15 percent, okay. So, that is a really interesting method to make such a natural product. Thank you.