 So, good morning welcome back to NPTEL course on Classics in Total Synthesis. The last lecture we talked about totals in the subprogesterone actually it is a semi-synthesis of progesterone from diogenin and we also discussed little bit about the history of diogenone and how Marker went to Mexico and then got the roots which essentially gave tons of diogenin and from diogenin how he converted that into progesterone. So, later the formation of syntax company all that we discussed. So, today what we will do we will move to another steroid called estrone okay this is a female sex hormone as you know. So, this is one of the three female sex hormones estrone, estradiol and estroial okay see if you look at estrone and estradiol you can see the carbonyl group is reduced okay already you have a hydroxyl group in the form of phenol in earring and in addition we have another hydroxyl group in estradiol whereas in estradiol you have one more hydroxyl group okay. So, these are the three you know estrogen molecules but what we will do we will talk only about the total synthesis of estrone today and estrone initially it was isolated okay initially it was isolated in the form of estrone sulphate from urine okay. People have collected lot of cows urine and from that they have done huge column huge column to get estrone sulphates okay. And from synthetic point of view if you look at this molecule there are four contiguous chiral centres that is the first and foremost challenge see. So, 1, 2, 3, 4 there are four contiguous chiral centres in addition you have an angular methyl group and the ring junction okay the ring junction if you look between BC and CD they are trans-antial relationship okay. So, this is something which is quite difficult particularly when you talk about the hydrodendron cell scrycon hydrodendron generally the cis relationship is more stable than the trans one okay. So, these are the challenging aspects when you talk about total synthesis of estrone so far the first synthesis of estrone was reported by Targo in early 60s in Tata Khan letter and the whole synthesis involved only 6 steps the whole synthesis involved only 6 steps and their strategy is based on they will start with AB ring okay they will start with AB ring first then they will add this D ring AB and then they will add AB D ring then they will construct the C ring. So, they start with AB ring bring the D ring then form the middle ring that is C ring okay and as I mentioned it was only 6 steps and that time it was considered one of the best synthesis and more importantly this route is still followed in industry okay this route is still followed in industry to make estrone and related steroids. The key reactions involved in the total synthesis of estrone are one the acid catalyzed cyclization acid catalyzed cyclization to get the C ring second the stereo selective reduction of dienes there are 2 double bonds which are formed at the end of acid catalyzed cyclization I will discuss that when I go into the total synthesis then the reduction stereo selective reduction of this diene to get the correct geometry of the ring junction okay. So, let us see how he started this he started with readily preparable starting material called 6 methoxy 1 tetralome 6 methoxy 1 tetralome and addition of vinyl grignard okay addition of vinyl grignard gave this tertiary allylic alcohol addition of vinyl grignard gave this tertiary allylic alcohol. Now he treated this with 2 methyl 2 methyl cyclopentane 1 3 diene okay 2 methyl cyclopentane 1 3 diene in the presence of base even use Triton B now this undergoes substitution reaction like this okay so what he got was this double bond next is one of the key reactions acid catalyzed cyclization so when he treated with acids first the double bond migrates here then intramolecular fluorocup like reaction takes place to give this diene okay the intermediate here is this couple okay this is the first step that is after the migration of this double bond then intramolecular fluorocup reaction will give this intermediate then dehydration will take place to give this diene dienome okay. Once you have this dienome you have to selectively reduce this double bond trisubstituted double bond then you have to reduce the tetrasubstituted double bond so these 2 were done individually first that trisubstituted double bond was reduced under hydrogenation condition in the presence of triethylsilane okay triethylsilane also can't give hydrogen first as I said this 5 ombre ring the trisubstituted double bond was reduced okay for the next one tetrasubstituted you need stronger condition so trifluoroacetic acid and triethylsilane was used to get the corresponding you can see trans and then trans okay system. So once you have that what is left is to remove the methyl or cleave the aryl methyl ether so that was easy by treating with BBR3 to get ST. So overall if you look