Welcome to part six of a lecture on designing organic syntheses. In the preceding lesson, we focused on one-two difunctional compounds, especially on amino alcohols.

So in general, alcohol functionality and one position further on, we had an amino group. Could be a primary, a secondary, or tertiary amine.

Means R's might be hydrogen, or alkyl, or aryl, or maybe acyl.

So might be other substituents attached. This is just the general structure. So and there are various ways to get to this situation. Well, for instance, from the corresponding nitro compound,

just by reduction, and then an acylation, or alkylation, or arylation. This is also possible, of course. So where does this derive from?

Well, we need a carbonyl plus nitromethane, or a nitro alkane. Under basic reaction conditions, we will observe, hopefully,

the nitroaldol addition process. Alternatively, we could start from a amino acid,

and reduction with lithium aluminum hydride will deliver the corresponding amino one, two, amino alcohol.

Or we had examples where we made use of an epoxide as a reactive functional group, which then is treated

with an amine. And an alpha bromo carbonyl compound, also treated

with an amine, will give an alpha amino ketone, or alpha amino aldehyde, which then subsequently might

be reduced to the alcohol. So that is done in two steps. We get to a structure like that. Well, here, in this case, with an alpha bromo carbonyl

compound, we also have already a one, two difunctionalized compound. So in general, let's have a look

how to set up something like that. OK, halogenation in alpha position of a carbonyl group.

Of course, in this case, we would have to face a selectivity problem. How to distinguish between this and that side, of course. Well, and here, for instance, the disconnection

we could plan at between these two carbons, and rather simple, let's take an acyl chloride on the one hand, and an organometallic species on the other hand.

And the acyl chloride then, as you know, has the advantage that we get relatively clean one to one reaction, whereas with an ester, for instance, the intermediate ketone is then generally more

reactive against a reaction with an organometallic species than the starting ester. Then you preferentially have a one to two product.

Another general scheme for setting up

a situation like that, one could think about starting from an olefin,

making use of a simple addition reaction to the olefin. Well, it should be used to that if you imagine that this could be, for instance, an interhalogen compound, for instance.

Of course, you would also have to face a selectivity problem. In that case, how do you make sure that the X part ends up at this position and not at the other one?

So let's change to 1,3-difunctional compounds. A very simple but highly interesting example

is this one. Let's start a retrosynthetic analysis in that case. Well, OK.

We could disconnect here. And then we would have this oxygen with a donator functionality, this synthon. Well, sodium methanolate would

be the compound that shows that reactivity of that synthon. But how do we get this one with an acceptor reactivity here?

If we would have a leaving group and halide as a leaving group there, then this compound already would give a poly-condensation product, of course, because you have that nucleophilic center within that molecule.

The same result or similar result we would get if we make the disconnection here.

Here, acceptor reactivity, and there then the donator reactivity. Well, let's take ammonia.

So the synthetic equivalent could be something like that. But how do we get this bromide? The bromide sitting at the terminal carbon

might not be that easy to get hands on. So there is a rather simple solution. Change the oxidation state.

This is part of functional group interconversion as we call it. So change oxidation state of that carbon.

Let's take a nitrile, and by reduction we can get to the amino group. And now it's really easy because this derives from a conjugate addition reaction of methanol

to that cyanacrylate. No, it's not this. It's acrylonitrile, cyanoacrylate.

Well, you know what cyanoacrylate is? That are compounds like that specially used for glue.

OK, so this is the rather simple solution for setting up a 1,3-difunctional compound like that with an alcohol or an ether functionality

and an amino group there. Other examples for 1,3-difunctional compounds very well known for you is, of course, this one.

Well, deriving from the aldol addition reaction of this ketone and that aldehyde.

If R prime has alpha acidic hydrogens, then of course

you have a selectivity problem. This would become more reactive for the deprotonation and will be then the nucleophilic center, which will react with the carbonyl group, with the higher carbonyl activity.

And this is, again, the aldehyde. We already addressed that problem in the lecture about stoichiometric organometallics. An alternative is this one with this SS ketal,

this thioketal. And you remember that reactivity unprolung involved

in this retrosynthetic plan, and of course in that synthetic step initially developed by Dieter Zebach.

So that lithiated dithioketal could react with an epoxide and will, of course, give then after hydrolysis

this intermediary product. And after treatment with mercury oxide, it's then possible to get to the ketone. OK, a 1, 3 amino alcohol you might get also

with involving a functional group interconversion, say a reduction of that ketone.

And this could derive from the alpha beta unsaturated ketone by a conjugate addition reaction.

So and this obviously seems to be a aldol condensation product, but not necessarily. There are other methods to set up alpha beta unsaturated ketone like that.

Well, for instance, some special Wittig type reactions, as you should know.

A very nice method for also setting up those 1, 3 amino alcohols, especially

if you want to achieve that Heide diastereoselectively is by reducing such a heterocycle, which

you can easily get as a racemate by a cycloaddition reaction of an olefin

with a nitrile oxide.

This is a nice example of a 1, 3 dipolar cycloaddition reaction, also known as Hüsken cycloaddition.

So the final step is just reduction,

for instance, by sodium borohydride has sufficient reactivity for this simple transformation.

1, 4 difunctional compounds.

Let's talk again about an amino alcohol, a 1, 4 amino alcohol. You could get that in principle from that type of ketone.

But be careful. This could give a condensation product like that.

