 Good morning and welcome back to the NPTEL lecture series on classics in total synthesis sub part 1. So in the last lecture we talked about the various methods for the preparation of beta lactams and also the first total synthesis of penicillins. So we continue our discussion on the total synthesis of the forenumbered lactams and this time we will talk about total synthesis of another closely related natural product called thynomicin. And if you look at thynomicin and it has a lot of similarities with penicillin, both have this forenumbered lactam and in the five-umbered ring there is a change, you can see that earlier in the five-umbered ring you would have noticed this is the five-umbered ring. Now that S has come here, the S has come outside the five-umbered ring and also in the side chain earlier in penicillin you used to have NH2 and that NH2 is acylite. But here what you have is CH3, CHOH. So these are the major changes one can easily notice when you look at the thynomicin core structure with and compare it with penicillin. So as I mentioned while discussing about penicillin, penicillin actually created real major effect on the applications of penicillin type natural products for the treatment of bacterial infection. And after some time the bacteria started developing resistance to the penicillins that is why the second level of antibiotics were really required to tackle all types of bacterial infection. So that is how in 1970s milk group, so they disclose the structure of thynomicin which showed significant antibacterial activities and also it was isolated from the fermentation broths of the soil microorganism called streptomyces catalya and it showed very good activity against pseudomonas and beta-lactamase producing species. So this was second major breakthrough in the antibiotic history and let us see how thynomicin was synthesized by Merck. Initially they did a enantioselective synthesis and later they also reported a bulk scale resemic synthesis of thynomicin. First let us look at the enantioselective synthesis of thynomicin and their idea was first they want to construct the carbobinum framework at a later stage that carbobinum framework is the bicyclic framework that they wanted to construct at a later stage and then they wanted to you know append cystiamine and hydroxy ethyl side chains at preformed ring system. Once the rings are formed then they can attach these two and initially they wanted to do the enantiosespecific synthesis start with enantiomerically pure starting material. So let us see how they proposed the retro synthesis for thynomicin and how they went ahead and completed the thynomicin. So thynomicin so if you look at this structure the first retro synthesis involved the cleavage of this mod CS mod the idea is this can be introduced through an addition elimination reaction. See for example if you have a beta keto ester okay if you have a beta keto ester so then one can make the corresponding enol ether one can make corresponding enol ether or you can make the corresponding vinyl chloride. So then if you treat with this corresponding thiol it can undergo a 1, 4 addition a conjugate addition followed by elimination. So that way it is easy to introduce this thiol group. Next that is a key reaction where he wanted to introduce the CN bond and make the five number ring through the carbene insertion okay CN bond formation through carbene insertion okay. So if you talk about carbene insertion obviously the precursor is the corresponding diacyl compound. The diacyl compound can be easily prepared from the beta keto ester, beta keto ester if you have and then treat with base and then tosyl acide you can easily introduce the diacyl compound okay. So that is a precursor for this. So now this is a monocyclic compound and one can easily do it through first you can see here this aldol reaction you generate anion and then do an aldol with acetaldehyde you will introduce the CH3, CHOH side check and here this can be made by simple alkylation that is if you have TMS13 diethion and treat with butyl lithium you can generate anion in that can attack and in ascent to substitution you can introduce this. And this can be obtained the four ombre lactam can be obtained from the corresponding ester and simple lactamization between these two protected amino acids can lead to the lactam and this is nothing but L aspartic acid which is commercially available okay this can be easily made from the commercially available L aspartic acid. Now let us see how they have accomplished the total synthesis of tiramacy L aspartic acid the both carboxylic acids were protected as benzyl ether okay. Then the NH2 was protected with the transient protecting group like TMS chloride why I am saying transient protecting group is you know there are different types of protecting group the transient means it is used for one or two steps okay label protecting group just use it for one or two steps and then cleave it. So the TMS is one such transient protecting group now after that you treat with base here now base is tercibutyl magnesium chloride so it generates anion and then attacks intramolecularly the carbonate group of the benzyl ester to form the four ombre lactam okay. Then once it is done that