 So, welcome back to NPTEL lecture series on total synthesis of natural products. The last 4 lectures we talked about many total synthesis of tychonanes and there are many more methods for making phymombered rings. So today I will just talk about few methods where phymombered rings can be made and also discuss one more total synthesis of tychonanes. Cousin con reaction is one reaction where routinely people use to make phymombered rings. See for example, if you have a double bond and a triple bond that appropriately placed then if you treat with dichopalt octacarbonyl and followed by oxidation with n-methylmorpholine in oxide or dimethyl sulfoxide one can get the corresponding cyclopentenol. So depends on the ring size you get the other ring can be phymombered, phyrombered or any ring but this pass and con reaction will give phymombered ring. Particularly this reaction works on the other side if it is 6-mbered and 5-mbered okay. So here you have a di-quinone structure. And this is another example where you can see you can put a hetero atom okay. It can be the hetero atom can be oxygen or hetero atom can be nitrogen. Still this reaction works well to give the corresponding cyclopentenol. And one can also use other reagents for example one can use Wilkinson catalyst the same condition you have a double bond you have a triple bond. But here for the carbonyl source you do this reaction in under carbon monoxide atmosphere and you also have to use silver triflate to get the corresponding bicyclic compound. One can also use molybdenum hexacarbonyl in DMSO and if you reflect at 100 degrees you can do the same thing and this is interesting combination where instead of double bond you have an allene okay. So allene that internal double bond undergoes pass and con reaction so you see this double bond the terminal double bond becomes exocyclic double bond in this case. And one can also use this for hetero triquinones in this particular case you have a nitrogen and with this nitrogen one could make the assort triquinones using pass and con reaction as the key reaction. And there are other methods as I said used for making five membered ring one of the methods which is quite frequently used is vinyl cyclopropane as you know vinyl group attached to cyclopropane can undergo like this rearrangement for example you can write like this the cyclopropane are like double bond and sometimes cyclopropane as you know because of this ring strain it tries to open and if you heat it this can undergo this type of cyclopropane vinyl cyclopropane rearrangement to give cyclopentene. So here is another example so this can undergo the vinyl cyclopropane rearrangement to give this dike unit. This is another interesting example where you have cyclopropane attached to the double bond and the double bond is part of a five membered ring. So this will give you this enol TMS ether and one can hydrolyze this to give the corresponding heat if you hydrolyze this with acid you will get the corresponding dike unit having a carbonyl group. So this vinyl cyclopropane rearrangement also has been used to make at least two five membered rings if not for 3 or 4. Then the standard reaction which is routinely used for making five membered ring is aldol reaction so you have an aldehyde here and methyl group so you can generate anion here that anion can attack this aldehyde followed by elimination of water you can get the five membered ring and same thing you can see you have methyl group you can generate anion add to this aldehyde so that also will give a five membered ring of course this has been used in the total synthesis of one of the trichunemes that is a linear trichunemes and this has been used this particular example has been used in the total synthesis of an angular trichunemes. So you can see you can generate anion and attack this aldehyde followed by elimination of water you get angular trichunemes. So alkylation aldol reaction sometimes even Michael addition or opening of the epoxides have been used successfully for making five membered ring. So if you look at this example it is a beta keto ester so one can easily generate anion here and intramolecular is sent to substitution will give this five membered ketone okay. So if you decarboxylate then you get corresponding ketone otherwise you get the corresponding beta keto ester. The next example you have cyanide of course because of the cyanide you can remove this proton once you remove this proton using a base maybe you need strong non nucleophilic bases like LDA that can immediately open this epoxide to give the corresponding five membered ring. This particular example is very interesting you have a Michael acceptor and you have Michael donor it is a keto ester, beta keto ester the anion can be easily generated selectively this can undergo a 1, 4 addition intramolecular 1, 4 addition to form 2, 5 membered ring it is a di-quinate. Now one can remove this ester because it is a beta keto ester so that will give symmetrical molecule then this double bond can either cyclize here or it can cyclize at this carbon so that is how