Lecture Stoechiometric Organometallics 15 - 02.12.13
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Dyker, Gerald
Metal-specific features: Cuprates in Organic Synthesis, conjugate addition reactions, crossed Wurtz coupling, Glaser coupling reaction
 Welcome to part 15 of Stochometric Organometallics. In the preceding lecture, we have learned that organocopper chemistry is especially renowned for highly selective conjugate addition reactions. Let us start with another example. As a substrate, we have mesotile oxide, you know that is the simple aldol condensation product of acetone. And we treat that with an organocouprate with this molecular formula, diphenyl copper on cyanide and to lithium counter-cut ions. Well, obviously this is an higher order cyanocouprate, which are known to be especially reactive and indeed in diethyl ether at low temperature, already at low temperature, minus 78 degrees, just one hour reaction time, we will get the conjugate addition product of course after hydrolysis. The phenyl group is introduced in the better position and please take note, a quaternary and therefore sterically crowded center is formed in this reaction. This reaction works very well with an 83% yield. Next substrate, also an alphabet and saturated ketone, which this time is a cyclic system. Three methyl groups, while this is a natural product with the name isoforone. And as you notice, while if you make a conjugate addition reaction, then we form again a quaternary center in all close proximity to another one. That means this position is sterically hindered. Reaction has been tried with the same reagent as, well in the first example, while they changed the solvent, it was THF, they started at minus 78 degrees, warming up to minus 15 degrees, hoping for this product and an attempt with these reaction conditions doesn't yield any of the product. It is rather unreactive under these reaction conditions. Well, but we can trigger the reactivity, increase the reactivity of this alphabet and saturated ketone by just adding a Lewis acid, Vf3 iterate, add the low temperature, do the reaction again and then we will obtain an excellent yield of more than 95% of the target compound. Once again, an example with a cyclohexanone system, now our target molecule is this one. So what do we have to do to get from here to there? Well, we need to add the methyl group here in a conjugate addition reaction, getting the enolate and then trapping the enolate, well, with a corresponding alderite, acrylic, methylacrylic alderite, in an aldol addition process. So how has been this reaction performed? Methylmagnetium iodide was used in ether and, well, reaction temperature minus 5 degrees, well, and a copper salt, copper iodide was present catalytically with just about 1.5%. So the message is these organocopper conjugate addition reactions can be performed catalytic in copper. Well, the reaction conditions have to be adjusted, somewhat lower temperatures, because otherwise the methylgrinier would react itself already, so but normally you do the grinier addition reaction at room temperature, so on. So it works the active species should be dimethyl cuprate magnesium iodide and this is clearly a lower order magnesium cuprate. Well, in the preceding lecture we exclusively had lithium as counter-cut iron, as we will see magnesium is just fine and later on, especially I think tomorrow, we will learn with organo zinc, the copper zinc couples have very special features and in terms of functional groups compatibility. Yeah, we will see that tomorrow. So 30 minutes reaction time and then this magnesium enolate should be the predominant reactive component of the reaction mixture. Then cooling down to minus 15 degrees, adding that conjugated alder height and warming up to 20 degrees, one hour additional steering and after hydrolysis this was isolated with again an excellent yield of 90%. So I think it's important to know that it works catalytically and this fact offers then the opportunity to try additional chiral ligands for chiral induction. Imagine that you could make a conjugate addition reaction with a nucleophile and this an ansioselectively. This is possible and here one excellent example from Ben Feringer's group presented in 1997. So they applied already organo zinc as I mentioned, we would discuss organo zinc tomorrow in more detail and succeeded in an ansioselectively performing an conjugate addition reaction with copper catalyst, copper 2 triflate, 2% catalyst, toluene, a solvent, 3 hours reaction time at minus 30 degrees and while we need a chiral ligand, 4% of chiral ligand, now to the structure of that ligand. It derives from binol and as you know binol is a trope chiral axial chiral compound. Until the derivative is a phosphor amidit So I admit that this is rather more a complicated structure but visualizing the structure is worth it since all the result of a reaction was a 94% yield with a better of 98% in ansiomeric excess. Well let's go on with examples applications of organo copper chemistry conjugate addition reactions for more complex targets. Well a chiral cyclopentanone derivative the transformation that is of interest is introducing two side changes Well and if you then get rid of the silyl protecting groups then you are of course in the field of hormones the prostaglendones. So just in principle how is this transformation achieved? You need an organo copper reagent and as we have already discussed there are well lots of examples how the organo copper could look like. In such a case it's clear that