 Good morning everyone, we will come back to NPTEL lecture series on classics in total synthesis part 1 and we just started discussing about total synthesis of natural products having three number ring and the last lecture we talked about total synthesis of iludine and there we talked about the utilization of carbonyl lights in making five number ring as well. We will continue our discussion on the total synthesis of natural products having three number rings and in that we will talk about total synthesis of a natural product called FR900848. This is a very interesting natural product isolated and reported in 1990 by Yoshida and this group and if you look at this molecule you can see there are 5 cyclo-propane. So it is indeed a complex natural product. It is a nucleoside having a long chain and then the long chain has 5 cyclo-propane and 3 double bonds and this was isolated from the fermentation growth of strepto-veticillium ferubens and it also showed exceptional activity against filamentous fungi such as aspergillus niger. So because of this structural complexity and also due to the biological activity many synthetic groups were interested in the total synthesis of this natural product and 5 years later the first total synthesis was reported by Tony Barrett and if you look at this molecule as you can see it is indeed a complex natural product. The major challenges posed by this molecule are one there are 14 chiral centers in this molecule. Of course you can say 4 are from sugar unit so that can be easily obtained from commercially available starting material but the remaining one they are not easy to make it and there are 5 cyclo-propane which I already mentioned and there are 3 E double bonds. So these are some of the major challenges one has to think about while planning a proper retrosynthesis and according to Barrett this can be first disconnection can be done by just cleaving this amide bond. So that is obvious disconnection when you have an amide and the easiest bond to cleave is the Cn bond. So that cleavage will give you the corresponding carboxylic acid and the nucleoside the whole nucleoside is the other fragment. So that actually simplified the retrosynthesis of FR900848 to making only this carboxylic acid if we can develop a good method for making this carboxylic acid and this is a known compound or it can be easily made okay and just coupling these 2 should give the natural products. So with that he further did retrosynthesis and this carboxylic acid can be made from this alcohol by oxidation and homologation using you know vitic type reaction to get the corresponding dienobiasis okay and this if you look at his original idea first if you have this material then one can do this cyclopropanation here and here and followed by converting this diol into double bond okay. So you have 2 double bonds and the 2 double bonds you do cyclopropanation then the diol which you get after removing this astronaut you can convert that into a double bond. So that was his plan and that in principle can be obtained from this aldehyde and this vitic salt okay. So now you should have proper method to make this particular fragment with 3 cyclopropanes okay and if you look at the literature what are the methods available for cyclopropanation okay. There are few methods but one method which should come to your mind immediately is Siemenswith cyclopropanation. So Siemenswith cyclopropanation is nothing but if you take an alkene and treat with diodo methane in the presence of zinc copper couple at ambient temperature you can easily cyclopropanate an alkene okay and this was reported way back in 1958. It is believed that it goes through a zinc carbinoid type mechanism okay. So like how if you have a carbinoid how it can undergo a cyclopropanation the same way when you have zinc as a metal. So the zinc carbinoid you know undergo cyclopropanation of a normal double bond and this is the mechanism. So it goes through a three-membered transition state and followed by removal of zinc iodide. So in the process zinc iodide comes out after delivering the CH2 and based on the evidence based on the products based on the mechanistic studies there was no free carbene involved in this reaction always the metal was involved the carbinoid was involved. Later so once you introduce the cyclopropane okay later many people were interested in introducing this cyclopropane asymmetrically because when you do a cyclopropanation you introduce two chiral centers. So if an asymmetric method can be developed then it will be very interesting. So that is how many people were interested in developing asymmetric strategy for cyclopropanation. The first method which was deported by Andy Charrette. So what he did he used a lelic alcohol and also a chiral auxiliary. So he started with