 Good morning, this is Professor Krishna Kalyapan from Department of Chemistry IIT Bombay and welcome back to the NPTEL course on Classics in Total Synthesis. So today what we will do, we will talk about Total Synthesis of steroids particularly one of the steroids called progesterone and the next few days we will continue to discuss Total Synthesis of few more steroids. So when you talk about steroids, you know the basic skeleton present in steroids has 4 rings, 3 of them are 6-numbered rings okay, you can see 3, A, B, C, they are all 6-numbered rings and the D ring is 5-numbered okay. The numbering of the steroids skeleton starts from the A ring, this is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. First you number fully the A, B ring then go to C ring 11, 12, 13, 14, 15, 16, 17 okay. So you can see there are 17 carbon atoms. Now then there are 2 angular methyl groups one at carbon 13 and other at carbon 10 okay, most of the steroids have these 2 angular methyl at carbon number 10 and carbon number 13 okay. So to give you an example, so this is a reduced version of cholesterol okay, cholesterol has a double bond here, cholesterol has a double bond here. So if you look at this you can see as I mentioned you have 2 angular methyl groups and the A, B ring is transfused likewise B, C also transfused and C, D also transfused and it has a long side chain okay. So this is the basic skeleton of most of the steroids okay, the A, B, C, D is common but in some steroids you will see 2 angular methyl groups at C10 and C30 okay and usually these substituents that is the angular methyl groups are beta, beta means above the plane okay and what are the well-known steroids okay. So this is cholesterol okay which we all have and if you introduce one more double bond okay, so one more double bond and the side chain also okay, there is a change in the side chain then this is called ergo sterol okay, this is called ergo sterol and if you have only the extra double bond come back to cholesterol this is called dehydrocholesterol, dehydro that means you removed one hydrogen okay, dehydrocholesterol. From dehydrocholesterol okay one can prepare vitamin D3, this whole structure is called pre-vitamin D3, the pre-vitamin D3 is obtained from dehydrocholesterol okay, dehydrocholesterol by an electrocyclic ring opening reaction okay, you can see this is a cyclohexadiene and this is hexatrylene okay, electrocyclic ring opening of dehydrocholesterol you get pre-vitamin D3 and this pre-vitamin D3 becomes vitamin D3 by 1, 7 hydrogen shift, by 1, 7 hydrogen shift pre-vitamin D3 under photochemical condition gets converted into vitamin D3, see all these are useful steroids. Then we also have other sex hormones for example male sex hormones, testosterone, so the testosterone has a enone in the erring, enone in the erring with the hydroxyl group in cd ring. Then there are some derivatives of that, so the dienobol where you have extra double bond and the extra methyl group in cd ring and trend bolan you can see you have 2 more additional double bonds and then angular methyl group is missing and nandrolone is not having an angular methyl group at c10 and bolanenone has only one extra double bond and the anterstylene dienobol that means the hydroxyl group in D ring is oxidized, these are all derivatives of testosterone okay, these are all derivatives of testosterone which is the male sex hormone. Then coming to female sex hormone and its derivatives, estrone is the female sex hormone, here the erring is aromatic, erring is aromatic and you have hydroxyl group at 3 position, now since the erring is aromatic the hydroxyl now is a phenolic hydroxyl okay and the D ring you have a ketone okay that is called estrone and if you reduce the ketone it is called estra diol and if you put one more hydroxyl group in D ring this is called estriol then if you add a triple bond to the ketone here, if you add a triple bond to this ketone on estrone then you get ethionyl estra diol, so these are all you know potential oral contraceptive. So then we have progesterone okay, the progesterone again it is not aromatic, so you have cyclohexenone and in the D ring instead of having a ketone or alcohol directly attached you have acetyl group attached to the D ring okay, so this is a major difference between progesterone and other female sex hormones, so based on this several oral contraceptives were synthesized these are all you know synthetic compounds okay, you can go through this leisurely, so these are all well known, well known in the literature and most of them use birth reduction as the key reaction as you can see here, there is no angular methyl group that means they all start from the aromatic compound and then do birth reduction followed by hydrolysis to get this compound okay, so the starting material obviously has to be estrone, from estrone they make all this oral contraceptives. Then we have corticosteroids and the basic unit is cortisol okay, again you have the same A, B, C, D ring but you have an additional hydroxyl group here, you have additional hydroxyl group in C ring, normally you in other steroids you do not see a functional group in C ring okay, only in corticosteroids you will see a functional group in C ring and in the progesterone you had CO CH3, now it is CO CH2 OH and also another OH attached to the same carbon in D ring okay and in prednisalome okay, you have additional double bond in A ring and texamethasone you can see a very important group fluorine, fluorine in B ring and you also have additional methyl group okay, texamethasone during