Thursday, December 27, 2012

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.