Lecture Designing Organic Syntheses 3 - 14.10.14
Dyker, Gerald
Additional Strategies and Tactics in Retrosynthetic Analysis
 Welcome to the third part of the lecture on designing organic synthesis. In the preceding lesson we have analyzed this target structure with the help of having in mind using an oxy-cope rearrangement within our plan for synthesizing this molecule. We noticed that we have the retron of an oxy-cope rearrangement within this molecule and this is the carbonyl here and alpha-beta-gamma-delta-epsilon and saturation. So the result of our considerations was that we have to synthesize this type of functionalized by cyclic ring system. So and well then we should check and we didn't do that in the preceding lesson should check what would be the result of the oxy-cope rearrangement. So reaction conditions, potassium hydride to synthesize the potassium alcoholate and then heating it up so that the rearrangement can occur. So what would happen? Wow! Carbonyl group is formed at this position finally. This position is connected with that connected with that. So well should be right okay. So and let's translate that all into our well drawing where we don't have a three-dimensional perspective in mind. So this structure with an oxy-cope rearrangement would lead to this product and if we compare that to our initial target we notice of course these are mirror images right. So that means well if we have a racemic resume as the target we wouldn't have to care about the absolute stereochemistry. But if we have that as a natural product in mind and want to target it in anse selectively then this pair is Rewang enanceumur to perform that rearrangement. So we need the mirror image. So and well in order to get to this substrate we should well consider using for instance chiral Lewis assets for an anseo selective deals all the reaction. That would be the solution to the problem. Well next let us draw again that structure we had a glimpse upon at the first lesson and now it's time for retrosynthetic analysis to this target molecule. The problem is where should we start. It's often a very good idea to look at the most reactive functional groups because the most reactive functional groups you want to introduce into your molecule at the end of the reaction sequence. So if you want to introduce them at the end of your sequence well then it would be of course we have a way around with one of the first steps in your retrosynthetic analysis. So and well for instance cleaning up or with oxygen and with water nothing will happen here. It's not possible to hydrolyze here such an ephomoyety under moderate reaction conditions. In this case also this is rather stable you shouldn't mind about that. On the other hand well of course these functional groups here are the most reactive in the molecule. So we should identify what we have here certainly a cyclic carboxylic amide. So here we have the amide. On the other hand an enamine here at that position. So how is an enamine formed simply by a condensation reaction? So why not focus on that enamine and the condensation reaction? For that condensation reaction you need a ketone of course. So let's directly introduce the ketone functionality without thinking about the synphone. It's directly a substrate which would give then on the other hand by condensation reaction the enamine. So next step where do we have a strategic bond for cleaving within the retrosynthetic analysis and getting to much more simple structure much more simple structure. On the other hand a bond which is easy to be formed well it could be this one. Donate a reactivity here accept a reactivity there and that accept a reactivity is translated into alpha-beta unsaturated carbonyl compound for the synthetic equivalent. Well actually this sequence this acrylic amide the treatment of the base and the protonating here the overall sequence to this target should remind you of the Robinson annulation. Well keep in mind that similarity here the acrylic amide and in the Robinson annulation you are normally dealing with methyl vinyl ketone abbreviated like that. Okay so nice initial idea now we have to check would that really work. So there might be some problems. First of all if we deprotonate here we form an enolate. So and the enolate is the base and on the other hand we have this quite acidic amide. So in equilibrium we would also get a deprotonation here that might cause some problems might cause occurrence of some competing reactions. Well we could try that if it doesn't work we should improve. So it might not be necessary directly having the amino group here we could think about using acrylonitrile instead. Okay so later on Zemi hydrolyzation of the nitride group will lead to the amide functionality. On the other hand well why not using an acrylic acid ester than we would have this as an intermediary product and could treat that simply with ammonia. Should work. You have to find out the right reaction conditions. Okay with these considerations do we already have solved all the problems connected with that step I'm afraid no. Because if we treat this with a base how do we get the selectivity that it is deprotonated here and up there. That's a problem. Actually I don't see any chance for any base to get this preferentially deprotonated here or there. So maybe we have to play a trick on that and perform well it's two steps or multiple multi-step sequence as a one-pot procedure. So for instance simply find it in a retry synthetic analysis to this alpha better unsaturated ketone plus this nucleophile. Donate a reactivity here accept a reactivity there putting on a metal there and of course M presumably should be some kind of copper complex. Organic coot rate we should use for that alpha better for this conjugate addition reaction to the alpha better unsaturated ketone. And of course if we perform that in a one-pot reaction having then already the enolate in there well you have to use some solvents that stabilize your enolate and then you can trap the enolate directly well for instance with the acrylic acid ester. Okay so we are now down to a structure as simple as this one a methyl cyclohexanone. Well let us assume that the tri-erosemic synthesis don't care about the absolute stereochemistry here. So what about this idea introducing