 Good morning and welcome back to NPTEL lecture series on classics in total synthesis. So we will continue our discussion on total synthesis of natural products. So today talk about total synthesis of a natural product called periplanonon B. So this is a very interesting natural product actually it was isolated from American cockroaches this is a sex pheromone and why this particular compound was important because very minute quantities of this pheromone was obtained less than milligram was obtained from these cockroaches and it took about 25 years it took about 25 years to report the isolation of two pheromones periplanons and periplanons A and B and if you look at their stretches okay. So first periplanon A it is little bit complex okay so it has two epoxides, two double bonds, one carbonyl group and one isopropyl group okay. The first synthesis of periplanon B was reported by still in 1979 actually before he completed the total synthesis of periplanon B initially he made two wrong isomers before he completed the total synthesis. The reaction which he used as a key reaction in the total synthesis of periplanon B still used anionic axicope rearrangement as a key reaction to form this cyclodecane unit okay. It is a 10 membered ring you can see so this 10 membered ring was cleverly formed using anionic oxicope rearrangement okay and according to him if you look at this molecule he thought the two epoxides can be made by two different methods one epoxide that is this epoxide can be made directly from the double bond using MCPBA or nucleophilic epoxidizing agent whereas the other epoxide can be made from the carbonyl group directly using sulfonium elide or sulfonium elide okay basically sulfur based elides if you treat with carbonyl group it can form epoxide so that is how he planned okay and this if you look at this particular cyclodecanone his idea was it can be made using anionic oxicope rearrangement so this is the key reaction this is the key reaction anionic oxicope rearrangement followed by when you do the anionic oxicope rearrangement what will happen you will get like this okay that enolate again if you add MCPBA then you will get corresponding alpha hydroxycheto okay so that is called rubatum oxidation so a combination of anionic oxicope followed by rubatum oxidation will give this corresponding alpha hydroxycheto so that was his idea and this as you can see if you have the beta gamma unsaturated ketone see alpha beta gamma so beta gamma and such a ketone then simply you can add vinyl lithium or vinyl magnesium bromide you will get this intermediate or precursor required for anionic oxicope rearrangement and that can be obtained from this cyclohexene which is commercially available or well known in the literature so he started with this compound then the primary alcohol was protected with ethyl vinyl ether and then PPTS so you protected this alcohol as ethoxy ethyl ether which is nothing but this one okay so normally primary alcohols are protected as TBDPS, TBS, TMS and also people olden days they used to protect it as THP ether okay they treat with the hydro pyrrole okay so this was prior to the TBDPS ether era then you generate anion and then quench with this aldehyde and that aldehyde was then trapped with acetic anhydride to get the corresponding acetate okay next this is a enone okay if you treat with trimethyl tin trimethyl tin hydride and butyl lithium that will generate the corresponding lithium okay lithium trimethyl stanine derivative so that can undergo a 1-4 addition to this enone and which can be trapped as the TMS ether so that is what he did okay so when you add this lithium trimethyl stanine it will undergo 1-4 addition the resultant enolate was trapped as the enol TMS ether at this stage he used a lithium dimethyl cuprate so lithium dimethyl cuprate is known to undergo a 1-4 addition like on allylic acetate so what will happen the methyl group will attack and the double bond will come and then your acetate will go okay so that is how he introduced the second methyl group which is required for making the isopropyl okay so right hand side is done now he has to generate the ketone so for that first he treated with the MCPBA sorry MCPBA you know it forms this and then elimination takes place you get the corresponding cyclohexenome so once you have the cyclohexenome now you have to add the vinyl gyrgnath or vinyl lithium species so addition of vinyl lithium you gave the precursor for anionic oxycopyriol okay as you can see 3-3 nicely located to get the corresponding anionic oxycopyriol so this was treated with potassium hydride in the presence of 18-6 so it underwent anionic oxycopyriol arrangement and if you quench with TMS chloride you get the corresponding enol TMS ether then you