you need something like that dummy ligand because you have invested a lot of time and money to synthesize this part. So but we don't discuss the details in this example in the next example we go into details. So you add the organo culprit it makes a conjugate addition reaction then you have an enolate. You can try to trap this enolate directly with an electrophile or you trap the enolate with for instance a silyl halide to form a TMS enol ether which you can purify and store of course. So either trap enolate or then directly letting this react with the electrophile and this one would be this allyl iodide or allyl bromide would be the electrophile of choice to get to the target compound. Now we are going to discuss in detail the synthesis of a drug related to prostaglandine hormones. Well as you notice this is closely related to that prostaglandine and this drug is called travoprost. It's meant for glaucoma therapy. So glaucoma in German is grüner star. So let's have a look for that marvelous multi-step synthesis. Obviously we need a cyclo pentane ring highly functional cyclo pentane ring and I think we had already before discussed something like prostaglandine as targets. Well the cheapest way to go into the synthesis is of course starting with cyclopentadiene or the cyclopentadiene dimer. Of course it is alder dimer which you have to crack. So first step in that synthesis freshly prepared cyclopentadiene is treated with dichloroacetyl chloride and triethylamine as base. Exane as solvent. Zero degrees reaction temperature. What will happen? The base deprotonates the acidic position here. HCl is eliminated and you form the dichloroacetyl as reactive intermediate. These dichloroacetyl generally don't undergo or deal alder reaction but a thermally 2 plus 2 cyclo addition reaction. So of course this fused and racemic. Next step you have to get rid of the chlorines. Just reduction. Zinc acidic acid 60 degrees. Of course still racemic. For treatment of glaucoma you of course will need an enunciamirically pure compound. That means on the stage of reaction you should try to separate the resimate into its enunciamir. A nice idea is forming the bisulfide adduct with SO2 in dichloromethane. So the SO2 will attack from just again a roof type molecule from the exo phase and in the presence of, so you have water there, we need another water there, and a chiral amine. We will form diasterioisomeric salts. This is the one we hopefully by crystallization will obtain and then if we destroy the bisulfide adduct then we will obtain enunciamirically pure our target. So again having this enunciamirically pure. So by destroying the bisulfide adduct then abomination in aqueous medium leads us to this secondary alcohol with the OH group on the ando phase of that roof type molecule. Protecting the alcohol with the silo chloride in the presence of emitter sol as base, which is quite typical. So and now this molecule is treated with potassium t-butoxide and toluene minus 20 degrees. So let's think about what will happen. Potassium t-butoxide base, let's have a look where could we deprotonate this molecule? Well one could think about an elimination reaction. We have nitrogen here, proton sitting, but it is Zyn to the bromide. Zyn elimination doesn't occur and moreover alpha to an alcohol or this case and silo ether this proton is of course less acidic than alpha to a carbonide group. Well we have two hydrogens here, one hydrogen there. What about the acidity of this hydrogen? This hydrogen is very low in acidity because the corresponding enolate for stabilizing the anion would have a very strange system with a double bond, well somehow at the at the bridgehead. Because of that strange cyclo-butene structure this is by far less acidic than those. So we deprotonate here. That means we have here a nucleophilic center and we have then intramolecularly an electrophilic center, this one. A nucleophilic substitution takes place with a C-C bond formation from this position to that one. So HBr is eliminated and C-C bond is formed from this position to that one. Let's draw that. And we should translate this structure or to a three-dimensional structure. It's this one. So a norbanane framework with an additional C-C bond in there. Let's call that A. And this is the compound we will treat with an organocopper reagent. So how do we get the organocopper reagent? We need a dummy ligand starting with thiophene and thiophene is treated with an equimolar amount of n-butylythium at minus 30 degrees and THF. Well some kind of DOM reaction as we know it in alpha position it is deprotonated. One equivalent of copper 1 cyanide minus 10 degrees, 20 minutes. And we will get the culprit. So the side chain we want to introduce we have synthesized before. So this arrow group is of course that meter trifluoromethylphenyl group. Now we have to lithiate this vinyl iodide. Selectively lithiate that. And what we want to get is this vinyl lithium. And this is achieved with tertiary butyl lithium to equivalence of tertiary butyl lithium minus 70 degrees. And now we just have to connect, combine the solutions. One equivalent of that, one equivalent of this to form our cool plate which we will apply in the reaction. Minus and well. So this higher order cyanide cool plate. So with now a minus 70 degrees one hour reaction time. This reacts with A. So where will it react? So we don't have an alpha better unsaturated ketone. However we have a cyclopropyl ketone and these cyclopropyl CC bonds, two of them, this one and that one, behave a bit like