at the total synthesis of estrone reported by TORGO is only 6 steps okay and involves 2 key reactions when is acetylcaldecyclication and then stereo selective reduction of the diene however the starting material 6 methoxy 1 tetralone okay 6 methoxy 1 tetralone was prepared in few steps but all in good yield the first step was the fredelkrafts acylation fredelkrafts acylation of anisol with Saxonic anhydride okay so that gave this keto carboxylic acid okay that gave this keto carboxylic acid. So now if you do Clemenson reduction if you do Clemenson reduction as you know Clemenson reduction is known to reduce the keto group to corresponding okay so this keto was reduced under Clemenson reduction condition to get CH2. Now from here to here from here to here can be done in 2 steps or even in a single step in single step means you have to use poly phosphoric acid okay poly phosphoric acid is known to cyclize the carboxylic acid and aromatic ring however many times it gives poor yield instead what one can do is one can convert the carboxylic acid to acid chloride one can convert the carboxylic acid to acid chloride. So once you have the acid chloride then intramolecular furcups acylation can be done with Lewis acid okay so the second step is the intramolecular furcups acylation once you have that then the keto group is deoxygenated the carbonyl group is deoxygenated with hydrogen and copper chromate and the last step is the regioselective benzylic oxidation with chromium trioxide. So we accept the last step all other steps if you see all the remaining 4 steps gave excellent yield okay so this is one of the key starting materials 6-methoxy 1 tetralone is one of the key starting materials in the synthesis of almost all the steroids as well as you know many other natural products okay that is why I thought it is better to discuss how the 6-methoxy 1 tetralone was prepared okay. So the synthesis reported by Targo was resemic synthesis so then people thought one can use the same strategy but somewhere if one can introduce chirality then that will be asymmetric synthesis. So EJ Coray it took this compound now you have 2 ketones is not it 2 ketones one can call this is symmetrical one this E reduced with is CBS catalyst okay CBS catalyst Coray Bakshi Shibata catalyst with that catalyst E could get this compound okay now you see it was resemic and E could get 2 chiral centers fixed okay 2 chiral centers okay using this CBS catalyst then what is there you have to do the acid catalyzed cyclization is not it. So you did the acid catalyzed cyclization and then oxidize oxidize the alcohol okay to ketone afterwards in 2 steps that is using hydrogenation and trifluoroacetic acid and tithylsilane one can convert this into estero followed by removal of the methoxy group okay. So in 3 steps this can be easily converted to estero but the difference is this is synthesis of estero of 1 enantiomer okay here it is plus enantiomer has been synthesized and for that the important reaction is the CBS catalyst mediated production of 1, 3 diketone to get exclusively this size okay this is the CBS catalyst the CBS catalyst is prepared from diphenylprolinol the CBS catalyst is prepared from diphenylprolinol okay then you will move to 2 more very interesting total synthesis of estero one was reported by Lutz Tietze here what he has cleverly used is double heck reaction to make or connect the A ring with C ring okay what did he do? So his idea is if you want to make a storm then you thought if we can introduce these 2 double bonds if we can introduce these 2 double bonds and these 2 double bonds he felt can be introduced by heck reaction okay his idea is like this the double heck reaction can be done on this substrate okay. So this is actually when you see this there is only 1 heck okay that is only 1 heck okay the second heck is obtained from this so this will be the first heck okay this will be the first heck reaction and this will be the second heck reaction so using a double heck reaction in the same part one can get from this compound directly this that was his original idea okay and how did he make this starting material particularly this one he made from the Hages Parish ketone okay he started from this and then selective reduction of the 5 ombre ketone and protection of that alcohol as terributal ether give this compound then one can reduce the enone okay here you have to do it at sub 0 okay you have to do it at sub 0 and 0.25 equivalent okay and this can be done at room temperature and of course you have to use cerium chloride otherwise the double bond also will be reduced and this is called Lucia reduction isn't it Lucia reduction is nothing but production of alpha beta unsaturated ketone to corresponding allylic alcohol with sodium borohydrate and cerium chloride okay. So now you got this allylic alcohol and this untreatment with formic acid formic acid pyridine