the COVID treatment initially people were given texamethasone, so this is the structure and beta methasone is an ointment normally given for skin treatment okay, generally people have psoriasis or related diseases, so they give beta methasone which you can apply, so that is also related to texamethasone, only thing is you have beta methyl group okay, then butasone, this is very interesting steroid normally given for people with asthma they can inhale taking this butanocyte, so all these are very very important steroids which are given for various treatments okay, then we have bile acids, so the bile acids the main difference is the A B ring junction, if you look at all other steroids which we discussed the A B ring junction is trans whereas in bile acids the A B ring junction is cis, so if you have 1, 2, 3 hydroxyl, 1 carboxylic acid it is called colic acid and if you have 2 hydroxyl, 1 and then 2, A and C ring then it is called deoxy colic acid and if you have same 2 hydroxyl but in A and B ring then this is called chino deoxy colic acid and if you have only one hydroxyl that 2 in A ring this is called litho colic acid okay there are 4 bile acids which you should remember and when you talk about conformation cholesterol that is reduced form of cholesterol have trans ring junction is not it, so the most stable conformation of cholesterol is this transdecoline, transdecoline and again trans hydride system whereas in colic acid as I said the A B ring is cis, the A B ring is cis so you can see this is cisdecoline and this is a transdecoline and this is transhydride okay, so only A B ring is cis fused and all other 3 rings are trans fused okay, so with this brief introduction so now let us see how steroids are synthesized in nature okay before that before steroid let us start with biosynthesis of simple terpenes okay, mono terpenes, sesquiterpene, di terpene then go to steroids, so normally if you have a double bond like this and a carbocation which is within the reachable limit then the double bond can try to neutralize the positive charge and generating a ring as well as a carbocation, so this is how in nature cyclization takes place to form a ring, somewhere carbocation is formed or you have a good leaving group once the leaving group is ready to leave the double bond can migrate and generate a carbocation, so this is the basic principle in many terpenes and steroid biosynthesis, so if you talk about C10 then they are called mono terpenes, if you talk about C15 that is 15 carbon atoms they are called sesquiterpene and if you talk about C20 they are called di terpenes and C30 we can talk about steroids, for all this there is a starting material in nature okay, so geronial if you start with geronial then that can lead to all mono terpenes and if you start with farnesol that can lead to all sesquiterpene and if you use geronyl geronial then that can lead to all di terpenes, likewise if you start with squalling that can lead to all steroids that is how all the biosynthesis are you know working, what is the basic building block if you look at terpenes or steroid, the basic building block is isoprene okay the basic building block is a 5 carbon unit called isoprene but in nature isoprene is in the form of isopentenyl pyro phosphate, this is pyro phosphate, so it is a good living group basically it is a good living group so that you know if you have geronial and then this is geronial pyro phosphate, so this is the starting material in nature for making all mono terpenes and this is farnesol pyro phosphate, you can see there are 15 carbon atoms, so this is the starting material for sesquiterpene, this is C20 geronyl geronial and that is a starting material in nature for di terpenes, this is squalling just 30 carbon unit okay, so that is the starting material for all steroids okay, so first let us see how these are all made in nature, then we will talk about synthetic approach to steroids okay, so when you talk about mono terpenes, there are many mono terpenes, I am just I am giving only few examples, limonin, carbone, polygone, menthol, camphor, I am sure all this you will know okay, you might have heard limonin, carbone, polygone, menthol, camphor, even citronilol you should know, geronial you should know, nirol you know, these two phylandrine and pereloid aid you may not know okay, so these are all you know reasonably well known mono terpenes, why I am insisting these mono terpenes are important because they are used as chiral starting material for synthesis of several natural products okay, most of them are chiral okay except nirol and geronial, most of them are chiral and they are used as starting material for synthesis of many other natural products. And some more mono terpenes you know alpha pynine and beta pynine and if you do allylic oxidation of alpha pynine you get verbenone and then if the allylic oxidation takes place at the methyl group, this is called mertinal, the nopal is a homologated compound of alpha pynine, then you also have 3 carine and 2 carines, all this you see they are mono terpenes okay. How mono terpenes are synthesized in nature, what is a biosynthetic pathway, as I said the starting material in nature for mono terpenes is geronial pyro phosphate, so that means this is a good living group, this is a good living group which means that you can generate a carbocation line. So this double bond which is very close to this can migrate and then pyro phosphate can move that will lead to this tertiary carbocation okay, so once this tertiary carbocation is formed there are many further rearrangements