Welcome to part 25 of the lecture on designing organic synthesis. Today's subject, let's call that magic money.

As I told you yesterday with the title magic money, Clayton Halfcock from Berkeley made a lecture tour about 20 or 25 years ago. Very impressive and well, we will have some especially impressive examples.

Let's call magic money if there is a combination of money type reactions with other powerful reactions procedures.

And today we will focus on the so-called Asa-Kopp-Mannich reaction.

Actually it is a combination of an Asa-Kopp rearrangement followed by a Mannich reaction. The main protagonist in this area is Larry Overman from the UC Irvine near Los Angeles

who started this type of chemistry in the early 80s. So, general scheme for this type of reaction.

We have an iminium cation as one functionality within a hexadiene system

and in addition we have in allylic position an OH functionality.

So, if that would be a carbon then it is the basic structure for an oxy-Kopp rearrangement. So, here it's an Asa-Kopp, maybe an oxy-Asa-Kopp rearrangement system.

But this sounds a bit too complicated, Asa-Kopp is just fine and Asa-Kopp Mannich reaction was how Larry Overman called that. So, Kopp rearrangement with a six membered aromatic transition state as you know certainly leads us to this structure.

And now we have an iminium cation here and an enol there.

Okay, so C-C bond formation represents in this case a Mannich reaction. Well, giving rise to a five membered ring, a tetrahydropyrrole ring with a functionality, a carbonyl functionality attached.

Well, you can discuss an alternative mechanism and this has of course

been discussed that the iminium cation attacks that olefin forming this intermediary carbocation.

And then a Wagner-Merwein rearrangement could occur, essentially leading to the same product.

So, let's keep that in brackets because the stereoselectivity which has been observed within this type of reaction is more in accord with such a sigmatropic rearrangement.

So, but we won't discuss stereocontrol today since the reaction itself is complicated enough.

And the structures we will analyze in the synthesis, we will follow or try to understand, then we will focus just on the synthesis of the skeleton without paying too much attention to the stereochemistry.

Well, so this is the basic, as I said, the basic scheme for the other Cope-Mannich reaction and therefore this structure here is the redrawn of this type of process.

Well, okay, so let's have a look at the first example of natural product synthesis.

It's about the synthesis of minus crinine, also done in the lab of Larry Overman. And first of all, the structure of this polycyclic alkaloid, well, not that complicated at all.

And first step, of course, is where could we find strategic bonds?

Well, so we have to analyze what we have here, an allylic alcohol, an acetal, we don't go for the acetal force, of course. This is rather stable and this is also a nice protecting group for those hydroxyl groups.

So it's nice that we can keep it within the natural product. We don't have to bother with this functionality. We have the tertiary amine here. So, well, what kind of heterocycle, what kind of alkaloid is that?

It's from the family of tetrahydroisoquinalins. So with this six-membered ring at the benzene, annihilated to benzene moiety, we have a tetrahydroisoquinalin.

Quinoline would be with nitrogen here. So we should think about what kind of tetrahydroisoquinalin synthesis do we know?

Well, for instance, a very famous name reaction, the Pikti-Spengler tetrahydroisoquinalin synthesis. So Pikti-Spengler simply is, you have an electron-rich aromatic system in the side chain, an amino functionality.

You form an iminium cation, which then attacks as an electrophile intramolecularly the electron-rich aromatic system.

So, and the iminium cation we are in need of simply consists of that nitrogen, that carbon, and the two hydrogens.

So that means we need the secondary amine condensating that with formaldehyde. And this is then the iminium cation that reacts as an electrophile here.

So, reaction conditions would be formaldehyde and, well, simply a Brunstedt acid.

Well, I'm wrong. Not in catalytic amounts, we need a bit more because otherwise our Brunstedt catalyst would just be trapped by the tertiary amine.

So, we need acidic conditions.

Well, maybe it's easier for you if I draw it similar to that structure, just skipping that methylene group.

It's this one.

So, that looks rather complicated, but what do we have here? We have a five-membered ring, a pyrrolidine, a tetrahydro-pyrrole pyrrolidine attached a six-membered ring.

So, same structure again. Let's draw that. Another perspective. I made a mistake.

Yes. So, from that nitrogen there's the CH group, the CH2 group and then the secondary alcohol.

Nitrogen, CH group, CH2 group, secondary alcohol. It's the same.

And the stereochemistry should be also the same. Now, let us compare this structure with that one. Okay, pyrrolidine and a carbonyl group there.

That it's more easy to analyse that in terms to find the retron. Therefore, I suggest you should change the position that we have the pyrrolidine on the right-hand side,

the six-membered ring, annihilated on the left-hand side.

At this junction, we have to draw the aryl group.

And, well, we have turned that around. This is in front.

And for having the retron you're looking for within this molecule, we have to add the carbonyl group. We need the carbonyl group here.

So, okay, that carbonyl group, that carbon is the same as that one. There should be some methods where you can transfer that in an olefin here with an alcohol functionality there. These are a couple of steps, okay?