and acetic anhydride you get the corresponding formate. Now the double bond migration that is you know allylic now you see this is allylic one so you can use palladium catalyst allylic transposition and you transfer the double bond at the same time this is being replaced the acetate the formate is replaced by hydrogen okay. So basically if you look at this in 5 steps Hages Parish ketone can be converted into one of the starting materials one of the starting materials required for a stone okay. For the other starting material you have to start from the corresponding aldehyde this aldehyde so it is a commercially available aldehyde you take this aldehyde then do a Wittig reaction okay. So you have to do a Wittig reaction to get the corresponding cis vinyl bromide okay. Take this and already you made this compound okay do the double heck reaction. So when you do the double heck reaction this is the first one first heck product and the second heck will give you this compound as the major isomer okay. Now you can do the hydrogenation followed by oxidation you will get corresponding estrone okay. The third synthesis the third synthesis of estrone not you know order wise but third synthesis which we are going to talk about involves a 2 plus 2 plus 2 cyclo addition okay of 3 triple bonds okay we can call it as cyclo trimerization okay cyclo trimerization also one can call. So 3 triple bonds will trimerize to form an aromatic ring so that was the key reaction so in the literature it is well known that if you use cobalt carbonyl cyclopentadienyl cobalt carbonyl or if you use Wilkinson catalyst this type of 2 plus 2 plus cyclo addition can be easily achieved. So this idea is this first the B and C ring will be obtained by an intramolecular Diels-Aldreaction intramolecular Diels-Aldreaction what is an intramolecular Diels-Aldreaction? So here if you heat it it will undergo first an intramolecular electrocyclic ring opening. So this is nothing but cyclobutane is not it? So it can undergo intramolecular electrocyclic ring opening to give this intermediate okay. So now this can undergo a 4 plus 2 IMDA type 1 that is intramolecular Diels-Aldreaction type 1 that will give you our discount okay. Now this can be obtained by the 2 plus 2 plus 2 cyclo addition reaction this is a alkyne this is an alkyne this is an alkyne there are 3 alkynes that can undergo cyclo trimarization to give the precursor to electrocyclicization followed by IMDA type 1 reaction and this can be obtained if you see this if you cleave this bond then this will be an electrophile. Now one can add vinyl copper okay if you add vinyl copper followed by Konjin with this you will get this point okay this is commercially available. So once you have this then you can do the cyclo trimarization and then followed by heating should give the electrocyclic ring opening and 4 plus 2 cyclo addition products. So now let us see how the di-ion was prepared di-ion. So you started with the known compound and then when you add excess n-butyl lithium at least 3 equivalents of n-butyl lithium is required 3 equivalents of n-butyl lithium is required. So first these 2 acetyl protons will be lithiated followed by removal of the propogelic proton. So you get a tri litheo species tri litheo species then you open with ethylene oxide you get the corresponding alcohol okay. This can be converted into the iodide first by treating with tosel chloride to get the toselate then Fingrelstein reaction with sodium iodide and methyl ethyl ketone you get corresponding iodide okay. So this is done and already as I told you the tri-trimethyl acetylene is a known compound so that can be directly used. So for the other fragment you have to start from 2-methyl cyclopentenone 2-methyl cyclopentenone then you carry out vinyl 1 4 addition with vinyl magnesium bromide and cuprous iodide and quench the resultant enolate okay quench the resultant enolate with the TMS chloride okay. So now what you got is you have done the vinyl 1 4 addition but the enolate is trapped the enolate is trapped as TMS ether okay. So the O TMS can be cleaved O TMS can be cleaved with either methyl lithium or lithium in ammonia so that what will happen you will generate the lithium enolate. Once you generate the lithium enolate you can quench with the iodide which we have already discussed. So the iodide already as I said can be prepared from this alcohol. Now you treat with lithium ammonia you generate the enolate lithium enolate and quench with the iodide and you get this as the major isop okay. So now you have this the next step is the cyclotrimerization that is 2 plus 2 plus cycloaddition. So this is normally achieved by either Wilkinson catalyst or cyclopentadienyl cobalt dicarbonyl compound. So that reaction worked well as you can see here that led to this Benzo cyclobutane this is called Benzo cyclobutane and this is one of the very good precursors