Podcast: Calcium Redux

My post on calcium catalysis didn't really engage a wide audience of readers the way I had wanted it to. A few kind souls helped me refine my approach, which I thought might work better as a radio blurb.

Dear Jake: Thanks, I took on your challenge. Here's my new entry:

Music: Hall & Oates, Bird and the Bee

Readers, whaddaya think? More accessible, less? Please let me know in the comments!

Catching Copper's Ghosts

Copper, copper, everywhere (and much more than you'd think). It's found in coins, wiring, statues, paints, and even as part of a balanced diet. Chemists, in particular, have long loved copper for its ready availability, well-defined redox states, and its wealth of reactions; just last week, Prof. Sherry Chemler (SUNY-Buffalo) recounted nearly 100 years of copper's catalytic successes* in a Science perspective.

Source: Ogle / Bertz group | Angew. Chem.

Though scientists have long studied copper-catalyzed reaction, several short-lived, unstable intermediates
have defied characterization. Now, Profs. Craig Ogle and Steven Bertz (UNC-Charlotte) may have caught one of these ghosts: an elusive C=O copper pi complex. Using rapid-injection techniques at -100 degrees C, the team "freezes out" the complex, which they study by 2D NMR (which shows relative positions of various atoms) and cryoloop X-ray crystallography (shows absolute position in a fixed crystal lattice).

When the team warms the compound much above -10 degrees C, it immediately falls apart.

Isolating otherwise reactive intermediates lets us peer inside** the "black box" of catalysis. In this structure, the lithium atom tugs at the oxygen's lone pair, allowing the copper to slip into pi-coordination in a "side-on" fashion. Though it's tough to see from this picture (left), the authors point out that five atoms (O, C, Cu, Me-a, Me-b) all sit together in one plane, which validates earlier NMR models. Finally, there's some hints of reactive fate here, as the "bottom" methyl group shortens up, preparing to jump off the copper atom and onto the central carbon, while at the same time, the copper atom cozies up to the oxygen. Remarkable stuff.

* And that was just on one class of reactions!
**The deeper we look, the more crazy, head-scratching stuff we find. Ask your local organometallic enthusiast for more info...

"Crystalline" CO - Saccharin's New Trick

Seems I'm posting an awful lot about artificial sweeteners these days!

This latest example, from the always entertaining and informative folks at Angewandte Chemie, employs our old friend N-formylsaccharin* as a carbon monoxide "equivalent" for Pd-catalyzed addition reactions:

Credit: Manabe Group | ACIEE

Quite a few benefits accrue: No pressure equipment. 'Medium' heat. Relatively low catalyst loading.  Cheap, off-shelf reagents. If they could figure out a slightly less exotic reductant, I'd use this all the time!

So, how does it work, anyway? The researchers confirm CO release by treating formylsaccharin with several bases and observing CO evolution.** The standard (boring) formylation model might be operative here - Pd oxidative addition, CO insertion, reductive cleavage (rinse, repeat). 

OR (more excitingly), the authors note that they detect a transient "acylsaccharin" by HRMS. This might imply that the formylsaccharin reacts directly with the palladated arene, or that the sodium saccharine byproduct plays a role in stabilizing / promoting reduction of the insertion intermediate.

Sweet.

*OK, so it's not saccharin itself, but pretty darn close. First developed by Cossy in 2011 for formylating amines.
**A great mechanism for those looking for cume questions!

Friday Fun: Thulium Breaks 'Em Down

Seriously, how often do you see thulium in the chemistry mainstream?

Prof. David Procter and Dr. Michael Szostak, of U. Manchester in England, want you to think of it a lot more often. Their latest ACIEE explores some crazy stunts thulium diiodide can do when mixed with a little alcohol: Blowing apart esters. Reducing arenes. Unwrapping amides (see below):

All thanks to the extra reducing power of this "non-classical" lanthanide salt. At a good 50% more than samarium diiodide, thulium diiodide can inject a single electron into just about any C=O or arene around, and there's evidence that it slips into neighboring C-N bonds to promote fragmentation:

Source: Szostak, ACIEE 2013

Bill Evans (organometallics, not jazz) previously explored this reagent over a decade ago, marketing it as a souped-up SmI2 / HMPA. His study looked at cyclic ketones, which formed adducts with primary iodides in less than a minute with a healthy dose of TmI2(DME). Despite these exciting early results, it appears that thulium took a back burner to the samarium 'craze' of the mid-'00s, and only now gets its chance in the limelight.

Keep an eye out for more TmI2 reactions; after 100 years of new bond-forming reactions, it's nice to see trends to the contrary.