the TMS group can be easily cleaved by treatment with two normal HCl. So the four ombre lactam is formed then the ester group should be reduced selectively in the presence of four ombre lactam okay so that is selectively done by reducing with sodium orythinol to get the primary alcohol. The primary alcohol should be converted into the iodide okay this was done in two steps first convert the primary hydroxyl group into mesalate and followed by Fingalstein reaction you treat this mesalate with sodium iodide in acetone you get the corresponding iodide. Now this NH the amide NH was protected as TBDMS by treating with TBDMS chloride then you take this two litheo two trimethylsilyl13 diethane you get the corresponding alkylated combo okay it is a simple SN2 reaction. Then you can generate anion with LDA quench with acetaldehyde so get the aldol product you get a mixture one is to one okay one is to one and in this case you see this stereo center is fixed okay whereas the hydroxy carbon the hydroxyl group attached to carbon there you got mixture one is to one okay. So what you did you took this mixture and then oxidized okay you took this mixture and oxidized and same thing the same ketone what he did he also got it in one step instead of doing aldol followed by oxidation he took this lactum and then treated with LDA and N acetyl imidazole okay you treat with LDA and treat with N acetyl imidazole he got the same product okay. Now when you reduce this ketone with K-selectride you got 9 is to 1 ratio of the expected product and one is the unwanted product unwanted isomer okay. So then you took the major one and then treated with mercury chloride and mercury oxide so that is to remove this ketone okay the ketone group was removed to get the corresponding ketone as you want acid the TMS group was treated with hydrogen peroxide to get the carboxylic acid okay. So once you have the carboxylic acid convert into the corresponding imidazole okay then you remove this or do a SN2 reaction with para-nitrobenzyl CO2 CH2 that CH-attacks this carbonyl and this imidazole comes out so what you get is this compound. So basically what they have done is to prepare the precursor for making or introducing the diosocombo for the introduction of diosocombo you need a beta-keto ester okay so that is what they have done and here R is still the TBDMS group. So once you have this treat with HCl methanol and treat with para-tolamine sulfonyl oxide pyethylamine. So HCl methanol removes the TBDMS group then the tosyl oxide as I said introduces the diosoglue the tosyl oxide introduces the diosoglue. Now you treat with dirodium tetracetate and it forms the carbene and NH insertion immediately takes place to get the firmum bird ring okay this is a very very interesting method to make the firmum bird ring but the stereo center is it important no because if you look at the natural product dynamosine you have a double bond here is not it. So that chiral center is not important so what you do take the beta-keto ester and treat with phosphoryl okay diphenyl phosphoryl chloride okay that forms the enol phosphate if you have beta-keto ester and then treat with diphenyl phosphoryl chloride it forms the corresponding beta-keto. So corresponding enol phosphate okay this enol phosphate again as I said it can undergo a 1, 4 addition followed by elimination that addition elimination reaction with this thiol will give you the expected products okay. So now what is required in the total synthesis of thiomysine you have to remove the para-nitro benzyl group without touching the double bond okay hydrogen analysis gives the corresponding carboxylic acid and you can see there are 2 para-nitro benzyl one here and one there. So this will lead to carboxylic acid and here this will also remove the carbon dioxide because that is a protecting group NH2 is protected as NHCOOPNB so when you remove the para-nitro benzyl group the carbon dioxide also will go and you will get NH3. So then that will be in the citroenic form so that is how they completed the MNCO specific total synthesis of thiomysine. And then they wanted to develop a scalable method for thiomysine and for that they first they develop a scalamic method that is resemic method for the synthesis of thiomysine. So what did they do and how did they do? So they started with this commercially available beta keto ester I can see. So this one has 2 esters isn't it? This one treatment with benzyl amine okay so it can form enamine isn't it? So in the presence of molecular sieves it forms enamine that enamine when you treat with key team when you treat with key team it can undergo at this position okay so it can undergo at this position basically you introduce a CO CS3 okay N acylation take place okay. So I have written the other way other side okay so 180 degree auto rotate so you will get this compound or you can I can write that structure so that you know you will not get confused because both are same. So this is NBN then CO CH3 you can see that. So this I have rotated 180 degree okay now when you reduce this ketone okay when you reduce this ketone with sodium cyanoboridate in the presence of acetic acid okay not only it reduces the ketone but also the enamine portion okay that gives you can