 So, good morning and I will come back to this course on classics in total synthesis part 1. In the last lecture, we briefly talked about the need for synthesis and basic requirements to become a synthetic chemist. Now, we will continue our discussion on brief history of organic synthesis and also little bit about retro synthesis, okay. So, when you talk about history, the first synthesis of a natural product or any other molecule, organic molecule was reported in 19th century. In fact, in 1828, the first synthesis was reported by Euler on urea. Interestingly, if you look at this, this urea was made from an inorganic compound and it was 100% autumn economy reaction. Then Colbey was the one who made acetic acid and he was the first person to use the term synthesis and afterwards, you know, people you started using synthesis. I will come back little later the difference between preparation and synthesis and many times still people make mistake where to use synthesis and where to use preparation. Then in 19th century, the most spectacular synthesis reported was by Fischer and Fischer who made glucose that was the first time a natural product with chiral centers were made, okay. So, it was a, you know, spectacular landmark synthesis in the history of synthesis, okay. So, if you look at 19th century, these 3 are great landmarks. First Euler's urea, then Colbey made acetic acid and also coined the word synthesis and towards the end of the century, Fischer made glucose with 5 chiral centers. Then of course, you know, there are many, many outstanding synthesis of natural products and natural product like molecules, it is very difficult to compile all or compile most of them. So, what I will do? I will try to do it in 2 to 3 slides and how the history evolved over the next century or so on total synthesis. In the 20th century, the first molecule which was reported was Topinone. So, Topinone was an alkali and 1901 Will Statter reported the synthesis of Topinone and 16 years later Sir Robert Robinson reported the synthesis of Topinone. Interestingly, when Robert Robinson reported the synthesis of Topinone, it involved 2 important concepts. One is green chemistry because all the reactions were done in water, okay. Two, he also involved a multicombinant reaction to make these natural products. So the 2 important concepts he introduced almost 100 years ago, green chemistry and multicombinant reaction in the synthesis of Topinone. And 2 years later, Camphor which we all know is a monoterapine, so it was reported by Compa and year later Perkin also synthesized Camphor. So the 1st decade of 20th century saw 3 reasonably complex molecules considering the time frame. The 3rd molecule again Perkin reported was the synthesis of alphaterpinol, another monoterapine, okay. And 3 or 4 decades later, the father of modern synthetic chemistry Robert Robinson synthesized the alkaloid called quinine. It was a formal synthesis and that got major attraction and this is one of the molecules which I will discuss in details a few weeks later and I will share lot of stories about this molecule as well as you know other related molecules. And 7 years later he synthesized a famous steroid called Cartisone. This also we will discuss in our synthesis and 3 years later he completed and reported the total synthesis of an alkaloid called strychnine which I already mentioned. There were 400 papers, there were 400 papers on the isolation and structural elicitation of strychnine. So it took several years to even report the correct structure of strychnine those days and finally 1954 Woodward was the first one to complete the total synthesis of strychnine. So since then there are many synthesis we will try to cover at least 2 or 3 total synthesis of strychnine in this course. Then in 1957 though 2 decades before penicillin was isolated but synthesis was very difficult. It is particularly because of this highly labile 4-membered beta lactob. There are many synthesis and in 1961 another dawn, another legend in total synthesis Kore started reporting synthesis of several complex natural products and one of them is Langefolin and the Langefolin is a classical synthesis followed by his synthesis of gibralic acid it is also very very difficult synthesis which deserves highest level of appreciation and considering the time in 1970s such complex natural product was made and around the same time Woodward also made another big complex molecule vitamin B12 and that time people never thought that molecules like vitamin B12 could be made but Woodward made it. So then in 1980s Nicolau joined the top group of total synthesis chemistry and his synthesis of end endic acid is one of the classical biomimetic type cyclization and use that cyclization to make 4-5 rated endic acid using very simple strategy and 10 or 12 years later another famous endic cancer agent now it is a drug called Taxol got major attention from many synthetic chemists Nicolau and Andre Halton were the first ones to make this natural product since then there are 10 more total synthesis of Taxol reported all of them are very interesting and we will try to discuss few of them in this course. Now that is a history of our brief history of total synthesis so when you talk about history of total synthesis initially how did they start? What were the targets? Did they start with bigger targets complex target? No they all started with simple target because it was see one should remember that when they started there were no NMR no IR no UV when they started. So all this spectroscopy techniques came much later so it was not that easy to choose complex molecules so they always chose simple molecules simple target molecules when they choose simple target molecules the target molecule will be very close to the starting materials which they use so that no it is easy okay it is easy for them to compare and then see whether they have made the compound then more and more complex natural products were isolated okay. So when you isolate complex natural products then synthetic chemists also will be very much interested in making these compounds so then you cannot start with equally complex natural product is not it see when you want to synthesize a natural product and when we talk about total synthesis the total synthesis means you should start from simple starting material is not it you should start from simple starting material and accomplish the