Happy Friday,
SAO

Update (6/14/13) - Added Prof. Procter and group website. 
(6/14/13) - Changed lactam to amide - thanks, Anon!

Tracking Reactions? AFM FTW

Thanks to @slugnads at Wired for pointing out this story!
Update 5/31/13 - Derek's also got a great review going at Pipeline.

Remember 2009, when you gasped for a moment at the beautiful IBM structure of pentacene? 

Credit: BBC News | IBM | Science

In 2012, just in time for the 2012 London Olympics, the same team helped to image "olympicene."

Credit: BBC | IBM

And now, just 5 months into 2013, a team of researchers from UC-Berkeley / LBNL and several physics institutes in Spain have watched cyclizations occur on silver surfaces, using AFM tips to detect the ghostly products in stunning resolution:

Credit: Science | LBNL | UC-Berkeley | Wired

HOLY. COW.

As if this couldn't sound any more amazing, the researchers were able to predict and visualize several products previously predicted by theory, but never directly observed (stabilized diradicals, anyone?). 

So, will this be a standard technique for the practicing chemist? I'm guessing not for quite a few years, since the hardware involved still isn't commonplace, and the technique probably works best at prohibitively high dilutions with flat molecules. Med chem? Sure, you could watch a Suzuki coupling occur, or watch a Cope rearrangement, but for "3D" molecules (read: alkaloids, vitamins, sugars, etc...) I think NMR and X-ray crystallography will still be your best bets. 

But to paraphrase the futurists, predictions ironically suffer from poor foresight - after all, just over a month ago, a Japanese group disclosed how to take on-demand crystal structures of just about anything. So, I'm sure someone will invent a "rugged" surface capable of guiding the AFM tip around points and curves to monitor, say, real-time Pictet-Spengler reactions. Can't wait!

What-a-Ouabagenin! Grams on Demand

I can't believe I got back from New Year's without finding a single post on ouabagenin* [wah-bah-jenn-in], the latest from Phil & Co. in Science this past week:

Ouabagenin, a polyhydroxylated (>5 -OH groups) cardenolide (steroid with an appended lactone) positive inotrope (helps heart pump more forcefully) had been completed only once before, in a 40+ step relay synthesis by Deslongchamps in 2008 (got all that?!?). Only a few mg were prepared, and those of you familiar with the Baran group know that the only real way to make natural products is with a shovel and bucket - gram-scale, baby!

Hulkster - Quite interested in
gram-scale ouabagenin precursors...

So, we start out with 20 g of cortisone acetate - just one reduction shy of Preparation H - and two steps later have a fully protected version of adrenosterone. The group first tries a porphyrin-catalyzed C(19) hydroxylation (the bottom-left methyl), which doesn't work, so they opt instead for some fancy solid-state photochem to generate a cyclobutane ring, which selectively pops open with NIS under sunlamp irradiation.

Selective de-ketalization and iodide hydrolysis sets the stage for a three-step sequence (peroxide, SeO2, peroxide) to generate a diepoxide (right, top), a.k.a. the "most difficult transformation to secure on scale." They toss a "gamut of conditions" at the molecule, only to receive mixtures of enones. Finally, they find that using in situ Al-Hg amalgam (we're talking foil / scissors here!) combined with Sharpless "on water" suspension produces the desired triol, which they wrap up as an acetonide.

Next, "superhydride" reduction both reduces the ketone and protects - as a boronic ester - the remaining two hydroxyl groups. A little Saegusa-esque dehydrogenation, a fluorous solvent-enabled bond migration, and a Co-catalyzed hydration produces 'protected ouabageninone' (right, bottom).

Endgame - We're not out of the woods yet, folks! Conversion of that lone ketone into the vinyl iodide (hydrazine, iodine, TEA) followed by a modified Stille returns a butenolide diene. They again toss in a 'kitchen sinkful' of reductants, only to find that dicobalt-borane (cool!) followed by Barton's base (N-tert-Bu-TMG) produces the correct butenolide orientation (3:1 dr). A touch of HCl in methanol liberates the natural product.

Despite the fact that they report the last few steps on just 30-60 mg, the group claims that they have >0.5 g parked at the protected ouabageninone (vide supra). With this synthesis, Baran also alludes to the overall usefulness of his "redox-relay" strategy, which has certainly served him well before.

*Bonus - In the Scripps press release, Phil calls ouabagenin "probably the most polyhydroxylated steroid known on planet Earth." Billions of yet-undiscovered microorganisms could not be reached for comment.