Welcome to part 28 of the lecture on designing organic synthesis. Our subject of today is the universal retron of the olefin metastasis. Well, olefin metastasis we already discussed in detail in the lecture on catalytic organometallics.

We also had already one example in retrosynthetic analysis within the synthesis of epitilone.

The crucial macrocyclisation was a ring-closing metastasis. However, olefin metastasis has revolutionised the way our target molecules are analysed within retrosynthetic analysis

and then of course synthesised and we should again have a closer look in terms of retrosynthetic analysis. Therefore we should ask what is the retron of an olefin metastasis and we will just concentrate on the ring-closing metastasis.

So a general, well not a general scheme, but an example, a simple example of a ring-closing metastasis is, well we have this diene, not conjugated diene, a non-conjugated diene.

We need generally ruthenium or ruthenium carbene complex, sometimes also molybdenum carbene complexes are involved.

And in this case we would observe that ethylene is eliminated and cyclohexene would be formed.

So now what is the details of the mechanism? Most of you should be aware of 2 plus 2 cycloaddition reactions and then cycloreversion

and also that story with somewhat dead end in the catalytic cycle but since it's an equilibrium process it will get out of this dead end again and so on. We discussed that before. So this would be the result of the ring-closing olefin metastasis.

So but what is the retron? Is it just an olefin moiety? Well, okay, we

should have a closer look what kind of olefins we can approach with this metastasis. And well, for instance, let's have a look at this nice example related to carbohydrate chemistry.

Most of the hydroxyl groups are protective with benzyl protecting groups but here we already have an enol ether

and at this position already an allylation has been performed.

So now it's the combination of an enol ether and an olefin. Does that perform ring-closing metastasis reaction?

Well, indeed 20% of the ruthenium catalyst at 60° and the reaction, the ring-closing metastasis will take place just nicely giving rise to these two transfused heterocycles.

Yield 89%. So and structure of the catalyst involved. An anheterocyclic carbene complex sterically hindering massitu substituents.

Here we have the ruthenium coordinated starting with this carbene

complex, chloride here, chloride there and hysterically demanding tris cyclohexylphosphine ligand.

Well, so, okay, also heteroatoms at that position are by choosing the right catalyst and right conditions also accessible as target molecules. Next example. What about this one? Could make a difference because if we

now eliminate ethylene then tetra, a tetra substituted olefin will be the result.

Does that work? Yes, it does. With about almost quantitative yield, albeit you need

somewhat modified ruthenium catalyst, well they succeeded in having a second anheterocyclic carbene coordinated.

With a special substitution pattern telling us that a lot of optimisation has taken place until they have developed this catalyst.

So, overall, obviously the ring closing olefin metathesis is able to provide an access to target compounds which will exhibit this kind of moiety.

So, R and R prime can at least be methyl groups. I'm not sure about having some other substituents there.

And X for sure can also be an oxygen. I didn't find any example for enamine formation in literature.

But I might be wrong. Maybe we are already on the way to developing the right catalyst for that. So, now we can complete our scheme. So, again, this is a retron.

And since this partial structure you can find in a lot of target molecules

or keep in mind, even if you don't have that olefin in your target molecule,

you just can add within your retrosynthetic analysis the olefin and then you have a retron of the ring closing olefin metathesis.

So, that means, well, there are so many examples you can think of. The name universal, some kind of universal retron is, I think, justified.

So, and starting material then for the ring closing metathesis would be then something like that, where you indeed also can have additional substituents here.

Well, mainly ethylene is eliminated, but sometimes even propylene or other examples are.

So, here we have a retron. And, moreover, enantioselective ring closing olefin metathesis is also known.

Let's have a look at some examples. This compound, as you have already noticed, is, of course, achiral since it's a meso compound.

And now, with a molybdenum carbene complex carrying a chiral ligand, an enantioselective ring closing metathesis was achieved.

Well, 90% yield of this structure of an aggregation pheromone of some beetles, while 60

% enantiomeric excess is not very good, but at least it was some kind of starting point.

And, meanwhile, there are more examples with better enantioselectivity. Again, benzyl protecting group, achiral, same type of catalyst.

Now, 83% yield, but already 87% enantiomeric excess, complete hydrogenation of

this double bond, that double bond, and hydrogenating of this benzyl protecting group. Then, you end up with the well-known alkaloid R-conyene.

Another very nice example is a combination, shows a combination of ring closing plus ring opening metathesis.

Metathesis, olefin metathesis between this olefin and that one.