a sugar unit. So you can see you have a sugar portion and then allyl group and this hydroxyl group actually helped in directing the cyclopropane. So he took this compound and then treated with the same combination that is CH2I2 and diethyl zinc which in situ prepares you know CH2Zn and Ii okay. So this gave about 98% yield with a diastereomic excess of 50 is to 1. So this was very very interesting method and this is the mechanism and this is how the free hydroxyl group okay. So first it forms a bond with zinc then it coordinates with zinc and CH2I and then intramolecularly the CH2 is delivered to the double core okay. And Waringdrager Wall in 2003 he reported another asymmetric cement with cyclopropanation using ephedrine type amino alcohol and here also it gives very good diastereomic ratio 98 to 2 and exactly following a similar part. So in these 2 cases what we have seen is you need a chiral auxiliary. You can see that this is a chiral auxiliary and you attach the allyl group that do the cyclopropanation. So it will be nice if you do not have to use chiral auxiliary and if you have to use a chiral promoter or chiral controller or chiral catalyst then this reaction will be much better. So with that charate prepared a very interesting you know you can call it as chiral controller dimethyl tartaric acid ester was used and he prepared this boronate ligand okay. So this was used almost you know stoichiometric amount nevertheless what you can see is the main difference is this is not attached to your allylic alcohol if this is not attached to your double bond okay. So you can add separately and then recover it if you want okay. So that way this reaction also gave very good E 90 to 94% high. So this reaction has been successfully used in many such cyclopropanation reaction where you take simple allylic alcohol and as usual zinc iodide and then diodomethane and add this ligand that gives very high E of the cyclopropanethanol okay and when you do this reaction you can also use hydrogen peroxide because why you have to use hydrogen peroxide is as you know you use boronate ester. So to remove the side you know side products from boron you will always use hydrogen peroxide work up to get the corresponding cyclopropanated methanol in good yield as well as in good E. So this is the mechanism so I will not go into the details as you can see here the boron coordinates with oxygen and later it forms the covalent bond with zinc and zinc also forms coordinate bond with oxygen of the amide then it transfers the CH2 from the same side. So that you get higher selectivity okay and then since it is a chiral controller or chiral promoter you can reuse this. Now coming back to the total synthesis of FR 90048 so E also started with diethyl tartarate the study material for one of the fragments is diethyl tartarate and protect the hydroxyl groups to hydroxyl groups as acetonide then reduce the ester esters as diol and protect one of them as it is symmetrical one of them can be easily protected as TBS ether then oxidize the other alcohol other primary alcohol under one condition to get the aldehyde. Once you have this aldehyde then you can do a Wittig reaction with ethyl bromide derived Wittig reagent and then use Manfred Schloss' condition that is you have to use excess phenyl ethyl so that gives trans double bond E double bond. Then remove the TBS group and oxidize so you get one fragment which is required for the total synthesis of FR 90048. Then the other fragment is started with this diene diol and used anticharates cyclopropanation and you could introduce these two cyclopropanes in one step it is a symmetrical compound so then protected one of the hydroxyl group so it is since it is symmetrical one can easily protect one of them as TBS ether so it could protect successfully one of them as TBS ether then the other alcohol was oxidized to aldehyde with PCC then a stabilized Wittig on that aldehyde gave the corresponding alpha beta unsaturated ester. Here the EZ ratio is 19 is to 1 which is separable then you reduce the ester to alcohol normally one can use LIH here use di-ball and do another cyclopropanation using same charates protocol okay. So now the next step is to convert the CH2 OH into CH3. So first he wanted to convert this CH2 OH into corresponding cell phone and then do reductive removal removal of the SO2 pH. So first the alcohol was converted into SPH using a Midsunobu type reaction by treating with tributyl phosphine and N phenyl sulfide okay so he could convert that OH into corresponding SPH. This was oxidized with oxone to get the corresponding cell phone but what he could not actually was the removal of this cell phone to get the methyl. So he tried several conditions one of them is Ranonical and ethanol and he could not get the corresponding