that methyl group also through a conjugated addition reaction with a methyl tri-erate wouldn't that be simple? No one with any doubts. So the problem that you have is where do you get this one from? At least you can't buy it and there is a simple reason under acidic as well as slightly basic reaction conditions which would of course readily I summarize under formation of the aromatic ring system it summarizes simply to for node. So therefore this is not a good idea of course. So how should one analyze the synthesis of that molecule? Well this is so simple you can be sure that someone has synthesized it and has published it and so in that case I would just have a look in sci-finder and figure out how they did it and maybe also thinking about improving if you are if the reaction sequence which has been done is not satisfying it's not completely satisfying. Well so simply let us have a look how this is synthesized already synthesized by others. Well there is a acidic acid ester as one component. This acrylic acid acid derivative as the second component. This is classical carbonyl chemistry so under the basic reaction reaction conditions with sodium ethanolate in ethanol or what would happen? This is of course the most acidic position double activated by carbonyl groups. Here you have the nucleophile and in a Michael addition reaction you get that conjugate addition product in equilibrium also every now and then that CH3 group will be then deprotonated and making another condensation reaction here. So this will result in that cyclohexane dione like that. So and after hydrolysis of that ester ethanol is formed and a decarboxylation will occur. Remember from organic chemistry too that better keto carboxylic acids are not stable. So we need now some kind of reduction. We need to double bond there and get rid of one of the carbonyl groups. Well with an ortho ester like that this is an ortho ester is an acetyl of formic acid ester. Under acidic conditions you will get this transformation done. Next step is reduce the remaining carbonyl group to give an alcohol and then simple hydrolysis under slightly acidic reaction conditions will give you that OH group as a leaving group and the hydrolysis will form our target intermediate. Let us go on with additional strategies and tactics in retrosynthetic analysis. One very simple but often used and very useful is functional group interconversion. Well often abbreviated as FGI for instance in the retrosynthetic synthesis books of Stuart Warren. One simple example. Okay normally you wouldn't bother about the synthesis of this molecule since you can buy that and it's not that expensive. However imagine we have more complex molecule in mind with some additional substituents maybe a long chain long side chain or something like that. Let's concentrate on these functional groups. So for instance we start looking at that disconnection. What do we need here? Donator reactivity for that amino group which we want to introduce and on the other hand here acceptor reactivity. Okay looks good on the first glimpse because donator reactivity is just the natural reactivity for an amine like that acceptor reactivity. Okay something like nucleophilic aromatic substitution. However we have a problem in translating it into synthetic equivalence simply because well let's put on a chloride there as the leaving group using for instance simply ammonia solution. We don't want to use sodium amide. This is much too reactive there. However this would react of course with the acid. So we would have to protect the acid. Let's try it as an ester. Well maybe then the nucleophile would still react preferentially than at the ester functionality. So we have a problem there. Let's try the other one. Aniline with a donator reactivity in power position and this synthone as a fragment acceptor reactivity here. Well again both are the natural reactivities of these positions. However if you try some Friedel-Crafts type stuff you have always kinetically preferred the reaction at the free electron pair of that amino group. You are always facing some serious problems. Therefore functional group interconversion is a good idea and in this case it's simple changing the oxidation state of a functional group. For instance here in this case let's leave the amino group and we go to the oxidation state of a nitrile group. Since it's usually no problem for reduction of a nitrile group with hydrogen and an appropriate capitalist. Next step in our retrosynthetic plan. Again changing the oxidation state now from the acid functionality. Just go back to the simple nuffle group and para-nitro toluene is easy to make of course. No problem in performing this reaction sequence. So another good idea is looking out for suitable starting materials. So identifying suitable starting materials. For instance from a chiral pool. You all know the chiral pool is consist of all those natural products we can get hands-on and having some chiral centers. You could make use of them starting that reaction. Starting the reaction sequence to our target molecule from a chiral pool compound. Actually this is then not the pure retrosynthesis anymore. We have our target molecule and we identify a natural product something from the chiral pool. We can buy or we can isolate from nature and while somehow they are related structurally to each other and we have to connect them within our synthetic plan. We make retrosynthetic analysis and try to get a structure where we know that we get to that structure from the other side starting from the natural product. Therefore it's in that case a bidirectional analysis. One example you will find in literature is the synthesis of a picrotoxinin. Well picrotoxinin has been synthesized from the Cori group and also from Barry Martin Trose group at Stanford. Kurt Hefner was the one who finished that synthesis. Let's draw that target molecule. You will notice this is rather complicated structure. Again Barry Trose and Kurt Hefner. They had to look for a natural product from the chiral pool which has a structural relationship to that and found that there are some similarities with carbon. It should be minus carbon. So we have that six-membered central ring with an isopropyl group here. Here the six-membered ring, the isopropyl group, the