 Good morning and welcome back to the course on Classics in Total Synthesis Part 1. And we have been discussing total synthesis of various natural products. In the last lecture, we talked about the total synthesis of a marine natural product called elitrobin and where we talked about the total synthesis reported by K.C. Nicolau. So today we will talk about another total synthesis but this time reported by Danyevsky and in the case of Nicolau's total synthesis, he started with the carbon, the monotterpin and here Danyevsky started with another monotterpin called alpha philandry and his work required you know lot of stereochemical studies particularly with respect to carbohydrate so that he could prove the correct isomer of the final natural product that is elitrobin. And his total synthesis involved 3 important key reactions. One is the Nosakhi, Kishi, Hayama, Rinklos reaction to form the five umbered ring and the second key reaction which is also very interesting rearrangement that is pyranose to furanose and furan to pyranose okay. So these 2 key reactions he had used to first convert the furan ring into pyranose and then later the pyranose ring was converted into five umbered furanose ring. The third key reaction was the stillly coupling between the carbocycle and the carbohydrate mighty to form the core structure of elitrobin. So from retrosynthetic point of view as you can see here it is very clear you have a complete carbocycle and a sugar unit okay. So the easiest way to disconnect is just you can disconnect either here or here. So if you are using stillly coupling then the disconnection of bond A is better than disconnection at bond B. So the stillly coupling disconnection gives Ranshevsky these 2 fragments and the left hand side you have the vinyl triplet and the right hand side you have the trivital tin derivative which is required for the stillly coupling. So now for the synthesis of the carbocyclic derivative that is the tricyclic compound the triplet can be obtained from this protected alcohol by removal of the pyrolyte group oxidation to ketone and followed by enol triplet formation. One can easily convert this into the required triplet in 3 steps after protection of this hydroxyl group. Now this five umber ring as I said this is one of the key reactions where the pyranose form okay where the pyranose form was converted into furanose form using acidic condition okay. This pyranose form again was obtained from furan okay. So here using this hydroxyl group an epoxidation of one of the double bonds of furan followed by the rearrangement one can easily get this 6 umber pyranose ring okay that was the second key reaction and the third key reaction is the intramolecular Nosakhi you see ring closer reaction between this the bromofuran and this aldehyde to form the 10 umber ring. Here now if you look at this it is very easy if you have this aldehyde and you can use the lithiobromo furan addition to this aldehyde to generate this chiral center with OH and for the southern hemisphere you need CH2CHO that can be obtained from this ester by reduction and homologation okay. So now these two substituted ones these two substituted ones on this 6 umber ring can be easily introduced from Philandrine a commercially available mono terpen using photochemical reaction as the key reaction okay. So as I said there are two key reactions which he has used at least I will talk about one key reaction that is Nosakhi Kishi reaction Nosakhi Kishi reaction is nothing but if you have a vinyl triplet or vinyl halide and this on treatment with aldehydes in the presence of chromus chloride you will get an allylic alcohol. This reaction can be done intermolecularly as well as intramolecularly basically if you want an allylic alcohol so this is one of the very important transformations and one can also get homolylic alcohol using similar conditions here instead of vinyl bromide what you need is an allylic bromide. So allylic bromide on treatment with aldehyde in the presence of chromus chloride it gives homolylic alcohol and if you have an ester at appropriate place then the homolylic alcohol which is formed can also intramolecularly attack the carminate group of the ester forming a lacto okay. So this Nosakhi Kishi reaction has been widely used for making allylic and homoallylic alcohols and also many pachyocycles. So now let us see how Dainishevsky's group synthesized eletrobin and as I said the synthesis of eletrobin requires synthesis of two different fragments one the carbocyclic ABC in fragment the other one is sugar fragment. So now let us start with the synthesis of sugar fragment for which he started with the commercially available D-arabinose and the first step was the peracetylation that is all the hydroxyl groups including the lactol hydroxyl