 So, good morning and welcome back to in pitel lecture series on classics in total synthesis. So, today we will talk about a natural product which is highly substituted androquinone as a core structure. So, that natural product is called veno mycinone B2 methyl ester. Actually this veno mycines have this common this dihydroxy androquinone as the core structure. There are quite a few veno mycines, but today what we are going to do is we are going to talk about a couple of total synthesis of this veno mycinone methyl esters. You can see this is there is a methyl ester, so that is why it is called veno mycinone methyl ester. So, all the veno mycines show exceptional activity against gram positive bacteria and also against some tumors in mice. The two synthesis which we are going to talk about today are from Danyevsky's group and Danyevsky's group. Danyevsky's synthesis used a very interesting heterodeal salt reaction to construct this dihydropyrene ring and they also used a Claisen rearrangement to introduce the side chain on the right hand side. In addition they also used a deal salt reaction to construct the androquinone point. Let us see how Danyevsky's group use these key reactions to complete the total synthesis of veno mycinone due to methyl ester. First let us look at the heterosynthesis. So they made this veno mycinone methyl ester from this methyl ketone using a reformatsky type reaction. So you one can easily see this CH2 CO2Me group can be added to this methyl ketone via reformatsky reaction and this methyl ketone if you look at carefully on the left hand side that is this dihydropyrene ok. So this was converted into the dihydroxyl group here using hydroboration ok hydroboration oxidation already there is a enol TMS one more hydroxyl group was introduced using hydroboration oxidation and as I mentioned this particular dihydropyrene unit was made through heterodeal salt reaction ok you start with that aldehyde and then you do a deal salt reaction with Danyevsky's diene you get corresponding dihydropyrene ok and this aldehyde can be obtained from this allyl group by isomerization of this double bond ok. Once you isomerize the double bond it goes to the internal alkene which upon was analysis will give corresponding aldehyde and if you look at this compound you can see here this also upon Claisen rearrangement followed by was analysis you can get this methyl ketone ok. So 3, 4 steps involving this reaction in this particular transformation and this can be obtained again. So this is the diene ok this is the diene and this substituted after Qn is the dienopoil they can undergo an intermolecular deal salt reaction and followed by aromatization to give this substituted anthroquinone ok and that can be obtained from commercially available natural product called Jouglou ok. Now let us see how the forward synthesis took place. So he started with again commercially available methyl protonate now if you treat with LDA if you treat with LDA what will happen this CH2 this will be picked up LDA will pick up this proton and it can generate anion here and that place one can quench with allyl bromide ok. So it picks up the gamma proton and then quenching with allyl bromide at alpha position. So that will give this alpha beta gamma. So beta gamma and saturated ester this ester as you can see this proton is still acidic isn't it. So you can generate anion and quench with TMS chloride. So that will give you the corresponding starting diene which is required for deal salt reaction with Jouglou ok. So once this is made then the Jouglou which is required for the deal salt reaction was deprotonated that phenolic hydroxyl group was deprotonated and quench with this allyl iodide to get the precursor not only for the deal salt reaction because as you can see this is the quinone moiety which can undergo deal salt reaction and here this allyl ether which can undergo the intramolecular glycine ring one. The other starting material that is tannerships is diene was prepared from this enone using LDA and TMS chloride. Now let us see how the deal salt reaction work. So first we started with this diene which was prepared from methylchrotonate and deal salt reaction with 2-5 dichlorobenzooquinone, 2-5 dichlorobenzooquinone gave this intermediate of course this is unstable so it was not isolated it underwent elimination of HCl also methanol to give this hydroxy laptoquino ok. Then the free hydroxyl was methylated ok the free hydroxyl was methylated followed by isomerization of the double bond that allyl group was isomerized using Wilkinson catalyst then the next deal salt reaction was done on this chloro laptoquino ok. So that gave this intermediate which was subsequently aromatized to give this compound ok. Now you can see here you have the double bond which can be was allized to get aldehyde and here also you can get this ketone ok. So this is one way they prepared the key anterquino. They also used another method to prepare the same intermediate where they started from juglone which I already mentioned and they allylated with this allyl bromide substituted allyl bromide then deal salt reaction with this diene followed by aromatization you could get this compound. Now you methylate this phenolic hydroxyl group and what you need is to isomerize the double bond to internal alkene. So that was done again with rhodium chloride you can isolate the double bond so you can isomerize the double bond and then when you heat it at 200 degrees then the glycent rearrangement takes place so that migrates the allyl group to ortho position. Then you can methylate this free phenolic hydroxyl group as well and followed by was analysis you get this side ketone this upon was analysis you will get ketone and in this side you will get aldehyde ok this is the highly substituted androchiron moiety which is the core unit of enium myceno p2. So what needs to be done is one has to do a hetero deal salt reaction on the aldehyde on the left hand side and then one has to add the CH2 COTME through preformatsky type reaction ok. So he carried out the hetero deal salt reaction with this diene followed by you know isolation when he did the deal salt reaction with this diene you could get this dihydrofuran which upon hydroboration ok which upon hydroboration followed by oxidation with hydrogen peroxide and sodium nitroxide you can see the