complete synthesis of the target molecule and if a target molecule is big then you cannot start with a similar similarly complex you know starting material so you have to start from very simple starting material then it becomes very very difficult. So that was the time you know one need very high level of intellectual planning skill curiosity and that time lot of outstanding synthetic chemists join and they started working on total synthesis and try to address synthesis the problems faced in synthesizing complex natural products and physical chemists inorganic chemists they all supported organic chemists and physical chemists you know they supported in terms of you know having spectroscopic techniques NMR IR UV X-ray all this helped organic chemists to solve structures and inorganic chemists inorganic chemists were concentrating on developing new reagents okay and these reagents were used by organic chemists inorganic chemists all normally they are interested in unstable compounds they are always interested in unstable compounds for organic chemists it is blessing you know why these unstable compounds are reagents for us so organic chemists use these unstable compounds prepared by inorganic chemists as reagents so that way inorganic chemists and organic physical chemists played a very very important role in the development of organic synthesis. When we continue further many times when reactions do not go that is the time one should try to understand the reaction mechanism why reactions do not go so this is where physical organic chemistry comes into play so all started with synthesis and branched out and they were started working on physical organic chemistry physical organic chemistry played a very important role in addressing some of the complex problems associated with total synthesis more and more new reactions were developed okay so synthetic chemists job is to understand remember large number of reactions and in the large number of reaction what is important is what are the reactions which are reliable and general because some reactions which will work specifically for particular transformation but they cannot be general so that is why the most reliable reactions one should consider when you talk about synthesis of complex molecule then important thing is when you talk about complex molecules then some of the molecules have several stereo centers some of the molecules have several stereo centers how do you incorporate or how do you install new stereo centers and some of them will give conformational problems okay so in one particular confirmation the reaction will work and the other confirmation it will not work and how do you make sure that your substrate is in that particular confirmation so that your reaction will work so the understanding of stereo chemistry and conformational analysis also played a very important role in 60s onwards okay then I already mentioned spectroscopy methods played a very very important role for synthetic chemists to grow and in 70s a very famous technique called retro synthetic analysis reported by Nobel laureate Ilya Skora actually helped all synthetic chemists to solve complex problems by dissecting the bonds into small smaller and smaller and smaller molecules you can take complex molecule by using retro synthetic analysis you can cut and go to the next molecule cut go to the next molecule until you reach commercially available starting so this retro synthetic analysis is one of the famous tools used by synthetic chemists in addressing and solving many synthesis problems so what is retro synthesis okay retro synthesis so that itself tells retro means reverse reverse of synthesis okay so when you talk about synthesis if you want to make B you start with A so A to B is called synthesis isn't it A to B is called synthesis A to B is called synthesis and B to A B to A is called retro synthesis you have B and how you can make B if you identify A then that process is called retro synthesis and that process is you if B is the target molecule okay and you break this B using some known reaction or using some functional group transformation and disconnection if we can convert that into A then that process is called retro synthesis and you also see another term called disconnection again the disconnection is opposite to the forward reaction see normally you talk about A giving B but in the disconnection you break a bond okay and when you break a bond you know you can identify so this will lead to another starting material okay so normally this retro synthesis the disconnection is represented by this double headed RO and normal one you write like this okay this is the major difference and TM again you will see in the literature TM is called a target molecule to be synthesized and FGI is called functional group interconversion or functional group transformation and synthesis what are synthesis when you break a particular bond when you break a particular bond and if it is if it is broken by homolytic cleavage then you get di-radical and if you break it by heterolithic cleavage one side you will get carbocation other side you will get carbonyl okay charged species so the charged species are called synthons when you break you get two different two different fragments they are called synthons and you also see another term called synthetic equivalent what is synthetic equivalent and what is the difference between synthon and synthetic equivalent. Synthon is a fragment is a charged species okay it can be radical it can be carbocation it can be carbonyl or the synthetic equivalent is a one is an actual substance for example RBR when you cleave if you get R plus that is synthon RBR is synthetic equivalent and sometimes you get R minus then also you can write RBR a synthetic equivalent because if you do Grignard then it becomes RMGBR it becomes R minus is not it. So that is a difference between synthon and synthetic equivalent which you should know okay so I will not go into the details because this Sandal as I said in the beginning this course concentrates mainly on the total synthesis and you should have known about heterosynthetic analysis and I am just doing a recap of what you know about heterosynthesis. I just give one example of heterosynthetic analysis of a very small molecule before we move to natural product synthesis so you look at this target molecule so when you look at this target molecule so you can write