Welcome to part 27 of the lecture on designing organic synthesis. Well, you already have noticed this exciting molecule drawn to the blackboard.

It's brevetoxin, brevetoxin B. And well, you can call that as some kind of one of those 8,000 mountains in natural product synthesis. Well, it's not actually the Mount Everest, maybe polytoxin with 64 stereogenic centers is the Mount Everest.

However, this with lots of annihilated oxygen heterocycles and well, if I see it correctly, 23 stereogenic centers is quite a nice target for a natural product synthesis.

Could be a nice target for an exercise or just kidding. We will try to analyze this structure, not completely, but that you get an

impression how one can solve a problem like this within terms of retrosynthetic analysis. Well, what kind of natural product is that?

It is connected to the so-called red tide, toxic algae, phytoplankton, very often with a red color but not always, lots of fish dying and well, caused by this poisonous food and it is a neurotoxin.

Well, it facilitates passing cations like potassium and sodium cations through cell membranes.

Well, okay, let's have a look at strategic bonds. First of all, one should look for strange, annihilated systems and here we see, well, there is an eight-membered ring.

Eight-membered rings always somewhat a problem in synthesis, you know, the problem with the formation of medium-sized rings. And here we have two seven-membered oxygen heterocycles.

So, first of all, let us have a look how one could synthesize a moiety like this.

And actually, new methods have been tested by the group of Casey Nicoleau at the Scripps Institute. I think at 1995, this synthesis was completed.

Let's have a look at the model reactions, modeling the formation of this type of structures. Two seven-membered oxygen heterocycles with two six-membered rings, annihilated.

We can easily imagine that it is not that of a problem synthesizing an ester like that, even as a macrocycle with two of those ester functionalities.

And now a reagent comes into play, which is called Lawson's reagent.

Well, at least I know that reagent because I worked with that during my own doctoral thesis. It's a bit smelly. Let's draw the structure in hydrolysis of Lawson's reagent.

Of course, hydrogen sulfide will evolve.

And with this reagent, you can nicely achieve an oxygen-sulfur exchange at a carbonyl group.

It's a bit related to Wittig-type reactions, where you exchange the oxygen of a carbonyl group by a carbon.

And here is sulfur. And this works rather nicely twice in this case. So let's draw that structure once again, just with thioastes.

And now the next step is a photochemical reaction performed in toluene, a solvent, but this is not that important.

And a 2 plus 2 cycloaddition reaction will take place.

So, well, just let us skip the time-consuming drawing of all those stereogenic centers.

The C-C bond has been formed all within that four-membered ring with two sulfur hetero atoms. Well, actually, this moiety is called a dithiothane.

And it's not very stable, as you can imagine. Either the thermal, just heating it up, or photochemical irradiation, then the S2 molecule is eliminated.

And then we have that C-C double bond, very electron-rich olefin.

Well, then we just need to hydrogenate this double bond. But before we talk about that, let's add the yields, which have been achieved 75% for that double thioester formation.

Well, approximately 65% is this transformation. And 90% yield was isolated from this olefin.

So, again, now for complete the model study, we would have to hydrogenate that. But have a look at the stereochemistry. It should be a trans-hydrogenation.

Of course, that is a problem. With transition metal catalyzed hydrogenation, this presumably won't work. So, therefore, the Nicolaou group changed the model study a little bit, skipping the macrocyclic system,

performing the photochemical transformation with this structure, having then the seven membered heterocycle here.

Well, and now it's clear, after an elimination process, hydrolysis of this system, we will get to this type of ketone.

So, after hydrolysis, we of course have the alcohol functionality here.

Well, and now we have to achieve this final transformation, hopefully stereoselectively, diastereoselectively.

Well, this transformation, well, obviously there is something like an hemiacetal formed. A bit, it reminds us of an reductive amination.

Well, we would have an amino group here, imine formation and reduction. So, in this case, it is similar. With TMS triflate, we will trap the hemiacetal, and in addition, with the silane, we can achieve the reduction.

So, while this step to that electron-rich olefin works in a 66% yield, and hydrolysis rather cleanly with a 95% yield,

then the final, well, how do we call that, or maybe a reductive ether formation, this step works also rather nicely with an 88% yield.

So, as I said, this is a model study. The real target needs, of

course, functionalization on this side and on that side, and the additional methyl group here. Again, back to the complete structure of a molecule. We were talking about the formation of this bond, that bond, here initially it was that ester

formation, and here in that final step, and by the photochemical process, that C-C bond was formed.

So, that means we now have that partial structure and the other one. So, let's now concentrate on this part of a molecule.

Well, here we have an olefin, a cis-olefin, and this cis-olefin formation with cis-selectivity, you rather nicely achieve by a Wittig reaction.

So, the idea is Wittig reaction for that double bond, and, well, later on we will see

that this is the other bond, well, that should be, its formation should be studied by model studies.

And here, the so-called hydroxy-dithioacetal cyclization was chosen as the method to form this bond.

So, let's have a look at the model study for this reaction. Here we have the hydroxyl group, that cis-olefin formation works just fine, as I

said, with a Wittig type reaction, and here we have this S-S acetal, dithioacetal.

Now you have to activate one of those thioethyl groups as leaving groups, and this works with N-chlorosacinimide in the presence of silver nitrate.

Okay, you have in addition a base that rutidine and molecular sieves, three angstroms, angstrom molecular

sieves, some silica gel and a solvent, a C2 nitrile, but then moderate reaction conditions, 25 degrees.

