Two Cyclizations for the Price of One!

Desjardins, S.; Andrez, J.-C.; Canesi, S. A Stereoselective Oxidative Polycyclization Process Mediated by a Hypervalent Iodine Reagent Org. Lett. ASAP May 27th, 2011

After a long overdue break, I am finally back! Not much to report, all I can say is chemistry is going quite well in our lab. Between the 3+ projects I’ve got on my plate, I certainly do enough reactions to keep any organic chemist happy. In fact, this week I did my first Wittig reaction (outside the realm of undergraduate chemistry) for a new project I’ve been working on. As I always say, there really is nothing that can beat old organic chemistry. Old reactions simply just work and they are always cool. Like this one turned a neon yellowish color. The only problem is the dreaded triphenylphosphine oxide, a byproduct that is analogous to a bad case of acne. No matter what you try, it just keeps coming back (or in this case back into your “purified” product). I’ve tried countless times to get rid of the stuff in one swift blow but it’s nearly impossible. There are always those trace peaks in the aromatic region which make you want to smack you head against the NMR computer monitor. The only effective way I’ve found is vacuum distillation (if your compound is low boiling) or running a long column (praying that it doesn’t run with your material). Appel reactions and the Mitsunobu are just as bad. I know you can triturate out the oxide with a ether-hexanes mix, but honestly, it’s just a pain. But that’s enough of an aside for now, let’s hit the chemistry!
Some of the best carbocation work was done in the context of steroids and sterols. Initially, much of the focus of sterol synthesis was as a testing grounds for total synthesis. Two of the classics of total synthesis were Woodward’s and Robinson’s preparations of cholesterol. Robinson started from a dihydroxynapthelene while Woodward used a methoxy-hydroquinone derivative. Both routes essentially construct one ring at a time using the standard tools of their time (condensation chemistry, Diels-Alder, hydrogenation, Michael-addition etc.). It wasn’t until the mid 1970’s that a truly revolutionary methodology was developed by Johnson and coworkers for the simultaneous annulations of 3 of the 4 rings in a steroid system. Johnson was able to take a monocyclic trienyne system (which could be prepared in 5 steps from known materials) and utilize what I could call a carbocation collapse (or a series of electrophilic additions to alkenes) to construct a complex and diastereospecific intermediate relating to the synthesis of methylprogesterone. I find it just a beautiful piece of mechanistic work:

This pretty much kicked off the field of biomimetic syntheses, or syntheses which are inspired by the way natural products are constructed in biological systems. Often in such systems, there are a series of cascade reaction facilitated by proteins which produce an extraordinarily complex compound in near perfect diastereo-and even enantio-specificity. Often by determining how the organism does this, synthetic organic chemists can devise a similar or analogous cascade. And the field of biomimetic syntheses has just been constantly growing. Some of the best names, such as Baldwin or Trauner, have utilized biomimetics to access complex compounds such as terpenoids or alkaloids. In a similar strain, Canesi’s group is interested in using biomimetics, specifically those similar Johnson’s, to access complex materials from relatively simple (and less costly) starting materials. In this particular example he was interested if he could activate enyne-phenols to induce dearomatization and cyclization. This is somewhat unusual considering the electron-rich nature of phenols (which we would expect to serve as nucleophile rather than as electrophiles). However, a whole methodology for activation of phenols to produce phenoxonium ions has been developed by Kita and coworkers starting with their first report of phenolic oxidation in the late 1980s. Kita uses Lewis acidic hypervalent iodide to facilitate phenoxonium formation in situ. In the presence of a nucleophilic species, this undergoes a substitution reaction at the para position. If the nucleophile is already attached to the phenol, cyclization occurs.

Seeking to take advantage of this activation methodology, Canesi and coworkers thought they could induce decalin formation by simple having a terminal alkyne hanging off the ring. They theorized that, upon cation formation, the alkyne would attack in a form of electrophilic addition. However, if you think about it this could be reversible and potentially unfavorable due such a strained transition state. However, the authors argued that the strain would actually be beneficial, in that it would pump up the electrophilicity of the now vicinal carbocation leading to an increased likelihood of solvent capture. Now here is where I was shocked. The solvent they used, which is supposed ideal for this sort of reaction according to Kita, was hexafluoroisopropanol (HFIP). I’ve worked with the stuff and its a great solvent but one of the main reasons I use it is because its extremely non-nucleophilic but very polar. Hence I was surprised to find that their monocyclization not only worked but was contingent on HFIP attack of the carbocation!

After establishing that this reaction works, they decided to screen substrates. They found that substitution at the ortho position with halogens, benzyl, and alkyl groups all were tolerated under their conditions. In fact, the more substituted the phenol core, the better the reaction seemed to go. The authors argued this had to do with oxidation at these positions if they were open. Hoping to increase the scope of their new cyclization, the authors investigated the possibility of extending their methodology to bicyclization.

This seemed analogous to much of Johnson’s work with steroids. Interestingly they found this particular reaction to be highly diastereospecific. However, it was highly dependent on the geometry of the double bond in the starting material. Initially they started with a mixture of (E) and (Z) isomers in a 2:1 ratio. This was reflected in the products in that they got a 1:2 mixture of diastereomers. Hence they developed a route to prepare the (Z) precursor selectively. They found that upon treatment of this isomer to their reaction conditions, they obtained a single diastereomer proving that the reaction was diastereomerspecific.

Overall, I really enjoyed this article. It was more bio-organic than I usual read but if it involves cations chances are I’m in. And this work was extremely well done and thorough. Congratulations Canesi and co-workers!



  1. removing Ph3PO: trituation with ether-hex mixtures is not very efficient. What worked for me in most cases to dissolve the crude product in a small volume of benzene, precipitating Ph3PO by addition of cyclohexane. followed by filtration. You can apply the filtrates directly onto a chromatographic column in hexane-EtOAc gradient

  2. Thanks! I plan on doing a few more wittigs this week so I will def give that a shot!

  3. This very stable arrangement is extremely loathe to be broken during any reactions. This contributes to the substitution reactions occurring and the very reality that addition reactions, i.e. these that would break the delocalised system of electrons, do NOT occur.

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