elephants. Why? Because if the nucleophile attacks here and this CC bond is broken then the stabilized anion is formed as the enolate. So in this case the cool plate attacks from this side as the nucleophile. The CC bond is broken. So here the nucleophile and this is the reaction path.. So back to the target. Molecule. We need a cyclopentane ring with two OH groups there. The OH groups should be on the same side. So here we have the protected hydroxyl group. So we need another hydroxyl group. Okay we already have the oxygen functionality there. However we also... oh no, no it's the wrong position. Excuse me. So we need an oxygen functionality here. On the other hand we need to build up this olefin here. Such an olefin, a synolefin, can be set up with vitich type reactions under certain reaction conditions which are known for the formation of synolefins. Selectively or rather selectively. So that means an aldehyde in this side chain and an OH group here. How can we get to that type of functionality? An oxidation process. Oxygen has to be introduced in this CC bond. You should know this type of reaction, a biavillier oxidation. And this goes selectively to the oxygen to be higher substituted carbon. So, acetic per acid in acetic acid and buffered with sodium acetate at 20 degrees. So now an abbreviation for that side chain. So we get that cyclic ester. As I said, we need the aldehyde functionality here. So we should reduce that. Selectively, one hydride transfer. First, well, biavillier oxidation. Secondly, di-ball H, di-isobutyl aluminum hydride. And we will get that cyclic semiacetyl, which we can treat with the appropriate Wittig reagent, because in equilibrium we will have the free aldehyde. So... This phosphonium salt, treated with potassium t-butoxide. Here is the acidic position, the most acidic position. And the phosphorylid will be formed, which then performs Wittig reaction with the aldehyde. And we should then get to this situation. So. Let us compare this molecule with travel prost. What remains to be done? Well, and is the first question is, well, are all those substituents on the correct side of the cyclo pentane ring? Well, both OH groups and this, this olefin should be on the same side. Yes, indeed. This one is on the other side. It's a cyclo pentane ring. Remains to be done is deprotect the remaining alcohols, this one and one in the side chain. And we have to form the isopropyl ester and that's it. I think while a very elegant synthesis and indeed done for producing that very valuable drug and I think you might have noticed lots of reactions which we already discussed or you know from undergraduate organic lectures are presented within this nice synthesis. So back to much simpler compounds, a domino process where we have the side chain with bromide. This is treated with a culprit, typical Gilman culprit at zero degrees. So and as an exercise, please try to figure out what will be the product of this reaction. Keep in mind, conjugate addition reactions are the predominant reactions for organocouperates. So as I said, this organocouperate conjugate addition reaction is the reaction we should guess that it will happen and this means a methyl group attacks as a nucleophile and C-C bond formation to this position and then the enolate is formed. So this is a racemic or should be a racemic starting compound. Nevertheless, the position or the configuration at this center will determine from which side of the ring the methyl nucleophile will approach. So and it will approach from the side which is opposite to that isopropyl group and this means all racemic but the methyl group from the opposite side. Okay. So now we have that enolate as the nucleophile justin-acent 2 process forming a six-membered ring. One, two, three, four, five, six. Then both methyl groups on the same side that means that this decaline ring system is cisfused. This should be the product. While in the original literature they claim that they obtain a yield of 20 to 30 percent that means they did reaction several times never got an excellent yield. However, it works. No, we can discuss why that yield is not that good. So there should be a competing reaction, the direct reaction of the nucleophile with this halide. So methyl, well what kind of reaction is that? This is some kind of Wurz coupling process. Organometallic reacting with an alkyl halide just often called Wurz coupling. Although the original Wurz coupling with sodium and alkyl halides is interpreted as radical process generally. And as I said, competing reactions normally the conjugate addition reaction is the preferred one, presumably also in this case. However, a quaternary center is for sterically hindered story here. And that makes the reaction difficult and therefore diminishes the yield which is obtained. So as I said, well presumably Wurz coupling reaction occurs here and indeed organo-cruprate chemistry found a nice application in Wurz coupling reactions, Wurz as cross coupling reactions. One nice example. So this substrate was synthesized from tartaric acid, forming the acetal with acetone and reducing the carboxylic acids with lithium aluminum hydride to get to the primary alcohols than a tosylation and you have those tosyll leaving groups and these indeed react with a Gilman-Riegen-Dyphenol copolysium THF 20 degrees, two hours reaction time and a yield of 47%. Carbonyl group protected as the acetal. Here now a deed on higher order cyanocuprate, THF and cyanocuprates, those higher order cyanocuprates, a special reactive that means also that