There's an unusual article in Nature that several folks have e-mailed me about. It's unusual for several reasons. For one thing, it's synthetic organic chemistry, and there's not much of that in Nature at all - it's an interesting choice of journal on the part of the authors, Phil Baran of Scripps and two of his students, Thomas Maimone and Jeremy Richter. The title also gives away the other odd feature (as a title should): "Total Synthesis of Marine Natural Products Without Using Protecting Groups".
I was talking about protecting groups here just a couple of months ago. In synthesizing complex molecules, they're often necessary, because there will often be several similarly reactive groups exposed at the same time, and you need to be able to distinguish them. Or you'll need to do something severe to another end of the molecule-in-progress, which an amine or alcohol somewhere either won't let you do or won't survive if you try.
The trouble, as any synthetic chemist can tell you, is that protecting groups introduce their own complexities. Ideally, you want to be able to put them on and remove them with no loss of material, but that's impossible. Ideally, you'd want each one to be removable under conditions that won't disturb any of the others, or anything else in your molecule, but that can be a tall order too as they start to add up. And ideally, you'd want all of them to be able to stand up to anything else you'd like to do, until it's time for them to leave, but that's not available in the real world, either. Sometimes a big part of the work (mental and physical) that goes into a total synthesis is figuring out how to manage all the protecting groups.
Baran makes the case that this has gone too far. He's made several complex molecules without protecting anything at all. There's a price to be paid, of course - some of the steps along the way have not-so-impressive yields because of the bareback conditions. But the counterargument is that the overall yield of the synthesis is often higher in spite of this, because there are so fewer steps, and the cost and complexity are cut similarly.
Of course, you can't do this by just plowing ahead with the same reactions that a protecting-group-laden synthesis would use. They're on there for a reason, and that method would send you right into the ditch. Baran tries instead to mimic the biochemical synthesis of these molecules as much as possible, since after all, cells don't use protecting group chemistry, either.
This is an idea with a long and honorable history in organic chemistry, starting with Sir Robert Robinson's startling one-pot synthesis of tropinone back in the 1917. That one is usually taken as the father of all biomimetic syntheses, although it's been pointed out (by no less an authority than Arthur Birch) that this is partly a legend. But it's a legend that has performed function of its reality, leading to a whole series of biologically-inspired syntheses. This latest paper is a call to make biomimetic synthesis the centerpiece of the field again.
I'm sympathetic to that view, but it's not going to be easy. Read closely, the paper shows that this kind of work can be very difficult indeed, even when the biogenic pathways to your target molecules have been studied (which isn't always the case). There are a lot of steps here that required careful coaxing to work in reasonable yields, or at all - no one should confuse the lack of protecting groups with a savings in time. And these difficulties also undermine the claim of reduced cost and complexity a bit, since they represent plenty of time and effort - and if they aren't synonymous with cost and complexity, I don't know what is. Academia may obscure this a bit, since we're only talking graduate student labor here, but it's a real issue.
Where I see this making an impact industrially is in process chemistry. Many times companies work out several parallel routes to an important drug substance, looking for the lowest overall cost. That's where attention to no-protecting-group methods could pay off. Process groups already try to avoid these steps anyway, for the same reasons.
But for the most part, drug substances aren't so complex that they need lots of protecting group manipulation. We could always try to get into more complicated structures through these routes, but this leads to a chicken-and-egg problem. The medicinal chemists generally don't have the time to investigate the picky conditions needed to make no-protection chemistry work, so they're not going to have access to the shorter, higher-yielding syntheses needed to do analoging work. (And there's the real problem that these analogs might need complete re-optimization of the trickier steps each time, which would be a real nightmare). The process chemists would have the time and mandate to work out the no-protection stuff, on the other hand, but if med-chem can't deliver a good drug candidate, then they have nothing to optimize.
The Nature link above is subscriber-only, but you can read the supporting information with all its synthetic details here if you like. It's a pretty big PDF file, though, so be warned. I'd be interested to hear what readers, both academic and industrial, think about this one.