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.

More Pictures in Supporting Information? Please!

Just stop what you're doing right now, and look at the gorgeous reaction setups in this Nature SI.

From SI page S16. Source: Nature / Baran lab

My kudos to Phil & co - they sure do capture a good visual chronology of their reactions!

Also prompted one of my more tongue-in-cheek Twitter exchanges in recent memory...

@P212121 - Would you say then (wait for it...) that it was JUST LIKE COOKING? @Dereklowe @Chemjobber

— See Arr Oh (@SeeArrOh) December 18, 2014

Do these pics remind you of anything? : )