lower temperatures minus 78 degrees, it works with less than 15 minutes reaction time. 83% of that product was obtained. So nice examples for crossed Wurz-type coupling reactions which proceed copper induced. So we should ask how about those Wurz-type coupling processes, especially cross coupling processes applying organolethium and organ or applying organomagnetium grignate reagents. Does that work or does that not work? So reaction we should briefly talk about is this one. Imagine a grignate reagent, a butylgrinier plus, well for instance, butyl bromide. Is this reaction possible? This is a nucleophile attacking that and forming octane. While it is possible, but it is a very slow process. Luckily it's very slow because if this would be a fast reaction we wouldn't be able to produce the grignate reagent itself. Okay, I think I hope that that is clear. So this alkyl bromide plus magnesium in for instance diethyl ether or THF. So as soon as a little bit of the magnesium has reacted and formed the grignate reagent, we would or the grignate reagent would face a huge excess of the remaining alkyl bromide. If it's a fast reaction, this process than the alkyl, alkyne formation, C-C coupling, should take place. This is actually the proof that it is a slow process. There is another problem connected with a cross coupling. For instance, let's take organolithium and here a bromide. Organolithium, as we have seen, is known for that halide metal exchange via eight complexes. And we have already learned that it's similar with organo magnesium. Remember that knuckle turbo grignate. So a fast process and much faster than the nucleophilic displacement here, where the attack of that carbon center is a nucleophile here is the formation of the eight complex. And this is an equilibrium. And here again, it could disconnect than to this one. So, and that means after a while, we have all those species in solution. They react rather slow in the woods coupling. And we would get then a mixture of all possible C-C coupling products. And of course, we would have some more competing reactions if we have better hydrogens to that bromide than also eliminations could take place as competing reactions. But as we have learned, organocouper, chemistry works just fine with words type cross coupling processes. And we have already learned today that we can apply copper salts in catalytic amounts. And also in this case, it is nice to know that just at 0.3% of copper chloride, THF, zero degrees, three hours reaction time. And while this has been done, under 78% yield of the octane was obtained. Now, octane is of course not that interesting. But one will find much more interesting applications. Finally, for today, another copper catalyzed process where we have organocouper intermediates. It's the glaser coupling reaction. If you have a terminal acetylene and you treat that with instance copper one chloride catalytic amounts, pyridine as a base, and you need molecular oxygen, then Wouter-Dienes are formed. What you have as an intermediate are bis alkenylcopper species. And under reductive elimination, this is the way we would call that a step. Copper zero is formed and this copper zero has then to be reoxidized and molecular oxygen under the appropriate reaction conditions is sufficient for that. Just one nice application from the work of Sondheimer famous chemist. This hexadeine with copper two acetate pyridine oxygen 55 degrees or typical conditions for glaser coupling reaction. And there goes the glaser coupling reaction. They did it under optimized reaction conditions described in organic synthesis. You know that journal where those pre-operative examples have been checked by other groups. Of course, we'll give a mixture of products. But this one was the target of the Sondheimer group. We started with 50 grams of that and isolated 16 grams of this macro cycle. Fascinating synthesis with that as well intermediate product. Potassium tibutoxide, interseributanol, under elevated temperatures. Well, what will happen in propagule position? Those are acidic and under these conditions, the double bond character can migrate within that chain. In well very moderate yields or you can say especially low yields.. They transformed this all trimeric butadiene system to this one. Finally, with the idea to selectively reduce those alkynes with a palladium catalyst. Combination of that palladium on that carbonate. So you can imagine hydrogenation is Zünd-Edition to the alkynes in this case and you get Van Cisolophins. So, I hope that the structure is correct. I should count. No, something is wrong. It should be 18. So, let's just start again. Okay, I think I've got it on the second attempt. Should be 18. Because this is the famous Zondheimer synthesis of the so called 18th anuline and the cyclic conjugated system with 18 electrons for N plus 2 obeying to rule for aromatic systems. So this is indeed a planar, monocyclic planar. It is an aromatic system and this has been proven. Well, for instance by the fact that well as you know as an NMR an isotropic effect. You have an isotropic downfield shift for all hydrogens outside the ring system and you have an extraordinary upfield shift for hydrogens that might be located above the ring system and with such large anuline you have hydrogens that are within that ring system and you have the chemical shift at minus PPM values for such rings. So enough for today. We meet again tomorrow with an organo zinc chemistry. Thank you for listening. See you tomorrow.