same stereochemistry, a methyl group at this position and an oxygen functionalization there. Here the same methyl group and oxygen functionalization. So bidirectional analysis, in that case having in mind some palladium-catalyzed inhalation reactions developed in the Trose group and the overall synthesis took about 24 or 25 steps. It's not easy to do of course. So in addition, stereochemical considerations. Let's explain that with this model compound. So in this simple, rather simple model compound we have three stereogenic centers. So and they are all in close proximity. Therefore it's a good idea to look for one stereogenic center which could be the control element of a stereochemistry through your reaction sequence. A bond which is easy to make is this one. So a malonic acid astronucleophile could be introduced here. Easily to be deprotonated. So this is the nucleophile then. We need an electrophilic center here. S and 2 process. That means we need the opposite configuration for that leaving group X here. And this lactone is now the target we have in mind. We analyze the next retrosynthetic step. So everyone who knows that reaction which is called the iodolactonization now has an advantage because you then can simply write down simpler structure. So now we know this stereogenic center should be a control element of that sequence. It determines the absolute of the relative configuration here and if you start from an enantiomer then we control the absolute stereochemistry of our target molecule. Just for reminding you of the Baldwin rules, how do we classify this cyclization reaction? So what kind of cyclization is that according to the Baldwin rules? Well the five-membered ring is formed. So we write down the five. This bond is formed. The double bond is broken to a single bond. That double bond is located outside the newly formed ring. So we have to add an axon here and reaction takes place at an sp2 hybridized center. That means a trigonal center. So it's a five exotrick cyclization. So the next good idea in retrosynthetic analysis sounds a bit complicated. Identifying strategic bonds by topological criteria. Sounds great, very well educated sounds. Well actually it's rather easy we talked already about that. A strategic bond is a bond if you disconnect it you get really a simplification. If it's not a simplification then it's not a strategic bond. Okay that's it. It becomes more clear with this example. So this one is not a strategic bond. It doesn't become more simple. Well we could disconnect here but then we still have that three-membered ring. But maybe it's possible to simultaneously form these two bonds and then it makes sense in our retrosynthetic analysis to break those simultaneously. And this looks already much simpler than that. So the idea is could we use some kind of 2 plus 1 cycloaddition reaction with a carbene or a carbene complex. I found funny if we analyze that again and disconnect so R1 here this as R2. Well we will notice that both structures are the same. So imagine we would generate this carbene. Would this carbene indeed give that cycloaddition reaction? No it doesn't because there is a competing reaction which is much faster. The insertion of the carbene functionality into the neighboring CH bond. This is indeed a very fast reaction. So you know in your undergraduate lab you worked for instance you made that cycloproplenation reaction with a dichlorocarbon. This will work but you can't do that with a dimethyl carbene because of this CH insertion. So therefore we have to modify our plan. We should not have hydrogen atoms here. Well okay let's change the oxidation state. This would give then. Is that correct? Yeah okay this would give that cycloproplenation and some kind of reduction which should be chosen carefully of course because of that sensitive cyclopropane unit here should give then bad result and where do you get that kind of carbene from? From that type of diazole compound for instance making use of the rhodium or a copper catalyst. Well of course one should then further analyze it. This is still not a simple starting material. So thank you for listening for today and see you tomorrow.
 Welcome to the third part of the lecture on designing organic synthesis. In the  preceding lesson we have analyzed this target structure with the help of having  in mind using an oxy-cope rearrangement within our plan for synthesizing this  molecule. We noticed that we have the retron of an oxy-cope rearrangement within  this molecule and this is the carbonyl here and alpha-beta-gamma-delta-epsilon  and saturation. So the result of our considerations was that we have to  synthesize this type of functionalized by cyclic ring system. So and well then we  should check and we didn't do that in the preceding lesson should check what  would be the result of the oxy-cope rearrangement. So reaction conditions,  potassium hydride to synthesize the potassium alcoholate and then heating it  up so that the rearrangement can occur. So what would happen?  Wow!  Carbonyl group is formed at this position finally. This position is connected with  that connected with that.  So well should be right okay. So and let's translate that all into our well  drawing where we don't have a three-dimensional perspective in mind.  So this structure with an oxy-cope rearrangement would lead to this  product and if we compare that to our initial target we notice of course these  are mirror images right. So that means well if we have a racemic  resume as the target we wouldn't have to care about the absolute stereochemistry.  But if we have that as a natural product in mind and want to target it  in anse selectively then this pair is Rewang enanceumur to perform that  rearrangement. So we need the mirror image.  So and well in order to get to this substrate we should well consider using  for instance chiral Lewis assets for an anseo selective deals all the reaction.  