 So, good morning and welcome back to the in-pital lecture series on classics in total synthesis part 1 and the last lecture we talked about total synthesis of natural products. There we talked about total synthesis of isochromines by Michael P. Reng's group and Fritzer's group. Today we will continue our discussion on again total synthesis of isochromines. This synthesis is reported by Veresh Rabel. So Veresh Rabel had reported the total synthesis of both alpha and beta isochromines and he reported this in 1994. His total synthesis involved 3 or 4 key reactions. One pattern of the key reaction as you know pattern of the key reaction gives an oxytane it is form number ring and it is an intramolecular pattern of the key reaction to get oxytane as the key step. Second opening of the oxytane to get homo-allylic alcohol, highly regioselective opening of the oxytane to homo-allylic alcohol followed by a simple fragmentation reaction which converts the bridge system into fused system. So, these are 3 key reactions which Rabel has used in the total synthesis of isochromines. Let us see what he has done and from retrosynthetic point of view so these are alpha and beta isochromines both can be obtained from one common intermediate and this is enone and it is very simple the phi xo radical cyclization can be used successfully to construct the third 5 ombre ring. See there are 2 5 ombre rings and the third 5 ombre ring can be easily constructed by this phi xo radical cyclization. So, once it is done then simple vitic will give one isochromine and isomerization of the double bond to endo-olipine will give the other one. And of course the bromide can be easily obtained from the corresponding alcohol and the first key step is this fragmentation. Fragmentation of the bridge system to the fused ring is the first key reaction from retrosynthetic point of view. So, this is the bond which is broken during this fragmentation and this can be obtained from this oxytane using regioselective opening of the oxytane followed by oxidation of the secondary alcohol you get this beta gamma unsaturated enone. And this can be easily obtained from this bicyclic compound by another key reaction which is pattern of the key reaction pattern of the key reaction is nothing but photochemical reaction between an alkene and a carbonyl group. So, this is an intramolecular pattern of the key reaction and this can be obtained from cyclopentadiene and this enone followed by alkylation. So, in 2 steps one can get this interesting bicyclic compound starting from cyclopentadiene. So, before we start discussing the total synthesis of isochromines reported by Ravel as I said there are 3 key reactions and we will briefly discuss about these 3 key reactions. First it is a pattern of the key reaction pattern of the key reaction is nothing but it is a photochemical reaction 2 plus 2 reaction between an alkene and a carbonyl group. Suppose if you start with benzophenone and isobutylene and the photochemical condition you get this 4 membered ring. And one can also do the same thing with an aldehyde basically it is a reaction between a carbonyl group and an alkene. So if you do the same thing with benzaldehyde and dihydrofuran you end up getting this bicyclic compound. And this was cleverly used in V-Rationables total synthesis. The second key reaction is the conversion of an ester into methyl ketone. So, this was reported by E.J. Coray where if you have an ester and then treat with this lithium dimethyl sulfoxide you take dimethyl sulfoxide and then generate anion here. This can add to your ester to form this beta keto sulfoxide. This upon reduction with aluminum amalgam that will give you a corresponding ketone. This can be easily cleaved under this condition, reducing condition. The third one which is very important from the point of view of synthesis of this isochromines is the opening of the oxidant ring. How this oxidants can be successfully open? So I will give one example which was reported by V-Rationable before we go to the total synthesis. If you do a Diels Hall reaction between cyclopentadiene and methyl vinyl ketone you get this endo product. Once you have this endo product then shine light to carry out the intramolecular pattern of the reaction to get this tetracyclic compound. This oxidant can be opened by strong base, it can be opened by strong base like LDA to get the corresponding alcohol. Once you have this alcohol then you can use any oxidizing condition. For example, sewn oxidation will give you the corresponding ketone. So now in 4 steps one could get successfully this tricyclic compound. Now what you need is you need to remove or break this bond to get a di-qnane skeleton. So that was successfully done with one of the 2 reagents. One either with lithium ammonia or with LIDBB. LIDBB is nothing but lithium di tertiary butyl biphenyl, lithium di tertiary butyl biphenyl. So basically both reagents give one electron. So one electron is added to this carbonyl group you get a radical anion. Then the radical opens up to give this required skeleton. So