required diol was obtained ok. So now the diol is there next is to carry out the corresponding Grignard reagent. So the Grignard reagent did not work actually original plan was to carry out reformatsky reaction. So here he tried this the alpha bromomethyl acetate and form the Grignard and this reaction did not go. So instead so what he did so they removed both methoxy group ok they removed both methoxy group with PBR3 with PBR3 both methoxy were removed then from methyl acetate this proton was deprotonated using lithium exomethyl disalicide that lithium derivative was added to the CH2 ok. And of course to facilitate that magnesium bromide the ethyl ether also was added. So now this reaction worked very well and that was converted into corresponding minium isoenone B2 methyl ester after removing the TMS ok. So that is how this total synthesis was accomplished and it started from commercially available natural product called juglone and it involved heterodeal sal reaction, normal deal sal reaction, glycine rearrangement as key reactions to synthesize this compound. Overall he took about 11 longest linear steps with a yield of 9 percent ok. So 9 percent overall yield is a very good strategy and now let us see the second total synthesis which is chiral one and this was reported by Marcus Tias. So he the left hand side glycol part he started from D-glucol ok. So D-glucol was the you know key starting material to introduce the chiral center ok and according to him it and this minium isoenone can be easily disconnected into 3 fragments. So this is one fragment and then middle the dihydroxyandroquinone is the second fragment and the third fragment comes from this intermediate ok. These are the 3 fragments you could easily disconnect very logical. Now let us see how he made these 3 fragments and then combined all. He started with beta hydroxycarboxylic acid this upon treatment with pivaloldehyde in the presence of acid it gave this protected compound ok. Now he wanted to introduce a double bond here so that was done first termination followed by elimination he got the double bond and still you can see there is one stereo center then the allylic bromination was carried out with NBS under photochemical condition. So one side chain is already prepared. The second side chain he started with D-glucol ok the triacetate was hydrolyzed to get the triol then the primary alcohol was mesylated then both the secondary alcohols were acetylate ok. The mesylate upon treatment with lithium iodide the mesylate is converted into the corresponding iodide. Now upon treatment with LIH so this iodide will be displaced by hydride and ester also will be reductively removed. So you basically what you have done is from the D-glucol the CH2OH is converted into CH3 ok. And both the hydroxyl groups were protected as TBS ethers then treatment with butyl lithium potassium butyl lithium one can generate anion here then that was exchanged with zinc for the legacy type coupling ok. Then for the middle portion this is a commercially available dihydroxyandroquinone take this and protect both hydroxyl groups as mom ether ok. Then reduce these two ketones reduce these two ketones with sodium borohydrate isopropanol completely to get the corresponding aromatic one ok. From androquinone that is dihydroxyandroquinone what we have done is dihydroxyprotected ambrosine ok. So then it is a symmetrical compound so treatment with TBS either it can generate here or here does not matter both are same then exchange it with tributyl tin chloride ok. So then you exchange that with iodine ok the tributyl tin can be easily exchanged with iodine by treatment with iodine. So this side you have iodine and that side you have zinc so then do the key legacy coupling to get or introduce the CC bond ok. Then this sodium cyanoborohydrate will reduce this enol ether ok. The sodium cyanoborohydrate will reduce the enol ether stereo selectively to get exact tetrahedral pyrone unit with all stereo centers fixed. Now what is left as you know you have to introduce a tin group here and then attach the CH2 side chain ok. So first introduce the tin by treating with enbutyl lithium and then try quenching with tributyl tin chloride and this upon coupling again this time it is like still like coupling so that gives the corresponding side right and side side chain ok. So if you look at this what is missing is a methyl group at this carbon but you have enol so one can easily introduce a methyl group using Gilman's reagent so that is what he did and that methyl 1 4 addition took place highly stereo selectively because of the presence of the tertiary butyl group ok. Then what needs to be done if you look at this middle ring of this andersine in the natural product it is androquilone that means this diene should be oxidized to diketone so that was done and to get the corresponding di substituted androquilone ok. So what is left you have to remove this tertiary butyl group you have to remove both moms and you have to remove both TBS group. So if you treat with HCl so this will remove and then you also will get methyl ester mom group will go and also TBS group will go so it is a complete global deprotection followed by esterification all were done in one step to complete the asymmetric total synthesis of enium is known B2. So in summary Markasthias and his co-workers completed the total synthesis of enium is known B2 in early 90s and they started with commercially available 1-8 hydroxy androquilone and also D-glucol on the left side and the other side they started with beta hydroxy carboxylic acid which is also commercially available ok. There are 2 key reactions which they used one negishi coupling on the left hand side and still a coupling on the right hand side and the last to introduce a chiral center on the right hand side chain they used Gilman reagent to introduce the quaternary center ok. So they took about 11 steps and overall yield was 4.6 percent considering the complexity of the molecule and also the first asymmetric total synthesis this is a significant achievement ok. So I will stop here and then we will continue our discussion with one more natural product and complete the syllabus of this particular course. So we will discuss tomorrow about the total synthesis of another complex natural product called Zaragozy acid ok until then see you thank you bye.