 So good morning and we come back to classics in total synthesis lecture series and we have been discussing many total synthesis of complex natural products and we will continue our discussion on one more total synthesis of a complex natural product called four ball. As you can see from here the structure is quite complex and this was isolated in 1934 from the seeds of purging cotton and it took about another 43 years to determine the correct structure of four ball which is understandable considering the complex structure it took much more time to propose the correct structure of four ball. And it took another 22 years for the first total synthesis of four ball reported by Paul Wender. Basically it has excellent biological activity profile and particularly it helped in the development of many chemotherapeutic agents for cancer and other diseases like AIDS. So I will not go into the biological profile of this four ball esters rather I will talk more about Wender's total synthesis, retro synthesis and how he constructed this interesting tetracyclic compound with so many chiral centers. You can see here it is highly congested natural product having many chiral centers and as I mentioned it took 22 years after the correct structure was proposed for four ball to come up with the first total synthesis and Wender's first total synthesis of four ball was started from commercially available simple starting material called furfuryl alcohol. There are 8 stereogenic centers in the molecule and in that 6 are contiguous you can see the whole ring here all have stereocenters so highly contiguous stereocenters and he used a very interesting reaction called oxidopyrilium arene cycloaddition reaction it is a sort of 5 plus 2 cycloaddition reaction oxidopyrilium alkene cycloaddition reaction I will come to that when I talk about retro synthesis as well as synthesis and this synthesis is a very very interesting synthesis and this retro synthesis if you look at he thought four ball can be made from this tetracyclic compound by few functional group transformation first you know from here to four ball what he has to do is to migrate the double bond from exocyclic to internal then he needs to remove the protective group and oxidize the secondary alcohol in the presence of tertiary alcohol and here he has to introduce the dimethyl cyclo propane as well as introduce the hydroxyl group so this functional group transformation though it is written in one step it requires about 10 steps or more to convert into four ball okay and here he comes the key oxidopyrilium alkene cycloaddition reaction so this is the alkene okay this is the alkene and this is the oxidopyrilium okay this oxidopyrilium can be made easily from this type of furan with an alcohol here okay so this can be easily made in one step and when it is made and if you have a double bond at appropriate place it can undergo an intra molecular 5 plus 2 cycloaddition reaction you look into this when we talk about total synthesis and how he got this tricyclic compound okay and this can be made from peripheral alcohol in few steps okay using standard functional group transformation okay so let us see how he completed the total synthesis of four ball starting from peripheral alcohol okay so first he took peripheral alcohol and protected the primary alcohol as TBS ether now he deprotonate or lithiated at the other side and quenched with lithium propionate to introduce the propionyl group okay then he carried out an intermolecular aldol reaction first you generate the enolate with the lithium exomethyl disoloside and quench with this pentenol okay the pentenol you generate the aldol okay so this is an aldol okay now you protect the hydroxyl group okay you protect the hydroxyl group as acetate then carry out the key reaction that is first you reduce this ketone as I said you need alcohol there for carrying out the key oxidopyrilium alkene cycloaddition reaction once you have this alcohol treat with MCBBA okay the MCBBA first it forms epoxide here then it undergoes achmatovich rearrangement okay so this I had already discussed and it when I talked about I think elitrobin I discussed about achmatovich rearrangement so that gives gamma hydroxy pyrano okay then the next key step is the oxidopyrilium alkene cycloaddition so this on treatment with acetic anhydride okay you protect this lactol as acetate then treat with DBU so the DBU it can form the enolates okay at the same time this lone pair okay this lone pair can push this acetate out okay so if you see this that forms this oxidopyrilium so this is a stable species okay this is a stable species and this double bond can undergo a 5 plus 2 cycloaddition reaction an intramolecular 5 plus 2 cycloaddition reaction so I leave it for some time so that you can visualize okay first it forms this is what happens now it can undergo cycloaddition like this okay so when that happens you get this product okay it is a tricyclic compound then you get this 6 membered ring here a 5 membered ring here and another 6 membered ring here while doing that what you can notice is this methyl group occupies the more stable equatorial position and the acetate also the major isomer has acetate in the equatorial position okay so the major isomer upon hydrogenation you can remove the double bond then it is simple we take to get the exocyclic double bond here after getting the exocyclic double bond when you treat with selenium dioxide you can introduce an oxygen functionality okay selenium dioxide is known to undergo allylic oxidation you get the corresponding allylic alcohol now when you treat with manganese dioxide manganese deoxides are known to facilitate allylic oxidation