 Good morning and welcome back to the NPTEL course on Classics in Total Synthesis Part 1. And today, so we will talk about very important natural product called taxol and we discussed at least 4 total synthesis of taxol and the first one we will talk about these total synthesis of taxol reported by Nikolaou. So this is a complex structure of taxol as you can see here there are 4 rings. So these 4 rings are A you can see A ring which is a 6 membered ring and B ring which is supposed to be the more complex one which is an 8 membered ring then we have C ring which is a 6 membered ring and D ring which is a 4 membered ring which is oxidized. In addition we also have an ester substituent. This was isolated from the bark of Pacific U tree way back in 1962 but the elicitation of structure took quite some time almost it took 10 years to get the correct structure of taxol. So this was isolated and elicited by 2 natural product chemists called Baal and Vani and they proposed the structure through x-ray. Obviously when you look at this molecule it is quite complex and more importantly this molecule showed a wonderful activity against the ovarian and breast cancer. So many groups across the globe so wanted to work on the total synthesis of this molecule and about 200 groups worked on this molecule and so far about 10 people have successfully completed the total synthesis of taxol. So why this molecule is so important ok and if you look at this molecule first of all this molecule was isolated from the Pacific U tree ok. The Pacific U tree is a very very slow growing tree ok and this was isolated from the bark of Pacific U tree and if you need 300 milligram of taxol ok you have to kill 1, 1 Pacific U tree which is 100 year old ok you can imagine a single 100 year old Pacific U tree may maximum give 300 milligram of taxol and that may be about sufficient for 1 single dose of a cancer patient ok then you can imagine if you want to produce more taxol then there should be other ways it cannot be from the natural source. Nature has shown a way ok here it is a molecule ok you can identify and then see this could be used for the treatment of ovarian and breast cancer now you make your own ok so that was the biggest challenge nature has given ok and interestingly the second major problem for taxol was the Pacific U tree is a very very slow growing tree as it was isolated from the bark of Pacific U tree if you have to isolate more of taxol you have to kill this tree ok and then it will take so many years to grow. But interestingly and surprisingly the leaves the leaves of Pacific U tree has another natural product called 10 D acetylbacatin 3 ok if you look at this structure 10 D acetylbacatin and compare it with taxol you will see there are 2 things which are missing in this 10 D acetylbacatin one is obviously the acetate group is not there here the acetate group is not there only free hydroxyl is there and the second major change is the hydroxyl this hydroxyl group in the case of taxol it has a long side shape with 2 chiral centers ok that is missing in 10 D acetylbacatin. But the good thing about this 10 D acetylbacatin which is being isolated from Pacific U trees leaves is that by simple functional group transformation one should be able to introduce the acetate here as well as the side chain here that will constitute the semi synthesis of taxol which I already discussed what is semi synthesis in the first lecture. So you have this isolated from the leaves of Pacific U tree now through functional group transformation one should be able to make taxol another most important thing about this is these leaves can grow faster unlike the tree the tree though the tree is a slow growing tree but the leaves grow can grow faster. So you can pluck the leaves and isolate the 10 D acetylbacatin from there you can can you can make taxol but after some time the leaves will do again ok again you can pluck the trees and then isolate 10 D acetylbacatin and so on. So that way so the leaves played a very very important role initially in the synthesis of taxol. However considering the complexity of the natural product now it was always you know big challenge for many synthetic chemists across the globe to think about a good synthesis for this interesting molecule. So as I said already 200 groups worked on this molecule and there were people who were also interested in making several analogs of taxol that is just because when you have 10 D acetylbacatin ok that is a core structure of taxol from there not only one can attach the side chain ok not only you can attach the side chain as well as acetate you can introduce different side chain ok. So when you do that who knows the analogs of taxol may be more active than taxol say that is how Portier he made a derivative of taxol and if you look at these two you can see there are two changes ok closely if you observe in the in this molecule there is no OAC you have free hydroxyl group and you have free hydroxyl group you know it is good for solubility ok it will have much better solubility. Another thing is in the side chain you have a tertiary butyl group whereas in taxol you have phenyl group these are the two major changes in this analog and this is called taxotier or dosy taxol ok this was reported by Pierre Portier from CNRS and later you know he licensed to now the company called Sanofi Aventis earlier it was Von Blom then as I said some of the analogs may be more potent than taxol and this was two times more potent than taxol ok so the dosy taxol is currently being used for the