Welcome to part 19 of the lecture on designing organic synthesis. The subject of today is the synthesis of epotilone A. Well, this is the general structure of epotilone, or at least epotilone A and B.

So, to be precise, for epotilone A, X is an oxygen, so we are dealing with a lactone, and R is just a hydrogen.

Epitolone B, X again oxygen, and R is the CH3 group.

So, this is a natural product, highly interesting natural product, partially from its structure.

And it is additionally a very interesting target for organic synthesis because of its biological activity.

Actually, it was isolated in Braunschweig from a sample of mud from the shores of Zambezi in the Republic of Congo. And it became very interesting since it was found out that it is very, very active against cancer cells.

And, indeed, nowadays, well, the derivative, the so-called atza epotilone B,

where, of course, again R is CH3, but the oxygen was transferred, or the lactone was transferred into a lactame. So, X is an H. This is indeed used nowadays, or applied nowadays, in chemotherapy, especially against breast cancer.

So, highly interesting target molecule. And, well, I would say have fun in an exercise analyzing this structure.

Well, of course, in the next ten minutes you won't succeed in completely analyzing that for retrosynthetic analysis.

However, please just try to find the crucial bonds you could break, strategic bonds. Where are the strategic bonds within this molecule?

And then you will find some partial structures one should further then analyze, which we will do together then. First of all, just the strategic bonds in this molecule. Well, it is not that difficult to find the strategic bonds in this case.

Far more difficult it is to decide which method will be used to introduce the chiral centers and so on. Well, certainly one functional group which is very sensitive is in this molecule.

And you don't want to carry this functional group through the synthesis. So, that's the epoxide.

It's a good idea to introduce the epoxide in the last step of the synthesis. Having an olefin here and an olefin there, they have different reactivity. This one will be more easy to access, especially if R is just hydrogen.

So, and well, we should aim for the analysis of epotilone A. And well, just let us draw this structure, the olefin.

It's a cis olefin and we want to get to that one. So, in the last step, epoxidation, for instance, with dimethyl dioxirane.

However, other strategic bonds we will try to find in this drawing. Well, okay, there is that heterocycle. You could think of introducing that heterocycle through a walled palladium catalyzed process,

maybe a heck-type reaction at an olefin. On the other hand, certainly not a bad idea to disconnect here.

And planning to make that double bond by a Wittig reaction. For instance, a Wittig-Hohner-Ammons reaction. So, that means we have this structure and we need later on to think about

how to get to an organophosphor compound like this.

On the other hand, well, here we need a carbonyl group. So, let's call that partial structure A or synthesis component A.

Then we have a strategic bond here.

So, we are talking about epitilone A, a lactone, well, esterification, of course. So, that means disconnect here.

We have a strategic bond there. This is formed by an Aldol addition reaction, for instance, could be formed. But we don't want to disconnect now here because this is such a small piece.

It doesn't make sense. On the other hand, here we have also an Aldol addition set up. So, we can disconnect there. And now we have another nice piece, this one.

So, let's call that C since that part then here as an olefin would be then B.

But if you think about how to get that olefin, remarkably, most groups that were targeting this synthesis

had the idea to form this double bond by a ring-closing olefin metathesis with a ruthenium carbene catalyst. Okay? So, that means you can transform that retrosynthetically to two terminal olefins, olefinium catalysis,

and so with a ring-closing olefin metathesis as the final but one step within the synthesis.

So, and then let's call this part B1 and this part therefore B2.

So, now let's start to analyse the synthesis of these building blocks of that then highly convergent synthesis plan.

So, first of all, structure A.

So, this moiety, the phosphor, you would attach simply by an Abusov reaction. You are well aware of, I think.

So, and that means, so Abusov, you need leaving group X here.

And that makes the analysis of that structure rather easy. So, let us assume that we have a nucleophilic nitrogen, a nucleophilic sulfur. Then we would just choose this thioacetamide as one component and this acetone derivative as the second one.