That would be the solution to the problem. Well next let us draw again that  structure we had a glimpse upon at the first lesson and now it's time for  retrosynthetic analysis to this target molecule. The problem is where should we  start. It's often a very good idea to look at the most reactive functional groups  because the most reactive functional groups you want to introduce into your  molecule at the end of the reaction sequence. So if you want to introduce  them at the end of your sequence well then it would be of course we have a  way around with one of the first steps in your retrosynthetic analysis. So and  well for instance cleaning up or with oxygen and with water nothing will  happen here. It's not possible to hydrolyze here such an ephomoyety under  moderate reaction conditions. In this case also this is rather stable you  shouldn't mind about that. On the other hand well of course these functional  groups here are the most reactive in the molecule. So we should identify what we  have here certainly a cyclic carboxylic amide. So here we have the amide. On the  other hand an enamine here at that position. So how is an enamine formed  simply by a condensation reaction? So why not focus on that enamine and the  condensation reaction? For that condensation reaction you need a ketone  of course. So let's directly introduce the ketone functionality without thinking  about the synphone. It's directly a substrate which would give then on the  other hand by condensation reaction the enamine.  So next step where do we have a strategic bond for cleaving within the  retrosynthetic analysis and getting to much more simple structure much more  simple structure. On the other hand a bond which is easy to be formed well it  could be this one. Donate a reactivity here accept a reactivity there and that  accept a reactivity is translated into alpha-beta unsaturated carbonyl  compound for the synthetic equivalent.  Well actually  this sequence this acrylic amide the treatment of the base and the protonating  here the overall sequence to this target should remind you of the Robinson  annulation. Well keep in mind that similarity here the acrylic amide and  in the Robinson annulation you are normally dealing with methyl vinyl  ketone abbreviated like that. Okay so nice initial idea now we have to check  would that really work. So there might be some problems. First of all if we  deprotonate here we form an enolate. So and the enolate is the base and on the  other hand we have this quite acidic amide. So in equilibrium we would also  get a deprotonation here that might cause some problems might cause  occurrence of some competing reactions. Well we could try that if it doesn't  work we should improve. So it might not be necessary directly having the  amino group here we could think about using acrylonitrile instead. Okay so  later on Zemi hydrolyzation of the nitride group will lead to the amide  functionality. On the other hand well why not using an acrylic acid ester than  we would have this as an intermediary product and could treat that simply with  ammonia. Should work. You have to find out the right reaction conditions. Okay with  these considerations do we already have solved all the problems connected with  that step I'm afraid no. Because if we treat this with a base how do we get the  selectivity that it is deprotonated here and up there. That's a problem.  Actually I don't see any chance for any base to get this preferentially  deprotonated here or there. So maybe we have to play a trick on that and perform  well it's two steps or multiple multi-step sequence as a one-pot procedure.  So for instance  simply find it in a retry synthetic analysis to this alpha better unsaturated  ketone plus this nucleophile. Donate a reactivity here accept a reactivity there  putting on a metal there and of course M presumably should be some kind of copper  complex. Organic coot rate we should use for that alpha better for this  conjugate addition reaction to the alpha better unsaturated ketone. And of  course if we perform that in a one-pot reaction having then already the enolate  in there well you have to use some solvents that stabilize your enolate  and then you can trap the enolate directly well for instance with the  acrylic acid ester. Okay so we are now down to a structure as simple as this  one a methyl cyclohexanone. Well let us assume that the tri-erosemic  synthesis don't care about the absolute stereochemistry here. So what about this  idea introducing that methyl group also through a conjugated addition reaction  with a methyl tri-erate wouldn't that be simple? No one with any doubts. So the  problem that you have is where do you get this one from? At least you can't buy it  and there is a simple reason under acidic as well as slightly basic reaction  conditions which would of course readily I summarize under formation of the  aromatic ring system it summarizes simply to for node. So therefore this is not a  good idea of course. So how should one analyze the synthesis of that molecule?  Well this is so simple you can be sure that someone has synthesized it and has  published it and so in that case I would just have a look in sci-finder and  figure out how they did it and maybe also thinking about improving if you are  if the reaction sequence which has been done is not satisfying it's not  completely satisfying. Well so simply let us have a look how this is  synthesized already synthesized by others. Well there is a acidic acid ester as one  component. This acrylic acid acid derivative as the second component.  This is classical carbonyl chemistry so under the basic reaction  reaction conditions with sodium ethanolate in ethanol or what would happen?  This is of course the most acidic position double activated by carbonyl groups.  Here you have the nucleophile and in a Michael addition reaction you get that  conjugate addition product in equilibrium also every now and then that CH3  group will be then deprotonated and making another condensation reaction  here. So this will result in that cyclohexane  dione like that. So and after hydrolysis of that ester  ethanol is formed and a decarboxylation will occur. Remember from organic chemistry  too that better keto carboxylic acids are not stable. So we need now some kind of  reduction. We need to double bond there and get rid of one of the carbonyl groups.  