add MCPBA okay that MCPBA as I said it is nothing but it will undergo rubatum oxidation to introduce a hydroxyl group next to the carbonyl so that is how he could introduce the hydroxyl group next to the carbonyl okay so he thought he is very close what needs to be done you have to make epoxide here and then sulfonium will I will make epoxide here and basically he also has to eliminate this to introduce the exocyclic double bond so he protected the secondary alcohol as TBS ether so then you can see the confirmation so this is how the molecule looks because it is a 10 membered ring so 10 membered ring can form several puckered shape so this is one of the stable confirmation on that he did first the epoxylation okay so epoxylation you know it is a electron deficient double bond so you can use tetrabutyl hydroperoxide and Triton B so when you look at this compound the epoxide will come from the backside okay epoxide will come from the backside so in the product you can see that it is alpha epoxide but for plenipelon B the epoxide should be beta okay what you are getting is alpha nevertheless he went ahead and then he treated with the corresponding sulfonium elide okay primethyl sulfonium elide to get the epoxide so again if you look at this compound one this is opposite stereochemistry second this is also opposite stereochemistry okay but nevertheless it is good to make more analogs of the natural product so for that what should be done you have to introduce the exocyclic double bond okay so you remove the ethoxy ethyl protecting group with acetic acid water so you get the primary alcohol and that primary alcohol if you treat with ortho nitrile phenyl celluloseionide so you get this particular intermediate it is well known this upon treatment with hydrogen peroxide or MCPBA it will form the corresponding selenoxide as well as later it will undergo elimination to introduce the double bond so that is how you could introduce the double bond and removal of the TBS group release the secondary alcohol which upon oxidation gave the ketone and this ketone none of the spectral data are matching with plenipelon B so that is obviously because of these two epoxides are opposite to the natural peripelon B okay you can see that so here it is beta and here the CH2 is beta so he went back okay he still did not know whether the epoxide here is the correct one or not so he thought he can work around and then get epoxide arising from the ketone so first he did the Peterson olefination introduce the double bond then on that he wanted to selectively do the epoxidation so for that it is better to remove the TBS group so that you will have allylic alcohol which can direct the epoxidation okay so he removed the TBS group then treated with vanadium macaque and then tercibutylhydroperoxide so now he could get the CH2 is beta okay then oxidation a ketone and followed by the same three steps protocol to convert this into double bond now if you look at this isomer you can see all are same except this epoxide here the epoxide is exactly opposite to periplanon B so again he has to go back so at this point what he thought was he will protect this hydroxyl now as TBS ether and at this stage that is the etoxy vinyl group he wanted to remove and then convert that into exocyclic double bond first so he did that now you can see you have everything except that these two epoxides okay so he took this compound and the low energy conformation if you look at so there are two conformation you can write and this can flip to this conformation and now if you look at this is the low energy conformation and if one has to do epoxidation of this double bond that will become beta okay so at this stage he did the epoxidation of the alpha beta and such a ketone selectively so he got the beta epoxide as a major isomer okay he could separate and then on that he did the sulfonimulite treatment to get the epoxide here now the left hand side epoxide also beta and the right hand side also that is the middle carbon also he got epoxide where the oxygen is alpha okay then remove the protecting group with the t-buff so TBS was removed and then oxidation with chromium trioxide pyridine that is Collins reagent he could get peripelanone B. So before he made peripelanone B he made two isomers in one isomer both the stereo centers of epoxides were opposite and the second one one was correct other one was not okay. So overall if you look at this synthesis of peripelanone B that was the first total synthesis reported by Clark still he used anionic oxycopere arrangement followed by rubatum oxidation as the key reaction to introduce alpha hydroxy ketone and overall it took about 15 steps and the yield the combined yield is about 9% which is really remarkable considering this