Welcome to part 22 of a lecture on designing organic synthesis. Our subject of today are two target molecules, both of them hydrocarbon terpenoids.

The first one we will discuss is the so-called longifoline, obviously sesquiterpene, with 15 carbons in its skeleton. Well, and a bicyclic structure here and a bridge there.

Here we see an axomethylene group. Well, it can't. I summarize to the endo olefin,

since this is forbidden by Brett's rule, as you know, with a double bond at bridgehead position. Well, okay, let us start with an exercise. Please try to figure out basic steps for the

retrosynthetic analysis. So first step in this retrosynthetic analysis should focus on that axomethylene group, since this is, well, the only functional group and therefore, of course,

the most sensitive one should be introduced in the last step. Well, as I already said, we don't have the problem that the olefin could migrate to the bridgehead position.

However, under acid catalysis, we would have a protonation here. Then we could have, we have a cation there and with this cation, Wagner-Mehrwein-type rearrangements

could occur, which are frequently observed at the norbonane skeleton and related compounds. So it makes sense to get rid of that olefin in retrosynthetic analysis. So

the first step is thinking about the transformation here. Having a carbonite there,

a Wittig reaction should be rather reliable to get to this structure. For the next step,

we need somewhat more fantasy. Well, at least what we have learned, there is a six-membered ring

and six-membered ring we could set up by, for instance, the Diels-Alder reaction. So that means in the next step, we would have or could introduce an additional double bond

for setting up a cyclohexene moiety as retron of a Diels-Alder reaction.

However, this connection here and there would then give a ketene as the dienophile, as we already know, that doesn't work. Ketenes usually give 2 plus 2 cycloaddition

as a result. However, in one of the first lectures, lessons of this lecture, we already learned that we could have another functional group, which is for the Diels-Alder reaction,

this one, having a cyano group here and a chloride there,

hydrolysis here, while replacing the chloride by a hydroxy group, then we have a cyanohydrin

and this could then decompose in equilibrium, giving the ketone. So, retro-Diels-Alder reaction as the next step within our analysis could lead us to this structure.

So, this is of course indeed a simplification. However, setting up that moiety, especially

this bond selectively without the isomerization of the olefins to the higher substituted position, well, this is a problem, which one could address. So, but nevertheless,

question mark, but one should keep in mind that the Diels-Alder approach is feasible. Well, we later on will see a synthesis making use of a Diels-Alder approach. But

at first, let us discuss another idea, which led to a complete synthesis by E.J. Coray's group.

So, Coray envisioned that, well, one could disconnect here, having

donator reactivity at this position and acceptor reactivity at this position. So, let us draw the corresponding symptom, donator reactivity here and acceptor reactivity there.

Donator reactivity at this position corresponds to the natural reactivity of the enolate.

For the acceptor reactivity, Coray had the idea that an alpha beta unsaturated ketone

could be here. Of course, this is only possible if you don't have a tertiary center here. Therefore, he has to eliminate one methyl group there and introduce a carbon group there. So, so cyclization, Michael, cyclization by Michael addition process. Secondly,

a methylation alpha to that carbon group. Later on, one has to get rid of that additional carbon group by some reduction method. Well, I have forgotten in the structure

the methyl group here. So, let's add the methyl group there. Next idea,

we have annihilated six and seven membered ring. Maybe one can build up the seven membered ring

by a ring enlargement reaction starting from a six membered ring. So, in this case,

following this idea, we get to this starting material for several step transformation

and identifying this as an easily accessible structure. Then we can say, well, okay, this is somehow a bi-directional analysis. We would like to start with that because we can

easily get to this. I hope everyone notices how you would build that up by a Robinson annihilation, of course. Typical structure for a Robinson annihilation.

So, what do you have to apply as starting components? This methyl cyclohexane dione

and, well, this alpha-beta unsaturated ketone. Actually, this structure is very well known and

has a name. It's the so-called Wieland-Miescher ketone, very well known as

one almost starting component for several steroid syntheses. So, with this basic

retrosynthetic analysis in mind, we should now have a look at the real synthesis that the group was undertaking. So, again, starting from, well, sorry, there is one mistake in there.

This is not the Wieland-Miescher ketone. This is the Wieland-Miescher ketone and one has

to start, of course, from methyl vinyl ketone. We will soon see or notice how that methyl group

is introduced. Okay, so Wieland-Miescher ketone. First, acetalization with ethylene glycol

catalyzed by powdery-insulphonic acid introduces the acetal rather selectively for that

carbanion group, 66% yield of that alpha-beta unsaturated ketone and the carbanion group

here. But we directly add the Wittig reaction already for that transformation.

