So why do huge natural product molecules still get made, if the thrill is gone?

Well, for one, not everyone agrees about the thrill. Total synthesis is one of the areas with real summits to plant flags on, and you really can be the first to climb them. And (unlike mountaineering!) you don't run out of mountains. They keep on coming, higher and trickier, year after year. Of course, as I went on about on Sunday, the technology keeps on improving, too. I'd argue that we're getting close to an expertise that allows us to hack our way up most any molecular mountain, one way or another.

Another reason the work goes on is that it used to be a great way to find totally new chemistry. Back in the day, you often had to invent new reactions just to have a chance of making these molecules, and that was one of the main justifications for the whole effort. Unfortunately, now that we don't necessarily have to invent the new reactions, many total-synthesis types don't.

I don't want to exaggerate, because it's still no cookbook. Many steps in a big total synthesis require lots of tricky modifications from the normal way you'd run a reaction. And there are lots of reactions that should work and don't; the first thing out of the book usually doesn't do the trick. But, still, very seldom now is new chemistry invented during a major synthesis. People will discover a new reaction, and think of a natural product to demonstrate it with, but they won't discover the new reaction in media res.

That's because it takes too long to do it. The advances in the science are making it gradually trickier to find totally new reactions, or new applications of old ones. If you're in a race to be the first to synthesize Megatoxin, you're not going to spend a few months (or a few years) to see if you can come up with a new reaction that'll save you six steps. You'll just hack out the six steps and get on with it - even if no one else is racing you, which is almost always the case these days.

There's one reason, though, that I can't argue with. Total synthesis is a great way to train chemists. You have non-stop problem-solving under very trying conditions, you experience all sorts of chemistry, and you end up with the hands to do just about any reaction there is. The drug companies love to hire total synthesis people. They figure (correctly) that dealing with the adversity of that work is good training for drug discovery, where most things don't work, either.