treatment of ovarian and breast cancer and the CNRS and the Pierre Portier got lot of royalty from Sanofi Aventis for this time and these are the people who completed a total synthesis or formal synthesis and starting from the different sources different starting materials ok. So they could complete the total synthesis of taxol but today what I will do I will talk about the total synthesis of Nicolo I in this lecture series I will talk about four total synthesis from Robert Alton in fact he was the first one to report the total synthesis of taxol and the second one from Casey Nicolos group who actually their work published in Nature and the third one by Samuel Danieshevsky's group and fourth one by Paul Wenders group ok. I will try to cover these four total synthesis and today I will let us start with Nicolos total synthesis as I said it is a very complex molecule there are many challenges you know to make this molecule and first of all if you look at this molecule there are so many chiral centers and they are all congested particularly in the C ring and V ring you can see they are all very very congested ok and the second problem which most of the synthetic chemists faced in the synthesis of taxol is the construction of 8-membered ring. The construction of 8-membered ring is not that easy so we all know so that has created quite a bit of problem for many many synthetic chemists and the third challenge is the tricyclic core that is 686. So these two that is A and B if you look at so they are bridge system they are they connected by through a bridge whereas B and C are huge system ok the 686 curbocyclic system different type of problems for synthetic chemists while attempting the total synthesis. So let us see how Nicolos thought about making this molecule. So first and then foremost retrosynthesis was obviously you know you can remove the side chain that is the easiest one keep the side chain out and what you get is this compound ok so one can always attach the side chain later so that will give you this intermediate ok. Now next one is you remove or break the CO bond the reason for breaking the CO bond is you know there is a double bond once you have the double bond you can do the allylic oxidation to get the hydroxyl that reduces the oxygen functionality in airing and this became the target molecule ok. Now if you look at this this could be obtained from this cyclic carbonate ok this cyclic carbonate if you treat with phenyl magnesium bromide or phenyl lithium then they should open up to give this benzoate and their free hydroxyl group so with that idea the two hydroxyl groups were protected as cyclic carbonate. Now this can be obtained from this double bond if you look at this from here if you do a hydroboration stereo and regio selective hydroboration one should be able to get hydroxyl group here once you have that then one can get this oxytane ring ok so that was the idea and if you look at this particular molecule then the 8-membered ring 8-membered ring can be obtained by a well-known reaction called McMurray coupling. So if you have a dialdihyde dialdihyde then under McMurray coupling it can give a diol ok. Once you have diol one should be able to differentiate the diol and then oxidize one of them ok. So the precursor for this keto this keto alcohol is this dialdi. Now if you look at this dialdihyde the dialdihyde can be obtained from corresponding primary alcohol isn't it? Protected primary alcohol normally it removes the proteting group and oxidize you will get this coupling. Now how do you get this so this is very interesting transformation what he did was he broke this bond ok and kept the vinyl lithium species on the left hand side and the other side you have non-lithium ok. This vinyl lithium species can be prepared by or through Asian motion reaction if you have a tosyl hydrosome and treat with butyl lithium it will generate vinyl lithium. Once you have vinyl lithium then you can quench with aldihyde to get the allylic alcohol ok. Now these two can be obtained from a simple precursor. So since you need a tosyl hydrosome to generate this vinyl lithium species the tosyl hydrosome can be obtained from the corresponding ketone isn't it? Now this ketone as you know can be obtained from this diene and that dienophile. So here the dienophile this is a ketene equivalent so you should have a diene equivalent like this alpha chloroachronitrile and this diene should undergo Diels-All reaction followed by hydrolysis one should get the ketone. And this can be obtained from this ester upon reduction and then production and that can be obtained from ethyl acetoacetate and aceto. So aldol reaction to get that. So the simple starting material which was used for the total synthesis of taxol by Nicolau is ethyl acetoacetate ok ethyl which is commercially available and very inexpensive. The other one again if you look at this this diol if you remove and then connect it here the primary alcohol if you connect it here you get a lactone ok. Now this lactone if you carefully look at it can be obtained by a Diels-All reaction. How this one this bond is broken now this alcohol is attacking here ok if that is the case then you will get this understand. This one I just leave it for a minute just to see the alcohol attacks this lactone and then this CO bond breaks and then you get a CH2 OH and then Brigitte alcohol is there. So this will become a six-membered ring and you can see this six-membered ring is the diene. This six-membered ring is the diene and this is the dienophile. So that means