possible okay. So if a proton is lost then you get limoni, this is called limoni and here once the carbocation if the double bond here neutralizes a positive charge then you get this intermediate and this intermediate one can convert later by loss of proton to give alpha pynine or beta pynine, exocyclic double bond is formed that is beta, if endocyclic double bond is formed then it is alpha pynine okay. Then direct attack of water will give you alpha terpenia, direct attack of water to neutralize the positive charge you get alpha terpenia, if the hydrogen migrates, if the hydrogen migrates then you get another tertiary carbocation okay, so that will lead to the formation of 3 carins and 2 carins okay and here the double bond when it migrates there are 2 possibilities, one the formation of this pynine precursor other one the formation of camphor precursor, once you have this carbocation water can attack followed by oxidation it can give camphor okay. Then simple loss of proton, simple loss of proton will give alpha terpenia, so basically if you look at all this biosynthesis the starting material is gerinial pyrophosphate okay that is for monoterpene, for sesquiterpene as I said fer mesel pyroposphate is the starting material okay, again the same way the pyrophosphate goes out and then you get a 6 mumble ring with a carbocation okay, so now what can happen this hydrogen can migrate, if that migrates the carbocation comes to the 6 mumble ring okay carbocation comes to the 6 mumble ring then you have a double bond here okay, this double bond can neutralize the positive charge, if that happens you get a pyrosystem, you get a pyrosystem and this will lead to a range of sesquiterpene, they are called aquarines okay and it depends on which double bond which side of the double bond neutralizes the positive charge, if this carbon neutralizes that will lead to a sesquiterpene type called aquarines and if this carbon neutralizes that will give another class of sesquiterpene called chamigreens okay, so all this start from the same starting material. Now you have another double bond is not it that double bond can neutralize this, that double bond can neutralize the positive charge that will give you this intermediate now loss of proton will give a sesquiterpene called sedrin okay, please remember so this is these 2 are the key intermediates okay, key intermediates that can lead to okay all mono sesquiterpene these 2 are the key intermediates that can lead to all sesquiterpene okay. What is important is when you do cyclization, when you do cyclization whether the stereochemistry of the double bond will be preserved or not, according to Stark and Escher Mosier whatever geometry your olefin has before the cyclization that will be preserved okay, if you have a trans-olefin then after cyclization what you get is transfused ring and if you have cis-olefin you will get cis-fused ring, so this is what they write you can see the center one is a trans double bond, can you see it is a trans double bond now after cyclization it forms a trans decaline system, basically the trans double bond geometry is preserved in the final product for dieterpene you have to go to geronyl, geronyl, geronyl pyroposphate and again the same way it can protonate and then you form the AB ring, now the carbocation is here then last a proton will form a double bond, then what happens the double bond will attack and this double bond will come and then pyroposphate goes and you get this intermediates okay. The next step is very interesting the hydrogen from here is lost and you get the internal double bond okay you get an internal double bond, now this internal double bond okay another internal double bond is formed because of conjugation through this mechanism okay and that leads to a natural product called abetic acid, that leads to a natural product of abetic acid and this is the key transformation and from here one can think of converting this abetic acid into many dieterpene many dieterpene, from dieterpene now we will move to steroid, so steroid it start with squalin and squalin epoxidize enzyme epoxidizes the terminal alkene okay. Now protonation takes place once the protonation takes place the epoxide will open and then series of double bond migration will take place that will lead to this carbocation you can see the epoxide opens then this double bond migrate, this double bond migrate, this double bond migrate and you get a carbocation. So now what will happen again in type reaction will take place, in type reaction will take place to utilize the positive charge, so that will give you steroid skeleton with the double bond with the side chain you can see side chain but what you do not need is you have a methyl group here and this methyl group should go to this position, so basically what you have to do again you have to protonate this carbon, you protonate this carbon okay then you get a carbocation okay then what will happen series of migration takes place first this hydrogen will migrate, this hydrogen will migrate followed by migration of this hydrogen then methyl group, this methyl group and loss of proton you get this compound and this is called lanosteroid okay then series of oxidation, decarboxylation takes place to give cholesteroid okay. The key intermediate formed in the steroid biosynthesis is lanosteroid from lanosteroid all other steroids are formed okay so why I thought I should give a brief introduction to biosynthesis of steroids before that biosynthesis of terpenes is important from the synthetic point of view whether can we follow what nature