dense functional groups present in the natural product. The second total synthesis of peripelanone B which we will discuss was reported by Stuart Schreiber's group in 1984 he also used anionic oxycopere arrangement but on a different substrate okay. He used anionic oxycopere arrangement followed by the electrocyclic ring opening as key reaction to introduce the diene present in this molecule okay. Let us see how he has done. So his idea was okay both epoxides can be introduced starting from this ketone and if you look at this diene he wanted to use electrocyclic ring opening to get the diene okay. So electrocyclic ring opening of the cyclobutene will give this diene and that can be obtained by anionic oxycopere arrangement. So you can see both groups used anionic oxycopere arrangement but both are using on different substrates. So that is how in synthesis when you want to work on total synthesis of one molecule the same reaction can be used on different substrates and essentially they can make the same natural product okay. So that type of flexibility and creativity can be seen in many total synthesis and this can be obtained from this bicyclic ketone and this bicyclic ketone can be obtained from this natural product which is commercially available with allene through a 2 plus 2 cycloaddition reaction okay. Let us see how he has done first it was a 2 plus 2 cycloaddition between the cyclohexenone and allene. So he got a mixture of 2 is to 1 and of course the major isomer is the required one he took that compound and then treated with vinyl magnesium bromide. So the vinyl magnesium bromide gave the alcohol the lyrical alcohol. So this upon treatment with potassium hydride and 18 crown 6 it underwent the anionic oxycopere arrangement as you see you can write like this. So now you have the 10 membered ring also the 10 membered ring is fused with a 4 membered ring okay and this 4 membered ring that is cyclobutene if you heat it it forms the diene but unfortunately this is cis double bond okay when you do this ring opening reaction what he got was exocyclic double bond and the internal double bond was cis but in the natural product the internal double bond was trans. Of course cis trans isomeration can be easily done under photocomal condition. So he tried the photocomal condition so he could easily isomerize the cis double bond to trans. So now one epoxidation another epoxidation and you have to introduce a ketone. So these are three things left. So first he introduced an sph group at the alpha position and then oxidized with sodium peroxide to get the current introduce the double bond okay sulfoxide and then sulfoxide was eliminated to get the double bond okay. So once you have the double bond you make the epoxide. So it is alpha beta and such a ketone electron deficient. So you have to use nucleophilic epoxidizing agent. So potassium iodide and the tertiary butylite peroxide gave the beta epoxide. So there is a major isomer. Now he introduced the double bond on the other side. So that is this side again using lithium-examethyl disolxide followed by quenching with penicillin bromide and instead of introducing the double bond okay. Here what you need is you need to introduce a hydroxyl group. So first you need to introduce hydroxyl group. So what he did he used a seleno pumoral rearrangement to introduce a hydroxyl group. So for that first he introduced a phenyl seleno group by treating with lithium-examethyl disolxide and phenyl selenyl bromide. Then you oxidize the phenyl selenide with hydrogen peroxide to form the phenyl selenoxide then you treat with acetic anhydride. So when you treat with acetic anhydride so what happens you get this OCO CH3 okay. So then intramolecularly you know this will attack and then this will come and then you will get the carbonyl group. So you get 1, 2 diketone okay. So this is selenoprumoral rearrangement. Now you have two ketones and selectively the trimethyl sulphonium elide added to this ketone. Not only regio it is stereoselective to get 62% yield of the required natural product periplanonon B. So it is one of the shortest synthesis of periplanonon B which involved again an interesting anionic oxicope rearrangement. So this is the mechanism of selenoprumoral rearrangement and also 2 plus 2 cycloaddition to get the precursor for the anionic oxicope rearrangement. Then he also used electrocyclic ring opening of cyclobutene and then selenoprumoral rearrangement to introduce a ketone next to the ketone and a highly stereo and regio selective epoxidation of ketone using trimethyl sulphonium elide. Overall it took about 13 steps and the yield was close to 2% okay. So with this I will stop here and then we will talk about more natural products in the next week okay. Thank you.