group where acetylated with acetic anhydride and DMAP then this particular anomeric acetoxy group okay can be easily displaced with ethane thiol under Lewis acidic condition and here you can see the alpha ion number is the major isomer okay. So once you have that then the three acetates okay three secondary acetates can be easily hydrolyzed by treatment with sodium ethoxy methanol. Now if you look at this triol these two hydroxyl groups are cis to each other and these two are trans to each other. So one can easily protect the syn diol to get the corresponding astronaut under standard conditions. Now what needs to be done is you have to introduce a CH2O SNBU3 and also protect this hydroxyl group. So these are the two things left for the synthesis of sugar fragment with tributyltine group which is required for stelaic coupling. So you take this free hydroxyl group now protect the hydroxyl group as TBS ether protect the hydroxyl group as TBS ether. Then treat this anomeric thiol ether with tributyltine methanol tributyltine methanol in the presence of methyl triplet. So that gives you the required and see CH2 SNBU3. So here beta isomer is the isomer which is required for the stelaic coupling. So now removal of the TBS group by fluoride reagents like Tbaff will give a hydroxyl and simple acetylation gives you the fragment required for the stelaic coupling. So now you have synthesized the sugar fragment successfully in few steps starting from D-Arabino's. Now let us look at the synthesis of ABC ring of elitrobin starting from a chiral monoturpin called phylandrine. So the phylandrine, so this is the structure of phylandrine. Now if you look at this structure of phylandrine there are two double bonds. One is a trisubstituted double bond other one is a disubstituted double bond. And as I mentioned when I talked about the retro synthesis it involves a photochemical reaction. It has two double bonds and selectively one of them has to undergo 2 plus 2 cycloaddition reaction. So as I said one is trisubstituted other one is disubstituted and between these two for stelaic reasons one can selectively carry out photochemical 2 plus 2 cycloaddition reaction with the disubstituted alkene. And the other alkene was the dichlorochetene. The dichlorochetene can be easily obtained by treatment of zinc with trichloroacetyl chloride or one can also get it from dichloroacetyl chloride with mild bases like triethylamine. So now once you do this reaction what you get is a mixture of two isomers and once the dichlorochetene is formed because of the presence of the bulky isopropyl group in beta position this dichlorochetene will come only from the alpha side. So that is how these two hydrogens you can see when it approaches from the alpha side these two hydrogens will be beta. So this is the major product once you have this the two chlorines can be easily exchanged with hydrogen by treatment with zinc methanol. So zinc methanol removes the two chlorines. Now we have to open the cyclobutanol drink. So one way is to introduce a functional group here okay you can introduce a functional group and open this cyclobutanol and if you use Bayer-Riegel oxidation. So then it will open up here which is not required you need to open the cyclobutanol at this place. So for that it is easy to introduce an aldehyde equivalent okay if you look at this. So this is an aldehyde equivalent if you hydrolyze this enamine okay this is an enamine basically it is an enamine derived from dimethyl formaldehyde protected dimethyl formaldehyde okay. So now this enamine upon hydrolysis with para toluene sulfonic acid. So what will happen? So you will get first you will get an aldehyde like this okay then under acidic condition and the acidic condition that is with methanol what will happen? The methanol will attack here and open up. So that will give you the corresponding ester that is you will have this aldehyde and ester you will have this corresponding aldehyde in ester okay this is the product you get is it clear? So now what you need to do one you have to add the furan ring to this aldehyde now it is protected aldehyde other one you have to homologate this ester is not it what you need is a CH2CHO already you have CH2CHO here but here you have only CO2MB. So that should be homologous okay. So first you remove this acetone okay para toluene sulfonic acid and water you remove the acetone you get the aldehyde. Now once you have the aldehyde take this 2-5-dibromo furan this on treatment with butyl lithium. So one of the bromines will be exchanged with lithium to get the corresponding lithiospecies this furan lithium that is bromofuran lithium will add to this aldehyde. So you have aldehyde and ester and as you know aldehyde is more reactive than ester. So once it adds to the aldehyde so what you