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August 8, 2007
Steve Ley, Azadirachtin, and Me (Very Much in That Order)
The latest issue of Nature has an article (subscriber-only) on Steve Ley's long-anticipated total synthesis of azadirachtin, which can be read, again subscriber-only, here and here at Angewandte Chemie. (For a open-source look at the synthesis, try Totally Synthetic). I'm quoted in the piece expressing numerous doubts about the merits of total synthesis, most of which made it into print.
I also expressed quite a bit of admiration for Steve Ley's work, most of which didn't make it into the article, so I wanted to get that on record over here. The reason I can hold both those opinions is, of course, that Ley has done a lot more over the years than just make azadirachtin. As I told Nature, if he'd been running one of the make-it-or-die total synthesis factories, he'd have no doubt been finished well before now. But he's introduced reagents and experimented with many new ideas and techniques, and those have (in my view) a greater chance of having an impact on the world than natural product synthesis does.
A lot of what goes on in that field seems to me to have about as much relevence and utility as do chess problems. It's to Ley's credit that he's made a molecule of this complexity while avoiding the large pitfalls in that part of chemistry - some of which are marked with names like "If You're Not First, You're Nothing", "You Worry About the Reactions and I'll Worry About the Yields" and "If You Can't Get This Coupling To Go, I'll Find A Post-Doc Who Will".
Back when I was finishing up graduate school in 1988, I had to put together a research proposal. I chose, like a fool, the polycyclic core of azadirachtin, and I cranked out a paper synthesis plan for it. Would it have worked? Not a chance in hell. Looking back, I can see that I was already falling out of love with total synthesis even back then, and time has not healed the rift. Steve Ley never lost the faith, but (to his credit) he hasn't let it define him, either.
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