Saturday, April 12, 2014

Doubt

(Reference: JLC1, JLC2, Derek1, Derek2)

Since February 2014, Prof. Tohru Fukuyama's group has issued corrections to 11 published papers in three journals: Angewandte Chemie, Journal of the American Chemical Society, and Organic Letters. Fukuyama's former colleague, Dr. Satoshi Yokoshima (now at Nagoya U), appears as a co-author on 10 of the 11 papers.

Chemical and Engineering News intrepid reporter Beth Halford recently interviewed the two men regarding their ongoing "Correction Crisis." Readers reacted skeptically:
[Sigh]...No, I don't.

Let's look at a few more recent correction scandals. After the Cossy group published some strange spectra, Prof. Cossy wrote a letter to the entire Organic Letters community, saying:
"I reach out here with the hope that all readers might learn from this experience as I certainly have. From now on, I will never let a student or postdoc from my group upload a manuscript and/or Supporting Information file to a journal submission site by themselves"
Succinct, supportive, reflective. Prof. Cossy even allowed the responsible lab member to speak through her, saying "I know my behavior is highly unethical. I am deeply sorry for what I have done."

When the Dorta group published a strange statement in the body of their Supporting Information, Dorta spoke to Organometallics Editor John Gladysz, claiming "...the statement [in the SI] was inappropriate." To my knowledge, Prof. Dorta has never blamed his student coauthor, Emma.

Now, let's take a look at the C&EN article. How do Fukuyama and Yokoshima address their spate of corrections?
“Almost all of our recent research accomplishments are the results of close collaboration between myself, Professor Yokoshima, and our students,” Fukuyama explains.
Team spirit! OK, I'm fine with that. Next? (emphasis mine):
“My impression is that some of my students who deleted minor peaks did not take seriously the idea that the spectroscopic data are important proof of the compounds’ purity,” Fukuyama says. “I myself have never manipulated the spectroscopic data or even dreamed that my students would do such a stupid thing.”
Wow. Did they just throw every one of their 19 coauthors (I counted!) under the bus?
Another (emphasis mine):
“It was our fault not to scrutinize every spectrum in the supporting information before sending them out for publication,” Fukuyama adds, “but my staff members and I simply believed that all of my students are honest.” As soon as they learned of the manipulations, he says, “we told our students never to do such a stupid thing. I can assure you that we will never send out manuscripts containing manipulated spectra again.”
To paraphrase the Bard - the Professor doth protest too much, methinks.

Note the "Yes, but..." structure of his argument. See how it lobs the blame squarely back on the coauthors? And the choice of language, calling one's apprentices "stupid" and essentially dishonest? Not cool.

In most scientific organizations, culture comes from the top. Even coauthor Yokoshima admits that...
“We have told our students that the NMR spectra should not contain peaks of residual solvents or impurities for publication...our comments and the limited machine time seemed to have forced them to use the ‘Delete Peak’ function.”
If your group focuses on "clean up your spectra" more than "purify your compounds better," that's a communications issue. If a professor with a large group sees nothing but perfect spectra all day, two thoughts should crop up:

1. "I must have the smartest, most efficient students in the world," or...
2. "Something's fishy here."

Even the busiest profs in the biz - traveling for international conferences, serving on NIH panels, consulting - must still see their students' work at least three times prior to publication. Group meetings, one-on-one office meetings, project round-tables, manuscript submission, reviews, galley proofs? All perfect opportunities to catch ethical errors privately before revealing them to the wider world.

Sadly, the professors don't seem to answer the real question: What went wrong here? Public shaming won't fix your lab's culture. By closing ranks and shutting out 19 potential collaborators, Fukuyama and Yokoshima invite even more scrutiny into their lab's motivations.

Update (4/12/14) - Changed the last paragraph to avoid any judgment on the interview style. I believe Ms. Halford conducted it just fine.

Friday, April 11, 2014

Friday Fun: Insane in the Membrane

...CARBORANES in the Brain!*

Source: ACS Chemical Neuroscience | Sydney University 

From the pages of the (relatively new) journal ACS Chemical Neuroscience, comes this report about development of new antidepressants with rather...interesting appendages. The adamantyl (1) and Cookson's diketone (3) molecules shouldn't surprise, but the rest? You're not imagining things - those are blood-brain barrier-penetrant lead molecules based on cubane (2) and closo- and nido-carboranes (4,5). At 20 mg/kg, compounds 2 and 5 restore significant function to mice following stress tests. The authors indicate that, although the caged compounds look pretty huge, they're actually fairly isosteric (similar size) to a phenyl group, yet possess rugged metabolic stability.