this should be able to prepare or synthesize from this diene and this dienophile. So Nicolau's total synthesis had two key reactions one that is the Diels-All reaction to make this A as well as C ring ok. You can see this is A ring and this is C ring. So both A and C rings are made by Diels-All reaction and this B ring the B ring was made by the famous McMurray coupling. So these are the two key reactions Nicolau has utilized in the total synthesis of Diels-All. So now let us see how he successfully made A ring as C ring and then combined them to get A, B, C ring and so on. For the A ring he started with ethyl acetyl acetate and then treated the base in the presence of acetone. So he could easily introduce the CCH3 and reduced the ester with the di-ball you get alcohol that alcohol was protected as TVAC there. So you get the diene which is ready for the Diels-All reaction. So heat it with alpha-covalent nitrile and you get this as the major product followed by hydrolysis with potassium hydroxide DMSO you will get the ketone. Now as I said you need for the A ring to interact with C ring you need tosyl hydrozone. So the tosyl hydrozone either simple tosyl hydrozone or 2, 6 diisopropyl tosyl hydrozone. So he made that and then it is ready. The A ring is ready. Now let us see the C ring. How he made the C ring? So these are the two starting materials. Now if you treat with phenyl boronic acid, phenyl boronic acid, see boronic acid what will happen? The boron will have a lot of affinity towards the hydroxyl group. So that way this is the first intermediate which will be formed. This is the first intermediate which will be formed. The two OHs attached to phenyl boronic acid will be replaced by these two. I have drawn this structure in such a way that this will undergo an intramolecular Diels-All reaction facilitated by the boron bridge. Intramolecular Diels-All reaction and of course when you talk about Diels-All reaction it will give endoisomer as the major product that is ester will be endo2 the diene which is going to be formed. So this is what you will get. Is it easy to visualize? Just to see the diene reacts with the diene of file. The diene of file is attached to the diene through boron bridge and it undergoes Diels-All reaction that is intramolecular Diels-All reaction where the ester is now in endo position. Now you have to replace the boron. Very simple, you treat with a diol. It is very easy to cleave boron by treating with a diol. So now what will happen? The boron will be cleave. Now if you look at this structure you have a diol and when you isolate the product this is not the product you get. What happens? Can you visualize how this compound you get? How do you get this compound? Think some minor rearrangement is happening. What type of rearrangement is happening? You can see this 6 membered lactone is being broken and a 5 membered lactone is being formed. So what happens? This lone pair, this primary alcohol attacks the carbonyl and breaks the 6 membered lactone. So that will give you directly your 5 membered lactone and free this secondary hydroxychrome. So once you have that now you treat with TBS triflate. So what do you expect? This alcohol will be protected as TBS ether, isn't it? No, what happens? This alcohol attacks the lactone and forms this hydroxyl group without TBS. That hydroxyl group is protected as TBS ether plus this hydroxyl also protected as TBS ether. Okay? It is not the protection of secondary hydroxyl group. The secondary hydroxyl group attacks the carbonyl of lactone and the final hydroxyl is protected as TBS ether along with the protection of test free alcohol. Now this helps in selectively reducing the ester to get the primary alcohol. Now once you have the primary alcohol, campersalphonic acid treatment, what will happen campersalphonic acid treatment? This is a, you know, ortho ester, isn't it? This is a ortho ester. So that will hydrolyze the ortho esters. So when it hydrolyze the ortho ester you get back. Basically, you know, if you look at this carefully, the ester group was selectively cleaved, ester group was selectively cleaved. That is all, that is the process which originally planned. Okay? Now the primary alcohol, primary alcohol can be easily protected. The presence of secondary alcohol by bulky protecting group. So here you use TB DPS chloride which protected the primary alcohol as TB DPS ether. Okay? Now what is left? You have to protect the secondary alcohol. So the secondary alcohol was protected as benzyl ether when you treat with potassium hydride and benzyl bromide. So primary alcohol is protected, secondary alcohol is protected. Now what is required? You have to reduce or open this 5 ombre lactone and functionalize the double bond to hydroxyl group. Okay? LIH will reduce the 5 ombre lactone to diol. Okay? Then when you treat this with dimethoxy propane and camphersulfonic acid, you get this compound. When you treat this with dimethoxy methane and camphersulfonic acid, you get this compound. That means under this condition this TB S also is getting removed. And 1-2 diol is protected. In the presence of 1-3 diol, 1-2 diol always gets protected faster if you use acetone or ketone. Okay? So that is how that was protected leaving the primary alcohol as such. Now when you oxidize the primary alcohol, when you oxidize the primary alcohol, you get the C-ring fragment. Okay? This is the C-ring fragment Niccolo wanted for the Shapiro reaction. Okay? So you take this tosyl hydrazone and then treat with 3, 3.3 equivalent of butyl lithium. That will generate the vinyl lithium species. Then quench with this aldehyde. So this reaction as I said is a Shapiro reaction. So you get this allylic alcohol. Okay? Now you see everything is there. C-ring is there. C-ring is there. And B-ring all the carbon atoms are there. Only thing is you have to connect these 2 carbon atoms. Before that you have to convert this double bond into a hydroxyl group. So you do epoxidize that double bond selectively that can be achieved by treatment with vanadium, agate in the presence of tertiary butyl hydroperoxide. You get this epoxide. Then if you treat with LIH, LIH or di-ball will give you 1-2 diol. So LIH or di-ball will give you 1-2 diol. So you get the 1-2 diol. Once you have the 1-2 diol, protect this 1-2 diol as cyclic carbonate. 