B.R.S.M. Yield isn't everything

Cycloadditions are great

This is my attempt at answering Rachel Pepling’s call for posts for her blog carnival over at CENtral Science. The theme is 'Your favourite chemical reaction'.

Update: 23/09/11 - removed some of the more egregious grammatical errors.

It only took me a few seconds of thought to answer the question 'What's your favourite chemical reaction', far less than if I'd been asked about my favourite book, meal or album. It's the Diels-Alder cycloaddition, obviously. I reckon I've done well over a hundred of these by now (including three today), and those two names will certainly appear in the title of my PhD thesis. On social media websites I usually list my interests as rock climbing, mountain biking and cycloadditions.[1]

I guess what I like about this reaction, and why it's a mainstay of total synthesis, is that it's a fantastic way to generate stuctural complexity blindingly fast. It can set up to four stereocenters, and you can even take simple achiral precursors and introduce asymmetry catalytically. But, unlike a lot of reactions which are capable of such synthetic leaps forward, it's also generally very  predictable. One of my favourite parts of the history of this reaction is this quote from the seminal paper by Diels and Alder:

"We explicitly reserve for ourselves the application of the reaction developed by us to [natural products synthesis]"[2]

Nice try guys, but the 1300+ papers published in 2010 on this transformation seem to indicate that this request has been largely ignored by the synthetic community. And why not - it's an all round great reaction, probably the hammer and/or duct tape of the total synthesis toolbox. It's also nice that it's named for an advisor and his PhD student, because the people who actually do the chemistry often don't get the credit they deserve. However, despite all of these things I'm not actually going to write about the Diels-Alder reaction here. The reason is that it's just too well known - we even teach it to first year undergraduates. Everyone knows what it is, and how good it is, and I think this carnival is a great opportunity to dredge up some lesser known reactions and hopefully get people thinking about some chemistry that's new to them.

It seems I'm not the first to think along these lines, and SeeArrOh definitely had the right idea with his excellent Crabbe reaction post last week. I was tempted to write about the amusingly named Duff reaction that got my masters student out of a tricky spot last year, or the Hugershoff benzothiazole synthesis, a named reaction so obscure that it doesn't even have a wiki page. And I've always had a thing for the Kowalski homologation. In the end, though, I have decided to stick with cycloadditions and will now tell you a little bit about a much less well known case - the [3 + 2] meta-photocycloaddition reaction of arenes and alkenes (which unfortunately doesn't have a name, as far as I'm aware).

Before I show you what it is, let me explain why I've picked it. I still remember the first time I encountered alkene metathesis as an undergraduate, and the feeling of awe that we chemists could had access to such an apparently magical transformation. I mean, to one beginning their chemical studies the ability to chop and change carbon-carbon double bonds without any activating groups nearby seems completely fantastic. Similarly, I was totally shocked when I saw my first [3 + 2] arene-alkene cycloaddition a few years later in Mulzer's 2009 total synthesis of penifulvin A.[3] It's just such an improbable looking reaction in which a benzene ring can be coaxed into forming two bonds simultaneously to a nearby alkene, also generating a cyclopropane and some of the hardest to draw intermediates you'll ever meet.

As I grew more interested in chemistry and started to read more and more literature I began to realise that Mulzer really was standing on the shoulders of giants when he chose this chemistry, thanks to the brave and ground breaking early studies of Paul Wender. Although the reaction had been known since 1966, I don't think synthetic chemists viewed it as anything more than a mechanistic oddity until Wender showed the synthetic community its power and potential by employing it in his breathtaking 1981 synthesis of α-cedrene. As this site is geared to an audience of  synthetic chemists, and I'd rather show you an example than write a description of the reaction, I'll summarise the route below (which won't take very long at all).

Work began with the preparation of the cycloaddition precursor, which was easily accomplished in a just couple of steps from commercial chemicals. When this was dissolved in pentane and blasted with a Vycor-filtered 450W Hanovia light source then a mixture of just 2 cycloaddition adducts were obtained in a quite respectable yield. This was an amazingly fortunate, although not entirely unexpected outcome as Wender explains in the paper. Let's just think for a minute about what could have been: considering the intermolecular case of this reaction between a trisubstituted arene and an alkene fragment with a single chiral centre then 168 possible products could be formed from this reaction. Tethering the alkene and performing an intramolecular reaction reduced this to 36 and when only the meta- outcomes were considered (a result determined by the electronics of system, among other factors) this was further reduced to 24 possible products. Model studies and careful consideration of the transition state then indicated that the actual number would be far fewer than that. The requirement for the sidechain methyl group in the starting material to end up β-disposed in the adduct was ensured by an A1,3 clash with the anisole methoxy group (see below). The reaction also showed a massive preference for the exo transition state which ultimately meant that only an inconsequential mixture of 2 vinylcyclopropane isomers were formed with all the stereogenic centres set in the correct relative sense. This mixture of products was not separated, but rather treated with bromine in dichloromethane to give a single bromoketone as the sole product. Finally, dehalogenation by heating with tributyltin hydride, followed by a Wolff-Kishner reduction of the ketone gave the natural product.

For most people, even given the starting material and the product of this synthetic sequence thinking of reactions to connect the two is incredibly difficult.[4]  To take the product and design an open ended retrosynthesis arriving at this starting material is amazing. And it's all thanks to this nifty little reaction!

1. This is not true.

2. The seminal paper was in German, which I don't speak. This translation is from Carriera's Classics in Stereoselective Synthesis.

3. Tot. Syn. also covered this in Chemistry World.

4. I once rather audaciously set this as a group meeting problem. I wouldn't recommend it if you want to stay on good terms with your coworkers.