 Welcome to part 15 of Stochometric Organometallics.  In the preceding lecture, we have learned that organocopper chemistry is especially  renowned for highly selective conjugate addition reactions.  Let us start with another example. As a substrate, we have mesotile oxide, you know that is the  simple aldol condensation product of acetone. And we treat that with an organocouprate with  this molecular formula, diphenyl copper on cyanide and to lithium counter-cut ions.  Well, obviously this is an higher order cyanocouprate, which are known to be  especially reactive and indeed in diethyl ether at low temperature, already at low  temperature, minus 78 degrees, just one hour reaction time, we will get the  conjugate addition product of course after hydrolysis. The phenyl group is  introduced in the better position and please take note, a quaternary and  therefore sterically crowded center is formed in this reaction. This reaction  works very well with an 83% yield. Next substrate, also an alphabet and saturated  ketone, which this time is a cyclic system. Three methyl groups, while this is a  natural product with the name isoforone. And as you notice, while if you make a  conjugate addition reaction, then we form again a quaternary center in all  close proximity to another one. That means this position is sterically  hindered. Reaction has been tried with the same reagent as, well in the first  example, while they changed the solvent, it was THF, they started at minus 78  degrees, warming up to minus 15 degrees, hoping for this product and an attempt  with these reaction conditions doesn't yield any of the product. It is rather  unreactive under these reaction conditions. Well, but we can trigger the  reactivity, increase the reactivity of this alphabet and saturated ketone by  just adding a Lewis acid, Vf3 iterate, add the low temperature, do the  reaction again and then we will obtain an excellent yield of more than 95% of  the target compound. Once again, an example with a cyclohexanone system,  now our target molecule is this one. So what do we have to do to get from here  to there? Well, we need to add the methyl group here in a conjugate addition  reaction, getting the enolate and then trapping the enolate, well, with a  corresponding alderite, acrylic, methylacrylic alderite, in an aldol  addition process. So how has been this reaction performed? Methylmagnetium  iodide was used in ether and, well, reaction temperature minus 5 degrees, well,  and a copper salt, copper iodide was present catalytically with just about 1.5%.  So the message is these organocopper conjugate addition reactions can be  performed catalytic in copper. Well, the reaction conditions have to be adjusted,  somewhat lower temperatures, because otherwise the methylgrinier would react  itself already, so but normally you do the grinier addition reaction at room  temperature, so on. So it works the active species should be dimethyl  cuprate magnesium iodide and this is clearly a lower order magnesium cuprate. Well, in the  preceding lecture we exclusively had lithium as counter-cut iron, as we will  see magnesium is just fine and later on, especially I think tomorrow, we will learn  with organo zinc, the copper zinc couples have very special features and in  terms of functional groups compatibility. Yeah, we will see that tomorrow. So  30 minutes reaction time and then this magnesium enolate should be the predominant  reactive component of the reaction mixture. Then cooling down to minus 15  degrees, adding that conjugated alder height and warming up to 20 degrees, one  hour additional steering and after hydrolysis this was isolated with again  an excellent yield of 90%. So I think it's important to know that it works  catalytically and this fact offers then the opportunity to try additional  chiral ligands for chiral induction. Imagine that you could make a conjugate  addition reaction with a nucleophile and this an ansioselectively. This is  possible and here one excellent example from Ben Feringer's group presented in  1997. So they applied already organo zinc as I mentioned, we would discuss organo  zinc tomorrow in more detail and succeeded in an ansioselectively performing  an conjugate addition reaction with copper catalyst, copper 2 triflate, 2%  catalyst, toluene, a solvent, 3 hours reaction time at minus 30 degrees and  while we need a chiral ligand, 4% of chiral ligand, now to the structure of  that ligand. It derives from binol and as you know binol is a  trope chiral axial chiral compound. Until the derivative is a phosphor amidit  So I admit that this is rather more a complicated structure but visualizing  the structure is worth it since all the result of a reaction was a 94% yield  with a better of 98% in ansiomeric excess. Well let's go on with examples  applications of organo copper chemistry conjugate addition reactions for more  complex targets. Well a chiral cyclopentanone derivative  the transformation that is of interest is  introducing two side changes  Well and if you then get rid of the silyl protecting groups then you are of  course in the field of hormones the prostaglendones. So just in principle how  is this transformation achieved? You need an organo copper reagent and as we  have already discussed there are well lots of examples how the organo copper  could look like. In such a case it's clear that you need something like that  dummy ligand because you have invested a lot of time and money to synthesize this  part. So but we don't discuss the details in this example in the next  example we go into details. So you add the organo culprit it makes a conjugate  addition reaction then you have an enolate. You can try to trap this enolate  directly with an electrophile or you trap the enolate with for instance a  silyl halide to form a TMS enol ether which you can purify and store of course.  