Encore, Encore!

Two hot areas of research served up second helpings online this week:

C-H Azidation: Remember John Hartwig's iron-meets hypervalent iodide combination from last March? It possessed the power to insert a late-stage amine equivalent into complex natural products. John Groves has raised the stakes, disclosing a "practical and complementary" Mn-porphyrin promoted version that takes solid sodium azide as the precursor. 

Source: Groves, JACS ASAP

The group finds it can enable late-stage azidation of a variety of complex bioactive substances (sclareolide, artemisinin, estrone, papaverine). Even more surprisingly, although likely a radical-induced transformation, using a chiral salen led to a single example of 70% ee material. Groves admits they have work to do, but the fact that this reaction operates with 1% loading in wet ethyl acetate at room temperature sure sounds promising!

Synthesis Machines: Over at Nature, Kobayashi published a flow reactor approach to syntheses of either enantiomer of rolipram, an anti-inflammatory. No MIDA-boronate 'handles' here; this is classic chemistry - olefination, 1,4 addition, reduction, hydrolysis, decarboxylation, cyclization - performed over heterogeneous catalyst beds encased in stainless steel tubes. The group spices up the synthesis by including their in-house chiral PyBOX-calcium catalyst to control the 1,4 addition, and developing a Pd / polysilane-catalyzed reduction for a troublesome nitro group. 

Kobayashi claims his synthetic engine can produce a gram of 96% ee material every 24 hours, and that the system remains stable and operable for about a week's time. In a complementary Commentary, Joel Hawkins of Pfizer presents a tantalizing future, where hood-sized continuous synthesis units chug through kilo quantities of drug precursors, using commercial reagents, sans column chromatography.

Oxidase Toolkit: C-H Azidation

Do you ever stare at your late-stage molecules, thinking "They're almost perfect, but I really wish I could add an amine right over there." Thanks to a new reaction, you might soon be able to.

Reporting in Nature, John Hartwig and coworkers have cracked the case: a mixture of iron (II), a tridentate nitrogen ligand, and a modified Togni reagent Zhdankin reagent reliably functionalize tertiary C-H bonds with an azide(N₃ group). The selectivity, yield, and mild conditions match pretty well with White's C-H oxidation, which utilized a similar catalytic manifold.

Hartwig's initial targets for this new reaction include two modified steroids and a gibberellic acid derivative. Sadly, precious few heteroatoms exist in these molecules to gum up the ironworks, but I'm certain they'll address that in the full paper. I'd especially like to point readers to Figure 3, in which the group shows subsequent transformations: heterocycle formation, amine reduction, chemical ligation, and capping with fluorescent tags.

These two reactions together, along with a variety of C-H halogenations and sulfidations, seem to support the growing "oxidase phase" approach to total synthesis. One could imagine that, in a few years, a naked carbon scaffold could be suitably decorated with O, N, S, or X at positions of the scientists' choosing. Wow.

"Everything is Catalytic," Scientists Claim

For Immediate Release
4/1/14

Grand Rapids, MI: Troublesome chemical reactions? Try adding a pinch of...anything.

Reporting today in the journal ACS Catalysis, researchers have discovered that every chemical element or molecular mixture catalyzes reactions when present in trace quantities. "As I've told all my students, catalytic inspiration + 10 equivalents perspiration produces beautiful molecules," remarked Scripps Professor Phil Baran. "I just never mentioned that I used drops of actual sweat!"

"Brilliant!" remarked Stuart Cantrill, Chief Editor of Nature Chemistry. "Chemists were always running reactions in beer and coffee, mostly to show off. The trick now will be discovering which obscure thing goes into what reaction."

"Indeed," remarked Chemistry World's Neil Withers.

As shown by the graphic abstract (above), scientists at the forefront of catalytic research often try just about anything they can get their hands on. "I wouldn't have believed it, myself, but the data convinced me," commented celebrated catalysis scion John Hartwig. "Our lab has already added ppm quantities of dryer lint, nose hairs, and soy sauce to asymmetric Ir allylations, with fantastic yields and high ee."

N.B. - Calls to Dow and DuPont were not returned by press time

Note to the humorless: This is fake. Happy April Fools' Day. Please don't sue me.