let us see how does it work. So once you have this enone and when you had this one electron as I said it forms this radical anion. So the radical anion is not stable so it has to open up. So if there are 2 ways a bond can break to give more stable compound or more stable intermediate you should know whether bond A breaks or bond B breaks because once you have that radical here so it can easily break. If bond A breaks you will get this enolate and an allylic radical and that should give you this enone. So you have a tykunine with the keto. So if you look at this automatically the double bond goes inside it is a more stable compound so you get internal alkene but this is not the product you get. What you get is based on the cleavage of bond B. If the bond B breaks okay now if you see this there is a conjugation that enolate or enol which is formed is conjugated. So that is why this is more favorable than this bond A breaking. So when the bond B breaks you get this dienol that tartarises to give this conjugated enol. So in one step you can convert this into bicyclic enol. This is the key step. There are three key steps, pattern of the key reaction and conversion of ester to ketone then opening of this. Now let us see how he achieved the synthesis of isocomics. So he started from cyclopentadiene and then did a Dielsall reaction with this dienophile methylchrotonate and you heat it you get this compound. Now the next step should be to remove the methoxy with methyl but before that you need to do alkylation at this carbon okay because you need a 3 carbon unit which should be attached here that 3 carbon is required for intramolecular radical circulation. So before you convert this methoxy into methyl what you should do is you should alkylate here because if you convert this methoxy into methyl then the alkylation can go to the methyl group. So that is why the alkylation should be done at this stage. So you take this ester then treat with LDA and then quench with this iodide. So this iodide is prepared in 3 steps from this propane 1, 3 diol okay. So you protect one of the alcohol as ma-meter then convert the other alcohol as mesolate and then treat with sodium iodide you get this iodic compound. Now you generate anion here and then quench with this iodide and it goes stereo selectively it goes to the exo position. So now what you can see here is the methyl group here and this side chain that is a 3 carbon unit they are cis to each other because this stereochemistry will be maintained when you do the next step okay. Next you have to convert this methoxy into methyl group as I said you can follow Cori's procedure so that reaction worked well to get the corresponding methyl ketone. So diol cell reaction is over you introduce the 3 carbon side chain and you also converted the methyl ester into methyl ketone which is required for intramolecular pattern of reaction. So the intramolecular pattern of reaction also worked very well to give the corresponding oxidant. So once you have the oxidant next you have to open the oxidant. So either you can use LDA or the strong base to get the corresponding Homo allylic alcohol. So this Homo allylic alcohol upon oxidation under one condition gave this enone and now upon treatment with LIDBB the reaction worked very well and opened the tricyclic compound to the bicyclic compound. So now you have already the diquinine okay. So what you need to do is you need to cyclize here that will give the third ring which is required. So that way you will achieve the synthesis of angular triquinine core structure then it is just the functionalization of the carbonyl group. So for that first you have to remove the mom group. So the mom group can be easily removed using lithium fluoroborate. So that will give the alcohol and this alcohol for the radical reaction you convert that alcohol into corresponding bromide by treating with NBS and triphenylposphine. So NBS and triphenylposphine gives you the corresponding primary bromide. So once you have the primary bromide then treat with tributyltrin hydride and AABN that will give you that radical here. So this will go and you form a radical that will attack here in a phi exofashion and give you the angular triquinine. So now once you have the angular triquinine simple vitic simple vitic will give you beta isochrome okay. So for the synthesis of alpha isochrome so basically one can isomerize this double bond but what he did he went back to the alcohol okay and converted that alcohol into iodine okay using triphenylposphine and iodine one can easily convert the primary alcohol into corresponding alkyl iodine. This on treatment with butyl lithium okay N butyl lithium you can exchange this lithium. Then that lithium undergoes a 1, 4 addition to this enone and once that happens it forms an enolate it forms a 5 umbered ring followed by enolate formation. That enolate is coincided with this reagent it is called commincy reagent that will give you the corresponding enol triplets. So once you have the enol triplet then you couple with Gilman reagent that is lithium