So either trap enolate or then directly letting this react with the  electrophile and this one would be this allyl iodide or allyl bromide would be  the electrophile of choice to get to the target compound. Now we are going to  discuss in detail the synthesis of a drug related to prostaglandine hormones.  Well as you notice this is closely related to that prostaglandine  and this drug is called travoprost. It's meant for glaucoma therapy. So glaucoma  in German is grüner star. So let's have a look for that marvelous multi-step  synthesis. Obviously we need a cyclo pentane ring highly functional cyclo  pentane ring and I think we had already before discussed something like  prostaglandine as targets. Well the cheapest way to go into the synthesis is  of course starting with cyclopentadiene or the cyclopentadiene dimer. Of course  it is alder dimer which you have to crack. So first step in that synthesis  freshly prepared cyclopentadiene is treated with dichloroacetyl chloride  and triethylamine as base. Exane as solvent. Zero degrees reaction temperature.  What will happen? The base deprotonates the acidic position here. HCl is  eliminated and you form the dichloroacetyl as reactive intermediate.  These dichloroacetyl generally don't undergo or deal alder reaction but a  thermally 2 plus 2 cyclo addition reaction. So of course this fused  and racemic. Next step you have to get rid of the chlorines. Just reduction. Zinc  acidic acid 60 degrees. Of course still racemic.  For treatment of glaucoma you of course will need an enunciamirically pure compound.  That means on the stage of reaction you should try to separate the resimate into  its enunciamir. A nice idea is forming the bisulfide adduct with SO2 in  dichloromethane.  So the SO2 will attack from just again a roof type molecule from the exo  phase and in the presence of, so you have water there, we need another water there,  and a chiral amine. We will form diasterioisomeric salts.  This is the one we hopefully by crystallization will obtain and then if  we destroy the bisulfide adduct then we will obtain enunciamirically pure our target.  So again having this enunciamirically pure. So by destroying the bisulfide  adduct then abomination in aqueous medium  leads us to this secondary alcohol with the OH group on the ando phase of that  roof type molecule. Protecting the alcohol with the silo chloride in the  presence of emitter sol as base, which is quite typical.  So and now this molecule is treated with  potassium t-butoxide and toluene minus 20 degrees. So let's think about what  will happen. Potassium t-butoxide base, let's have a look where could we  deprotonate this molecule? Well one could think about an elimination reaction. We  have nitrogen here, proton sitting, but it is Zyn to the bromide. Zyn elimination  doesn't occur and moreover alpha to an alcohol or this case and silo ether  this proton is of course less acidic than alpha to a carbonide group. Well we  have two hydrogens here, one hydrogen there. What about the acidity of this  hydrogen? This hydrogen is very low in acidity because the corresponding  enolate for stabilizing the anion would have a very strange system with a  double bond, well somehow at the at the bridgehead. Because of that strange  cyclo-butene structure this is by far less acidic than those. So we deprotonate  here. That means we have here a nucleophilic center and we have then  intramolecularly an electrophilic center, this one. A nucleophilic  substitution takes place with a C-C bond formation from this position to that  one. So HBr is eliminated and C-C bond is formed from this position to that one.  Let's draw that.  And we should translate this structure or to a three-dimensional structure.  It's this one. So a norbanane framework with an additional C-C bond in there.  Let's call that A. And this is the compound we will treat with an organocopper  reagent. So how do we get the organocopper reagent? We need a dummy ligand  starting with thiophene and thiophene is treated with an equimolar amount of  n-butylythium at minus 30 degrees and THF. Well some kind of DOM reaction as we  know it in alpha position it is deprotonated. One equivalent of copper  1 cyanide minus 10 degrees, 20 minutes.  And we will get the culprit.  So the side chain we want to introduce we have  synthesized before. So this arrow group  is of course that meter trifluoromethylphenyl group. Now we have to  lithiate this vinyl iodide. Selectively lithiate that. And what we want to get  is this vinyl lithium. And this is achieved with tertiary butyl lithium to  equivalence of tertiary butyl lithium minus 70 degrees. And now we just have to  connect, combine the solutions. One equivalent of that, one equivalent of  this to form our cool plate which we will apply in the reaction.  Minus and well. So this higher order  cyanide cool plate. So with now a minus 70 degrees  one hour reaction time. This reacts with A. So where will it react? So we don't  have an alpha better unsaturated ketone. However we have a cyclopropyl  ketone and these cyclopropyl CC bonds, two of them, this one and that one, behave a  bit like elephants. Why? Because if the nucleophile attacks here and this CC  bond is broken then the stabilized anion is formed as the enolate. So in this case  the cool plate attacks from this side as the nucleophile. The CC bond is broken.  