one can make angular tri-quinates so Michael addition followed by an aldol reaction one can construct a tri-quinate and in this case it is an angular tri-quinate. So there is another reaction which is called Nazaroh cyclization see this Nazaroh cyclization is nothing but if you have a dienome like this you have then this on treatment with acid you get corresponding 5 membered ring and more substituted double bond you get a cyclopentenome and the double bond is more substituted okay and you can also control the region selectivity of the double bond form say for example if you take this example okay so there are 2 possibilities one what I have written here another one it can also form like this is not it but between these 2 only this forms the reason is as soon as it coordinates with Lewis acid more than this double bond migrating this double bond will migrate and because of the lone pair here next this double bond will migrate so that will give you this as the major product. So depending on what you want you can use a substituent in the dienome to get exactly where the double bond is required you can also use silicon silicon also used to control the double bond which is required. So for example if you want the double bond to be here in this double bond here so then what you do you put a silicon at that curve okay so now what happens instead of this double bond migrating first this will migrate followed by migration of this. So what will happen silicon is known to stabilize carbocation or beta carbon so this is called beta silicon effect silicon carbon bond can be easily cleaved okay and particularly if it has to neutralize the positive charge of the beta carbon then this can be easily cleaved to get this dienol ether this upon hydrolysis will give you this ketone. So basically under normal natural cyclization you get more substituted double bond whereas if you use a silicon then you can also get less substituted double bond as the major product okay. Then there is another very interesting methodology is a tandem reaction where oxycope rearrangement followed by ring closing methodology it is almost like oxycope rearrangement followed by intramolecular Mukayama type aldol reaction okay so that also could be successfully used or has been used for the synthesis of trichonics. So for example this bicyclic compound if you treat with vinyl lithium if you treat with vinyl lithium you get this intermediate. Now if you look at this intermediate this intermediate is a classical oxycope intermediate classical oxycope intermediate so this will give you the corresponding 8-membered ring. So this will this 4-membered ring also will break and here it will form 6-membered ring so overall it will form an 8-membered ring. And if you look at this particular product in that process you are generated an enol TMS ether and also another double bond which is in conjugation with enol TMS ether okay so you can call this as vinyl augus enol ether. So this what will happen this lone pair or this silicon bond come here this will come and this will attack the carbonyl so that will give you the corresponding trichonics. So linear trichonics you have 5-membered, 8-membered. So the 8-membered ring cyclizes intermolecularly to give this linear trichonics okay. So what I will do I will talk about one more total synthesis as I mentioned that is about the synthesis of Corialing this is reported by Paul Wenders group and interestingly what he has used is again little bit extension of the method which I discussed in the last slide where you convert the 8-membered ring into 2 5-membered rings and this 8-membered ring he made using 4 plus 2 4 plus 4 cycloaddition. So 4 plus 2 will give 6-membered, 4 plus 4 will give 8-membered ring and this 4 plus 4 can be done using photochemical condition okay. How he successfully accomplished the total synthesis of Corialing using this 4 plus 4 cycloaddition and also the trans anolar cyclization which I briefly discussed. For that his starting material is methyl isobutrite so you take isobutric acid and methylate that upon treatment with LDA you generate anion here and that you conge with this allyl bromide substituted. So you introduce a diene so you have already introduced one diene as I said the key reaction is 4 plus 4. So now you have already a 4 pi unit you need another 4 pi unit. So you reduce the ester to corresponding primary alcohol and oxidize that under one condition to get aldehyde. So now use another 4 carbon unit that is the corresponding lithium add to this aldehyde you can see you got a tetraene okay diene here, diene here so a tetraene and this tetraene can undergo an intramolecular 4 plus 4 cycloaddition reaction okay. So the intramolecular 4 plus 4 cycloaddition it can undergo. So before that you have to protect the hydroxyl group, you protect the hydroxyl group as ma-meter then you do this photochemical reaction. So there are two ways to look at it one it undergoes 4 plus 4 cycloaddition or one can think about doing a 2 plus 2 between these two followed by co-prearrangement, 2 plus 2 followed by co-prearrangement to