Friday, May 30, 2014

Donor-Acceptor Cyclopropanes

Now this one is not my area of expertise... but it's closer than carbon-fibers, though due to my last job that could be a little debatable. The background for the review is laid out very nicely in simple terms in the introduction, namely that a cyclopropane has a lot of ring strain, and reactions that open up the ring or expand it are thermodynamically favored. Nonetheless, it's quite a stable motif and in general it's hard to to get a simple cyclopropane to react. However, when one carbon is substituted by an electron accepting group, and another one by an electron donating one, then you can draw convincing zwitterionic resonance structures with the ring being open, and now, it's a lot easier to get things to insert inside like a double bond, a keteone, a nucleophile, or an electophile. The possibilities are many and after a very nice introduction, the review quickly delves into the details one well organized topic after another, based on the substrate. It's the donor-acceptor motif that makes cyclopropanes such a powerful precursor for making large ring structures. The use of chiral ligands for a catalyst that can further activate the acceptor gives access to enantioselective transformations and you can obtain something that looks like a complicated natural product from something that looks like a deceptively simple cyclopropane.

It did remind me of my undergraduate organic classes, about how you could certainly memorize the reactions, or you could try and push the electrons around since all of organic chemistry is basically about adding an acid to a base. For the latter two substrates mentioned above, the nucleophile will attack the more positive site on the resonance structure of the donor-acceptor cyclopropane, and hydride transfer will occur to the more negative site to complete the reaction. Even though the products can get pretty complicated, and you often need a pen and some paper to scetch out the right product, it's pretty easy to figure out the mechanism and what is happening. It can get pretty complicated to follow in your head once you get one catalyst activated cyclopropane opening up and inserting into another one, and even though the review does give some intermediates (and in the case of that reaction it is essential to draw one intermediate), you really have to draw it out yourself on paper to see how to get from the starting materials to the product based on which partially negatively charged carbon attacks the partially positive charged carbon on the other cyclopropane.

So, going through the review was a bit hard at first, but eventually it all started to click in my head and I was following electron movement and even the most complicated transformation became easy to follow. That why, despite the awesomeness of the review, Section 3.3. and Scheme 14 is the part that stands out where I got stumped. This is on cycloadditons of alkenes to a cyclopropane to make a five membered ring. There a tin catalyst is used and if the aryl substituting one of the cyclopropyl carbons is electron donating, you get one regioselectivity, but if it's not you get another. I really got stuck on this for a while, because the scheme was suggesting that electronics are a factor, but the aryl is always the electron donating group no matter what the substituent, compared to the acceptor that has two CO2Me groups... surely it is sterics which should be the driving force for the product here? And the scheme doesn't mention the subustituents on the alkene and I was too lazy to look up the original papers... Anyways, I decided that since you get the other product at -30 degrees, then that's where sterics predominate, but it doesn't help that in that case the aryl can't be too donating as well, since you lower reactivity of the cyclopropane. The moment you increase it a bit, you only get the other isomer (even at -30 I assume?). Well eventually, I decided to move on, since thinking about it too much would lead me to look up the original paper and I did mention that I was lazy above. I suppose that my reading through of giant reviews on topics that are not related to mine is not laziness then. Maybe masochism of some sort? Doesn't feel exactly like that though...

Anyways, cycloaddition of nitrones and allenes got me back in the mood, and I found Scheme 15 to be particularly elegant (right below that Scheme 14 that stumped me for a bit). You get a really cool and complicated bicyclic structure of just a plain old cyclopropane with an intermolecular allene addition based on the conditions. The ring enlargement section 4, and especially 4.3, shows how you can get something that really looks like a natural product from a cyclopropane in Scheme 24. It's all really impressive actually, and as the authors mention, a lot of the results are really recent as the field is undergoing a Renaissance. Plus, there are still not many results about making six and seven membered rings (even though there was a section about 3+3 cycloaddition). However, one minor quibble which is very much evident in that last Scheme 24 that I spoke just so glowing about at the start of this paragraph, is that cyclopropanes like compound 115, which lead to complicated products such as 120, are themselves sort of complicated. I'm not disputing that the reactions are very elegant and you can get complex products with lots of stereocenters under mild conditions through the judicial use of catalysts, but, you know. 115 looks really hard to make on its own. Plus a lot of these really complex transformations need an acceptor, which in most of the cases is two CO2Me groups. How are you going to get rid of these methyl ester groups if you don't want them in your final product?

Maybe new ways of making cyclopropanes from metal carbines will become a really hot field in the future and my point will be moot. Or maybe I don't know enough about organic chemistry and it really is not a problem to have all these strange acceptors hanging off of your final product. Whatever the case, I have really enjoyed reading this review and it definitely revived some atrophied part of my organic electron pushing brain mass. Kudos to the authors, a recently tenured German professor and two of his students. I will definitely not be dissuaded to look at paper after I see an abstract with some cyclopropane, a few lines, and some crazy looking complex product, in the future. After all, it's only a simple Donor-Acceptor cyclopropane reaction.

"A New Golden Age for Donor–Acceptor Cyclopropanes
Tobias F. Schneider, Johannes Kaschel, and Daniel B. Werz"

DOI: 10.1002/anie.201309886

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