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.

Acylboronates Enter the Mix?

Just a few days removed from the great Synthesis Machine debate of '15, a new paper has appeared that prompts me to wonder: might other protected boronates work in this chemistry?

The Bode group, now at ETH-Zurich, discloses in JACS ASAPs some intriguing bifunctional acylboronates. Much like their MIDA boronate cousins, these, too, are stabilized by an N,O-chelating ligand, demonstrate a shelf-life of several months, and are easily prepared in one step from their potassium trifluoroborate salts.

Do you suppose these reagents could survive the strongly basic aqueous conditions used for MIDA deprotection and subsequent cross-coupling? The authors, comparing MIDA-acylboronates against NOF-acylboronates under aqueous hydrolysis conditions, claim:

"In all cases, the bidentate, monofluoroacylboronates were much more stable than the MIDA variants and should be sufficiently stable* for most applications." 

If this holds true, one could imagine capping Burke's automated syntheses with carboxylic acid derivatives without resorting to bulky t-Bu esters or exotic silyl-protected esters.

*Now I'm just brainstorming, but could catalytic conditions be found to transmetalate the acylboronate to, say, Rh or Pt? 

Friday Fun - Jobs from the Future

Who wants to help me construct a job description for the brave new world of automated synthesis?
Leave your suggestion in the comments, and I'll modify our advert as needed...

March 13, 2025 - Automated Synthesis Engineer

Our company seeks a motivated individual to work in our growing Automated Synthesis division.

Experience: Qualified candidates should have 5+ years previous experience in chemistry, mechanical engineering, or robosynthesis. Ideally, you'll have completed 10 (or more) previous multi-step total syntheses using 3D-Flow ModuloChem-XLs.

Software: Candidate should feel comfortable using the IBM SynBlox suite for fragment assembly, exploring GDB-23 for potential lead molecules, and assessing synthetic feasibility using the OPRD Engyn iPhone 9 app.

Special skills: Our synthesizers often require adjustments, thus experience in a trade - plumbing, welding, electrical - would be highly valued. Candidates interested in creating holographic "how-to" vidlets especially encouraged to apply.

Source: Burke Lab historical archives