to give alpha beta and saturated ketone then you carry out a 1 4 addition with vinyl copper okay or you can introduce an allyl group here already a double bond you add a vinyl so it becomes allyl group next to the carbonyl group okay then the ketone you can add TMS cyanide basically you are adding a cyanide to the ketone since you are using TMS cyanide the cyanohydrin is seen C2 protected as TMS ether okay so that is how you get the corresponding TMS protected cyanohydrin so this can be rewritten or redrawn like this again I will leave this for few seconds you just see how this was redrawn okay you can see this CH2O TBS here and this is the 7 ombre ring okay you can see the 7 ombre ring okay then this oxygen bridge is alpha oxygen bridge is alpha okay then of course you have a cyclohexyl group with methyl alpha and hydroxyl beta but both are equatorial okay is it clear then you treat with diabol what will diabol do diabol will do 2 things one it will reduce the cyanide to aldehyde 2 it will also reductively remove the acetate group is not it yes there will be cleave so you get corresponding hydroxyl group and then cyanide will be reduced to corresponding aldehyde okay in one step you do 2 things yesterday is hydrolyzed reductively hydrolyzed and cyanide is reduced to get the corresponding aldehyde now you treat with hydroxyl amine to form the oxyne the aldehydes are known to undergo oxyne formation upon treatment with hydroxyl amine then when you treat with hyposolution when you treat with hyposolution this oxyne okay this oxyne will form a nitrile oxide okay this oxyne will form nitrile oxide once the nitrile oxide is formed it will undergo an intramolecular dipolar cycloaddition direction intramolecular 1, 3 dipolar cycloaddition or you can call it as intramolecular 3 plus 2 cycloaddition reaction to give the corresponding phi ommbutery okay when you get this you have to cleave this NO bond as well as hydrolyze the C double bond N both can be done in one step under hydrogenalysis condition hydrogenalysis condition NO bond can be cleave and under same condition if you use water and acetone the imine the double bond NH which is formed that can be cleave to get the corresponding ketone okay so if you look at this that is how the phi ommbutery the next phi ommbutery was made then what is required you have to protect the hydroxyl groups as benzoate so both primary as well as the secondary hydroxyl groups were protected as benzoates then if you treat with DBU okay if you treat with DBU then this can undergo elimination okay this can undergo elimination to give exocyclic double bond okay the exocyclic double bond particularly when it is in conjugation with ketone they are little unstable so once this enone was formed immediately it was reduced under Lucia condition so Lucia condition is nothing but you treat with sodium borohydride in the presence of cerium chloride okay so that facilitates the 1, 2 reduction so you got the allylic alcohol once you have the allylic alcohol then you can selectively remove the OTMS in the presence of OTBS okay with the Tbuff if you take one equivalent of Tbuff OTMS will be removed faster than OTBS okay so that was done then this is 1, 2 diol is not it the 1, 2 diol can be protected as acetonide so there are many ways one can protect 1, 2 diol so what vendor used was treat with 2 methoxypropene so 2 methoxypropene is this compound so treat with 2 methoxypropene propene in the presence of PPTS you protect the 1, 2 diol as acetonide okay now from there what you have to do is you have to reduce the double bond to get the beta methyl and also the benzoate should be hydrolyzed and oxidized to keto so this was done in 3 steps first reduce with Wilkinson catalyst so that you get high selectivity you get the beta methyl then benzoate was removed by reductive removal by ball removed the benzoate to get the alcohol then the alcohol was oxidized with PCC okay so now you have got the ketone what is to be done is you know you have to introduce the dimethyl cyclopropene as well as a hydroxyl group so 2 things have to be done so what you need first you have to introduce the enol the double bond should be introduced you treat with LD and TMS chloride so it forms the corresponding enol TMS ether okay it forms the corresponding enol TMS ether this untreatment with phenyl sulfenyl chloride you can introduce SPH basically as I said what you need to do is you need to introduce the double bond next to the ketone so there are many methods so he used this method once you have the SPH the sulfide phenyl sulfide should be oxidized okay so what he did he treated tetra tracetate to introduce the acetate alpha to the sulfur okay this is a famous rearrangement okay try to find out what is this rearrangement okay now you oxidize the sulfide oxidize the sulfide with MCPBA okay yes becomes sulfoxide the phenyl sulfoxide if you heat it it will undergo elimination phenyl elimination to introduce the double bond so what you have done if you look at this from the ketone not only introduce the double bond you also introduce an acetate okay you need a hydroxyl group at that position and the double bond is required for introducing the dimethyl cyclopropane so both are done using the enol TMS chemistry to introduce a double bond as well as acetate once this is done then you do the sulfur elide reaction the sulfur elide reaction to introduce the dimethyl cyclopropane okay so that is like one for addition and then when it comes back it will expel diphenyl sulfide okay so successfully the dimethyl cyclopropane was introduced and it also has the acetate now what you need to do you have to reduce the ketone and also open this oxygen