It wasn't done as a one-pot reaction. 66% yield of that was isolated and this diene system then with 96% yield, of course, as a mixture of cis-trans stereoisomers here.

With osmium tetroxide, the bis hydroxylation succeeded and now it already becomes

clear, I hope for everyone, how chorri was planning the ring enlargement

by a pinacol-pinacolone rearrangement. So you need the leaving group here of selectively transform the secondary hydroxyl group into a leaving group.

Well, no problem because this is sterically more hindered. Therefore, the combination of para-toluosulfonic acid chloride, pyridine, as base will lead to this

intermediary tosylate which already under rather moderate conditions

will eliminate para-toluosulfonic acid with that migrating vinyl group

and therefore we get to the seven-membered ring product, this one, 48%.

Next step, well, with two normal or two molar HCl in ethanol at 100 degrees,

this acetal is hydrolyzed and partially the olefin is already migrating, nevertheless

most of it is still located here. And you see during this reaction, here is the additional

muffled group already. So this transformation just 100%. The next step is the crucial one

with potassium t-butoxide. It's deprotonated here, conjugated

then to that olefin and it's reprotonated then you have alpha-beta-unsaturated. In the same reaction flask, when you have that alpha-beta-unsaturated, you can also deprotonate here and get this as a nucleophile reacting there.

Okay, all in one pot, unfortunately with a lot of possibilities for competing reactions, of course. Well, but nevertheless the initial idea works, you get to this structure, you can isolate that

with a 20% yield. Not a good yield but the idea works.

Next step, I won't draw the intermediary structures anymore, is the methylation. You have to get in that at this position the additional methyl group. Well,

then I have to add that the Wieland-Nieche ketone went into this process as a resomate. You might know the other structure with a five-membered ring. You can easily,

here with a five-membered ring there, you can easily get that by organocatalysis with proline with 95% EE. Unfortunately, this doesn't work that well

targeting the Wieland-Nieche ketone. To my knowledge, there is then 75% EE. Maybe, meanwhile, in the last 10 years where the field of organocatalysis has rapidly developed, there has been some improvement. However, at that time it was necessary to separate

the enunciomers and that was done at the stage of the compound having the two

methyl groups already at this position. So, resolution of the enunciomers, which of course then loses a lot of material. Third,

hopefully reductive, reducing this selectively, maybe having to protect that and therefore a third step and a fourth step, a couple of steps to get to the hydrocarbon. After all, they got then longifoline and isolated that in an amount of 17 milligrams

while having started with 20 grams of a Wieland-Nieche ketone. They might not have applied

all the stuff in every step, but this is a fact. They started with 20 grams and had 70 milligrams of that. Telling us that it is a nice idea, but still longifoline is far better

isolated from nature. Far more easy. So, next example for an approach to longifoline.

So, that is the Diels-Alder approach. The leading scientist, Xing Yang Liu in 1992. He was at that time at least at the University of Alberta in Edmonton,

Canada. So, and the Diels-Alder approach was making use of an interesting

intermolecular Diels-Alder reaction of this structure. Well, okay, you can easily get this structure by a condensation process between cyclopentadiene and acetone.

And these type of structures are called fulvenes. This is a fulvene, dimethyl fulvene. Cheap compound deals alder reaction with malenic anhydride toluene 100 degrees

24 hours reaction time. This gives then rather selectively the axial Diels-Alder product.

You know the endo product is a result of secondary orbital interactions with the electron density of the of the diene. Well, here we have also some additional electron density, electron rich part. Well, this is the result. The exo in second

exo Diels-Alder product in 67 percent yield compared to the endo Diels-Alder product in 0.25

percent. So the Leo group was in need of that targeted for that and now a couple of steps. First, treating this with 50 percent sulfuric acid for 48 hours at 20 degrees.

What happened? It is protonated at that carbon. Then you have a tertiary cation here. This is the electrophile which indeed, well here, which indeed gets close

to the free electron pairs of one carbonyl group. Either this or that makes the both

enantiomers. And here by protonation of course the hybridization is changed from sp2 to sp3. So that makes sense. As I said, protonated there, tertiary carbocation there,

cyclization while having the acid moiety there. But I will draw it already as an ester

because secondly methanol acid catalysis esterification and well third already the hydrogenation. Let's wipe out that double bond. Therefore this is hydrogenated.

Overall yield through these three steps is 50 percent. Not bad. Now basic reaction conditions

methanolate in methanol epimerization will take place here. Yeah okay let's draw that again.

Next step. This is treated with phosphor pentoxide and trifluoromethane sulfonic acid.

Rather acidic conditions. Dichloromethane some pressure cause otherwise can't get to 65 degrees.

And this results in the transformation to this structure. We have a CC bond formed.

Thinking about is that correct here. Here we have it. Okay this is correct.