for electrocyclic ring opening followed by intramolecular Diels-Ald reaction. So once you have that next you have to heat it so heating gives the electrocyclic ring opening dye and that immediately undergoes intramolecular Diels-Ald reaction to give these 2 products. One the intramolecular Diels-Ald reaction product the other one the other one is the isomerized product this one you get back the starting material but this is isomerized. Nevertheless if you heat this further if you heat this further it gets converted into the expected product okay that means the 56% which you are getting is converted into the expected product in 95% yield. So that means close to you know how much you get close to 70% you get this as the product okay. So with this next step should be to remove this TMS group and exchange this TMS with hydroxyl group okay one of the TMS should be selectively removed or you can call that as proto desylation whereas the other TMS group should be converted into OH. So before actually he tried to do this reaction he thought it is better to use a model system and then study whether the silicon can be easily selectively removed. So you took a model system that is a tetraline system and then first he tried with palladium trifluoroacetate okay but what he got was the mixture so then he thought okay this is not a good method then he used first acetylation it is well known in the literature if you have TMS group attached to aryl ring, TMS group attached to aryl ring then if you treat with acetyl chloride aluminium chloride the TMS will be replaced by acetyl group that means TMS will be replaced and then you are putting this acetyl group okay. So that was the first step and the second step is the Bayer-Villager oxidation. So once you have the acetyl group acetyl then O acetate it forms. Meanwhile the TMS is intact only one of them reacts okay. So with this he thought okay so after he was successful in doing this he thought he should extend this to real substrate and for that if he has to use this Bayer-Villager oxidation the keto group which is present in D ring should be protected otherwise that keto group also can undergo Bayer-Villager oxidation. So his idea is now to get this keto group protected. So for that what he did he started from the starting material before the cyclotrimerization then you protect the ketone as the ketol by treating with 1 to ethane diol or ethylene glycol. So now you carry out the trimerization. So here what happened when he did this you could get 2 is to 1 ratio of the required one then he did the cyclotrimerization and the cyclotrimerization gave this as the major product. You are required one as the major product and this where you can see unmodded C-isomer is the minor isomer okay. So now the next step is to take the major isomer and treat with acetyl chloride and aluminium chloride okay but contrary to the model system when he tried this reaction on this real system he got complex mixture. So again he has to revise. So what he did he simply added bromine and pridine, bromine and pridine because that is also known to replace the TMS group okay. So he wanted to know whether it can be selectively done. So he tried to do this reaction with bromine and pridine and here if you look at this he got a mixture bromine which is at the required place because later this bromine should be replaced as OH that as the minor product 4 is to 1 okay that means the required product is 1 okay. Nevertheless he took the mixture and then try to replace that okay try to replace it with OH what you can do you can treat with butyl lithium. So once you treat with butyl lithium the CBR bond will be exchange and then you will get CLI and then treat with trimethyl borate followed by treatment with acetic acid and hydrogen peroxide you can convert that into hydroxyl group okay you can convert that into hydroxyl group. So now you could separate at this stage so once you have polar group you know it is possible to separate. So you could separate this required compound and the next step is to remove the TMS as well as the keto if you can remove these two one is proto desalination proto desalination other one is to remove the ketol so if you can do that then you achieve the total synthesis of S2. So that is very simple and after separating these two he took this compound that is required compound and then treated with mineral acid okay once you treat with mineral acid dilute mineral acid. So the ketol is removed and then TMS also is removed and that gives your S2. So this is how Wollard has completed the total synthesis of S2 and here the key reactions which he used are cyclotrimerization then he also used electrocyclic ring opening of benzocyclobutane followed by intramolecular dilsal reaction IMDA type 1 to construct the ABC 3 okay. So with this I will stop here and then we will continue our discussion tomorrow okay thank you.