It is the ruthenium catalyst, an equilibrium reaction, but the driving force that the reaction goes in this, mainly in this direction, simply derives from the fact that these norbornene moieties are already somewhat strained.

So, the olefin metathesis will combine or connect this carbon with that one, and this one with the terminal one.

We could do that as an exercise, but I will just write it to the blackboard. It's not that difficult.

97% yield, and well, maybe I was wrong here, and I think it's again that chiral molybdenum catalyst since an 88% enantiomeric excess was obtained.

So, the dimethyl of the lean group here at that position. So, this is the crucial step in the synthesis of this target terpenoid, cyclopropane ring here.

And indeed, the final step in the synthesis of plus africanol was introducing the cyclopropane ring with Simmons-Smith cyclopropanation.

So, in the context of the synthesis of another terpenoid, the so-called ingenol, or the synthesis of the group of John Wood from Yale University, I won't write down the structure of ingenol, but on the way to ingenol, one was very much interested in getting hands of this structure.

Here, we have that seven membered ring and five membered one,

analyte protected aldehyde functionality.

And actually, two seven membered moieties form that bicyclic ring system with the analyte cyclopentane.

And in addition, cyclopropane ring here, here, another methyl group, here is just a hydrogen, and there another stereogenic center.

So, we presumably agree that this structure looks rather complicated. So, let's try a retro synthesis.

Well, this 1,2-diol, cis-diol, could be made by, well, oxidation with osmium tetroxide.

And therefore, we can simplify this structure to this olefin. I will now skip one or the other stereogenic center.

So, and now, with the cyclic olefin, we have a universal retron found in here.

Let's assume that this double bond has been formed by a ring-closing metathesis. So, that will simplify the structure.

So, then we have that seven membered ring here, cycloheptanone with an allylic sidechain here.

And a spiro annihilation there.

Actually, now, some of the stereogenic centers are important.

All are important, but these are especially important to understand the next steps within retro synthetic analysis. Since it's important that this vinyl group here and the protected aldehyde are on the same side of the cyclopentane ring.

Well, next step, alulation.

So, next simplification is easily achieved if you say,

well, this moiety, the aldehyde.

There we can imagine that we get that aldehyde by an oxidative cleavage of this C-C bond.

And now, next retro synthetic step is, well, how can we call that?

This is a ring-opening metathesis. Okay, I should write that down. Not ring-closing, but ring-opening, but again, a metathesis.

So, here we have the norbonine ring system. And if you treat that with a catalytic ruthenium carbene complex providing ethylene under pressure,

then it's a ring-opening metathesis giving rise directly to this cyclopentane ring system

with two vinyl groups on the same side of a ring. This has indeed been performed. So, this is then a ring-opening metathesis and works indeed with a nice 98% yield,

just 2% of a ruthenium catalyst.

So, here we have a couple of steps. Oxidative cleavage, well, this time not with an ozonolysis.

First of all, 1,2-diol formation with osmium tetroxide. This is somewhat less sterically hindered than that. Therefore, it worked rather selectively for this olefin. And then cleavage of the diol with an oxidation, with a periodate.

And of course, acetalization. Overall yield over these three steps, 73% of that.

Here now, base and just allylic bromide. So, the alpha alkylation stereoselectively with 92% yield.

So, and here, this is the ring-closing metathesis, while forming this strained ring system.

Somewhat strained ring system was obviously not that easy. They applied catalyst loading of 80% ruthenium catalyst

and got, well, 45% yield of that. Nevertheless, elegant. Not efficient, but elegant, of course. So, and this osmium tetroxide oxidation, that works nicely 82%.

Let us go back to this structure. How can we simplify that with the next retrosynthetic step?

I hope every one of you noticed that we have a cyclohexene moiety. This is the retron of the Diels-Alder reaction. And indeed, we have to generate this alpha beta unsaturated ketone with the exocyclic methylene group

and try a cyclo, Diels-Alder reaction, cyclo addition process,

while catalyzed by BF3 etherate and a 59% yield of the stereoisomer

that synthesis was in need of was obtained about 26% of another stereoisomer.

Again, as I said, I think rather clever synthetic plan, synthesis plan and it worked out rather nicely, maybe, but this 45% in the crucial step.

So, I think it's time for an exercise.

Let's try to develop a plan for synthesizing a rather prominent target molecule

plus Moscone, a very well-known flagrance

and, well, in addition, you should try to synthesize that starting from another flagrance, namely from citronenal as the right isomer, as the right anansomer.