it as Tm okay now there are two double bonds is not it there are two double bonds one is a disubstituted double bond the other one again it is a disubstituted double bond the difference is here it is one one disubstituted here it is one two disubstituted okay. So now when you look at a molecule first thing you have to look at a molecule is whether the molecule has a functional group okay so now when you look at this it has two functional group two double bonds okay and next question is whether you want to make both the double bonds in one step or you want to make only one double bond if you are making only one double bond which double bond you will make okay so that way you have to think and simplify so now are you going to make this double bond or going to make this double bond. So it is very easy from the look of this molecule if you want to make this double bond it can be made using Wittig reaction is not it if you want to make this double bond one can easily make using Wittig reaction. Then what should be the precursor the double bond two double double sorry double bond two can be made by Wittig reaction that means this is the precursor is not it this carbonyl group when you look at simple methyl Wittig will give you a target molecule simple methyl Wittig is not it if you take this Wittig will give you your double bond and now when you look at this precursor you can see a cyclohexene okay you can see a cyclohexene whenever and wherever you see a cyclohexene one reaction which would come to your mind immediately is Diels-Alder reaction okay one reaction which would come to your mind immediately is Diels-Alder reaction okay. So now that tells how you can break this compound and make it as Diels-Alder starting material it is very simple if you do that you get cyclopentadiene which is the 4 pi component and methyl vinyl ketone has the 2 pi component and this can undergo 4 plus 2 Diels-Alder reaction when it undergoes Diels-Alder reaction as you know Diels-Alder reaction gives end product as the major product and you get this compound. So basically this compound the target molecule can be made in 2 steps from commercially available starting material commercially available starting material that is cyclopentadiene and methyl vinyl ketone. So now to make it complex okay the same starting material I make it complex and then say instead of this compound Tm I write this compound I revise the target molecule and the target molecule does not have any functional group target molecule does not have any functional group okay. So this is also very important when you look at a natural product when you look at a molecule and if you want to do retrosyndetic analysis normally what you look at is a strategic bond or if there is no strategic bond you look at a functional group. If both are not there as in this case then what you should do you should introduce 1 or 2 functional groups 1 or 2 functional groups because these functional groups will be the handle for you to carry forward the retrosynthesis without functional group without strategic bond you cannot do retrosynthesis okay. So that is what when you look at this hydrocarbon it is a high simple hydrocarbon and it does not have functional group. So first thing if your target molecule does not have a functional group or does not have a strategic bond introduce either introduce a functional group or introduce the strategic bond. So now it is very simple this target molecule can be made from the earlier target molecule is not it? How do you do it? Very simple hydrogenation this compound can be easily obtained from this hydrogenation. So that means the precursor is this you introduce two strategic bond two double bonds you introduce that will simplify the whole process. So in retrosyndetic analysis why I chose this particular example is one you should know the strategic bond if you do not have introduce your strategic bond that will simplify the process okay. So when you talk about any synthesis synthesis generally involves two stages okay these two stages are very important normally nobody will teach but you should know that synthesis involves two important stages one is analysis okay I will come to that later. Second is the execution as a synthesis part. So what is analysis? Very very important many times this is where people make mistake. The first thing is select the target molecule why select the target molecule as I said there are 10,000 natural products which are being isolated every year okay. So you cannot synthesize all the molecule is not it? So you have to synthesize the target molecule you have to synthesize a target molecule either the target molecule should show exceptional biological activity very important or highly complex in nature or you have some methodology or you have developed some new reagent or you have developed some new catalyst that could be used to synthesize this target molecule okay. So you cannot simply choose any target molecule you have to choose target molecule based on this okay. See that is the first and foremost step many times people make this mistake simply they choose randomly target molecule no choose a target molecule based on this once you choose the target molecule then from retrosynthetic point of view next thing you have to look at that molecule is whether it has any functional group or it has any strategic bond okay these two are very important once you have that then you can use known reactions to break the bond or convert the functional group yeah. Once you see the functional group then use the disconnection method okay disconnection method using the known reaction and of course when you talk about known reaction reliable and general reaction to break the bond okay. Then next step is you continuously do that continuously repeat the disconnection as much as possible to reach the starting material which is available commercially okay. So that is very important okay continuously do it is the starting material when you write the retrosynthesis never compromise this is very important okay it may happen it may not happen no problem I will write no you have to be very very strong you should be 100% sure that when you do your retrosynthesis this can be obtained from this you have to be sure then only that pathway you can proceed further there is no compromise during the planning stage okay. Then when you do a total synthesis it is very important it should