And here, the idea is not only applying one functional group interconversion, but two, also changing the oxidation

state here. And then it's simple. A Michael type addition process, conjugated addition process under basic reaction conditions

with nitromethane corresponding carbon ion as a nucleophile. And I think, hopefully, it should be possible to directly reduce this to the amino alcohol

without having to isolate those. And if a reduction is faster than that condensation process, you have good chances to get to that product.

Here, an interesting case where you have already

two, 1, 4 relationships. 1, 2, 3, 4. And again, 1, 2, 3, 4 here.

Also an interesting idea to get to a structure like that,

changing oxidation states of various positions. Let us get to a higher oxidation state here and to a lower oxidation state here at this position.

Since this trans isomerization might not be a big problem,

we could think of this lactone as intermediate in our synthesis. And now this intermediate offers the idea

to have methyl vinyl ketone as one starting component. And this moiety as a nucleophile

means an ion here. So and just write down tautomer like that.

Highly nucleophilic there, electrophilic here. Conjugate addition process.

One more idea for setting up a 1, 4 relationship between functional groups.

Olefin plus dichloro ketene. Dichloro ketene is preferred because it's more easily accessible than the parent ketene.

Just treating dichloroacetic acid chloride

with an appropriate base. Some tertiary amines are mainly applied for cases like that. And I think we talked about that these ketenes tend

to give a 2 plus 2 cycloaddition product, forming indeed cyclobutanones.

You can get rid of the chlorides by reduction.

And now with the biaviliger oxidation, treating it with a pear acid, you will get to the lactone.

And also lactone like that has a 1, 4 relationship

between functional groups, this position and that position. 1, 2, 3, 4, of course. OK, it's time to go to examples for 1, 4

difunctional compounds.

For one of the interesting examples, we need an allylic alcohol. And well, you can get to an allylic alcohol

from an aldehyde and a vinyl metal species, vinyl lithium or vinyl magnesium halide. An oscillation of that allylic alcohol

leads to this interesting compound, which enables you to perform an Ireland claysen rearrangement.

So deprotonating here, maybe trapping it as a TMS,

ester enolate, and while already at rather moderate temperatures, that claysen rearrangement will occur, leading to this gamma delta,

unsaturated carboxylic acid.

With a base in the presence of iodine, you will then observe a Yodo, a Yodo lactonization.

So you have then a 1, 4 relationship between those two positions and a 1, 5 between this and that.

Cycloaddition reactions, again, will also help for setting up 1, 5 relationships.

The first example is a Diels-Alder reaction with singlet oxygen as the dienophile,

leading to such a peroxide. And reduction will lead to this product.

And now I notice that, well, we don't have 1, 5 relationship in here, but exclusively 1, 4 relationships.

OK? Let's see what the next examples will offer. Oh, again, another 1, 4 relationship. Again, a cycloaddition process with this nitroso olefin

as a heterodyne and this olefin as a dienophile.

So and reduction of this heterocycle will reduce the imine functionality

and the oxygen nitrogen bond. Since you've set that up as a cyclic system, the hydride will approach diastereoselectively.

So presumably, you will get a high diastereoselectivity and therefore stereoselectivity for that 1, 4 relationship.

So and please take that example also down within the examples of 1, 4 relationships. So but finally, we will now see an example for, really,

1, 4 difunctional compounds. And again, a cycloaddition reaction. Again, a hetero Diels-Alder process.

So hetero Diels-Alder reaction.

Here we have an enol ether. Hydrolyze that enol ether.

And you will get to that carbonyl compound with the OH group in delta position.

So a 1, 5 relationship. And you can, of course, also get to 1, 5 diols simply by reduction.

Finally, we should have a look at this target molecule as an exercise.

Please try to figure out a route to synthesizing a structure like that. While looking for strategic bonds, certainly this carbon heteroatom bond

is a strategic bond since, well, very often, carbon heteroatom bonds are strategic bonds, as we know. Especially this one since, of course, as a synthon, we would say, well, we should have the donator reactivity here, there, acceptor reactivity,

and acceptor reactivity in better position of a carbonyl group is a good idea since alpha-beta unsaturated ketones exhibit acceptor reactivity in better position. So the first retrosynthesis step, therefore,

is straightforward alkyl functionality here. There, that olefin alpha-beta unsaturated ketone. OK.

On the other hand, you can nicely set up alpha-beta unsaturated ketones. We talked about that already today. Aldol condensation or Wittig type

that Horner, Watsworf, Ammons, Wittig type reaction. So I'll take it simple, that ketone,

and this functionalized furan as the second component. You might observe some difficulties

since compounds like that have the tendency to form these hemiacetals, but in equilibrium.

Well, then, as always, there are normally several ways

to get to a target. But one idea in this case would be, well, let's make the disconnection here,

having this epoxide as one component, and for instance, acetic acid, acetoacetic acid,

ester, as the other component. You can nicely deprotonate here since it's double activated, reacts as a nucleophile

after hydrolysis, while ethanol is formed and it will decarboxylate as a beta-keto ester. And then you have set that up.

Could be a good idea. While one would have to make a literature survey about that epoxide, for sure, this will be very sensitive since,

under the influence of Brunstedt or Lewis acids,

this epoxide will easily open up since this carbocation iron is even more stabilized than a carbocation iron at the benzylic position, of course, because the furan is even more electron rich

than a benzene ring. So I think this is enough for today. Tomorrow, we will again have a look at 1-N relationships, but especially for dicarbonyl compounds.

So we will analyze the situation with 1-2 dicarbonyl compounds, then 1-3, 1-4, 1-5, and even how to set up 1-6 dicarbonyl compounds. Thank you for listening. See you tomorrow.