That's all. X might be chloride or bromide, actually in the synthesis generally was chloride.

The whole process works very well. So, A is no problem at all. Now, let us look at C and we will follow the research plan of Dieter Schinze,

also at that time at Braunschweig University, close to the group which identified epitilone.

And Dieter Schinze decided to go for C via this compound, just having another oxidation state here.

Should be no problem. Later on, de-protect and then selectively oxidize at that primary alcohol.

No problem. Okay, let's call that C prime. So, how can we synthesize C prime? Well, we could introduce such an aful group here by starting from a corresponding aldehyde and in Grignier and then oxidizing.

No problem. So, that means this aldehyde, first aful Grignier, secondly an oxidation,

for instance, tempo oxidation. While Dieter Schinze didn't apply the tempo oxidation, to my knowledge it wasn't known at that time.

So, tempo is more newly discovered at the end of the 90s, I think. Where to get that aldehyde from?

For instance, from the olefin.

It's an oxidation, a selective oxidation to the aldehyde. You know one oxidation, the ozonolysis. Ozonolysis should come to your mind. But very often, another protocol. Catalytically, osmium tetroxide and adding a periodate does the job nicely with about 80% yield or even more.

So, why this allyl group? Well, because it is known that you can transfer enantio selectively an allyl group with certain chiral allyl boranes.

Highly enantio selective reaction. Then you have the diol in principle. One was protected and to transform that to that acetal is of course no problem at all.

Well, where can you get this one from? Well, that's simple. You start with propane 1,3-diol.

Protect one alcohol functionality and the other one is oxidized nowadays by a tempo oxidation.

So, we know now how to get to C'. So, next I would like to explain how one can synthesize B2.

So, let's draw B2.

It's this structure. Let's count RV right here. So, okay, we need carbon atom here.

1, 2, 3, 4, 5, 6, 7. Oh, 1, 2, 3, 4, 5, 6 and then it's a double bond. Okay, 7 carbons.

1, 2, 3, 4, 5, 6. Well, I think it should be this one. Let's check again.

Yes, should be right. Okay.

So, general plan is for instance having already that chain and introducing a methyl group.

Enunciate selectively alpha to the carbonyl group. Well, one can think about which oxidation state that carbon should be when you introduce that.

And a nice starting material would be this one, caprolactone.

This is rather cheap. You have 6 carbon atoms. We need 7. Well, hydrolysis here. Later on oxidizing that alcohol to the aldehyde and with the vittic olefination adding the terminal olefin.

Should be no problem. So, methods for introducing the methyl group enunciate selectively.

Well, let's draw a couple of structures where in every case the chiral auxiliary is attached here.

The most renowned one is of course Evans enolate chemistry.

One example. Another example is this one.

This as an NH is the so-called opulsors saltane.

It's a derivative of CAM4 sulfonic acid.

So, you start from CAM4. You can produce directly the one step synthesis, a remarkable easy synthesis, the corresponding CAM4 sulfonic acid.

So, CAM4 is this structure. So, you can form the sulfonic acid, you form the amide and, well, then some kind of reductive amination will form this one, opulsors saltane.

And now you can form corresponding emits similar to this one and that is

then, well, the structure who waits to be enunciate selectively methylated here at this position.

Another known method, once again this is Evans enolate chemistry. Well, another method, Anders reagent developed by Dieter Anders in Aachen.

So, and it's this, a hydrazone.

Sorry, well, no, it's correct. It's a pyrrolidine ring. So, and you, of course, all know from which chiral pool compound Anders starts and synthesizing that, of course, from the amino acid, pyrrolidine.

So, in any case, deprotonating, forming enolates and then with, alkylating with methyl

iodide will form highly enunciate selectively steiogenic center here in the alpha position. Of course, you could alternatively start with the ethyl group here, deprotonate there and then alkylate with that chain.

So, what do you need then? Something like that. You could do that, of course, same result.