methyl group. So then he thought this may not be the right strategy say he revised the strategy and for that he started with this diol which he already prepared okay. So he took the diol then he did the vitic reaction oxidation with PCC then did the vitic reaction that is the stabilized vitic only difference is in the earlier case he protected one of the alcohol as TBS ether then oxidized the other alcohol to aldehyde. Here he oxidized both the alcohols with PCC to get the dioldehyde and the dioldehyde treated with the stabilized vitic reaction to get this alpha beta unsaturated ester. So here he got a mixture of both required EE and EZ of course this is a major isomer but this minor isomer also he could convert into the major isomer by treating with phenyl thiol or benzene thiol and titanium tetra isopropoxide and butyl lithium okay. So this is a nice reagent combination which isomerizes the cis or Z isomer to E isomer okay. So since he needs only the E isomer so the E isomer was taken and he has taken it forward reduction with the excess diol gave the diol once you have the diol here you can do 2 cyclopropanation here and here. So now you can see he has introduced 4 cyclopropanings overall how many cyclopropanings he has to introduce 5 but these 4 are contiguous then you have a double bond in between followed by another cyclopropane and methyl group. So this diol then he selectively protected one of them as TBS okay. So since this is symmetrical you take this alcohol and protect it as TBS ether then oxidize the other primary alcohol then do the Wadsworth Iman's Pittick reaction to get the corresponding diene ester. Again he got a mixture of E E of course E E and E Z that E Z can be converted into E E by following the same process which I had already discussed and this upon further reduction with the diol H he got the diene alcohol okay. So this is again now it is full E E okay then this allylic alcohol he could successfully selectively do the cyclopropanation. As I said what you need is another cyclopropane and this 4 cyclopropanes and this cyclopropane should be linked through a double bond okay. So he could selectively do the cyclopropanation on the terminal double bond which is now allylic alcohol. So he could successfully do so you can see all the 5 cyclopropanes required for the synthesis are here for 900848 are done. Then now he tried this conversion of CH2OH to corresponding SPH so this reaction worked and at this stage he removed using parenical okay. Then the SPH was removed and then we got the methyl group then ammonium fluoride removed the TBS got the alcohol and oxidation of this primary alcohol with PCC he got the aldehyde and again he had Swarth Eman's modification of this vitic reaction gave the diene ester okay. And again he got a mixture of E and Z that was converted into E E using the conditions which he already used twice then he tried to saponify this ester to carboxylic acid. So all the conditions gave decomposed product so finally used a simple KOTMS hydrolyzed the ethyl ester to carboxylic acid. So now if you look at the structure of FR900848 so this is the side chain which should be attached to the nuclear side. The side chain is prepared now let us see how the nuclear side is prepared so the nuclear side is here then what he has to do he has to combine this amine with the carboxylic acid to make the natural product. So he took this commercially available alcohol okay this is made in three steps from D ribose in you know in kilogram scale. This primary alcohol was converted into meselate and then meselate underwent an SN2 reaction with sodium acide to get the corresponding N3. Then N3 is reduced to get the corresponding NH2 and the astronyte okay the protected astronyte was cleaved with 80% acetic acid to get the nuclear side which is required for the DCC coupling with the carboxylic acid. So what he did he did not do the DCC coupling he took the carboxylic acid and then treated with this phosphoryl chloride so this is called BOPCl okay then added this amine okay also that gave directly this F bar 900848. So if you look at this whole synthesis the key reaction is nothing but introduction of cyclopropane there are 5 cyclopropanes you could successfully introduce and also he established 3 EE double bonds and of course he did not face much problem in making this nuclear side. So overall the total synthesis of for 900848 was accomplished in 15 longest linear steps by Barrett's group and Richard's asymmetric cyclopropanation was used as the key step in introducing all the 5 cyclopropanes okay. So with this now we have discussed total synthesis of 2 natural products having cyclopropane. Now we will move to natural products and non-natural products having 4-membered ring as the key substructure okay so thank you.