Well with an ortho ester like that this is an ortho ester is an acetyl of  formic acid ester. Under acidic conditions you will get this transformation  done. Next step is reduce the remaining carbonyl group to give an alcohol  and then simple hydrolysis under slightly acidic reaction conditions will give you  that OH group as a leaving group and the hydrolysis will form our target  intermediate. Let us go on with additional strategies and tactics in  retrosynthetic analysis. One very simple but often used  and very useful is functional group interconversion. Well often abbreviated as  FGI for instance in the retrosynthetic synthesis books of Stuart Warren. One  simple example. Okay normally you wouldn't bother about the synthesis of  this molecule since you can buy that and it's not that expensive. However imagine  we have more complex molecule in mind with some additional substituents maybe  a long chain long side chain or something like that. Let's concentrate on  these functional groups. So for instance we start looking at that  disconnection. What do we need here? Donator reactivity for that amino group  which we want to introduce and on the other hand here acceptor reactivity. Okay  looks good on the first glimpse because donator reactivity is just the natural  reactivity for an amine like that acceptor reactivity. Okay something like  nucleophilic aromatic substitution. However we have a problem in translating  it into synthetic equivalence simply because well let's put on a chloride  there as the leaving group using for instance simply ammonia solution. We  don't want to use sodium amide. This is much too reactive there. However this  would react of course with the acid. So we would have to protect the acid. Let's  try it as an ester. Well maybe then the nucleophile would still react  preferentially than at the ester functionality. So we have a problem there.  Let's try the other one. Aniline with a donator reactivity in power position and  this synthone as a fragment acceptor reactivity here. Well again both are the  natural reactivities of these positions. However if you try some Friedel-Crafts  type stuff you have always kinetically preferred the reaction at the free  electron pair of that amino group. You are always facing some serious problems.  Therefore functional group interconversion is a good idea and in this  case it's simple changing the oxidation state of a functional group. For instance  here in this case let's leave the amino group and we go to the oxidation state  of a nitrile group. Since it's usually no problem for reduction of a nitrile  group with hydrogen and an appropriate capitalist. Next step in our  retrosynthetic plan. Again changing the oxidation state now from the acid  functionality. Just go back to the simple nuffle group and para-nitro toluene is  easy to make of course. No problem in performing this reaction sequence. So  another good idea is looking out for suitable starting materials. So identifying  suitable starting materials. For instance from a chiral pool.  You all know the chiral pool is consist of all those natural products we can get  hands-on and having some chiral centers. You could make use of them starting  that reaction. Starting the reaction sequence to our target molecule from a  chiral pool compound. Actually this is then not the pure retrosynthesis anymore.  We have our target molecule and we identify a natural product something  from the chiral pool. We can buy or we can isolate from nature and while somehow  they are related structurally to each other and we have to connect them within  our synthetic plan. We make retrosynthetic analysis and try to get a  structure where we know that we get to that structure from the other side  starting from the natural product. Therefore it's in that case a bidirectional  analysis. One example you will find in literature is the synthesis of  a picrotoxinin. Well picrotoxinin has been synthesized from the Cori group and  also from Barry Martin Trose group at Stanford. Kurt Hefner was the one who  finished that synthesis. Let's draw that target molecule. You will notice this is  rather complicated structure.  Again Barry Trose and Kurt Hefner. They had to look for  a natural product from the chiral pool which has a structural relationship to  that and found that there are some similarities with carbon. It should be  minus carbon. So we have that six-membered central ring with an isopropyl group here.  Here the six-membered ring, the isopropyl group, the same stereochemistry, a  methyl group at this position and an oxygen functionalization there. Here the  same methyl group and oxygen functionalization. So bidirectional analysis,  in that case having in mind some palladium-catalyzed inhalation reactions  developed in the Trose group and the overall synthesis took about 24 or 25  steps. It's not easy to do of course.  So in addition, stereochemical considerations.  Let's explain that with this model compound. So in this simple, rather  simple model compound we have three stereogenic centers. So and they are all  in close proximity. Therefore it's a good idea to look for one stereogenic  center which could be the control element of a stereochemistry through your  reaction sequence. A bond which is easy to make is this one. So a  malonic acid astronucleophile could be introduced here.  Easily to be deprotonated. So this is the nucleophile then. We need an  electrophilic center here. S and 2 process. That means we need the opposite  configuration for that leaving group X here. And this lactone is now the target  we have in mind. We analyze the next retrosynthetic step. So everyone who knows  that reaction which is called the iodolactonization now has an advantage  because you then can simply write down simpler structure. So now we know this  stereogenic center should be a control element of that sequence. It determines  the absolute of the relative configuration here and if you start from  an enantiomer then we control the absolute stereochemistry of our target  molecule. Just for reminding you of the Baldwin rules, how do we classify this  cyclization reaction? So what kind of cyclization is that according to the  Baldwin rules? Well the five-membered ring is formed. So we write down the five.  