Thursday, August 29, 2013

Bruceollines: Short and Sweet

You can't put your finger on it, but sometimes you just feel compelled to read a paper. This one, from Org. Lett. ASAP, scratched all the usual itches: protecting-group free total synthesis (check), traditional medicine (check), tropical diseases (check), and cool off-the-shelf reagents (check).

I must admit, Gordon Gribble's name at the top caught my attention, but his co-authors hail from the University of the West Indies, a school I've always been curious about.*

The goal? Fast, selective production of bruceollines, medicinal compounds isolated from the roots of a Chinese shrub. The authors initially try to assemble the common indole (the 6-5 aromatic ring) core of the bruceolline family using Fischer conditions, but the starting materials have other ideas and form non-productive intermediates. Starting over, palladium catalysis proceeds smoothly, then relatively gentle oxidation (DDQ) produces the fully oxidized bruceolline E (see picture).


To access the final compound, Gribble & Co. must reduce just one of E's two ketones. The authors attempt borane reductions, but the "usual suspects" (CBS, Alpine) fail miserably. Optimization with (+)-DIP-Cl produces the final bruceolline J in high yield and ee. To make the unnatural enantiomer, the authors turn to a personal favorite: Baker's yeast, more commonly found in breads than labs. After 14 days in a warm, sweet slurry, the wee beasties return ent-bruceolline J in 98% ee.

The synthesis, only 4 short steps, should open the door to develop new antimalarial compounds.


*First, the Hawaii paradox - recruiting high-end, serious grad students to work 4-6 years in a tropical paradise. How does that work? And how do shipping delays from the mainland impact project selection? I can imagine that protecting group-free, relatively robust chemistry would have to be the norm, to survive storms, delays, humidity, etc.

6 comments:

  1. If you are interested in going there, you've got to visit on your own dime, I think - one of the people visiting schools when I was was interested in natural products isolation, which was one of Hawaii's strengths. Since people wanted to visit, whether or not they were serious about going, they didn't cover the trip cost (or only covered a part of it). It's sort of hard for an undergrad to pay that kind of money if they're not really sure they're interested. On top of that, the cost-of-living is probably significantly higher, but the stipend probably isn't.

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    1. Interesting info, thanks! (Luckily, I'm past the "deciding on grad schools" phase by a comfortable margin - went to a nice, cheap state-side school that paid for my relo, even!)

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  2. I worked with a Danish postdoc who did his grad school in Hawaii, o total synthesis of cannabinoids, and he was not speaking too glowingly about the university - apparently it is a giant dysfunctional organization, living expenses are very high, and the chemicals go by boat. But it was the university bureaucracy he was most unhappy about

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    1. Yeah, the travel delays must be killer! What happens when you're near the end of a total synthesis, and you have to screen conditions? "Gee, I'll order LAH, NaBH4, and sodium, and then sit on my hands for a month"

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    2. It requires a bit of foresight, or heavy borrowing from other labs in the department. At my place (Singapore), most stuff gets shipped in as well, and it can take up to 2 month for stuff to arrive. The trouble is that sometimes, I forget completely I ordered something in the meantime.

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    3. Same deal for Hong Kong if you're ordering from Sigma-Aldrich, which is something you probably want to do because most companies from the mainland have a terrible reputation. We ordered a bottle of isopropanol only to find it contained about 10% methanol in it.

      I hear similar things about long lead times Australia and New Zealand - just have to have a couple of things going at the same time to get round it.

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