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December 9, 2002
Sweet Maybe, But Trouble, Too
As I mentioned in that last post, I did carbohydrate-based chemistry back in grad school. (I still break out the sugars once in a while, but there aren't as many opportunities in medicinal chemistry.) Back then, I was on a project that was using them as starting materials to try to synthesize a large antibiotic molecule from scratch. The idea's fairly sound - the antibiotic has a lot of chiral carbons in it, and sugars are a rich source of strings of chiral carbons.
But there were complications. There's no carbohydrate with just the sort of backbone you'd need (if there had been, the synthesis would have been pretty trivial.) So the project involved taking some of the available ones and tweaking them around - remove a hydroxy group here, flip one over down there, change this to a branching carbon over around this way. The synthetic steps really start to add up after a while, I can testify. A lot of the difficulties came from starting out with such highly functionalized molecules. You had to first protect all those hydroxy groups, and do it in such a way that you could take each protecting group off at just the time you needed it. Pretty soon, you run out of possible protecting groups!
I pulled the plug on the whole thing at about 27 linear steps, and it wasn't finished then. It really seemed to me that we had reached the point of diminishing returns, which opinion of mine time has completely confirmed. It would have taken me another year, at the rate things were going, and that would have been a really bad trade. Even as it was, I was spending most of my time making starting material (as my readers in the organic synthesis field can readily imagine.) And no matter how large a flask (flask? how large a bucket) I started the chemistry off in, I always seemed to get to the frontier of the synthesis with about 20 milligrams. I felt like the guys painting the bridge - as soon as I finished, it was time to start again.
Some time I'll tell the story about what my PhD advisor did when I shared the news with him that I wasn't going to finish the molecule. He wasn't taken with the idea.
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