Favorite Reaction

When I read Rachel Pepling’s call for a carnival of favorite reactions, I almost did not respond. Which reaction to choose? So many cool little reactions: rearrangements, cascade cyclizations, exquisitely set up displacements. But when I thought to limit to things I’d actually done, it became a little easier.

Still, I’ve run more than a few reactions over the years. How about one of those that got me into chemistry: something like the Thermite Reaction (anything involving setting light to magnesium ribbon has to be fun) or the volcano? Or the first Grignard formation I ever did, which as I was laughing at my neighbor as their’s climbed out of the top of their condenser, when mine did the same thing (painting the hood ceiling in the process). Strangely that actually encouraged me to continue in this career rather than try something safer.

I like working out mechanisms, particularly when something unexpected turns out to be important in the sequence. It might be old hat to me now, but when I found out the mechanism of the Swern Oxidation involved the oxygen of the dimethylsulfoxide reacting with oxalyl chloride, I was taken aback: I had never considered something like that happening before. I also like running a reaction with several steps – I’m not sure why, it is just more satisfying than throwing everything in the flask and setting the oil bath to 90 ⁰C. So I came up with an alkylation of Cyclosporin A.
Cyclosporin A
The chemistry was discovered by Dieter Seebach. It is involves the formation of an anion, which is then quenched by an electrophile. That in itself does not seem so remarkable, but first consider that Cyclosporin A is a undecapeptide and in order to obtain alkylation at the desired point (the sarcosine residue), a polyanion needs to be formed, to account for the amide NHs and one hydroxyl group as well. In all, 6 equivalents of LDA are required (formed in situ naturally – does anyone really trust the commercially available LDA?), all with careful temperature control. Then the electrophile is added (in my case it was a disulfide), it reacts with just the part of the molecule you want and then you work it up.

And after that, with so much that can go wrong, if you do it right you get your desired product, cleanly and in a highly satisfying yield.

It is one of those reactions that makes chemistry such a joy. The practical science in its essence.

One comment on “Favorite Reaction

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