get is a mixture of this alcohol which is as a result of direct addition of this lithiospecies to the aldehyde and the second product is nothing but this alcohol attacking the ester carbonyl and forming the 6-1-butlacto okay. So these are the 2 products and the major product is this alcohol okay. So now you have the alcohol next step is to protect the alcohol. So the alcohol could be protected as TBDPS ether and the standard condition then now you need to homologate this ester okay. How do you do okay you have to first reduce then that CH2OH should be homologated. So the reduction is normally done with the dye ball if you use excess dye ball you will get the corresponding alcohol. So here they use excess dye ball so that you get the primary alcohol. Now the primary alcohol can be homologated through mesylation. So first you mesylate the primary alcohol to get the mesylated compound this upon treatment with potassium cyanide okay when you this is a good leaving group mesylate. So now if you treat with potassium cyanide in the presence of 18 crown 6 ether you get the corresponding cyanide CH2Cm okay. So what we need now this cyanide should be reduced to aldehyde then the intramolecular cyclization should takes place okay. So dye ball reduction of cyanide will give you aldehyde so that was a very clean reaction. Then the second key reaction okay so the second key reaction in the total sense of Tanishib ski is the Noshaki-Kissi reaction. So this upon intramolecular Noshaki-Kissi reaction gave the corresponding 10 membered ring wherein the alpha isomer was the major product. The hydroxyl group which is alpha is the preferred product which you can see they got 15 is to 1 ratio of alpha and beta. So now if you look at this particular structure you have the 6 membered ring in place the B ring that is the 10 membered ring is in place. Now what you need to do is you have to convert this furan convert this furan one you have to get a double bond here you have to introduce a methoxy group here and you have to introduce a methyl group. So 3 things one has to do one introduction of methyl group introduction of double bond and introduction of methoxy group here. But at the same time you should know this 2 double bonds should not be there in furan okay. So what did they do? Before you do this you need to protect the newly formed hydroxyl group okay. So that was protected as pyrolytester by treating with pyrolyl chloride. Then you can remove the TBDPS group okay. So standard Tbuff tetrabutylaminium fluoride treatment will remove the TBDPS to give the corresponding alcohol. So once you have this alcohol if you look at the relationship between this double bond and this hydroxyl group it is an allylic alcohol okay that hydroxyl group will direct the incoming peroxidizing agent so that you will get alpha epoxide. So what happens once you treat with dimethyl dioxide DMD you get the corresponding pyronos ring. So not only epoxide is formed it undergoes a rearrangement okay it is a well known rearrangement to form this hydroxy pyrono. How does it happen? It is very simple it is well known in the literature. The first as I said it form the epoxide of the double bond which is close to the hydroxyl group it is like allylic alcohol epoxidation. Once it is formed then you can see the arrows the opening of this phymober ring gives rise to this enedio okay. It is basically nothing but if you have 1,4 diketone on treatment with acid you will get furan okay 1,4 diketone if you treat with acid you will get furan. The same thing it is a reverse reaction but since you are using oxidation you get extra double bond okay it is just the reversal of acid treatment of 1,4 diketone to furan. Here what you are doing is you are using an oxidizing agent so that is why you introduce a double bond as well. Once this enedione is formed then intramolecularly the hydroxyl group here will attack the ketone to form the 6-mombard ring okay. So what you have done now you have oxidized the furan ring and while doing that it underwent a ring expansion reaction to form a hydroxy pyromo okay and this is also good in one sense that if you look at the natural product, if you look at the natural product you need to introduce a methyl group here, you need to introduce a methyl group here. So now this has become easy because you have an enone okay you have an enone then it should be easy to introduce the methyl group here. So how did they do? First you protect this lactone okay so protect it as TMS ether then you add methyl lithium okay. So methyl lithium addition to the enone comes from alpha side that methyl group comes from alpha side to get the beta alcohol then you treat with acid okay. Here when you treat with acid this pyronos ring rearranges back to the furanos ring. Here the pyronos ring