Straightforward Synthesis

I am sure every chemist who has done even a small amount of research will recognize the following: a target compound is set, a synthetic sequence proposed that looks reasonable with literature precedent and then someone makes the mistake of saying that it looks like a nice straightforward synthesis. So shouldn’t take more than a week, right?

Cue two months of sweat and failed reactions and muttered curses to the gods of chemistry.

It might be quicker to relate the tales of syntheses that DID go to plan than didn’t. A typical story from a former life was a request for a scaffold, with a few examples. It was a little unusual, with 3 fused rings, but the request came with a proposed route including an intramolecular Heck reaction as its centerpiece. I swear I tried that reaction every which way, tried it intermolecular, with different catalysts and ligands. Nothing worked. It will make a long story quite a lot shorter to say that I eventually made the thing with some Stille chemistry – with the side-note that I sent in the requested samples and then never heard about it again.

I have been working on one just recently. It will be really excellent if we can get it to the finish line and I feel we are almost there. But this one teased us a little. We were adapting some work from the Merck process group and that is a good recommendation for some chemistry. I’ve heard that Merck likes to push their best chemists into process and the results show. Anyway, our molecule was pretty similar but it did have a tertiary amine that the Merck guys didn’t so a potential complication there. But the first 3 steps went like a dream, exactly like the published procedure (and it is not often I get to say that). Then came a hydrogenation and that was a wall. The transfer hydrogenation conditions didn’t work, so I went to the hydrogenation suite with the Parr shakers. A special bonus, as I didn’t know we had one. But that didn’t go too well either. Worse actually, as we seemed to lose material and given the work-up is pretty much filter and evaporate, I am unclear as to how that occurred. With enough heat and pressure, it worked, though I am not really sure how well, given the recycling of materials from reactions that had not gone. The toll from here and from the next step (which worked, just not very well) meant I had only a little material to take on the end game and that just didn’t work out, especially as this is the part that is less established chemistry. But that is science, right? We take what we have learned and the next time we do it, we do it better.

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