So here the nucleophile and this is the reaction path.  So back to the target.  Molecule. We need a cyclopentane ring with two OH groups there. The OH groups  should be on the same side. So here we have the protected hydroxyl group. So we  need another hydroxyl group. Okay we already have the oxygen functionality  there. However we also... oh no, no it's the wrong position. Excuse me. So we need an  oxygen functionality here. On the other hand we need to build up this olefin  here. Such an olefin, a synolefin, can be set up with vitich type reactions under  certain reaction conditions which are known for the formation of synolefins.  Selectively or rather selectively. So that means an aldehyde in this side chain  and an OH group here. How can we get to that type of functionality? An oxidation  process. Oxygen has to be introduced in this CC bond. You should know this type  of reaction, a biavillier oxidation. And this goes selectively to the  oxygen to be higher substituted carbon.  So, acetic per acid in acetic acid and buffered with sodium acetate at 20 degrees.  So now an abbreviation for that side chain.  So we get that cyclic ester. As I said, we need the aldehyde functionality here.  So we should reduce that.  Selectively, one hydride transfer. First, well, biavillier oxidation. Secondly,  di-ball H, di-isobutyl aluminum hydride. And we will get that cyclic  semiacetyl, which we can treat with the appropriate  Wittig reagent, because in equilibrium we will have the free aldehyde. So...  This phosphonium salt, treated with potassium t-butoxide. Here is the acidic  position, the most acidic position. And the phosphorylid will be formed, which then  performs Wittig reaction with the aldehyde. And we should then get to this  situation.  So. Let us compare  this molecule with travel prost. What remains to be done? Well, and is the first question is,  well, are all those substituents on the correct side of the cyclo pentane ring? Well,  both OH groups and this, this olefin should be on the same side. Yes, indeed. This one is on  the other side. It's a cyclo pentane ring. Remains to be done is deprotect the remaining  alcohols, this one and one in the side chain. And we have to form the isopropyl ester and that's  it. I think while a very elegant synthesis and indeed done for producing that very valuable  drug and I think you might have noticed lots of reactions which we already discussed or you  know from undergraduate organic lectures are presented within this nice synthesis.  So back to much simpler compounds, a domino process  where we have the side chain with bromide. This is treated with a culprit, typical Gilman  culprit at zero degrees. So and as an exercise, please try to figure out what will be the  product of this reaction. Keep in mind, conjugate addition reactions are the predominant reactions  for organocouperates. So as I said, this organocouperate conjugate addition reaction is the  reaction we should guess that it will happen and this means a methyl group attacks as a nucleophile  and C-C bond formation to this position and then the enolate is formed. So this is a racemic or  should be a racemic starting compound. Nevertheless, the position or the configuration at this  center will determine from which side of the ring the methyl nucleophile will approach.  So and it will approach from the side which is opposite to that isopropyl group and this means all  racemic but the methyl group from the opposite side. Okay. So now we have that enolate as the  nucleophile justin-acent 2 process forming a six-membered ring. One, two, three, four, five, six.  Then both methyl groups on the same side that means that this decaline ring system is cisfused.  This should be the product. While in the original literature they claim that they obtain a yield  of 20 to 30 percent that means they did reaction several times never got an excellent yield.  However, it works. No, we can discuss why that yield is not that good. So there should be a  competing reaction, the direct reaction of the nucleophile with this halide. So methyl, well  what kind of reaction is that? This is some kind of Wurz coupling process. Organometallic  reacting with an alkyl halide just often called Wurz coupling. Although the original Wurz coupling  with sodium and alkyl halides is interpreted as radical process generally. And as I said,  competing reactions normally the conjugate addition reaction is the preferred one,  presumably also in this case. However, a quaternary center is for sterically hindered story here.  And that makes the reaction difficult and therefore diminishes the yield which is obtained. So as I  said, well presumably Wurz coupling reaction occurs here and indeed organo-cruprate chemistry  found a nice application in Wurz coupling reactions, Wurz as cross coupling reactions.  One nice example. So this substrate  was synthesized from tartaric acid,  forming the acetal with acetone and reducing the carboxylic acids with lithium aluminum  hydride to get to the primary alcohols than a tosylation and you have those tosyll leaving  groups and these indeed react with a Gilman-Riegen-Dyphenol copolysium THF 20 degrees, two hours  reaction time and a yield of 47%.  