see 3 stereogenic centers okay that fixes of course it is a racemic okay. So you get the exactly opposite isomer also. Now if you treat with concentrated HCl if you treat with concentrated HCl so this bond rotates okay this bond rotates so what you will get is what you will get is this one and that will undergo intramolecular cyclization to give this lacto. So what you got is 6-mombard lacto of course the ester also will be hydrolyzed to carboxylic acid okay. Next the benzyl group you do not want it has served its purpose so you cleave it under hydrogenalysis condition to get the corresponding amine then you open it up open the lacto with benzyl alcohol okay then you open the benzyl alcohol this is what you get okay. Now what you need to do you have to make the beta-lactam so that is normally done with DCC that is dicyclic acyl carbadimide you get the beta-lactam then protect both secondary hydroxyl group as well as the beta-lactam in which with TBS okay then you remove the benzyl group of the ester under hydrogenalysis condition then treat with CDI that is carbonyl diimidazole okay you get this compound then you treat with meldron sassid okay. So the meldron sassid what it does it generates anion here and then attacks is carbonyl and this comes out okay. So now it is like tri ketone okay ketone here you have ketone and then you have two ester so because of stability the ketone will be in the form of enol okay once you have this then you treat with para-nitrobenzyl alcohol. So the para-nitrobenzyl alcohol okay it attacks here okay then this acetone which is a stable group it will come out okay and this is in the ketone form then this carbonyl group attacks so what you get is this beta-keto ester okay basically what you get is beta-keto ester. So once you have this then you remove the TBDMS group okay both O protected N protected TBDMS group you remove then you take this hydroxyl group you can see this hydroxyl group which is alpha but in thynomycin it should be beta. So how one can do either you can oxidize and then reduce it or one can also think about mitzvinova reaction because by this time this synthesis was started mitzvinova reaction came into came into place so one can use mitzvinova reaction which is nothing but it will invert the stereocenter. So the acid which he used was formic acid so he got OCHO then if you do hydrolysis OCHO gets hydrolyzed and then you get OH. So now you can see this is the key intermediate is not it this is the key intermediate in the total synthesis of thynomycin reported by the same group but that was synapsia specific this they wanted to do in large quantity. So what is left is you have to generate the carbene here and then Cn bond formation okay then the enol ether and then addition of thiol will complete the total synthesis. They also tried intramolecular mitzvinova reaction okay so intramolecular mitzvinova reaction they tried with formic acid they also tried intramolecular mitzvinova reaction when they started with this lactone what they did they just hydrolyzed they hydrolyzed this lactone to carboxylic acid hydroxy carboxylic acid then they treated with triphenylposphine dead okay so that is a mechanism as you know the carboxylic acid first triphenylposphine attacks the diaso and then diaso picks up the proton from carboxylic acid and then you form the CO2 minus. Now this OH will attack the triphenylposphine and you get this intermediate it is OPPH3 and then the carboxylic acid will intramolecularly attack and in a stentu fashion you get this copper okay this upon hydrolysis you get you have inverted the stereocenter here okay. So then you can follow the same process okay one can follow the same process to get this intermediate once you have this intermediate then diacetatization carbene insertion okay and then enol ether formation and then thiol addition will give thiolomacy. So standard you have alcohol diacetatization you introduce the nitrogen then treat with dirodium tetracetate to generate the carbene and that undergoes intramolecular MH insertion and then followed by treatment with diphenylposporyl chloride in the presence of unix base gives the enol phosphate and one for addition followed by elimination and removal of this benzyl para-nitrobenzyl group gives thiolomacy. So this they have done in a racemic method but this can be done in large quantity compared to the earlier method. To summarize so what metxindist have done is they have reported two total synthesis of thiolomacy. The first one is an inertia specific one and the second one is a racemic synthesis in both cases they have used intramolecular carbene insertion reaction as the key reaction to make the phymome budding. In the inertia specific synthesis they started with commercially available aspartic acid as the chiral amino acid so that they ended up with optically active thiolomacy. In the second case that is a racemic one so they used intramolecular as well as intermolecular mitzvonov reaction as one of the key reactions and overall yield also was much better compared to the first one. Nevertheless the second method is a racemic one. So thank you I will stop here and I will talk about one more total synthesis in this before we move to other natural products. Thank you.