Retrosynthesis for the Common Man

I’m just a lowly student of chemistry. That’s why it scares me when a professor walks into class and immediately starts drawing azadirachtin on the chalkboard–not content to introduce the concept of retrosynthesis slowly and using small examples, he’d rather drop a bomb at the start and scare our pants off! But let’s be honest, that’s just his style. 🙂

As most people reading this probably already know, retrosynthesis is the process of determining what starting materials and reactions can be used to make a particular target molecule. The field is full of crazy jargon, mostly and sadly due to the tireless efforts and departmental clout of one man [1]. While the systemization of putting molecules together was certainly a step in the right direction, I feel like the formalism takes a little something away from the mystique of organic synthesis. First of all, it’s all based around localized disconnections, which can sometimes lead to a “forest for the trees” effect, especially in people new to the field (like I’m one to talk :-P). This is a physical chemistry blog after all, and the physical chemistry of molecules often extends far beyond their local bonds (aromaticity anyone?). Secondly, the retrosynthetic formalism tends to discourage the development of new reactions by drilling certain molecular frameworks, or retrons, into the mind as perfect for a reaction that has already been done. This can be useful, of course, but you can’t use the formalism alone to look at the target in a truly new light, if that’s necessary.

Which brings me to what I see as the saving grace of the retrosynthetic formalism: it serves as a gateway to innovation. It can put a ton of existing information at your fingertips, but integrating this information, possibly into something 100% never-before-seen, is all creativity and no formalism. And that’s where the mystique comes back–getting to the point where you’re about ready to throw your hands up in the air and give up, and being touched by a spark of divine inspiration.

Hallelujah! 🙂 This JOC paper made me feel much better about retrosynthesis. Straightforward but interesting stuff.

[1] My New Year’s resolution is to be less bitter. It’s not going too well.



  1. Nah, it’s usually pretty useful. Although…maybe more so for natural products chemists. (535 is kinda focused toward them anyway…ew, chirality!)


  2. I wish you could’ve seen the room when RBG came in and started drawing azadirachtin. People were looking around like “wtf?”


  3. Natural products guys are cocky, aren’t they? “Hey, look everybody, I can synthesize, for millions of dollars and on the crushed bones and spirits of dozens of graduate students, what a goddammed sponge does in 20 seconds without a NIH grant or a rotovap.”

    I have respect for their abilities. I find their attitude almost impossible to abide. I’m happy to swipe any technique they develop, but I’m not going to make sponge dung when there are an infinite number of unnatural products a-waitin’ for me to discover them.

    Besides, I might have to make something that won’t pi-stack. Feh.


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