rearranges back to the furanos ring so how does it happen? It is a very interesting again a rearrangement it is like shuttle trip rearrangement. Once it was 5-mombard ring that is furan, furan to pyronos now pyronos to furanos okay it is like shuttle trip rearrangement how did this happen? The moment you protonate what happens this oxygen gets protonated then this lone pair on the O TMS opens this so what you get? This oxonium ion okay. Now if this hydroxyl group attacks back, if this hydroxyl group attacks back you get the same pyronos ring whereas if this tertiary alcohol attacks this carbonyl then you will get furanos ring is not it? So that is what happens here the tertiary alcohol attacks the oxonium ion carbon to get the 5-mombard ring. So now this is very easy to see all the functional groups required for the synthesis of elitrobin is in place. You have a hydroxyl group here okay then the OME is there methyl also and what you need to do is you have to convert this into enol triflate and also the northern hemisphere hydroxyl group you have to esterify okay these are the 2 things he needs to do to complete the total synthesis of elitrobin okay. So what you need to do first is you protected the hydroxyl group okay you protected the hydroxyl group as TBS ether okay so that you can remove the pyrolyl group and make it as vinyl triflate and then couple with tributyltin derivative of the sugar to attach the sugar fragment okay. So you protected the hydroxyl group then you reductively remove the pyrolyte ester so pyrolyte ester can be reductively removed because it is an ester is not it. So if you reduce with the di-ball the pyrolyte ester gets cleaved and then you will get the hydroxyl group hydroxyl group was then oxidized with tetra n-propyl ammonium perruthanate T-BAP and NMO to get the ketone. So once you have the ketone the next step is to make the enol triflate. So this was successfully done by making the enolate with lithium exomethyl diselicide and the triflate was introduced using well known comminceration okay. So now the enol triflate is made so that means the whole carbocyclic core structure of elitrobin is ready and already we have discussed the synthesis of sugar fragment. So what we need to do is we have to couple this triflate with the tin derivative using steely coupling and the steely coupling worked very well with tetra case palladium to give the complete structure of the elitrobin. So what is left now is you have to remove the TBS, attach the side chain then remove the astronaut and acetyl group. So these are the 3 things left for the total synthesis of elitrobin. So first easiest is to remove the TBS group okay treatment with T-BAP you remove the TBS next you have to attach this side chain okay. So this alpha-vita and such an acid is a known compound and now using DCC you can couple this carboxylic acid with the alcohol to introduce the side chain on the northern hemisphere okay. Now what is left you have to remove the acetate and you have to remove the acetone right okay. So both are done in one step actually if you look at the elitrobin this acetate is intact acetate is required in elitrobin only you need to remove this astromate okay you have to remove only the astronite and that was done easily by treatment with PPTS methanol you remove the astronite and that gives elitrobin so that is how you could complete the total synthesis of elitrobin and if you look at the total synthesis of elitrobin reported by Danieczewski so he started with two commercially available as well as naturally occurring compound for the carbocycle he started with a monotirpin called alpha phylandrine and for the sugar fragment he started with D-arabinose commercially available sugar okay monotirin. Then there are three key reactions which he used one the Nosaki Kishi reaction to form the 10 membered ring and then second the ring expansion of furan ring to pyranose and the third one is the pyranose to furanose that is 6 membered to furanose 5 membered ring was done under acidic condition that is the fourth key reaction that is that still like coupling between the carbocyclic triphlate and then tributyldin tin derivative of sugar fragment okay so these are the four key reactions which Danieczewski used to synthesize elitrobin overall this total synthesis was accomplished in 26 longest linear steps and with an yield of 0.25 percent so considering the molecule considering the complexity of the natural product 0.25 percent overall yield is really a healthy one okay so this way if you look at the two total synthesis which we have discussed on elitrobin, Nikolaou Nikolaou's total synthesis and Danieczewski's total synthesis actually involved some key reactions and also new chemistry were developed during these two total synthesis okay thank you.