 So good morning and welcome back to NPTEL lecture series on classics in total synthesis. So yesterday we talked about total synthesis of epithelon by Nikolaus Grubh. In fact, we discussed two synthesis of Nikolaus Grubh. So today we will discuss two more total synthesis of epithelon A, one by Schinser's Grubh, other by Dany Szepski's Grubh. So Schinser's Grubh what they wanted to do was again they wanted to use the aldol reaction, the highly serious selective aldol reaction was the key reaction and then also the ring closing metathesis as the key reaction to get the double bond followed by epoxidation. So if you look at the retrosynthesis on the right hand side, the aldol, the cleavage of aldol followed by you know the ring closing metathesis, you can see the left hand side you have this homoalic alcohol, right hand side the aldehyde, this is almost similar to what professor Nikolaus has done and the southern hemisphere is this ethyl ketone, the case of Nikolaus Grubh, this used to be carboxylic acid, here the 1, 3 diol is protected as a ketone, okay. Now these three fragments were synthesized using the standard asymmetric route, now let us see one by one how these groups synthesize all the three fragments, okay. First he carried out a reformatsky reaction on this ester with 3 pentanone, so the alpha buromo ester upon reformatsky reaction with 3 pentanone you get this beta hydroxy ester, okay. This beta hydroxy ester then upon treatment with acid, it underwent dehydration to give beta gamma unsaturated ester, okay. This beta gamma unsaturated ester was reduced to get the corresponding alcohol, then it was oxidized under swan condition to get the aldehyde. Now this aldehyde is ready for asymmetric aldol reaction, for asymmetric aldol we used a very interesting chiral oxalate, so what we used was this ester, this ester is obtained from mandalic acid, if you see, so this is mandalic acid, okay. The mandalic acid ester upon treatment with excess phenyl trigonade you will get the corresponding tertiary alcohol and the secondary alcohol was acetylated. Now this upon treatment with LDA, you generate anion here and that enolate attacks this aldehyde, you introduce a chiral sender here now, okay. So once that is served you have to remove the ester, so reductive removal of the ester gives your chiral oxalary as well as the 1-3 diol, the 1-3 diol if you rotate it by 180 degree, okay, if you rotate this by 180 degree followed by protection of this 1-3 diol with acetone you get this ketone, okay. Then you need ethyl ketone here, you need ethyl ketone, so that is easily done by cleavage of this double bond to have the fragment A, so the fragment A was easily synthesized in few steps using reformat-skier reaction and asymmetric aldol reaction with a chiral oxalary derived from mandalic acid. Then the fragment B was synthesized using Yvonne's chiral oxalary, first this was deprotonated and quenched with heptidoil chloride, okay, then deprotonation followed by quenching with methyl iodide, you could introduce the chiral center here with a methyl group and then removal of the chiral oxalary with LAH gave the primary alcohol and oxidation with T-POP that is tetra N-propyl ammonium peri-ruthanate with co-oxidant N-methylmorpholine oxide gave the fragment B which is aldehyde, okay, so now aldehyde is ready and then that side ethyl ketone is ready, so now the fragment C, so which is made from 1-3 propane diol, so you take 1-3 propane diol and protect one of the alcohols as TBS ether and then oxidize the other primary alcohol to aldehyde, this upon Grignard reaction, this upon treatment with Grignard reagent derived from 2-bromopropene gives this allylic alcohol, as you know when you have allylic alcohol one can think about sharp plus asymmetric epoxidation, but when you have a resemic allylic alcohol one can think about sharp plus kinetic resolution, so sharp plus kinetic resolution you could get exclusively this alcohol, of course the yield will be less than 50%, that alcohol was protected as TBS ether and followed by osonolysis you get the ketone, now the thiosol unit should be attached to this ketone, so that was done using stabilized witty reaction, now this phosphonate ester derived from the corresponding bromide was treated with butyl lithium as well as quenched with this ketone to get this double bond, so now you need to remove the TBS group selectively oxidize and then convert into double bond for the enclosing metathesis, so selectively the primary TBS was removed, Desmartine peroionine oxidation gave the aldehyde, that aldehyde of hermitic reaction gave the double bond, okay, so then you do not need the protecting group here, because that is that alcohol is required for the esterification, so removal of the TBS gave fragment C, so you could make fragment A fragment B fragment C, now let us see how he combined all the 3 fragments and then completed the totals synthesis of apothelon, so first he started with the ketone, that is