1-2 diol now is protected as a cyclic carbonate. So A-ring is ready. C-ring is ready. B-ring is almost ready except that they have to carry out McMory coupling here. For carrying out McMory coupling here, what you need is aldehyde on both sides. So if you treat with T-buff, both TBS and TBDPS could be removed. Then oxidation with the tip of tetra-n-propyl ammonium perrothenate gives you the dialdehyde. Now the dialdehyde under McMory coupling Titanium-0 you could get the corresponding diol. So you have the diol now. So now if you look at this carefully, you are constructed A-ring, you are constructed B-ring and you are constructed C-ring. Now what you need to do, you need to do for some functional group transformation and also attach the side chain. So before that, whatever we have done, they are all racemic. We have not started with any asymmetric chiral starting material. So we have started with all racemic starting material. So this product is also racemic. If you want to convert this into a chiral one, obviously you have to resolve. So the resolution was done with campinic chloride. The campinic chloride reacts with this alcohol and this can be both diol can be beta, both diol can be alpha. These are the 2 plus and minus diol but present in 50-50 and using this you can separate this isomer. And then hydrolysis of this will give you the diol. Now this is chiral. Now this is chiral. So once you have that acetic carbohydrate D-map, so selectively one can acetylate the allylic alcohol. Then you oxidize the secondary alcohol, oxidize the secondary alcohol with tip-up to get the ketone. Now if you look at this, B-ring is fully functionalized. B-ring is fully functionalized. Now what is required is fully functionalized C-ring. So for that you need a hydroxyl group here. So that was successfully done with borane THF and then further oxidation to get that alcohol. Now removal of this acetonide. When you remove this acetonide you get a triol. The triol if you look at carefully, if you treat with acetic carbohydrate D-map, only the primary alcohol will be acetylated. The secondary and tertiary will be as such if you use only one equivalent. Then you want to form an oxidant intermediate. For that the secondary alcohol should be made as a good leaving group. So before that so the benzyl group was removed and then protected as T-acether. Then subsequently this was mesylated. The secondary alcohol was mesylated to get the corresponding mesyl go. Now potassium carbonate methanol hydrolyzed selectively the primary acetate here. Then you get the primary alcohol. This upon treatment with tetrabutyl ammonium acetate in the presence of methyl ethyl ketone gives the oxidant ring. It is an acetyl reaction. So for the C-ring to complete the C-ring you need acetylation. So that was then easily with acetic anyl D-map. Now you have to open this cyclic carbonate with phenyl lithium. You can see selectively open this cyclic carbonate to get the benzoate. If you look at this is CH2 isn't it? This is CH2. You need CHOH. So PCC and sodium acetate carries out that allylic oxidation to alpha, beta and such a ketone. Then if you reduce the sodium borohydrate methanol you get the corresponding alcohol. And this alcohol upon treatment the sodium exa-methyl disol-sine and this beta-lactam. I will tell you how this beta-lactam is made. commercially one can make in large quantity. So that free hydroxyl will open up and you get this intermediate. Now if you look at this intermediate except these two all are present in taxa. So basically you have to remove the TES group. So removal of the TES group in this intermediate with HF-peridine gave taxa. So it is so simple straight forward but thinking wise you know very very you know complex molecule. And the side chain was made from this chiral alcohol that is phenyl cyclohexyl alcohol and then this was attached to that. Now if you treat with LDA this hydrogen is abstracted by LDA and then it forms the enolate. That enolate upon enolate upon quenching with this emine. It forms this beta-lactam. Now PMP is parametoxyphenyl group that can be cleared with CAN and then protect it as benzyl chloride. So N benzoate and that is the one which was used to attach the side chain. So overall if you look at the total synthesis of Nikolaou. Nikolaou used cleverly two reactions. One the Dielsall reaction, intermolecular Dielsall reaction to construct the A ring and intermolecular Dielsall reaction to construct the C ring. Later he used McMurray coupling to make the highly strain 8 number ring. You know all those you know standard functions of transformation. So you could successfully complete the total synthesis of Taxol. So tomorrow what we will do we will talk about the total synthesis of Taxol by Robert Halter. Okay. Thank you.