B.R.S.M. All this happened, more or less.


On Retrosynthesis, Logic and Swords

Dear internet, I'm a little busy this weekend, so please accept this rambling semi-rant and I promise I'll put up some real content soon.


Has anyone else noticed the variety of arrows used in retrosyntheses in the literature? A lot of people seem to be using closed arrows these days (for a recent example from someone who should know better, see the abstract of Baran's cortistatin full paper from last month), rather than the more traditional open ended ones (Þ).  I can't easily give an example of the incorrect kind above, because as far as I can tell there isn't a character for it in any font. That's because, as far as I know, it doesn't mean anything. The open arrow, on the other hand, predates the concept of retrosynthesis by a long way, as it's the logical operator for the  implication relation. So A Þ B means that the presence of A implies B. Which kind of makes sense. Eager to find a supportive quote from E. J. Corey, who coined the term retrosynthesis, I dug out my copy of The Logic of Chemical Synthesis, and was pleased to find the following:

"It is customary to use a double arrow (Þ) for the retrosynthetic direction in drawing transforms..."[1]

Excellent. However, during my search this sentence in the preceding paragraph caught my eye:

"Woodward’s account of the state of “organic” synthesis in a volume dedicated to Robert Robinson on the occasion of his 70th birthday indicates the spirit of the times. Long multistep syntheses of 20 or more steps could be undertaken with confidence despite the Damocles sword of synthesis - only one step need fail for the entire project to meet sudden death."

I've never heard anyone talk about the "Damocles sword of synthesis" before, but I think it nicely describes the feeling of impending doom which I've felt a few times during my time as a synthetic chemist. If you didn't get the benefit of a classical education, let me explain the origin of this phrase (with a little help from the wikipedia article).

Damocles was a member of the court of Dionsysius, an Italian tyrant of the fourth century BC. One day, Damocles remarked that Dionysius was very lucky, having great power and always getting his own way. Dionysius then offered Damocles the chance to switch places so he could experience first hand what it was like to live as a tyrant. Damocles eagerly accepted the throne, surrounded by every luxury, but Dionysius placed a sword overhead, suspended by the pommel with a single hair, and ready to fall at any moment. The story ends with Damocles begging to return to his previous position, not wanting the luxury and power any longer, and now aware of the fear in which the king lived.

Total synthesis is a wonderful pursuit, and we have a lot of power to choose the routes we take and the chemistry we use, but when you're waiting for an NMR or TLC from the 15th step in your reaction sequence do you ever look up and see the sword of Damocles looming, and wonder if maybe you'd be better off doing some nice methodology?

[1] The Logic of Chemical Synthesis, page 6. If you don't have a copy, Corey's written a few articles in journals which contain a lot of the same ideas - check out the Angewandte version of his Nobel lecture (I hate the term carbogen), and his Sir Robert Robinson Lecture in Chem. Soc. Rev.

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  1. If the Sword of Damocles wasn’t enough, there’s also Bob Ireland’s “arithmetic demon” to contend with.

    Beautiful blog, great content by the way. And a fantastic choice of name.

  2. Yeah, between those two, we synthetic chemists have a pretty hard time of it! I’ve always loved that Ireland quote, but I’ve never been able to find where he actually said it – never seen a reference or anything attached to it…

    Your own website is most excellent; the diagrams, explanations and analogies are great. Love the piece on the power of laziness – made me think again about the assumptions I let people make when I’m explaining stuff. Wish I’d had your site when I was doing introductory organic chemistry – some really important concepts continue to be explained so badly. But do you not find it strange, and sometimes even a little dull, to be teaching this stuff after working for such a big name on the cutting edge?

    I agonised over the name of this blog for a while, but I think it’s quite appropriate. After all, if you see a sweet enough step (in a total synthesis) you don’t much care that the reaction only works on Tuesdays, has to be run in 1:1 HMPA:Unicorn tears, and has those familiar four letters at the end.

  3. It comes from a small black book he wrote in the late 1960’s, just called organic synthesis IIRC. Bob used to be an english major, so a lot of the chapter headings are colorful (e.g. “In which stereochemistry rears its ugly head”). Very enjoyable little read, I think I bought it at some point but it has sadly been displaced in the move.

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