has been doing so that we can prepare the starting material and try to replicate what nature is doing okay so that we can call it as biomimetic synthesis you are just trying to mimic what nature is doing okay so there was one synthesis of progesterone reported long time ago more than 50 years ago by W. S. Johnson where he exactly followed the principles adopted by nature to make progesterone okay so that is why we call it as biomimetic synthesis. So here the retro synthesis is like this so when you have progesterone this can be obtained from this 5 membered ring okay how if you cleave this double bond you get a diketone that is 1 5 diketone this 1 5 diketone upon aldol reaction can give progesterone okay now how you can get this 5 membered ring so this is where he wanted to use this biomimetic reaction so here if it forms a carbocation the tertiary alcohol upon protonation you get a carbocation then this bond will migrate this bond will migrate this bond will migrate this bond will migrate then water will attack that will give you the corresponding ketone okay and this is how you know the chair like transition dates chair like transition state chair like transition state okay so basically what you need to do is you have to prepare this tertiary alcohol how you can prepare this tertiary alcohol okay this preparation of tertiary alcohol is quite easy okay and if you have ketone then you can prepare the Krugnall addition will give the tertiary alcohol and this 5 membered ring can be obtained from this diketone okay this diketone just aldol reaction will give 5 membered ring followed by Krugnall addition you will get the tertiary alcohol and this can be obtained by a Wittich reaction okay if you break this bond you can generate you have the Wittich salt and this aldehyde okay and this Wittich salt can be made from this corresponding bromide so the bromide is used for making the Wittich salt and this furan normally as you know you can make it from 1,4 diketone so if you treat with acid furan will open up and then you get corresponding 1,4 diketone that in C2 if you protect it with ethylene glycol you get this compound then the other aldehyde can be obtained by Claisen reagent and before that this can be easily obtained from 2 methyl furan and then you generate lithium species and quench with this 1,3 what is the 1,4 dibromocom the other aldehyde can be easily prepared if you look at this aldehyde it is alpha beta gamma delta so gamma delta and saturated aldehyde is normally you know prepared from allylic alcohol via Claisen reagent okay this is called Johnson ester Claisen reagent so you can get this aldehyde from this you will get an ester that ester can be converted to aldehyde so now that can be prepared from this allylic alcohol and that allylic alcohol can be prepared from this alpha beta and saturated aldehyde and the Grignard reagent so it is a very very simple retro synthesis and the synthesis started with this aldehyde and you do the Grignard reagent in THF you get the allylic alcohol which is required for the Johnson Claisen reagent so for that you treat with triethyl orthoformate with catalytic amount of propionic acid very important you cannot use excess otherwise it will form corresponding ester okay very very catalytic amount of propionic acid and it forms this intermediate okay once you have this intermediate as you can see here is a 1,5 diene it can undergo the Claisen rearrangement to give the corresponding actually ester that ester is reduced and oxidized to get the corresponding aldehyde okay in 2 steps after this you have to reduce with LAH 1 then oxidize under one condition you get the aldehyde once you have this aldehyde then the other side can be easily prepared from 2 methyl furan treat with butyl lithium and 1,4 dibromo butane and monoalkylation takes place now if you treat with PTS para toluene sulphonic acid it opens up the furan to give 1,4 diketone and then 1,4 diketone is in-situ protected by ethylene glycol in-situ protected by ethylene glycol so with this now you have the bromide and then using Fingalstein reaction you exchange that with sodium iodide and then triphenylposphine you make the vitic salt now treat with n-butyl lithium you generate the elide then add this aldehyde and you get this alkene so you get a mixture of transensis and where trans is 97 okay so once you have that now remove the ketol remove the ketol and then treat with sodium nitroxide you get the aldol products okay the cyclopentenol so what is left now you have to add the Grignard reagent so you can add either Grignard or you can add methyl lithium to get the tertiary alcohol now you treat with acid okay trifluoroacetic acid and quench with this compound okay so as I said here protonation will take place this double bond will migrate this double bond will migrate this double bond will migrate then triple bond will migrate then water will attack you get the corresponding ketone okay now from here to polystyrene is very simple osanalysis will give the diketone okay osanalysis will give the diketone now aldol reaction okay simple aldol reaction will give you the corresponding natural product that is progesterone so here the advantage of this method is just follow the nature where you can carry out the polyene cyclization under acidic condition and followed by osanalysis and aldol reaction one can get progesterone so this is one of the classical synthesis of one of the steroid molecules called progesterone in subsequent lectures we will discuss about more steroids and more total synthesis of steroids okay thank you.