Wednesday, April 15, 2015

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 complementaryMn-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.

2 comments:

  1. rolipram is not really antiinflammatory: it is a failed phosphodiesterase inhibitor with a rather dirty profile (the original indication was antidepressant)

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  2. also, 63% ee celestolide with Jacobsen salen-Mn catalyst can be explained by possible cooperation of TWO molecules of catalyst in the transition state, one of them coordinating to the substrate keto group and the second one delivering azide. Dimeric salene ligands are known and can be made quite easily, it would be interesting to test them to see if there is acceleration or improvement in ee

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