In this video we'll take a look at the first total synthesis of reservoir drone and two interesting reservoir drone derivatives. During this work we learned some important lessons about our epoxide olefination reaction which gave us a better idea about its mechanism and thus allowed us to do some further optimization. But first things first, what is reservoir drone? You will probably have heard about reservoir drone. It and a couple of other hydroxys stillbans have risen to some prominence as ingredients of red wine to which several healthy benefits were attributed. And who doesn't like to hear that the daily glass of wine isn't a boozing habit but the valiant act protecting one's cardiovascular system? Well, unfortunately we have to pour some water into your wine here. These health benefits seem somewhat debatable. But we are not here to talk about reservoir drone, but reservoir drone. Reservoir drone can be generated from reservoir drone by irradiating it with UV light. This results in a highly fluorescent molecule and the interesting thing about reservoir drone is that there is some evidence that it allows for two photon absorption. Before we start talking about the synthesis, let's have a quick and very basic recap of fluorescence in order to see why this is so interesting. Usually it takes absorption of a photon with quite a lot of energy to excite a fluorescent molecule. In order to revert to the ground state, some energy is usually emitted as heat, so the photon that is re-emitted has less energy and thus a higher wavelength than the photon which was absorbed. That's why we usually use UV lamps to excite fluorescent molecules. However, this is far from ideal for biological applications, as many cells don't really like being smashed with UV light. Two, photon absorption on the other hand proceeds via a virtual state which is kind of halfway between the ground state and the excited state. This means that a photon with less energy is required to reach this virtual state. But from it, a second low energy photon is enough to reach the excited state from which fluorescence can occur. So a longer wavelengths can be used to excite molecules that allow for two photon absorption, which makes res-retron an interesting candidate for a biological label. So, how can we get our hands on it? Res-retron was isolated and named by Kim and co-workers after irradiation of trans-res-retron and isolation by preparative TLC. They also proposed a mechanism for this photochemical transformation. Since the relationship between res-retron and res-retron is not that obvious, we color-coded the relevant parts. Their mechanistic proposal relies on its cis-transitomerization, which is followed by a six-pie electrocyclic ring closure that closes the naphthalene moiety. In order to break up the blue cyclohexadiene, a second electrocyclic ring closure is proposed, which builds up this blue bicyclohexanol. A total memorization to the corresponding ketone generates a classic fragmentation precursor in which the carbonyl group acts as an electron sink and the binologous enol acts as an electron donor. And the product of this fragmentation is only two total memorizations away from res-retron. So, it is possible to make res-retron from cheaply available res-retron this way. However, the synthesis is quite cumbersome and involves large solvent volumes and extensive purification. Therefore, developing a total synthesis for this molecule seemed quite attractive. For this, we envisioned a globally protected intermediate which could in turn be made from enough two boronic acid, derivative and a known epoxide precursor by using our epoxide olefination reaction. This olefination, which was published by us in 2019, relies on the lithiation of an epoxide and sub-sequent formation of an 8 complex with a boronate. The A complex can then undergo a metasent type 1-2 rearrangement which delivers a beta-alcoxy boronate which then undergo some type of zoon elimination upon heating. The cute thing about this chemistry is that the resulting alkene could be turned back into an epoxide again so that it can be applied iteratively. However, there is a problem. In order to get good yields out of this reaction, two equivalents of the boronate precursor are usually necessary. The reason for this might very well be that the alkoxide that results from the 1-2 rearrangement reacts with another equivalent of the boronic acid. That means if the 1-2 rearrangement which could also be catalyzed by excess boronate is as fast or even faster than the A complex formation, one molecule of lithiated epoxide will take two molecules of boronic acid out of the equation. The second equivalent of boronic acid is re-liberated after the elimination but for alkyl substituted alkene that requires heating. And since a lithiated epoxide is a classic carbeneoid, it will certainly not survive such a harsh treatment. This was an interesting challenge for our proposed respiratory synthesis as the NAFTA-LINE building block would be about as precious as the epoxide. But there was some good news as well. The alkene we were about to make was conjugated to an aromatic system. And this should speed up the elimination step and thus re-liberate the boronic acid. We tried this out on a simple styrene derivative first. For this we were able to reduce the required excess of boronic acid ester to only 1.3 equalids. Motivated by these results we then set out to make the required pinnacle boronic ester by heart-vik miara-boilation. While the yield of this reaction was quite good, there was almost no regioselectivity. Which unfortunately is quite typical for this type of substrate. However, separation by reverse phase MPLC gave us both regi-isemis. And only one of those underwent partial decomposition in the methanol water allient. This can be rationalized as the boronic ester in this position can activate a nucleophilic attack on the silo group. Nevertheless, with both of these compounds in our hands, we followed Blonsky's procedure to the required epoxide precursor. And this one proceeds in very good yields. We then reacted it with the appropriate NAFTOT boronator derivative and WOLA got the desired coupling product. While the yield was less satisfying than with the less electron rich test system, we were nevertheless able to get our hands on Reseratrone after globally protection of this olefination product. Similar yields were also obtained for the regi-isemir, which we called iser-reseratrone here. However, since the boronic ester necessary for making Reseratrone is somewhat unstable, it was quite easy to get our hands on the one necessary for making iser-reseratrone. And since the UV spectra of both compounds looks similar enough, we decided to apply our synthesis to an iser-reseratrone derivative that can be used for click reactions and thus might be very useful as a label for biological applications. Starting from commercially available for bromobuterole chloride, we prepared this propagul ketone, which was then protected as an acetyl and converted into this alkene by Lindler reduction. Substitution of the bromide and epoxidation with oxone delivered the necessary epoxide precursor. Since here the epoxide was somewhat more precious than the boronic ester, we felt justified to use a slightly greater axis of boronic ester for the epoxide-oilification. And this led to a 51% yield based on the epoxide. This a-zite derivative might serve as an interesting label since it can now be connected to the alkyne of your choice. We just used phenyl acetylene as a cheap model substrate here, and we were quite surprised by the low yield obtained after chromatography. However, according to mass spec, this was due to partial desilulation of the phenyl ethers under the aqueous conditions. So using a different click protocol or avoiding chromatography after this step might be a good idea. However, global deep protection under acidic conditions worked very well and furnished the desired label product. So if you want to learn more about this chemistry, check out our article available in chemistry open. Thanks to a special deal between Wiley and the University of Dysbook Essen, the article is available free of charge. Talking about money, we would also like to thank the DFG for funding. Without their support, we wouldn't be able to do this research. If you want to read the article, you can find a direct link in the video description below. If you'd rather like to watch another video, why not take a look at the video abstract of the original article in which we described the epoxide olefination for the first time and also talk about its iterative application for making dry or even petrous substituted alkenes. You can find this video behind the left link. Or check out the video on the right, in which we take a more general look into transition metal-free olefination chemistry that employs boronic esters and similar elimination precursors as the ones shown in here.