Two to tango? No you just need a cation!


Winne, J. M.; Catak, S.; Waroquier, M.; Speybroeck, V. V. Angew. Chem. Int. Ed. Early View, Sept. 9th 2011.


It feels like a century since the last time I’ve posted a review (even though it’s only been two weeks or so). So much has happened in those two long weeks. First, I’m nearing completion on the project started by some of the undergrads this summer. The yields are high and everything is falling into place (which is unusual for chemistry, because there is usually a pitfall lurking somewhere :P). We only have a few experiments left, to which I am enlisting the aid of another grad student in our lab and one of our undergrads to help finish it off. In the meantime, Mike and I will be able to return to working on our collaborative work with Dr. Tilley. Our goal is to have several high impact publications in by the end of the year. Our paper with Dr. Fenteany (which you all have been hearing about for ages now) will finally, finally, finally be submitted shortly. So, I am hoping to have at least four papers with my name on it in big journals halfway into my second year. I’d say that would be a pretty awesome accomplishment (though obviously not even close the amazing Dr. Phil Baran)! But really, there is nothing like finishing up a project (it’s a very freeing sensation). The best part? I have plenty more ideas to try both based off our collaborations and of my own design.
It wasn’t until recently did I really begin to appreciate the importance of total synthesis. Now don’t get me wrong, I always thought it was cool (though in many cases impractical considering the cost of scaling up and the sheer number of steps) but after some conversations I’ve had with other grad students in other groups, I have seen the light so to speak. Total synthesis, in many ways, spawns new methodologies. Suppose you need to need to insert a halogen into your molecule for some reason. Well, you try every method in the book and nothing seems to get you to your goal. You’re options are take a huge detour in your synthetic plan (or even scrape it and start over) or develop your own way for getting that desired functionalization. Now the latter may not be the best path but occasionally it is and leads to some awesome methods. Moreover, methods themselves can spawn new methods. Suppose you want to test a theory on a particular class of substrates. Well, turns out that class of substrate doesn’t have many viable synthetic routes. So you develop one and get a small (or possibly large) paper out of it. I guess that’s what I love about organic chemistry, how interconnected everything is and, most importantly, how creative you can be! But enough philosophy, onto the literature!

This week’s article comes from Organi…I mean Angewandte Chemie (phew, a change of pace). If you ask most organic chemists, especially classical trained ones, what their favorite reaction is invariably you will get a high percentage that say the Diels-Alder. Diels-Alder reaction are especially good for those in the realm of total synthesis. They are usually pretty simple, they often introduce several stereocenters, and they can be extraordinarily selective. Even better, they have a great atom economy (especially if they are uncatalyzed thermal [4+2] reactions). I’ve done several Diels-Alders since coming to grad school and I always enjoy them. A less common (but gaining popularity) type of cycloaddition is a [4+3] annulation. In their most basic form (and here’s a great link to learn about them), these reactions involve allylic (or oxyallylic) cations (as the “dienophile” equivalent) and a simple conjugated diene. Stereochemistry is difficult to control in these cycloadditions and terminology is somewhat different in [4+3]s, particularly when dealing with cyclic dienes. Take my favorite cyclic diene, cyclopentadiene or Cp. If the methylene in Cp aligns with the substituents off the allylic cation system in a cis relationship, the reaction is thought to have proceeded through an extended (exo) transition state. If they are found to be trans, the reaction proceeded through a compact transition state.



Cyclic dienes, like our friend Cp, tend to favor compact transition states. The amazing (and synthetic useful) part about [4+3] is the fact that they spit out hard-to-generate 7-membered ring products. And that is where Winne and his group come in. Some time ago, Winne reported on an approach to the synthesis of rameswaralide, a polycyclic diterpene isolated from Indian coral. In his approach, he stumbled onto a highly selective, high yielding [4+3] reaction between a putative furfuryl cation and a diene during a deprotection step.



Winne decided to revisit this to see if this observation could lead to a broader methodology for the construction of elaborate bicyclic or tricyclic systems. As a further experiment, Winne wanted to know whether the reaction was simply a [4+3] reaction or a much rarer higher order pericyclic reaction, a [6+4]. What I really enjoyed was the fact that Winne was open to the possibility of utilizing computational support to back up his findings and states so from the beginning of the article. To me, if you have the capability to use computational model to support your claims, why not use them?

So to begin their study, they took the simplest (and cheapest) furfuryl cation source, furfuryl alcohol in combination with Lewis acids (TiCl4, TFA, TMSOTf). Unfortunately, this didn’t fair all that well for them. While they did generate the cation they “…invariably observed a swift polymerization reaction to give a black tar” much like all my experiences with furan and Lewis acids. However, once they blocked off the 5-position (to inhibit polymerization) they actually managed to get product (only 17%, but hey, better than nothing!).



With this initial hit, they decided to stick with a stoichiometric loading of TiCl4 as a Lewis acid and modify some other reaction conditions. They found that increasing the substitution pattern at the carbinol and using a 2:1 ratio of the diene to the furfuryl alcohol improved their yields substantially. At first, they stuck simply with cyclohexadiene, but then they began to choose other dienes (Cp, furan etc., some of which were elaborate (such as (+)-nopadiene). Yields were reasonable and dr was surprisingly good, favoring the exo diasteoromer on a number of substrates.



To get a good idea of how the cyclization was occurring, they combined some density functional theory (DFT) with some practical organic know-how. They initially ruled out a 4- or 6- exo trig– cyclization due to the fact that the products would be unable to aromatize without rearrangement of the carbon skeleton (and no rearranged products were detected). However, 5- and 7- endo trig as well as a concerted [4+3] pathways were all equally viable. By using DFT, they ruled out the 5-endo trig path as being too high in energy, and hence a 7-endo trig would be preferred if the reaction was not concerted. Moreover, they found that the energy of the concerted path was 3 kcal/mol higher than the stepwise pathway. While this does not preclude this path, it makes me believe that an asynchronous path is more likely.
I really enjoyed this article (mostly because I really love cycloaddition reactions) and I have a funny feeling we will be seeing this method utilized more often. Hats off to Winne and coworkers on an excellent job! That’s it for now, Ckellz…Signing off…

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Two new ChemSpider pages!

So when I had a fraction of a second of free time, I wanted to do something relatively enjoyable but also productive. So I decided to submit two of my procedures to Chemspider’s synthetic pages. Here are the links:

Link 1: Esterification Procedure

Link 2: Silylation of Phenylacetylene

Both of these reactions gave excellent yields (though they aren’t the most complicated in the world). As a note, the esterifcation procedure is probably the best I’ve used and it works with most esters I’ve made! Hope you all like them!