Carbonyl group protected as the acetal. Here now a deed on higher order cyanocuprate,  THF and cyanocuprates, those higher order cyanocuprates, a special reactive that means also  that lower temperatures minus 78 degrees, it works with less than 15 minutes reaction time.  83% of that product was obtained. So nice examples for crossed Wurz-type coupling reactions  which proceed copper induced. So we should ask how about those Wurz-type coupling processes,  especially cross coupling processes applying organolethium and organ or applying organomagnetium  grignate reagents. Does that work or does that not work? So reaction we should briefly talk about  is this one. Imagine a grignate reagent, a butylgrinier plus, well for instance, butyl bromide.  Is this reaction possible? This is a nucleophile attacking that and forming octane. While it is  possible, but it is a very slow process. Luckily it's very slow because if this would be a fast  reaction we wouldn't be able to produce the grignate reagent itself. Okay, I think I hope that that is  clear. So this alkyl bromide plus magnesium in for instance diethyl ether or THF. So as soon as a  little bit of the magnesium has reacted and formed the grignate reagent, we would or the  grignate reagent would face a huge excess of the remaining alkyl bromide. If it's a fast  reaction, this process than the alkyl, alkyne formation, C-C coupling, should take place.  This is actually the proof that it is a slow process. There is another problem connected  with a cross coupling. For instance, let's take organolithium and here a bromide. Organolithium,  as we have seen, is known for that halide metal exchange via eight complexes. And we have already  learned that it's similar with organo magnesium. Remember that knuckle turbo grignate. So a fast  process and much faster than the nucleophilic displacement here, where the attack of that  carbon center is a nucleophile here is the formation of the eight complex. And this is an  equilibrium. And here again, it could disconnect than to this one. So, and that means after  a while, we have all those species in solution. They react rather slow in the woods coupling.  And we would get then a mixture of all possible C-C coupling products. And of course, we would  have some more competing reactions if we have better hydrogens to that bromide than also  eliminations could take place as competing reactions. But as we have learned, organocouper,  chemistry works just fine with words type cross coupling processes. And we have already  learned today that we can apply copper salts in catalytic amounts. And also in this case,  it is nice to know that just at 0.3% of copper chloride, THF, zero degrees, three hours reaction  time. And while this has been done, under 78% yield of the octane was obtained. Now,  octane is of course not that interesting. But one will find much more interesting applications.  Finally, for today, another copper catalyzed process where we have organocouper intermediates.  It's the glaser coupling reaction. If you have a terminal acetylene and you treat that with  instance copper one chloride catalytic amounts, pyridine as a base, and you need molecular  oxygen, then Wouter-Dienes are formed. What you have as an intermediate  are bis alkenylcopper species. And under reductive elimination, this is the way we would call  that a step. Copper zero is formed and this copper zero has then to be reoxidized and  molecular oxygen under the appropriate reaction conditions is sufficient for that. Just one  nice application from the work of Sondheimer famous chemist. This hexadeine with copper  two acetate pyridine oxygen 55 degrees or typical conditions for glaser coupling reaction.  And there goes the glaser coupling reaction. They did it under optimized reaction conditions  described in organic synthesis. You know that journal where those pre-operative examples  have been checked by other groups. Of course, we'll give a mixture of products. But this  one was the target of the Sondheimer group. We started with 50 grams of that and isolated  16 grams of this macro cycle. Fascinating synthesis with that as well intermediate product. Potassium  tibutoxide, interseributanol, under elevated temperatures. Well, what will happen in propagule  position? Those are acidic and under these conditions, the double bond character can  migrate within that chain. In well very moderate yields or you can say especially low yields.  They transformed this all trimeric butadiene system to this one. Finally, with  the idea to selectively reduce those alkynes with a palladium catalyst. Combination of  that palladium on that carbonate. So you can imagine hydrogenation is Zünd-Edition to  the alkynes in this case and you get Van Cisolophins.  So, I hope that the structure is correct. I should count.  No, something is wrong. It should be 18. So, let's just start again.  Okay, I think I've got it on the second attempt. Should be 18.  Because this is the famous Zondheimer synthesis of the so called 18th anuline and the cyclic  conjugated system with 18 electrons for N plus 2 obeying to rule for aromatic systems.  So this is indeed a planar, monocyclic planar. It is an aromatic system and this has been  proven. Well, for instance by the fact that well as you know as an NMR an isotropic effect.  You have an isotropic downfield shift for all hydrogens outside the ring system and  you have an extraordinary upfield shift for hydrogens that might be located above the  ring system and with such large anuline you have hydrogens that are within that ring system  and you have the chemical shift at minus PPM values for such rings.  So enough for today. We meet again tomorrow with an organo zinc chemistry.  Thank you for listening. See you tomorrow.
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