the ethyl ketone, generate anion and then quench with this aldehyde, okay, so 1.1 equivalent of LDA generates the enolate quench with aldehyde, so you get the aldol product, remove the asteroid, so you get now the triol, okay, take the triol and then treat with TBS triplet, okay, now all the hydroxyl groups, one primary, two secondary hydroxyl groups were protected as tri TBS ethyl, okay, then the primary one can be selectively removed by treating with campersalphonic acid, so now the primary TBS is removed, you have the primary alcohol, as you know the primary alcohol should be converted into carboxylic acid to make the ester, so that was done with excess PDC in DMF, so once you have the carboxylic acid already, the homolylic alcohol was already prepared, so couple this with DCC, you get a precursor for ring-closing metathesis, so then the ring-closing metathesis with perhaps first generation catalyst gave a mixture of cis and trans alkene, okay, you took the mixture and then went ahead, removed the TBS groups, okay, to get the precursor for apothelan A, treatment of these two alkenes, cis and trans, A, the mixture of apothelan A and the other isomer, the apothelan A is the major isomer, that is how he completed the total synthesis of apothelan A and as you know the key reactions involved in the synthesis are alder reaction, esterification and ring-closing metathesis, overall he took about 16 longest linear steps and yield was close to 3 percent, the fourth synthesis of apothelan which we discussed today was reported by Naneshevsky's group, okay, so here I have written the molecule in a different way, so do not get confused, sometimes any complex molecule can be written in so many ways, but people write the structure according to their convenience and then according to their retro-synthetic analysis, okay. Now let us see how ES synthesized apothelan A and what are the key reactions ES used, Naneshevsky's group used two key reactions which is completely different than the three synthesis which we already discussed, he used a Suzuki coupling, okay and macro alderlization, so that is the last step, he used alder reaction, it is a macro alder reaction as the last step to form the macro actons, let us see how he has done, the first retro synthesis is obviously the epoxy formation, that means the double bond is the precursor for apothelan A, then what he thought was he can use a Suzuki coupling, so that means this side you have boron and this side you have iodine, then you can carry out a Suzuki coupling, so that means he divided that molecule into 3 or 4 fragments, so now if you look at these two fragments, now if you look at these two fragments, this double bond upon hydroboration will give the precursor for Suzuki coupling, okay that can undergo Suzuki coupling with this iodine, vinyl iodine, the other side you can see these two can undergo vitic reaction to get the double bond, okay and this molecule, this particular molecule in principle can be obtained between this substituted Dainichelsky's dyeing and this aldehyde using hetero dill solder reaction, so overall if you look at the synthesis of apothelan A reported by Dainichelsky, hetero dill solder reaction, Suzuki coupling and aldehyde reaction, these are the key reactions he has used to complete the total synthesis of apothelan. Now let us see how he made fragment A, the fragment A, this molecule was prepared from Rowshester, we already discussed about Rowshester when we talked about total synthesis of discodermaline by Schreiber's group, okay. Now he did a hetero dill solder reaction between his dyeing and this aldehyde, so that upon hydrolysis gave this hexagonal bond ENO, okay, so in this process what he has achieved is two new chiral centers, two new chiral centers were established using this intermolecular hetero dill solder reaction, okay. Now the third chiral center he could introduce by reduction of this ENO with lithium aluminium hydride, okay. Now using this chiral center he carried out a cyclopropanation, the hydroxyl group played as a handle to deliver the CH2 group from the same side, okay, the alpha cyclopropanation was carried out using Charrette's protocol. Now the cyclopropanes can be opened, how if you use N iodo-saxonamide, N iodo-saxonamide then this can break and that will lead to oxonium ion and CH2 ion, the six membered ring will become oxonium ion and at third position you will get CH2 ion, okay, so that is what you get, that oxonium ion if you use methanol or any other alcohol that alcohol will attack and neutralize the positive charge on the oxygen. So now you need dimethyl group, so that means the iodide should be removed, so that was easily removed using tributyltin hydride, so you got the methyl group, okay. Now the OME is a lactol protected lactol, okay, so before you do something you have to protect this hydroxyl group, so that was protected as triphenyl silyl ether, okay, that hydroxyl was protected as triphenyl silyl ether, then