These are sufficient for achieving the activation here without affecting the olefin, and you have a very electrophilic carbon than here.

The cyclization takes place, although an eight-membered problematic ring is formed, an astonishing 92% yield was achieved.

Well, of course, we have to get rid of the other thioethyl group, and this works nicely by a radical chain reaction reductive process.

Trifenyl tin hydride catalytically, this isobis isobutylene nitrile, toluene reflux, 95% yield of the step.

So, the whole combination for this cyclization and reduction above 85%. Great reaction, and of course this is necessary for a rather tedious synthesis of that whole molecule.

So, okay, now we know we could build up this eight-membered ring, of course having some protective group chemistry here.

Well, and these three rings, this is called the ring A. You know from, for instance, steroids, rings A, B, C, D.

Also here, A, B, C, D, E, F, G, H, I, J and ring K. So, the target now, which is in focus, is a structure like this.

This should be ring I, having an aldehyde functionality here for the Wittig process, and that dithiocetal at this position for the cyclization we have just discussed.

Here then, ring K with a silo-protected alcohol functionality and another sidechain.

And it is certainly clever to avoid leading this extremely sensitive and reactive moiety throughout the synthesis.

You want to get this introduced in the last steps, in the final steps of the total synthesis.

So, having just a protected alcohol functionality here should be the right choice. And one should choose different silo groups here that you can selectively de-protect one of those.

So, now this is the target we will now discuss. And the NicoLau group had the idea for a bi-directional approach.

We started with an easily accessible natural product, having already quite a lot of the stereogenic centers provided.

So, and well, we started with a carbohydrate. So, this should become ring K.

We don't need to define that anomeric, the stereo configuration at the anomeric center.

Having a look at the target compound, for sure we have to get rid of this OH group.

And we have to add, well, to make a CC bond here at the anomeric center. So, indeed classic carbohydrate chemistry was applied, protecting those two alcohol functionalities just as an acetone.

Introducing an allylic side chain here at the former anomeric center.

And protecting the silo group, the hydroxyl methyl group. Few steps, 62% yield.

How to get rid of this OH group? Reductively, and we again decided to use a radical chain process. First, functionalization of the alcohol moiety as a so-called thioimidesolate.

Which is then, this time with tributyltin hydride as a reducing agent. And again, with the start of the radical chain process, radical chain reaction.

This achieves the important step to get rid of that hydroxyl functionality.

66% yield, quite nicely. So, we will skip a couple of steps until the stage of this intermediate, what happened meanwhile.

Nothing changes here. And, well, they had to introduce that methyl group.

This is done by hydrolysis of the acetone functionality. Somehow selective protection of the benzyl group of this oxygen.

Oxidizing this OH group then to the ketone. And then methyl grignon or methyl lithium will introduce a methyl group. Here again, in those analyses, introduce the carbanile functionality.

So, you have the oxygen here. This is the oxygen. And then, with a couple of more steps, this functionalized side chain was introduced. And now this is set up for a simple conjugate addition process.

Well, this is K and then forming the ring J. Well, unfortunately, during this couple of steps they were losing quite a lot of material.

And overall yield through these steps of approximately 7% was achieved.

Well, nevertheless, the next step that conjugate addition process works again nicely with 92%.

So, with this intermediate, while all reactive functionalities are protected except the ester.

And therefore, we can reduce the ester until the stage of the aldehyde with a reagent which transfers just a single hydride.

This is preferentially this diisobutyl aluminum hydride.

Again, this is ring J.

So, now with an aldehyde functionality, again a Wittig reaction, maybe some Wittig-Hohner type process,

some additional redox chemistry was necessary to get to the following stage.

Epoxide here, meanwhile a chain elongation, one, two, three, four.

So, at this stage the next cyclization was achieved.

And we now should draw the structure we then have. Then the hydro, the pyrane ring I is completed.

J we already had. Also the K ring. Okay, so let us compare now this structure with the one we had discussed before we need as an intermediate.

So, what has to be done except final deprotection?

And, of course, an elongation and modification of this side chain as we discussed before. This should be within the final steps of a total synthesis.

Well, one has to oxidize this secondary alcohol to the ketone and then form the dithiocetal.

And, in addition, an ozonolysis of this alpha-beta-unsaturated ester will lead to the aldehyde at this position. Okay, that's it. Well, overall what we have discussed is how do you get by considerations of retrosynthetic

analysis for two, well, this as one port, this as the second one over here.

How do you get this ring form, that ring form? And then we have had a closer look how to construct these three annihilated rings.

And the method for synthesizing these two annihilated rings and these three annihilated rings are rather similar to what we have discussed before. I think this is enough as an impression how to target a molecule like that.

What you need is, of course, a lot of skillful doctoral students, moreover, post-docs. And if we count together all the years, over all years.

So, ten post-docs working one year each makes ten years. Well, to my knowledge it was once calculated for the synthesis of polytoxin that Mount Everest synthesized in the Kishi groups.

Well, over all 300 years of hard work were needed in the lab to synthesize polytoxin, if only one person would have done it. So, somehow between 30 and 70 persons are very often involved in projects like that.

So, now you have an impression of doing so. Well, it could be fun. Nevertheless, we finish that type of synthesis and we'll discuss next

Friday some additional examples of olefin metathesis in natural product synthesis. Since this reaction, as we have already discussed at one example, has somehow revolutionized the way how natural products and other interesting targets are approached.

So, thanks for listening. See you on Friday.