Finally…Total Synthesis: NOS Day 4

I'd been at the NOS since the start, and there'd been nary an instance of what I'd call a traditional "total synthesis talk". That changed on Thursday morning, when Dale Boger and Phil Baran took the stage. Boger described what his group has learned over the years about vinblastine, a natural product that he quipped "needs no introduction". (Just to be polite, I'll briefly introduce it anyway- periwinkle plants make it, and it has potent anticancer activity, via a unique mechanism of action.) VindolineThe first section of the talk was about vindoline, one of the pieces that makes up vinblastine. Vindoline has 5 rings, and Boger's group used a cycloaddition reaction cascade to form three of them, along with several stereocenters, in one pot. The group's explored this reaction extensively- Boger described at length how different tethers and substituents affect the reaction. They plumbed the depths of this cascade to see how useful it would be to build vindoline analogs that, once incorporated into vinblastine, would help them probe how changes in vinblastine's structure affect its activity. Turns out it is a good way of building analogs, of making what Boger called "point changes" in the structure. He spent the rest of his talk on this area. One of the drawbacks of the vindoline synthesis was that the team had to use a chiral HPLC column to get at chirally pure material. During the talk, Boger described a second generation synthesis of vindoline where that's no longer the case. The key seems to be introducing a chiral center into one of the tethers participating in the cascade reaction. During the Q&A, someone asked Boger whether and how the cascade might be applied more generally. Boger thought that the reaction is likely generally applicable, mentioning that in the case of vinblastine, his team needed to use a nitrogen-containing substituent that was deactivated, so his group was actually dealing with a particularly challenging case. One could imagine using different, more activated tethers with the oxadiazole system his team used and have success with the cascade, he said. Next (and last) up was Baran. He had a theme in mind (chemoselectivity in syntheses) and he used examples from several molecules his team has tackled to drive that point home. I won't go into all the stories he talked about (others have done a great job of it already!), but I will mention one-- his Nature paper (2009, 459, 824) with postdoc Ke Chen, which contains concise syntheses of a family of terpenes from the eudesmane family. The syntheses in this work are cool in their own right, but make no mistake, this is a strategy paper for the Baran group. They're thinking long term here. The point Baran emphasized is that Nature makes terpenes in what is essentially a two phase process, but synthetic chemists still aren't very good at mimicking one of those phases-the oxidase phase-where complex carbon skeletons get oxidized at specific places with laserlike precision. TerpenesTo give folks in the audience an idea of the "someday" project, each slide in this section of Baran's talk had the same reaction diagram atop it- one that contained the carbon skeleton of Taxol, followed by a hypothetical reaction arrow leading to the fully-functionalized natural product. So the "someday" project is clear-- make Taxol (and other complex terpenes) in this way. The first person to ask a question cut right to the chase- asking Baran if his group now plans to use this two-phase strategy to try for Taxol, or whether they'll take baby steps first. Taxol is so complicated, the project by definition would have to go in baby steps, Baran answered. What's exciting to him is that when Nature makes as many members of a molecular family as exist in the taxane family (there are a few thousand out there), many of the steps up the ladder are likely to be natural products themselves. His team's goal along the way is to plan their syntheses in a way that sets them up to innovate- invent selective oxidations and transformations here and there. UPDATE 6/12:Changed the terpene picture... I'd missed a carbon on one of the structures...

Author: Carmen Drahl

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  1. Believe me, there’s *always* a sodding carbon atom missing…

    The Baran talks are like nothing else… I walked away from his talk at BOSS last year feeling like a kindergarten kid in a stat-mech class. But I wish he’s spend more time on fewer syntheses, and worked-in more depth.

  2. Ha- true that.

    I think the audience felt similarly shell-shocked.. at first, when the lights came up, it seemed like no one was going to ask a question. Baran said something like, “Well, it looks like everyone wants to go rock climbing. I can’t blame them.” That woke us up, I suppose, because that’s when questions started.

    I heard him speak at Roche back in ’05-I miss when he used to have hand-drawn structures from his students’ notebooks in the talks. I might experiment with that some more on future blog entries.

  3. I don’t believe that Boger’s synthesis is as good as he claimed. I’ve heard about what happened on the cascade reaction. It is fantascid outside. Actually, it is ugly. Sometimes total synthesis means total shit. At least Boger’s is.

  4. @ is it true: Hmm. Maybe I don’t understand because I don’t know what “fantascid” means (I even checked urbandictionary).. legitimate questions about and critiques of stuff we talk about on the blog are welcome. If you’ve tried similar cascades and learned something helpful, we’d love to hear about it. But keep the hearsay to a minimum, and please play nice.

  5. I will say that I know much much much much more details than you about boger’s vindoline and this methodology. You can imagine where I have been and why I know that.
    And also, since I know boger’s chemistry, I also know baran’s. It’s really funny that an org. lett. paper goes to nature. ridiculous, that’s the only thing I want to say.

  6. I fully expect you to know more about the methodology than I do-I only learned about it from one lecture. As I said, feel free to share relevant information. Please be considerate and respectful.
    Regarding your second statement- let’s adhere to Totsyn’s policy about discussing a paper’s suitability for Nature.

  7. I knew the guys who did the vindoline work; The cascade was a very tricky reaction in the case of vindoline, but worked with little issue on a number of other substrates, many of which are covered in the methodology papers Boger published in JACS a while back. A great deal of effort by a number of chemists went into optimizing each step in the vindoline synthesis – it certainly wasn’t an easy road, but clearly it was good enough to make all of the those vinblastine/vincristine analogs.