82 percent yield. Of course we should now try to understand what is what is going on here.

So if you eliminate here you have the olefin. Okay so and then under these conditions

highly acidic with phosphorous pentoxide you will get an anhydride there with this carbonoid group as highly electrophilic and this highly electrophilic one will then attack

the olefin. Okay electrophilic attack at the olefin. Similar to Friedel-Crafts type reaction. Well in this case I think you would call that an ene reaction. Okay if you figure it out in

detail the mechanism. So but I think one can rather easily understand this type of reaction and it works indeed very well. So now getting in the other methyl group.

So that simple with an organocoupe rate 96 percent yield. So we will now discuss

just two more steps. Then we have at least the framework of the final longyfoline. We treat this compound with a diazo reagent.

Diazo acetic acid astro to be easily synthesized starting from glycine

ethyl ester. So and what you now are able to perform is well a tifenu

reaction a tifenu ring enlargement with this additional ester group.

Up to now you have always learned that with diazo methane but it also works with a stabilized system like that. Okay what's tifenu? This is the nucleophilic center attacks

the carbonyl group. Then you have the O minus there and have an nitrogen leaving group there. Nucleophilic replacement with ring enlargement.

I hope you still remember the tifenu rearrangement. Well maybe i should draw a result. You get a mixture of this plus the isomer

where you have to change the position of that ester and the carbonyl group. Well this is a good result. You get that with above 90 percent yield.

Next step is the hydrolyzation of the ester then it decarboxylates at the because it's a

keto ester and well for the longifoline synthesis you don't have to care about the position of

that carbonyl group because you have to get rid of it by reduction anyway. Okay so a couple of more steps are necessary of course but well in principle you have already set up the

longifoline structure while you need an additional methyl group there of course. So okay enough about the longifoline. Always having that problem that getting rid of the

carbonyl groups and completing the reaction sequence you will lose a lot of yield there.

So therefore let's have a look at a very renowned synthesis of another tepine called isocamine synthesized by Michael Pirung's group published in 1979.

This is the target so this is isocamine and this synthesis by Pirung is so renowned because

it was it succeeded in a rather high overall yield. So retrosynthetic analysis the idea

again is making use of well a ring enlargement at the same time

the second ring that got smaller. Okay we know these type of reactions again pinacol pinacolone

rearrangement type processes. Okay let's see or not pinacol pinacolone just a mervine rearrangement in in this case. So basic idea is we have two annihilated five membered rings

there is another one here with a carbocation there h plus eliminates.

So and this carbocation iron could derive from a rearrangement having a four membered ring

here a six membered ring there carbocation iron at this position it's simply the migration

of this electron pair that's it should be no problem especially because well you get rid of

strained four membered ring two five membered rings are of course in terms of strain ring strain energy far better than a six membered with a four membered ring. Okay

so having olefin here just treating that with an acid just treating this with h plus

should directly transform it make the transformation to that target structure.

So and now one could analyze this one here of course we would introduce the carbonyl group there in the next step in retrosynthetic analysis having a carbonyl group there. Okay so and cyclohexanone with an annihilated four membered ring how would you introduce the

four membered ring by a two plus two cyclo addition process of course making use of photochemistry. So this is the basic retro synthesis so let's draw that what you need is

something like that so let's see how the synthesis worked in

reality starting from this simple substrate which of course

derives from that dione which we are already noticing today as a starting

material for the Wieland-Mieser ketone. So with LDA methyl iodide the methyl group has been introduced here a yield 81 percent next step a Grignard reagent

so nucleophilic center will react with this carbonyl group you then

have the alcohol as an intermediate i will write it down because it's then more easy to follow that synthesis after hydrolysis you will have this intermediate and this is highly sensitive

during hydrolysis because under acid catalysis this returns into the OH group it returns into leaving group HCl again H2O heating it up a bit will lead to this functionalized product with

a 90 percent yield. So now next step i should write that at the next blackboard

is the photochemically induced cyclization highly diastereoselective 77 percent yield of that

of course this is a racemic synthesis but highly diastereoselective. So Wittig reaction

introducing the axo methylene group let's call this structure A then we already have A then treating it with a p-toluenesulfonic acid heating it up and indeed the reaction

reaction to give isocamine then final rearrangement succeeded in 90 80 percent 98 percent as already written to the blackboard of course it's a racemic synthesis however indeed

really impressive so let us count we can buy that let's assume we have bought that so then

first step second this is not isolated the third step fourth fifth and after six steps all in high yield the synthesis was done well indeed highly impressive

next lesson will take place on next friday we skip tomorrow subject of

friday will be of course also natural product synthesis but we will focus on free radical reactions as a key step in these synthesis thank you for listening see you next friday