not be a routine total synthesis your synthesis should have at least one interesting interesting I do not use the word novel also people use novel one interesting disconnection okay where you can make 3 4 bonds or you can use a multicombinant reaction something unique about that particular step one interesting disconnection you should have then only that synthesis will be attractive. So you are writing retrosynthesis when you do retrosynthesis you can see there will be several branches so many pathways for the same molecule you should be able to write 10 different retrosynthesis then you write all the pathways all the pathways separately all the pathways analyze which one is better in terms of number of steps in terms of commercial availability of starting material cost all that you calculate and then see yes root C is the best route okay choose that route now you have done the analysis part the second part is synthesis that is the execution but at the end of analysis what are the advantages you have one that leads to readily available and inexpensive starting material okay that is the first and foremost advantage of analysis then you never compromise while doing the retrosynthetic analysis so all the reactions you have planned are very efficient okay you know that these reactions will work the third one the conditions so when you while doing the retrosynthesis itself you have seen whether these reactions can be carried out in our lab okay some reaction may not be able to be carried out in our lab so you should you should have thought about it so you should be practical and it should be possible to do in our lab so this is a third third advantage when you do analysis and while doing retrosynthesis also when you know one particular step does not work what are the other alternatives what one can do that you would have planned so you know if there is a problem you can always fall back and then go to another side route and come back okay and last but not the least is when you do this one can also synthesize several analogs of natural product using this strategy and that will give you an opportunity to take care of structural activity relationship studies to of course the route which you have finally done is very quick and elegant and now the second part is the execution part as I said you write all the pathways and choose the best one okay that is the second step then the third step is forward synthesis what you have done during the analysis is the retrosynthesis but in the during the synthesis you have to write the forward synthesis each and every step you write and with reagents and condition so then only you know for moving ahead what are the chemicals you need okay and before that for each and every step go to the library collect all literature and experimental procedure for each step okay then what you do order the chemicals reagents required for all the steps then only you should go to lab okay before doing all this you cannot go to lab and straight away start doing this so after doing all this then you go and then start the first step okay now you have done all this you go to lab start the reaction first step itself does not work it happens sometimes second step will not work sometimes the last step will not step but last step will not work so what you do then you should try to change the reaction conditions try to understand the mechanism change the reactants or if nothing works change the strategy okay this is what you should do and if it does not happen again go back try to change again the reaction conditions mechanism reactant strategy so according to Paul Wender from Stanford University this is what one should do okay but as you know it is easier than and easier said than done then if nothing works you have to change the student because you do not know whether the the synthetic problems given it was because of student or because of the reaction conditions so you supervisor thing will think that after doing all this it is because of the student the scheme did not work but the student will think that the supervisor is given you know unworkable problem so otherwise you know he or she would have thought easily that project would have been complete well I will not get into that but one thing which is obvious is it is easy to do this but difficult to do this okay changing student or supervisor is not easy once you join for PhD somehow you know should make sure that you successfully complete the PhD and then go so the last slide I will just briefly talk about a linear and convergence synthesis and what are the advantages of convergence synthesis linear as the name suggests that means you are synthesizing that target molecule in a linear fashion whereas convergence synthesis you are making two or more fragments and then converge it okay try to couple so why convergence synthesis is better than linear synthesis let us see a synthesis of the same target molecule using linear synthesis as well as by convergence synthesis assume that the linear synthesis as well as convergence synthesis is of 5 steps and in the case of linear synthesis you can say each step gives 90 percent so your target molecule at the end of 5 steps you get 59 percent okay the same thing you do via convergence synthesis here you make two fragments C and F each by two steps then try to come combine now the overall yield is 73 percent so you can see clearly there is a difference in yield one and the second important thing is when one does a complex total synthesis convergence synthesis is better for a simple reason that the fragment C can be made by one student okay and and fragment F can be made by another student so more students can work on the same project but each student will work on different fragments so the speed in which you can assemble and then complete the synthesis is much faster so convergence synthesis always is advisable and sometimes it is not possible but given a choice you should plan for convergence synthesis so with this I will stop here to summarize you know in this lecture I talked about mainly retro synthesis and also how you have to plan your synthesis start with analysis and then execution and also why convergence synthesis is better than linear synthesis in the next class we will talk about a total synthesis of three membered rings and we will start with synthesis of iludins and we will go ahead with another natural product okay so thank you