Should be possible. But now we have the retron of our acer-cope rearrangement within this structure. I think that is clear.

Now, as an exercise, please try to figure out what is the structure we have to start from to get to this one via an acer-cope Mannish reaction.

Okay, once again, basic principle of the acer-cope Mannish reaction. This is the retron. If we have identified the structural subunit, we can, as a retro-synthetic approach,

or make two transformations, first a retro Mannish, then a retro-cope rearrangement.

You can use numbers attached to the general scheme, helping to find the solution. Well, let's try it just with that structure within the Mannish reaction. Yet here we iminium cation, there we enol, forming this C-C bond.

So, retro Mannish, enol here, iminium cation there, and the arrow group at this position.

So, for retro-cope, then, we have the hexadiene system there.

And, well, sometimes it's just easier to draw that again.

And now, well, this bond, double bond, changes to a single bond.

This also to a single bond, moving in this direction. This is broken, and this position is connected with that one.

Okay, and of course, the cationic charge remains in there. This drawing doesn't look nice, of course, we have a five-membered ring here. So, let's draw that again, allylic alcohol, iminium cation.

Okay, so, and indeed, this structure should rearrange to this one.

So, let us discuss how one could synthesize that one. Well, just following the synthesis, actually the enantioselective synthesis by Larry Overman's group.

He started from cyclopentene oxide, letting this react with the easily accessible secondary amine, enantiopeure.

Well, they methylated that, actually it was an aluminate. And next step, it reacts with the epoxide, giving rise to an amino alcohol.

Actually, two enantiomerically pure diastereoisomeric amino alcohols.

So, because it can react here, or it can react there, as a nucleophile.

Therefore, these two, again, pure enantiomers, but, well, mixture of diastereoisomers.

In the ratio, approximately one to one were formed. But since these are diastereoisomers, they have different physical properties.

And they could easily be separated by chromatography. So, and by chromatography, this one was isolated with a 43% yield.

That's just fine, okay? You can't get more than 50% of that with that cycloselectivity. Well, next step, treat that with a mixture of potassium cyanide and paraformaldehyde, add some HCl.

Okay, you form, of course, HCN. And, well, you will form an iminium cation, again, of that secondary amine. Oh, sorry, this secondary amine will form aldehyde.

And, again, this iminium cation is an electrify. Where do you have a nucleophile? That's the cyanide. That iminium cation is trapped by the cyanide. And you end up with a 92% yield of this structure.

Next step, swirn oxidation. Very well known type of oxidation. Very reliable if you have dried all your compounds, ingredients, thoroughly.

Then you usually get a rather high yield of the carbonyl compound.

In this case, 95% yield are reported. At minus 72 degrees, presumably in THF, an organolithium compound was added.

I have to draw that once again.

This one. The low temperature is necessary because starting with about minus 60 to minus 50 degrees,

also the cyano group is reactive enough for the reaction of the organolithium compound. But we want to add that to the carbonyl group.

Again, excellent yield, 91%.

Well, this is already the setup for the azeocope Mannich reaction as we need it.

We just have to eliminate cyanide. That's all. We can eliminate that. We get an iminium cation here having that azeocope system and the reaction can proceed. Indeed, this elimination of the fragmentation here of that C-C bond is induced by stoichiometric amounts of silver nitrate,

just 25 degrees, 3 hours reaction time,

and that domino process we are focusing on proceeds leading to this product in an 80% yield.

Obviously, this azeocope Mannich reaction as a domino process gives rather excellent yields,

80%, we will later on see other examples, up to 90 or 95% yields are indeed reported. So, for completing the synthesis to crinine, we have, first of all,

to get rid of this essentially chirobenzolic protecting group, just hydrogenating that off, that means hydrogen palladium on car coal,

the deprotected secondary amine is then obtained with a 94% yield.

So, and the next step is then picte-spengler reaction, which then leads us to the skeleton of a crinine with a carbonyl group here, a ketone there,

and well, we have already this bridge.

The picte-spengler reaction, again with a yield above 91%,

then a couple of steps, four steps more are needed to transfer that carbonyl functionalized six-membered ring to an allylic alcohol double bond here and the OH group there.

Four steps are needed, overall yield of these four steps, unfortunately only 26%, and up to that stage we had a 26% yield, we lose another 74%,

but finally, nevertheless, impressive synthesis of crinine was achieved in the early 80s. Next example, so let's just abbreviate that,

we have a BOC, tertiary butyloxy carbonyl amide here, a BOC protecting group,

here we have the allylic alcohol, the amino functionality.

So, first with formaldehyde H+, catalysis, 100, no, not 110 degrees, it was benzene reflux,

then a 96% yield of, well, a rearrangement product that went through that acer-cope-mannish reaction was obtained,

and then, well, a deprotection under basic conditions, somewhat unusual conditions for the n-BOC deprotection,

well, then a pentacycle, the pentacyclic final product, which is already an alkaloid,

which is called the 16-methoxy-tabersonine was obtained.