So, we are trying now as an exercise to develop a short synthesis with making use of a bidirectional retrosynthetic analysis

and, of course, making use of the ring-closing metaphysis. So, just have a try. Okay, so, we want to include that carbon chain into the one of the Moscone ring system

and since we are planning a ring-closing olefin metaphysis, that means that this isopropylidine moiety will be eliminated.

So, we want to include one, two, three, four, five, six carbons. Let's count from here. Here is the carbon with the oxygen functionality. One, two, three, four, five, six.

Okay, so, the olefin that should be formed through ring-closing metaphysis should be located at this position, then leading us to this intermediary substrate.

So, let us count that again.

One, two, three, four, five, six, seven. One, two, three, four, five, six, seven. One, two, three, four, five, six, seven, eight, nine, ten.

Okay, how to get this chain attached to the aldehyde?

So, I've got a fancy idea. What about hydroacylation, a rhodium-catalyzed hydroacylation,

having that this olefin, this decadiene with two olefinic terminal moieties. The problem with that is how to avoid, then, the intramolecular hydroacylation at the citronal layer.

I should look that up. Is that known? Connecting this carbon, one, two, three, four, five, six, with that one and forming a six-member ring. I will look that up in SciFinder.

But, of course, you would have that problem if you try to get the intermolecular hydroacylation done preferentially compared to the intramolecular one. So, let's stay with simple chemistry from the course Organic Chemistry I.

Then, why not simply adding a grignier reagent to the aldehyde and then oxidizing it. So, let's draw the alcohol functionality here.

So, and we just need one, two, three, four, five, six, seven, eight, nine, ten.

Okay, and magnesium, grignier. And then an oxidation. Well, of course, one could already try the olefin metathesis at the stage of that secondary alcohol.

And then hydrogenation or, well, you could either or.

Hydrogenation and secondly, oxidation or the other way round. Well, the Grubbs group did the cyclization indeed at the stage of the secondary alcohol.

And through this sequence, from here to there, they achieved a 56% overall yield.

I think that is already quite nicely. So, up to now we have only talked about ring closing metathesis, one ring opening metathesis. What about doing a ring closure at all across intermolecular cross catalysis?

Well, it is already quite nicely developed, but you have some problems of selectivity and you will address these selectivity problems.

For instance, with combining a cross metathesis of an electron rich and an electron poor olefin. This is possible, somewhat complicated. Well, an alternative is, nevertheless, do the cross metathesis intramolecularly by introducing temporary bridges.

Temporary silicon bridges, for instance. So, these temporary bridges we already discussed in the lecture about stoichiometric organometallics.

And now we meet some new examples in the context of olefin metathesis.

So, first, treat that with two equivalents, with one equivalent of diphenosyl dichloride.

Of course, you need a base, in this case it was ruthenium. Secondly, then, a ring closing olefin metathesis with a ruthenium catalyst.

You get in a very good yield than this product. After hydrolysis, you have the diol.

And performing that intramolecularly forming a seven membered ring that guarantees that you get selectively the cis olefin. Very often in olefin metathesis you have a problem of mixtures of cis and trans products.

Another example which I found rather intriguing, since it has a phosphor atom as temporary bridge, a phosphoric acid, astro, triastro.

Here you have a vinyl group in axial position and there a vinyl group in equatorial position.

Ring closing metathesis then provides this product.

So, in literature they treated that reductively with lithium aluminum hydride than hydrolyzing.

Maybe the direct hydrolysis will cause some problems because we have an astro here which is sensitive against nucleophilic displacement.

Maybe activated with H plus and then just water nucleophilically attacks here as an SN2 prime process. Presumably that is the reason why they reduce in one example than hydrolysis.

So, and the result then is this nice building block which certainly will find some applications.

And treating this compound with organocuprates as soft nucleophiles and then also reduction and hydrolysis.

Then the R group is introduced as a nucleophile, an SN2 prime process here leading then to this type of building block.

Last example. You certainly remember there are various methods

for enantioselectively constructing cyclopentene moieties with two different functional groups. Maybe OH and acetate and so on. Various methods, for instance in the context of synthesizing prostaglandins and so on.

Well here we have a temporary silicon bridge. So with 7% of a ruthenium catalyst,

two, well as a domino process, one ring opening metathesis combined with two ring closing metathesis.

These were observed in this case. I'm not sure on which side the reaction will start. Nevertheless the result is clear.

This one. And just a few steps deprotecting here, eliminating there under protolysis.

And this then finally is again an alkaloid with the name minus halosine.

Also a very nice synthesis especially because this time that domino process nicely worked with 97% yield as reported.

So final example, lecture today. Final lecture in this lecture series also overall.

So thanks for listening and good luck with your own synthesis.