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.

Oxidation? Just Add LEDs

Researchers at the University of St. Andrews recently reported an extremely short synthesis of melohenine B, just two steps from a related commercially available alkaloid. The (6-9-6-6) core skeleton of melohenine B, a rare duck for sure, had only just been disclosed in 2009.

Ready for the kicker? The final step requires nothing more than dye, air, and light.

After LAH reduction of commercially available (-)-eburnamonine (a vasodilator), the chemists needed to find a reliable method to blast apart the indole 2,3 pi-bond to bring about the core 9-membered ring. Various "go-to" oxidants such as m-CPBA or sodium periodate gave N-oxide or returned SM. Hitting the compound with a molecular piledriver - ruthenium oxide - produced the product in a stingy 21% yield, along with elimination side products.

Taking a cue from an early photo-oxidation example, and perhaps the ozone-based Witkop indole oxidation, the researchers tried methylene blue-promoted singlet oxygen cleavage. This worked much better than anticipated ("quantitative" yield) and returned a single diastereomer resulting from hemiaminal ring-opening and substrate-controlled closure.

Now I've seen a lot of photochem go by in the past 10 years, most of which requires 1) sunlight, 2) a CFL bulb, or 3) an array of blue LEDs. But this may be the first time I've seen such simple conditions; the reaction requires a single red LED! Check out the protocol, lifted from the SI:

"The substrate (12 mM) in methanolic methylene blue (40 uM) was irradiated by a 627 nm 3 W LED with vigorous stirring under an air atmosphere. The progress of the reaction was monitored by TLC (generally 3-24 hrs)."

That 627 nm light shouldn't surprise anyone, since it's right in the middle of methylene blue's absorbance spectrum. Still, the application of technology usually found in day spas to organic synthesis makes me smile.