This bond is formed. The double bond is broken to a single bond. That double bond  is located outside the newly formed ring. So we have to add an axon here and  reaction takes place at an sp2 hybridized center. That means a trigonal center. So  it's a five exotrick cyclization. So the next good idea in retrosynthetic  analysis sounds a bit complicated. Identifying strategic bonds by topological  criteria. Sounds great, very well educated sounds. Well actually it's rather easy  we talked already about that. A strategic bond is a bond if you disconnect it  you get really a simplification. If it's not a simplification then it's not a  strategic bond. Okay that's it.  It becomes more clear with this example. So this one is not a strategic bond. It  doesn't become more simple. Well we could disconnect here but then we still  have that three-membered ring. But maybe it's possible to simultaneously form  these two bonds and then it makes sense in our retrosynthetic analysis to break  those simultaneously. And this looks already much simpler than that. So the  idea is could we use some kind of 2 plus 1 cycloaddition reaction with a  carbene or a carbene complex. I found funny if we analyze that again and  disconnect so R1 here this as R2.  Well we will notice that both structures are the same.  So imagine we would generate this carbene. Would this carbene indeed give that  cycloaddition reaction? No it doesn't because there is a competing reaction  which is much faster. The insertion of the carbene functionality into the  neighboring CH bond.  This is indeed a very fast reaction. So you know in your undergraduate lab you  worked for instance you made that cycloproplenation reaction with a  dichlorocarbon. This will work but you can't do that with a dimethyl carbene  because of this CH insertion. So therefore we have to modify our plan. We  should not have hydrogen atoms here. Well okay let's change the oxidation state.  This would give then.  Is that correct? Yeah okay this would give that cycloproplenation and some kind  of reduction which should be chosen carefully of course because of that  sensitive cyclopropane unit here should give then bad result and where do you  get that kind of carbene from? From that type of diazole compound for instance  making use of the rhodium or a copper catalyst. Well of course one should then  further analyze it. This is still not a simple starting material. So thank you  for listening for today and see you tomorrow.
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Welcome to the third part of the lecture on designing organic synthesis. In the preceding lesson we have analyzed this target structure with the help of having in mind using an oxy-cope rearrangement within our plan for synthesizing this molecule. We noticed that we have the retron of an oxy-cope rearrangement within this molecule and this is the carbonyl here and alpha-beta-gamma-delta-epsilon and saturation. So the result of our considerations was that we have to synthesize this type of functionalized by cyclic ring system. So and well then we should check and we didn't do that in the preceding lesson should check what would be the result of the oxy-cope rearrangement. So reaction conditions, potassium hydride to synthesize the potassium alcoholate and then heating it up so that the rearrangement can occur. So what would happen? Wow! Carbonyl group is formed at this position finally. This position is connected with that connected with that. So well should be right okay. So and let's translate that all into our well drawing where we don't have a three-dimensional perspective in mind. So this structure with an oxy-cope rearrangement would lead to this product and if we compare that to our initial target we notice of course these are mirror images right. So that means well if we have a racemic resume as the target we wouldn't have to care about the absolute stereochemistry. But if we have that as a natural product in mind and want to target it in anse selectively then this pair is Rewang enanceumur to perform that rearrangement. So we need the mirror image. So and well in order to get to this substrate we should well consider using for instance chiral Lewis assets for an anseo selective deals all the reaction. That would be the solution to the problem. Well next let us draw again that structure we had a glimpse upon at the first lesson and now it's time for retrosynthetic analysis to this target molecule. The problem is where should we start. It's often a very good idea to look at the most reactive functional groups because the most reactive functional groups you want to introduce into your molecule at the end of the reaction sequence. So if you want to introduce them at the end of your sequence well then it would be of course we have a way around with one of the first steps in your retrosynthetic analysis. So and well for instance cleaning up or with oxygen and with water nothing will happen here. It's not possible to hydrolyze here such an ephomoyety under moderate reaction conditions. In this case also this is rather stable you shouldn't mind about that. On the other hand well of course these functional groups here are the most reactive in the molecule. So we should identify what we have here certainly a cyclic carboxylic amide. So here we have the amide. On the other hand an enamine here at that position. So how is an enamine formed simply by a condensation reaction? So why not focus on that enamine and the condensation reaction? For that condensation reaction you need a ketone of course. So let's directly introduce the ketone functionality without thinking about the synphone. It's directly a substrate which would give then on the other hand by condensation reaction the enamine. So next step where do we have a strategic bond for cleaving within the retrosynthetic analysis and getting to much more simple structure much more simple structure. On the other hand a bond which is easy to be formed well it could be this one. Donate a reactivity here accept a reactivity there and that accept a reactivity is translated into alpha-beta unsaturated carbonyl compound for the synthetic equivalent. Well actually this sequence this acrylic amide the treatment of the base and the protonating here the overall sequence to this target should remind you of the Robinson annulation. Well keep in mind that similarity here the acrylic amide and in the Robinson annulation you are normally dealing with methyl vinyl ketone abbreviated like that. Okay so nice initial idea now we have to check would that really work. So there might be some problems. First of all