Cellphone Charger Electrochemistry

I'm frankly amazed at chemists' rugged pragmatism. Our ilk often repurpose seemingly innocent household items - floodlights, LED strips, paraffin wax - adapting them for making new molecules in interesting ways. Have a peek at this new paper, which appeared* last week in Angewandte Chemie. 

The Aubé group, recently of UNC, wondered whether expensive setups from scientific vendors were potential roadblocks to wide adoption of electrochemistry. Their ideal recipe called for a direct current (DC) source capable of removing two electrons and an H from a lactam to generate an N-acyliminium ion. Looking around, the researchers realized that today's ubiquitous cellphone chargers might just do the trick. Shave back some wires, attach some copper clamps, and presto! Cheap, effective electrochemistry.**

Using their DIY e-chem setup, the Aubé group traps a wide variety of stereochemically-rich acyliminiums as the corresponding methanol adducts (19-93% yields). Now the real fun starts: there's a whole bunch of interesting arylations and other additions to these species one can access using off-the-shelf Lewis acids like titanium tetrachloride or boron trifluoride:

Adapted from Aube, Angewandte Chemie, 2015 ASAP

I'll be excited to see small libraries of diversified products emerge from this work. However, a "one-pot" functionalization - electrochemistry with the desired nucleophile already present - still seems a distant dream.

Hopefully, the apparent ease of operation of "cellphone charger e-chem" prompts other groups to give it a try. If your group dips their toes into this field, please drop me a line in the comments section.

--
*Thanks to Professor Brandon Findlay (@Chemtips) for pointing out this paper!

**I'm tickled pink at how many organic synthesis papers these days include photographic records of reaction setups. I'd like to believe that Blog Syn played a small role in advancing this change.

Acc. Chem. Res. = Suddenly Cool Again

Accounts of Chemical Research - located at the "left of your ACS radio dial"- may be as unloved as the random college radio stations one finds there. Yet it somehow seems to be catching fire with the chemistry "It" crowd.

Seriously...it's on the left!

I'd heard plenty of knocks back in grad school: "Self-reviews." "Citation fluffing." But, know what? I can't help but want to read most of these recent papers.

Take the upcoming Special Issue organized by Paul Wender. Entitled "Synthesis, Design and Molecular Function," it offers plenty of pizzazz. There's...

• Tom Hudlicky, whose "...20 years of effort [in synthesizing morphinans]...may qualify as obssession." 
• Karl Gademann "...unlocking secrets enshrined in molecular structure" towards neuroengineering.
• Brian Stoltz wants to show you "effective and broadly general methods for the formation of quaternary stereocenters."
• Phil Baran wants students "...to face challenges from the 'real world' at an early stage of their career"
• Frank Glorius wishes chemists would realize "...the value of negative and qualitative data" in reaction screening
• Glenn Micalizio advances "...an area of chemical reactivity not represented in the few well-established [C-C bond-forming] strategies" namely, metallacycles.
• Sam Danishefsky and Chi-Huey Wong tackle cancer vaccines. Need I say more?
• And Vinca alkaloids stalwart Dale Boger dives into vinblastine analogues.

I'm sure more will find their way onto the ASAPs, but this is an illustrious way to start the next issue.
Bravo, editors!

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? : )

Honoring Carlos Barbas

Carlos F. Barbas III, a synthetic chemistry professor at Scripps, passed away just over a month ago. I remember first reading about his proline-catalyzed aldol reactions early in my graduate career; I assumed he'd one day share a Nobel Prize for organocatalysis.

In Angewandte Chemie, Phil Baran eulogizes Prof. Barbas well. I hadn't known, for example, that he had earned almost 60 patents (!), had founded three companies (Prolifaron, CovX, Zyngenia), and had mentored hundreds of students, all before the age of 50. Unbelievable.

To close, I'll use Prof. Baran's words:

"He had so much to live for and lived life to the fullest when he could.  

He would want all of you to do the same."

A Cage-y Déjà Vu

I love finding molecular "diamonds in the rough." Especially when they look, well, a bit like diamonds.

While strolling through the literature, I did a double-take at this polycyclic caged structure reported by Santiago Vázquez  (Universitat de Barcelona) and coworkers. Wow!

Source: ACIEE 2014, Vasquez et. al.

Spawned from a "highly pyramidalized" (nonplanar) olefin dimerization, it features three cyclobutanes, four "envelope" cyclopentanes, and four cyclohexanes locked in their "boat" conformations (Even worse? All those eclipsing methyl groups on each end . . .jeepers). One might expect a thing like that to fall apart in a minute with a little heat, but, amazingly, the compound remains stable up to 500 degrees Celsius.

Model of the "highly-pyramidalized" olefin monomer.
Phil Baran used to say that you could judge the strain based
on how badly your model's bonds bent...

A little reference digging proved that similar caged olefins were first produced almost half a century ago at Smith Kline & French, using a seven-step prep reliant on chloroketals and long-duration sulfuric acid stirs (yuck). A major step forward came in 1970, when Avila and Silva (San Fernando Valley State U) realized that blasting UV light at a double-Diels Alder adduct of acetylene dicarboxylic acid led to a symmetric anhydride precursor.

Vázquez extended this little gem of a starting material towards finding active antiviral analogues of amantadine. Using the imide version of Silva's anhydride, Vázquez produced a caged secondary amine (see right) that exhibits activity against mutant versions of the H1N1 flu virus. His compound also inhibits the influenza A wild-type proton channel; molecular dynamics simulations indicate that it performs a "flip" relative to bound amantadine that plugs up this pore more effectively.

Let's just hope that these new polycycles get an easier-to-pronounce nickname. 
Octopane? Rocketane? Congestane? I'm open to suggestions!

"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.

Scalable Ingenol? Phil Strikes Again!

Update: Want the inside scoop? Check out Open Flask!

I'm officially declaring it: Every 6-7 months, we should expect another huge molecule to fall to Phil & Co:

May 2011: Cortistatin
November 2011: Taxane Cores
May 2012: Ten Meroterpenoids.
December 2012: Ouabagenin

July 2013: Seen the latest* over at ScienceExpress? I think this scheme sums the whole thing up quite nicely:

And that's why it's in Science, kids...
Source: Baran Group | ScienceExpress

Ingenol falls! LEO Pharma, in collaboration with Scripps, may soon make gram-scale batches of ingenol analogs - something that used to take entire groups years to make. This paper cheers from so many different bleachers, I can't even count 'em all:

Total synthesis accesses trace plant metabolite!

Investment in basic research reaps huge Pharma dividends!

Imitating nature makes stitching together complex terpenes look easy!

Enzymes, Schmenzymes...

This paper really does have something for everyone. A volatile intermediate gumming up the works. A surprise crystallization. X-Ray structures. Some allenic Pauson-Khand reactions. A low-temp vinylogous pinacol rearrangement. Even some C-H activation / oxidation tossed in at the end.

If you want some more ingenol goodies, head on over to Chemistry World's fantastic write-up.
And, of course, join me on PhilWatch somewhere around January 2014...

*Thanks again to Brandon for a copy.

Podcast: Long Time, No See, Tetrahedron!

Link to July 8 issue

Sanford Group

P.S. I'm still figuring out rudimentary audio engineering. Helpful comments welcome!