My biggest complaint about the Science & Nature section is a distinct lack of organic chemistry. So I thought I'd take it upon myself to change that, and create a thread where I hope to summarize a cool synthetic study once in every while (spare time & motivation permitting). The advantages I see (beyond satisfying my own interest and learning a thing or two along the way) is bringing interesting synthetic research to people who don't have access to scientific journals (probably most of you), and hopefully to stimulate conversation about the exciting field which currently garners very little discussion here. Who knows, it could interest no one else but me, but it can't hurt. So I will start with a recent paper published in Organic Letters by the Gademann group from the University of Basel, Switzerland, outlining their elegant and protecting group-free syntheses of taiwaniaquinone F and taiwaniaquinol A. These two natural products belong to the taiwaniaquinoid family, which are diterpenoids boasting unique 6-5-6 tricyclic structures. These have attracted wide interest from the scientific community, and their biological activity is noteworthy (including potent cytotoxicity against epidermoid carcinoma (KB) cells). The former statement is exemplified by the fact that this paper I speak of was published only weeks prior to a second publication from an independent group in Shanghai who published their own synthesis (which I will not cover*). Gademann initiated the syntheses of both from the commercially available (-)-abietic acid (which is a major constituent of resin from pine trees, is what violinists rub on their strings, and conveniently possesses two of the required stereocenters - chiral pool strategy). This was converted to the natural product (+)-sugiol methyl ether in 36% yield over nine steps on multigram scale, following literature procedures. This intermediate was then diazotized using p-acetamidobenzenesulfonyl azide (p-ABSA) and DBU (a base), to lay the foundations for the first key step in the total synthesis. With the diazoketone intermediate in hand, Gademann employed a Wolff rearrangement. Here, the carbene intermediate generated from light underwent a particularly interesting ring contraction (I attempted to show the mechanism), thus establishing the 6,5,6 fused tricyclic scaffold together with the connected carbonyl group as a methyl ester. Indeed, Wolff rearrangements are catalysed by light, the source of which was a mercury lamp here (presumably the fastest acting source), but the author noted that the reaction proceeded under sunlight with identical results - remarkable (and more on solar power to come)! Although the reaction proceeded with 20:1 diastereoselectivity, the unwanted isomer was favoured. In English - they got the mirror image of what they desired. The author suggested that was due to steric effects, whereby protonation occurred at the less hindered face of the molecule leading to the unwanted isomer. Unperturbed, the chemist(s) treated the methyl ester with sodium methoxide in methanol under microwave irradiation (100 degrees Celcius), effecting epimerization (flipping the group pointing the wrong way to the right way) to provide the desired diastereomer (not the mirror image) in quantitative yield, with a diastereomeric ratio of 33:1. This compound was further reduced with lithium aluminium hydride to the corresponding alcohol in quantitative yield, setting the stage for the next key step in the synthesis. I'd like to note that lithium aluminium hydride (LiAlH4) - affectionately known as "LithAl" by many including myself, is one of my favourite lab reagents given how reliable it has been to me (and to Gademann, giving him a 99% yield, beautiful stuff). But it is a force to be reckoned with - a previous member of my lab received 3rd degree burns to the face after stupidly cleaning out a plastic bag covered with it, using methanol. Methanol + LiAlH4 = raging fire. Anyway, back to the story now. With the requisite alcohol in hand, Gademann could employ standard procedures to brominate the ring, which would then undergo a notably succint oxidation to the phenol using dioxygen (a stream of O2 is bubbled through the reaction mixture) with n-BuLi (a very strong base) and TMEDA (a ligand to activate the aforementioned base). This novel approach is particularly attractive as standard procedures would employ a relatively clunky hydroboration strategy, which the author originally sought, before developing this simplified method. A second oxidation to the quinone again employed dioxygen, alongside Co(salen) - a cobalt ligand that acts as a vehicle for oxygen. It should be noted that these steps and purification of the light-sensitive intermediates were carried out in completely light-free conditions. I can tell you that it's particularly frustrating when dealing with light sensitive compounds... chemistry is hard enough in a brightly lit room, so my hat goes off to the poor bastard who did all of this in the dark... particularly the purification part, as this was carried out by conventional chromatography. I imagine that they used brown glass columns. All that stood between Gademann and (-)-taiwaniaquinone F was a simple oxidation of the hydroxymethyl group to the required aldehyde, which was carried out in quantitative yield using Dess-Martin periodinane (DMP). The story does not end here, however. As what I (and likely the authors) find to be the most novel aspect of this study is the conversion of taiwaniaquinone F to taiwaniaquinol A. As I mentioned, synthesis of intermediates in the previous diagram were marred by light-sensitivity. The keen chemist(s) performing these reactions did not overlook the fact that one impurity's NMR had a striking resemblance to taiwaniaquinol A! They leapt upon this observation by intentionally exposing an ethereal solution of the light-sensitive taiwaniaquinone F to sunlight, remarkably affording a 30% yield of taiwaniaquinol A. Mechanistic insights into this transformation are forthcoming from the authors, however they postulate that an elaborate C-H functionalization takes place, whereby an alkoxy radical (generated by irradiation) may participate in a 1,5-H abstraction of the methoxy group. In other words, the oxygen radical rips off one of the hydrogens attached to the nearby methoxy (OMe) group, forming the bridgehead. However true that might be, it is clear that this natural product readily undergoes photolysis to furnish a methylenedioxy group in one way or another - without the use of any complex materials or protecting groups, just sunlight will do. The authors acknowledge that this is quite likely the mechanism employed by Mother Nature - which is corroborated by the fact that taiwaniaquinol A is present in the leaves of the producing tree (Taiwania cryptomoides), whereas taiwaniaquinone F is only isolated from its roots. This entails that other non-enzymatic biosyntheses of these methylenedioxy-containing natural products could be occurring elsewhere, too. And that concludes my summary of this elegant natural product synthesis. I'd like to again acknowledge that this is purely for a little education, and of course all credit goes to the authors of the original publication (which I did not plagiarize, everything here was reproduced honestly). I hope someone out there enjoys this chemistry as much as I did, and hopefully I'll produce another story from the literature in time. *When I originally conceived the idea to cover this synthesis I was unaware of this paper. Those chemists were unlucky as they were writing their manuscript when Gademanns' paper was published, and did not manage to take prize for being the first to synthesise taiwaniaquinol A (Gademann earned that). Their synthesis is impressive, though. They went a step further and started from the extremely simple precursor 1,2,4-trimethoxybenzene, rather than 'cheating' with a chiral pool precursor like abietic acid. Furthermore, their synthesis is divergent and accessed not only taiwaniaquinone F and taiwaniaquinol A, but also taiwaniaquinols B and D. Interestingly, they too arrived at a nearly identical Wolff rearrangement step discussed here, however they found difficulty with methanol and opted for the benzyl derivative. Their synthesis suffers in that it is racemic, and is certainly not as sleek as the approach I outlined above (no bromide-oxygen exchange or sunlight-induced C-H activation!).