if we deprotonate here we form an enolate. So and the enolate is the base and on the other hand we have this quite acidic amide. So in equilibrium we would also get a deprotonation here that might cause some problems might cause occurrence of some competing reactions. Well we could try that if it doesn't work we should improve. So it might not be necessary directly having the amino group here we could think about using acrylonitrile instead. Okay so later on Zemi hydrolyzation of the nitride group will lead to the amide functionality. On the other hand well why not using an acrylic acid ester than we would have this as an intermediary product and could treat that simply with ammonia. Should work. You have to find out the right reaction conditions. Okay with these considerations do we already have solved all the problems connected with that step I'm afraid no. Because if we treat this with a base how do we get the selectivity that it is deprotonated here and up there. That's a problem. Actually I don't see any chance for any base to get this preferentially deprotonated here or there. So maybe we have to play a trick on that and perform well it's two steps or multiple multi-step sequence as a one-pot procedure. So for instance simply find it in a retry synthetic analysis to this alpha better unsaturated ketone plus this nucleophile. Donate a reactivity here accept a reactivity there putting on a metal there and of course M presumably should be some kind of copper complex. Organic coot rate we should use for that alpha better for this conjugate addition reaction to the alpha better unsaturated ketone. And of course if we perform that in a one-pot reaction having then already the enolate in there well you have to use some solvents that stabilize your enolate and then you can trap the enolate directly well for instance with the acrylic acid ester. Okay so we are now down to a structure as simple as this one a methyl cyclohexanone. Well let us assume that the tri-erosemic synthesis don't care about the absolute stereochemistry here. So what about this idea introducing that methyl group also through a conjugated addition reaction with a methyl tri-erate wouldn't that be simple? No one with any doubts. So the problem that you have is where do you get this one from? At least you can't buy it and there is a simple reason under acidic as well as slightly basic reaction conditions which would of course readily I summarize under formation of the aromatic ring system it summarizes simply to for node. So therefore this is not a good idea of course. So how should one analyze the synthesis of that molecule? Well this is so simple you can be sure that someone has synthesized it and has published it and so in that case I would just have a look in sci-finder and figure out how they did it and maybe also thinking about improving if you are if the reaction sequence which has been done is not satisfying it's not completely satisfying. Well so simply let us have a look how this is synthesized already synthesized by others. Well there is a acidic acid ester as one component. This acrylic acid acid derivative as the second component. This is classical carbonyl chemistry so under the basic reaction reaction conditions with sodium ethanolate in ethanol or what would happen? This is of course the most acidic position double activated by carbonyl groups. Here you have the nucleophile and in a Michael addition reaction you get that conjugate addition product in equilibrium also every now and then that CH3 group will be then deprotonated and making another condensation reaction here. So this will result in that cyclohexane dione like that. So and after hydrolysis of that ester ethanol is formed and a decarboxylation will occur. Remember from organic chemistry too that better keto carboxylic acids are not stable. So we need now some kind of reduction. We need to double bond there and get rid of one of the carbonyl groups. Well with an ortho ester like that this is an ortho ester is an acetyl of formic acid ester. Under acidic conditions you will get this transformation done. Next step is reduce the remaining carbonyl group to give an alcohol and then simple hydrolysis under slightly acidic reaction conditions will give you that OH group as a leaving group and the hydrolysis will form our target intermediate. Let us go on with additional strategies and tactics in retrosynthetic analysis. One very simple but often used and very useful is functional group interconversion. Well often abbreviated as FGI for instance in the retrosynthetic synthesis books of Stuart Warren. One simple example. Okay normally you wouldn't bother about the synthesis of this molecule since you can buy that and it's not that expensive. However imagine we have more complex molecule in mind with some additional substituents maybe a long chain long side chain or something like that. Let's concentrate on these functional groups. So for instance we start looking at that disconnection. What do we need here? Donator reactivity for that amino group which we want to introduce and on the other hand here acceptor reactivity. Okay looks good on the first glimpse because donator reactivity is just the natural reactivity for an amine like that acceptor reactivity. Okay something like nucleophilic aromatic substitution. However we have a problem in translating it into synthetic equivalence simply because well let's put on a chloride there as the leaving group using for instance simply ammonia solution. We don't want to use sodium amide. This is much too reactive there. However this would react of course with the acid. So we would have to protect the acid. Let's try it as an ester. Well maybe then the nucleophile would still react preferentially than at the ester functionality. So we have a problem there. Let's try the other one. Aniline with a donator reactivity in power position and this synthone as a fragment acceptor reactivity here. Well again both are the natural reactivities of these positions. However if you try some Friedel-Crafts type stuff you have always kinetically preferred the reaction at the free electron pair of that amino group. You are always facing some serious problems. Therefore functional group interconversion is a good idea and in this case it's simple changing the