So, deprotonating here, connecting there. It's the same result if deprotonating here and adding another group there.

So, next step we should discuss is synthesizing B1, partial structure B1 and, well, connecting that already with that heterocycle.

So, let's draw B1, carbonyl group there, that's it, that's all.

So, I'm going to outline the synthesis of B1, this compound we already discussed today.

So, starting with the propane 1,3-diol protecting one side, oxidizing on the other side.

Okay, no problem at all. Then isopropenyl grigner will lead to this allylic alcohol, of course, as a resomate.

Then the so-called Sharpless Kinetic Resolution, making use of the Sharpless epoxidation of allylic alcohols.

But now, well, you have already a chiral center there and one enantiomer will react faster in the Sharpless epoxidation than the other one.

And therefore, on the right condition reactions, there will be a good yield of one enantiomer of the allylic alcohol remaining.

So, well, that Sharpless epoxidation, that kinetic resolution, will lead us to this.

Yeah, well, this is then the enantiomer we were targeting for.

So, we then need again an oxidative cleavage here. Well, actually, the oxidative cleavage works selective when you have also protected that secondary alcohol by a silyl group.

So, first, silylation. Secondly, again, that oxidative cleavage with osmium tetroxide and the periodate, we already talked about that also.

So, now we can perform the Wittig reaction with reagent A.

So, we precise the Horner-Wattsworth-Amens-Wittig-type olefination.

So, and after a couple of steps more, first of all, selectively

deprotecting to the primary alcohol, oxidation to the aldehyde, and then Wittig olefination.

We get to this alcohol with the terminal olefin. Okay. So, what else?

So, which structures do we have? We have now this one. This is already the combination of A plus B1 as one unit.

Now, where do we have C prime? We have C prime here. Here is that synthesis outlined.

C prime has that CH2 group here, alpha acidic.

And now, we would try an aldol addition process with B2.

Okay. So, next, C prime plus B2 aldol addition.

And then, well, what would we have there? We have then this unit, stereogenic centers here, and at the end, the olefin. Okay. So, deprotecting here and oxidizing there until the stage of the carboxylic acid.

So, we should protect all the alcohols that should not form an ester later on. So, and again, please remember our unit A plus B1.

We have the heterocycle there, there the alcohol, and a side chain with an olefin.

So, and now, we just have to form an ester between this alcohol and that carboxylic acid. And, just an analogy to the formation of a peptide bond induced by using carbo deimides, as you know.

So, for instance, so these are these deimides and forming urea derivatives, trapping the water there,

but also, first of all, reacting with the carboxylic acid group and forming a nice leaving group. And then, this is the nucleophile, which will attack there. So, then, we have that ester, the heterocycle there, OH, or still protected, side chain, side chain with olefin here and there,

and then just the olefin, the taphysis, and this usually works very well in a macrocyclization like that. The only problem they were facing then was that they had a mixture of the cis and the trans olefin in the ratio nearly one to one.

So, of course, that is one remaining problem, which remained unsolved at least at that time.

So, the final epoxidation worked just fine, and while getting rid of siloed protecting groups is also no problem. So, I hope you have learned that even such complicated structures with lots of

stereogenic center is relatively easy to be analyzed with your knowledge of organic chemistry. Of course, working out the details, deciding which of those methods to use, evidence enolide, opulsor, sultane, or endos reagent.

Well, after all, all of those methods have been applied within the synthesis of epotilone. Well, this is, of course, working out the details, and the synthesis itself, that takes quite a lot of time.

I know that in the Schinzel group, they worked about six months with about, well, five to six doctoral students, and they worked day and night.

So, to be somewhat faster than others. It was a head-to-head finish, after all, with the groups of Nico Lau and Sam Donyshevsky.

Well, okay, enough for today. We skip next Tuesday. We will meet again next week, Wednesday, and we will discuss the synthesis of some interesting and normally rather strained hydrocarbons.

Thank you for listening. See you next week.