bridge okay you do not need oxygen bridge so you have to open the oxygen bridge so first the ketone was reduced to get the alcohol and when you know when you use diabol not only the ketone will be reduced but also the acetate will be reductively removed okay so you get a syn diol and that was protected as cyclic carbonate once you have syn diol either you can protect it as acetonide or you can protect as carbonate okay the cyclic carbonate protection was done by treating with carbonyl diimidazole carbonyl diimidazole is a very good reagent for converting one to diol into cyclic carbonates then you remove the TBS group okay since there is no other silal protecting group it is very easy to remove the TBS group the T-Baff to get the primary alcohol. Next the major step as I said is to cleave this oxygen bridge because you need a hydroxyl group here okay and also you need a double bond here so the hydroxyl group was first converted into triplet then using Fingalstein reaction the triplet was converted into iodide. So for opening this oxygen bridge it treated with tertiary-butyl lithium so the tertiary-butyl lithium what will happen this will exchange with tertiary-butyl lithium to form the corresponding lithium derivative then that can open up this bridge to give the exocyclic double bond and the hydroxyl group okay. So that was the idea but at the same time what happened the tertiary-butyl lithium added to the cyclic carbonate also okay it added and he got this ester okay. Next step the hydroxyl group you need beta so you have to invert that either one can do a Midsunov reaction or you can oxidize and then reduce it so Wender followed the second method that is you oxidize the secondary alcohol with PCC to get the ketone then you reduce with bulky reagent sodium triacetoxy borohydrate okay. So you get the required beta alcohol then reduce with di-ball okay reduce with di-ball again the pyrolyl group was detectively grieved to get the corresponding di-ball okay. Now both alcohols the secondary secondary and tertiary were protected as benzoate okay were protected as benzoate and this hydroxyl group okay which is sterically little bit crowded was not protected. Then this exocyclic double bond this exocyclic double bond first it has to go inside so for that what he did was he did allylic oxidation with selenium dioxide catalytic amount of selenium dioxide in the presence of more than stoichiometric amount of tertiary-butyl hydro peroxide to get the allylic alcohol. Now the double bond migration oxidative transposition the double bond migration was done by treating with thionyl chloride thionyl chloride and propylene epoxide. So the double bond migration took place as well as the hydroxyl group was converted into the chloride okay it is a S and 2 prime reaction. Then the chloride was treated with silver benzoate silver benzoate it is a typical S and 2 reaction and the chloride was replaced by O benzoate and again now you have introduced the benzoate here already there are 2 benzoates. So what we need to do is after protecting these 3 hydroxyl group now we have to remove the austenite here and oxidize the secondary alcohol keeping the tertiary alcohol. So the austenite was cleaved using perchloric acid to get the diol once you have the diol as you can see here one is secondary alcohol other one is tertiary alcohol secondary alcohol can be easily oxidized. So what he has done is he has treated with SO3 pyridine and DMSO to get the ketone now the next step is to introduce the double bond here okay. So for that he has to protect the tertiary alcohol so that was protected as TMS ether then you generate the enolate okay. So the enolate was generated and coincided with TMS chloride to get the corresponding enol TMS ether once you have the enol TMS ether you can brominate if you treat with NBS you get the alpha bromo ketone. Once you have alpha bromo ketone then elimination of HBr is possible and that was done with lithium bromide, lithium carbonate and the high temperature elimination takes place to introduce the double bond okay. So now if you look at the structure it has almost all the functional groups in correct place. So what he needs to do you have to remove the TMS group to get the tertiary alcohol then the 3 benzoate 3 benzoate should be removed. So that was done with potassium cyanide and methanol that underwent clean hydrolysis of benzoate to give the 4 ball. The 4 ball synthesis was one of the classical total synthesis accomplished in 80s. Now once you have this of course the primary hydroxyl group can be easily treated with various carboxylic acid or functionalized carboxylic acid to form many esters that is how the structural activity relationship studies on 4 ball esters were done for medicinal chemistry. So if you look at the total synthesis of Pender. So he has used a very important key reaction, one Ashmetovic rearrangement to the oxidopyrilium alkene cyclo addition okay. Then he also used a very interesting opening of the oxygen bridge using tertiary butyl lithium. The number of steps involved in the synthesis of 4 ball is reasonably high but considering the complexity one should understand that it is not easy to accomplish the total synthesis of 4 ball without taking too many steps. So the total number of steps involved in the synthesis of 4 ball was 53 with an overall yield of point close to 0.2 percent okay. Nevertheless this was the first total synthesis of 4 ball and of course there are other synthesis later and with this we complete the total synthesis of some complex natural products. We will continue our discussion on synthesis of some more complex natural products in the next few lectures okay. Thank you.