give this cyclo-octadiene okay it is a symmetrical compound cyclo-octadiene symmetrical compound is it symmetrical? No because you have two methyl groups mom group it is not a symmetrical compound. Nevertheless you can selectively do hydroboration on one of these double bonds which double bond will undergo hydroboration that too if you have to use 9BBN, so 9BBN is a bulky hydroborating agent so obviously it will not go to tetrasubstituted and it will go to the disubstituted and then even disubstituted there are two possibilities one this way it will add other one so this is A this is B so obviously the addition of hydroboration will take place by A and not by B the reason is BBN is bulky okay so this side you have already methyl group so it will not go to left hand side. So this upon hydroboration with 9BBN and oxidation with hydrogen peroxide will get the secondary alcohol and this secondary alcohol you can oxidize using PDC to get the corresponding ketone okay. Then you treat with BF338 so BF338 what will happen it will coordinate here and this double bond will come followed by elimination okay so when you have when the double bond comes here so you will have carbocation and that carbocation will lose a proton and you will get this okay. So now you have got the linear dry coating so few more functional group transformations should be done so what are the functional group transformation again you have to do hydroboration oxidation so you have a tri substituted double bond and if you do hydroboration oxidation this carbon you will get or you will introduce a hydroxyl group okay so you introduce a hydroxyl group and once you have this hydroxyl group oxidize with PDC you get a ketone and basically you need to introduce double bond here and you have to introduce a double bond both sides you have to introduce double bonds. So if you treat with mesyl chloride not only it will become mesylate but also it will undergo elimination to get the corresponding enone okay so once you have this enone basically you need a epoxide epoxide here and you need epoxide here that means you also have to introduce a double bond here so what you do before that you migrate this double bond here so potassium terributoxide you migrate the double bond then reduce the ketone to alcohol now if you treat with MCPVA you get corresponding epoxide okay then as I said you need an epoxide here and also this should be ketone so you oxidize the alcohol using PCC to get the ketone later a double bond should be introduced so that can be done in two steps first you generate enolate using LDA and that time what happens when you generate enolate with LDA the epoxide also will be open the epoxide also will be open so you get corresponding alcohol now this side you have the enolate that upon conching with this reagent where this will go to the corresponding carbon so this is nothing but oxidized version of diphenyl disulfide one of the sulphur is oxidized other sulphur is remaining as such the sulphide upon further oxidation with MCPVA it gives phenyl sulfoxide this upon heating it undergoes elimination of phenyl sulfenic acid to get the exocyclic double bond okay to complete the total synthesis you need epoxide here and you need epoxide here so this was done by treating with alkaline hydrogen peroxide you get both the epoxides and finally to complete the total synthesis what is required is removal of this mob group so that was done using HClTHF and that gave the final product that is Coriolin if you look at this molecule how many chiral centers are there 1, 2, 3, 4, 5, 6, 7, 8 out of 11 core carbons if you look at the triquinane there are 11 core carbons in that 8 are chiral centers 8 are chiral centers see that is the beauty of this synthesis okay so highly selective total synthesis and here he has used the intramolecular cyclization as well as 4 plus 4 cycloaddition to get the strike unions. So he reported this total synthesis way back in 1987 and he started with methyl isobutrate and key step involved in this total synthesis are 4 plus 4 cycloaddition one can also give explanation that it can be a combination of intramolecular 2 plus 2 followed by another electro cyclization that is you have a diene 1, 5 diene that can undergo cycloaddition reaction and finally a trans-cellular cyclization takes place between the 8-membered ring diene the doctor diene so one of the double bond you oxidize to ketone then you carry out this intramolecular cyclization using trans-cellular cyclization protocol overall this total synthesis was accomplished in 4 longest linear steps but the yield was not very high so yield was about 0.23. Nevertheless if you look at the total synthesis of this molecule reported by Corioli it involved 3, 4 key reactions and this key reaction actually really worked well so that you could accomplish the total synthesis of Corioli. So with this we have completed the total synthesis of all the trichunanes whatever we plan to cover and next week onwards we will start talking about 6-membered rings and then slowly we will move to alkaloids and terpenoids so thank you.