Well, as an exercise, please figure out that intermediary structure and the structure of the final product. Okay, the solution to our problem, all these are obviously reaction conditions for forming the iminium cation there with this secondary amine.

Well, this iminium cation, the hexadiene, acer-hexadiene system, here we have the OH group,

and let us abbreviate that simply as an aryl substituent. So, now the cope rearrangement will close the ring here and open up that ring.

Now we have here the acceptor reactivity at this position, the donator reactivity, we form the C-C bond from this to that position, and this means that we will have a one, two, three, four, five, six-membered ring again here.

Here's the nitrogen and the five-membered ring here.

There is the carbonyl group and there the aryl group.

Well, actually, this structure I should have drawn within here. This is the one with the 96% yield.

And, well, the aryl group has an amino functionality in the awful position after the deprotection. These are the reaction conditions for the deprotection. Having an amino group in awful position to the arene, that will form a condensation and imine functionality.

So, final product of the reaction sequence, then,

amine functionality with a carbonyl condensation to form the imine.

Okay, indeed, this is the target molecule. Okay, everything correct? Yes, I think so. Final subject, or better, final target molecule of today is this rather complicated structure.

While a compound with a rather bad reputation, this is the highly toxic strychnine. And the Overmans group approached the synthesis of these molecules about ten years later,

compared to the structure we have discussed before.

Well, the structural elucidation originally started in the lab of Wieland and, of course, at that time they didn't have an MR spectroscopy, an X-ray crystal structural analysis.

They had to try some degradation processes and an oxidative degradation led to this aldehyde, which has been isolated.

And this aldehyde is still known as the Wieland-Gummlich aldehyde, as it turned out by a knöwenagel condensation just applying malonic acid in the presence of acetic anhydride.

And acetic acid and sodium acetate, 110 degrees, then a 65% yield of strychnine can be obtained.

Within that knöwenagel condensation domino process involving decarboxylation and then after the knöwenagel condensation you have that lactame formation

and since you have an alphabet unsaturated system initially, also a conjugate addition reaction of the alcohol functionality takes place forming that ether bond here. Therefore, the Wieland-Gummlich aldehyde regularly is an intermediate in various syntheses for strychnine as a target.

And therefore that knöwenagel condensation very often the final step in the complete synthesis.

So, do we have a chance for synthesizing or approaching that Wieland-Gummlich aldehyde by that acer-cope-mannich process?

Yes, of course. Well, we have again that pyrrolidine moiety here, there is an amine functionality but you

can get an amine functionality here at this position by reductive amination of a carbonyl compound. So, let's draw that.

We need a nitrogen here, amino group may be protected somehow. Then here the six-membered ring, there the carbonyl group.

Let's draw two of those retro-synthetic arrows. Nitrogen here, okay. So, this could be an intermediate on the way to the Wieland-Gummlich aldehyde and to strychnine.

So, since here again is the pyrrolidine ring with that carbonyl group and

therefore we have the retron of the acer-cope-mannich reaction within this structure.

Again, let us try that retro-synthetic step now.

Well, this is again a perspective we are not used to.

We should turn that around. Well, let's abbreviate that again as an arrow-group there.

Just turning that around. Well, the retro-synthetic step, then we have a six-membered ring here and it's very similar to what we have already discussed before.

We start with the five-membered ring initially and if you try that step by step

you will figure out that again here the allylic alcohol with an arrow-group is involved.

There, the iminium cation and this cation is now connected with this allylic alcohol or AT here.

Well, okay, this looks still rather complicated and sometimes it's maybe the most important

step within planning a synthesis, finding a more appropriate perspective for drawing the molecule. So, let us translate that. So, an acer-cyclohexane moiety and here we have the iminium cation functionality.

So, and from this perspective you will find as a typical drawing in the publications concerning this synthesis. Well, the transformation from here to that cyclized product also worked, well that worked with a yield above 90%.

However, that is of course a rather complicated structure.

So, it needed 20 steps from this starting material.

Well, initially of course synthesized starting from cyclopentadiene with a singlet oxygen. This older reaction and then of course, well, some further steps to get this enantiomerically pure.

Well, 20 steps from here to there. Then extremely high yields. However, overall yield of the whole synthesis to strychnine was 3%.

Meanwhile, a new record was achieved, a 10% yield for a synthesis of strychnine done by Virish Rawal's group.

But he made use of cycloaddition, Diels-Alder cycloaddition and some palladium catalyzed steps as the key steps of his synthesis. Nevertheless, again an impressive example for how spectacular, complicated structures are made in just one crucial step as a domino process.

And well, we will finish for today.

Next week, Wednesday, we will go on with magic Manich part 2, targeting some reactions, Manich reaction combined with cycloaddition processes from the lab of Clayton Halfcock.

It's a synthesis of Daphnophilum alkaloids. Thank you for listening. See you next week.