the lactol should be opened, so the lactol, the lactol methyl ether, first it has to be hydrolyzed, then it has to be protected, but these two can be done in one step if you use propane 1, 3 diol in the presence of Lewis acid, so what happened? You form a lactol and the lactol is protected, okay, so once you have that the free hydroxyl group should be protected again and this is protected as TBS ether by treating with TBS triphylate, then DDQ selectively the primary benzyl ether can be cleaved using DDQ to get the primary alcohol which upon oxidation and Dress 1 condition gave the aldehyde, now Wittig reaction because you need to homologate, so for homologation we carried out enol ether Wittig reaction to get the corresponding enol ether which upon hydrolysis gave the corresponding homologated product, this upon Wittig reaction simple methyl Wittig you get the double bond, okay, now the diethane could be cleaved using BI AB, that derivative of BI AB and since you use methanol as a solvent the aldehyde which is formed is in situ protected as acetone, okay, so now the fragment A is ready, for fragment B is started with the glycidol, okay, which is commercially available and protect the primary alcohol as tetrahydro pyronyl ether, okay, then open the epoxide, open the epoxide with lithiotrimethylsiline propane, okay, so that opens and then you can see this chiral center is formed, okay, that is already you started with the chiral center and next you protect the hydroxyl as mom ether and remove the tetrahydro pyronyl group using PPDS methanol, okay, so once you have that, so an oxidation will oxidize the primary alcohol to aldehyde and treatment with methyl magnesium bromide followed by oxidation with tetra n-propyl ammonium perruthenate gave the methyl ketone, okay, now this vitic reagent upon treatment with butyl lithium you can generate anion and quench with that ketone you get this double bond, okay, now the TMS group can be removed and iodine can be introduced in one step by treatment with niodosexanomy and silver nitrate, okay and this upon reduction with you can call it as hydroboration and reduction, okay, so normally if you have triple bond and then do hydroboration oxidation you will get enol but if you treat with acetic acid it will just reduce the triple bond that is syn addition, so you get the corresponding cis vinyl iodine, then the mom group was cleaved using benzene thiol and BF3th rate to get the corresponding alcohol, this was protected as acetate by treating with acetic aldehyde and deba, so now the fragment B is ready, already we saw the synthesis of fragment A and now let us see how B and A can be combined, as I said this double bond should be converted into corresponding borane derivative so that we could carry out Suzuki coupling reaction, so we took this AA and treated with 9BBN, okay, so then the terminal position you have 9BBN, then Suzuki coupling with this vinyl iodide, now you could see the cis double bond dismount, okay, so for the last step that is a formation of macro lactone, so what is required, the protecting group of the aldehyde that is now acetal, that should be hydrolyzed to the aldehyde and the intramolecular aldol reaction of the acetate with the aldehyde will give the corresponding aldols, so para toluid sulfonic acid removed the acetal to aldehyde, then the key reaction that intramolecular macro aldol reaction was done with potassium exomethyl diselicide, after the aldol now you have to remove the TBS and TPS group, okay, but if you look at this carefully, this TBS, TPS can be selectively removed, okay, so with HF pyridine in the presence of TBS, TPS that is triphenylsilane group can be cleaned, then protect the other hydroxyl as TBS ether, okay, then you oxidize this hydroxyl group, if you look at apothelan, this hydroxyl should be keto, okay, but if you look at the precursors all 3 are hydroxyl groups or protected hydroxyl group, so now you need this as keto, so that is why selectively one has to remove the triphenylsilane group in the presence of TBS and protect the aldol, other side aldol as TBS ether, then oxidize this secondary alcohol to keto, now you have to epoxidize and then remove both TBS group, okay, so that was done first by treating with HF pyridine for little longer time, so both hydroxyl groups are removed, then followed by treatment with dimethyl dioxinane, you could get apothelan in good yield, so overall if you look at this in the CIS, the key reactions are Suzuki coupling, okay, first is Suzuki coupling, then the macro aldolization, so that is not easy, actually macro aldolization is a risk taking reaction for doing such a complex totals in the CIS, but somehow he succeeded the macro aldolization to complete the totals in the CIS of apothelan A, overall it took about 20 steps starting from R-glucinol and yield was close to 2.6 percent, okay, so now we will move to two more natural products and then complete the syllabus tomorrow and after tomorrow, okay.