oxidation state of a functional group. For instance here in this case let's leave the amino group and we go to the oxidation state of a nitrile group. Since it's usually no problem for reduction of a nitrile group with hydrogen and an appropriate capitalist. Next step in our retrosynthetic plan. Again changing the oxidation state now from the acid functionality. Just go back to the simple nuffle group and para-nitro toluene is easy to make of course. No problem in performing this reaction sequence. So another good idea is looking out for suitable starting materials. So identifying suitable starting materials. For instance from a chiral pool. You all know the chiral pool is consist of all those natural products we can get hands-on and having some chiral centers. You could make use of them starting that reaction. Starting the reaction sequence to our target molecule from a chiral pool compound. Actually this is then not the pure retrosynthesis anymore. We have our target molecule and we identify a natural product something from the chiral pool. We can buy or we can isolate from nature and while somehow they are related structurally to each other and we have to connect them within our synthetic plan. We make retrosynthetic analysis and try to get a structure where we know that we get to that structure from the other side starting from the natural product. Therefore it's in that case a bidirectional analysis. One example you will find in literature is the synthesis of a picrotoxinin. Well picrotoxinin has been synthesized from the Cori group and also from Barry Martin Trose group at Stanford. Kurt Hefner was the one who finished that synthesis. Let's draw that target molecule. You will notice this is rather complicated structure. Again Barry Trose and Kurt Hefner. They had to look for a natural product from the chiral pool which has a structural relationship to that and found that there are some similarities with carbon. It should be minus carbon. So we have that six-membered central ring with an isopropyl group here. Here the six-membered ring, the isopropyl group, the same stereochemistry, a methyl group at this position and an oxygen functionalization there. Here the same methyl group and oxygen functionalization. So bidirectional analysis, in that case having in mind some palladium-catalyzed inhalation reactions developed in the Trose group and the overall synthesis took about 24 or 25 steps. It's not easy to do of course. So in addition, stereochemical considerations. Let's explain that with this model compound. So in this simple, rather simple model compound we have three stereogenic centers. So and they are all in close proximity. Therefore it's a good idea to look for one stereogenic center which could be the control element of a stereochemistry through your reaction sequence. A bond which is easy to make is this one. So a malonic acid astronucleophile could be introduced here. Easily to be deprotonated. So this is the nucleophile then. We need an electrophilic center here. S and 2 process. That means we need the opposite configuration for that leaving group X here. And this lactone is now the target we have in mind. We analyze the next retrosynthetic step. So everyone who knows that reaction which is called the iodolactonization now has an advantage because you then can simply write down simpler structure. So now we know this stereogenic center should be a control element of that sequence. It determines the absolute of the relative configuration here and if you start from an enantiomer then we control the absolute stereochemistry of our target molecule. Just for reminding you of the Baldwin rules, how do we classify this cyclization reaction? So what kind of cyclization is that according to the Baldwin rules? Well the five-membered ring is formed. So we write down the five. This bond is formed. The double bond is broken to a single bond. That double bond is located outside the newly formed ring. So we have to add an axon here and reaction takes place at an sp2 hybridized center. That means a trigonal center. So it's a five exotrick cyclization. So the next good idea in retrosynthetic analysis sounds a bit complicated. Identifying strategic bonds by topological criteria. Sounds great, very well educated sounds. Well actually it's rather easy we talked already about that. A strategic bond is a bond if you disconnect it you get really a simplification. If it's not a simplification then it's not a strategic bond. Okay that's it. It becomes more clear with this example. So this one is not a strategic bond. It doesn't become more simple. Well we could disconnect here but then we still have that three-membered ring. But maybe it's possible to simultaneously form these two bonds and then it makes sense in our retrosynthetic analysis to break those simultaneously. And this looks already much simpler than that. So the idea is could we use some kind of 2 plus 1 cycloaddition reaction with a carbene or a carbene complex. I found funny if we analyze that again and disconnect so R1 here this as R2. Well we will notice that both structures are the same. So imagine we would generate this carbene. Would this carbene indeed give that cycloaddition reaction? No it doesn't because there is a competing reaction which is much faster. The insertion of the carbene functionality into the neighboring CH bond. This is indeed a very fast reaction. So you know in your undergraduate lab you worked for instance you made that cycloproplenation reaction with a dichlorocarbon. This will work but you can't do that with a dimethyl carbene because of this CH insertion. So therefore we have to modify our plan. We should not have hydrogen atoms here. Well okay let's change the oxidation state. This would give then. Is that correct? Yeah okay this would give that cycloproplenation and some kind of reduction which should be chosen carefully of course because of that sensitive cyclopropane unit here should give then bad result and where do you get that kind of carbene from? From that type of diazole compound for instance making use of the rhodium or a copper catalyst. Well of course one should then further analyze it. This is still not a simple starting material. So thank you for listening for today and see you tomorrow.
additional strategies and tactics in