dimethyl cuprate that will give you corresponding isocomium. So he used cleverly the Diels-Aubreaction, Patronubicke reaction and opening of the oxidane and also opening of the bridge system to fuse system to synthesize both alpha and beta isocomium. And his synthesis started with commercially available inexpensive cyclopentadiene and these are the key reactions which he used to synthesize both beta and alpha isocomium. Overall the total synthesis was done in 14 linear steps and the yield was close to 20 percent. Overall yield is really very good considering the triquinane complexity. Now since we are talking about this Patronubicke reaction and application of Patronubicke reaction in the total synthesis we will continue our discussion again reported by Viresh Ravel in the synthesis of another triquinane called sylphyperphol 1651. So this was isolated in 1980s by Bolman and if you look at this molecule this is also an angular triquinane and here yet again Viresh Ravel used the same sequence that is Patronubicke reaction opening of the oxidane and followed by opening of the bridge system he could successfully synthesize this compound but importantly he could achieve this in 5 steps. So that is significant improvement compared to what he had earlier reported for the total synthesis of isocomins. So let us see how he has done not only you know sylphyperpholines there are so many other natural products which are having almost similar structure with some minor modification in the functional groups here are some. His retro synthesis actually started with you know this oxidane as you know already we discussed how oxidane is the key intermediate in the synthesis of isocomins. So this precursor is this oxidane that oxidane can be redrawn like this. Now this oxidane as soon as you look at this oxidane you know what should be the precursor the precursor is nothing but this tricyclic system. So one can do and Patronubicke reaction to get this intermediate okay and this can be easily synthesized from Diels Alde reaction if you start with 2, 4 dimethyl cyclopentadiene and this cyclopendene having a carbonyl group as dienophile this Diels Alde reaction will straight away give this tricyclic compound. So he started this synthesis with 2, 4 dimethyl cyclopentadiene and cyclopendene having a carbonyl group for the Diels Alde reaction he used a European salt okay this 10 mole percent actually helped in getting exclusively the endoisomer okay. So now if you look at this he got how many chiral centers though it is a resemic synthesis now so 1, 2, 3, 4, 5 okay so all these chiral centers are fixed in one step that is Diels Alde reaction okay. So it is a relative stereochemistry but still you get only one relative isomer once you have that then you carry out the intramolecular photochemical 2 plus 2 cycloaddition that is Patronubic reaction to get this oxidant okay this also worked very well though you can see this slightly congested system but photochemical reactions are known to give sterically as well as you know ring strained compounds okay. So once you have that then using the LIDBB you could easily open the oxidant to get the allylic alcohol okay. How many steps 1, 2, 3 in 3 steps you could get the core structure of this natural product and what is left for the synthesis of a selfie perfol 1650 is just oxidation if you oxidize this that is a natural product. So simply it took this compound and oxidized with PDC you got the natural product. For the other compound other natural product one more natural product that is without the carbonyl group that is called selfie perfol 16 he needs to remove this carbonyl group. So he tried several conditions to remove this carbonyl group but all of them gave poor yield of the required compound plus complex mixture. So he has to go via a two step process first he acetylated the allylic alcohol to get the corresponding acetate then he treated that with lithium in 1, 2 diamino ethane. So that gave the other natural product which is selfie perfol 16 okay. If you look at the synthesis as I said both the natural products are made in 4 steps and 5 steps. The first one was made in 4 step and the second one was made in 5 steps. And this was reported by various novel group in 2000 and synthesis started from 2, 4 dimethyl cyclopentadiene as in the case of isochromines here also the key reactions are intramolecular patronomic reaction and the cleavage of oxytane and cleavage of the C-C bond using lithium diethase rebutyl biphenyl and more importantly if you look at the total synthesis it involved only 4 and 5 steps okay. So the first natural product it took only 4 steps and for the second natural product it took only 5 steps and the overall lead is extremely high 33 percent and 35 for synthesis of angular tricunin is extremely high one of the very efficient synthesis of angular tricunin reported by variation novel. So with this we have completed the total synthesis of 4 tricunin and we will continue our discussion on the synthesis of more angular tricunin followed by linear tricunin okay thank you.