Organic chemisty can be a real high-wire act. If you’re taking a compound along over a multistep sequence, everything has to work, at least to some extent: a twelve-step route to a compound whose last step can’t be made to work isn’t a route to the compound at all. To get the overall yield you multiply all the individual ones, and a zero will naturally take care of everything that came before it.
Even very respectable yields will creep up on you if you have the misfortune to be doing a long enough synthesis. It’s just math – if you have an average 90% yield, which shouldn’t usually be cause for distress, that means that you’re only going to get about 35% of what you theoretically could have after ten steps (0.9 to the tenth). An average 95% yield will run that up to 60% over the same sequence, and there you have one of the biggest reason for the importance of process chemistry groups. Their whole reason to live is to change those numbers, to make sure that they stay that way every time, and without having to do anything crazier than necessary along the way.
When you’re involved in something like this and you know you’re going to be approaching a tricky step, the natural temptation is to try it out on something else first. Model systems, though, can be the road to heartbreak. In the end, there are no perfect models, of anything. If you’re lucky, the conditions you’ve worked out by using your more-easily-available model compound will translate to your precious one. But as was explained to me years ago in grad school, the problem is that if you run your model and it works, you go on to the real system. And if you run your model and it doesn’t work, well. . .you might just go on to the real system anyway, because you’re not sure if your model is a fair one or not. So what’s the point?
This gets to be a real problem in some labs. While ten steps is medium to long for a commercial drug synthesis, it’s just the warmup for a lot of academic ones. Making natural products by total synthesis can take you on up into the twenty- and thirty-step levels, and some go beyond that, most horribly for everyone concerned. In such cases, you’d much rather have several segments of the big honking molecule built separately and then hooked together, rather than run everything in a row.
But what if you spend all that time on the segments, but you can’t put the things together? The most famous example of that I know happened in Nicolaou’s synthesis of Brevetoxin B. The initial disconnection of this terrible molecule into two nearly-as-awful pieces turned out to have been a mistake. Despite repeated attempts, no way could be found to couple the two laboriously prepared pieces to make the whole molecule, and untold man-hours of grad-student and post-doc slave labor had to be ditched for a new approach. If you want to see the approach that worked, here’s a PDF of a talk about it.
But if you go linear, you’re taking the same risk, and the math will absolutely eat you alive. A 90% average yield will ensure that you throw away 95% of your material if you keep going for 28 steps. And keeping a 90% average over twenty-eight steps is just not possible with real-world chemistry, either – and yes, I’ve seen those papers where they do, but I don’t believe them. Do you? Make it 25 steps of average 90%, and three 60% losers, and now you’re down between one and two percent of your material left. Which is no way to live.
I note that the above summary of the Brevetoxin synthesis counts 123 synthetic steps. It calculates an average yield of 91%. A 2004 synthesis from Japan comes to 90 steps with an average yield of 93%.