*With apologies to Cypress Hill

Friday Fun: Happy Birthday, Percy

Today's Google Doodle honors the 115th birthday of Percy Julian, chemical entrepreneur and first to synthesize physostigmine:


Note that, with the exception of the (ugh) "resonance circle" of the aromatic core, that physo structure is spot on! Ditto cortisone, on the left, for which Julian developed one of the first commercial-scale processes.

Want more? This NOVA special tells it well (thanks, Dr. Ru!). Highly recommended.

Thursday, April 3, 2014

Gold Steps Up

Update, 4/5/14: On Twitter, Yunus chimes in to recommend this Hashmi paper, showing a mononuclear Au(I) catalyst - with crazy adamantyl appendages - that gets down to 0.0001% loading!

--
Catalyst: A substance that increases the rate of a reaction without modifying the overall standard Gibbs energy change in the reaction (IUPAC Gold Book).

Though most chemists agree on the above definition, there have always been two camps: "Academic" catalysis (1-20 mol%, 5-100 turnovers), and "Industrial" Catalysis (<0.01 mol%, >10,000 turnovers). As more researchers seek to translate early discoveries into efficient, "green" processes, the desire for robust organometallic species has skyrocketed.

Right now, a few such homogeneous catalysts have made the jump: the Grela Ru metathesis catalysts (0.001%), copper catalysts for boron addition (0.005%), and some iridium and palladium species.

Gerald Hammond and Bo Xu (Louisville) want to add one more to the list: a highly-stable gold catalyst. Their new catalyst, dubbed "BisPhePhosXD-AuCl" (Phew!), takes development lessons from Buchwald (electron-rich, C-to-metal bond) and Widenhoefer (steric bulk to discourage off-cycle species). 

Now here's the fun part: the authors run several typical gold-catalyzed reactions side-by-side with their improved catalyst. In most cases, they're able to shave off 99.9% of the catalyst loading, with comparable yields. Granted, certain reactions take more time with this approach, but a few finish ahead of their literature counterparts. Wow.

Aldrich sells the precatalyst, if you're itching to try it yourself. I'll be very interested to see the next generation of bulked-up ligands, and whether this reactivity transfers over to other precious metals, namely platinum, iridium, or rhodium.

Wednesday, April 2, 2014

Fukuyama, Round 2

Update, 4/3/14 - On a hunch, I looked through major publishers' databases for more recent Fukuyama corrections sharing a specific author's name. Found this (Chartelline C) at ACIEE, alleging "[im]properly processed NMR spectra." Since this author published >40 papers with Fukuyama, more may be coming.


ACIEE, 2014 (above) and 2012 (below)
An astute commenter has clued me in to the latest round of corrections coming from the Fukuyama research group (see 1, 2, 3, 4). Targets affected include lyconadins A-C, ecteinascidin 743, and mersicarpine, and publication dates range from 2010-2013. This time, they're in JACS which, to my knowledge, does not (yet) employ a full-time data analyst like Organic Letters does.

The corrections read much the same as the last raft, released two months prior in Org. Lett., alleging spectral manipulation for multiple intermediates and final molecules, including removal of solvent peaks. Here's one example showing 13C spectra* for intermediate 7, from the synthesis of lyconadin A:

Original spectrum (2011)*

Corrected Spectrum (2014)*
Clearly, there's a bunch of "stuff" in 7 that had to be digitally removed by one of the authors. And this is just one compound; each paper contains several such examples of "improperly manipulated" spectra (direct quote!).

So, what's going on here? I have a theory, although it's a bit of hearsay since I'm not privy to the inner workings of either journal. However, the astute reader will note one author whose name appears on nine of the ten corrected papers from Feb-April...uh-oh.

Was there a bad apple in the Fukuyama lab? More details as I have them.

*Apologies for the different shading, due to my computer and not their SI files.

Tuesday, April 1, 2014

"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.

Friday, March 28, 2014

Friday Fun: Sweet Cardamom (Peroxide)

Rice pudding. Ginger snaps. And...malaria?

That's what'll be going through my head next time I cook with cardamom, thanks to Tom Maimone and coworkers (UC-Berkeley) and their under-the-wire JACS ASAP from yesterday afternoon. The title and abstract scratch all the Baran lab alumni itches: 1) biosynthetically inspired, 2) novel mechanisms, 3) scalable, 4) just four steps! And hey, we're making stable endoperoxides, which all the cool kids are into nowadays.


Not their actual abstract graphic...
As Maimone points out, the latent symmetry of the final product offers a really neat assembly strategy. The group McMurrys together two units of (-)-myrtenal, then hits it with singlet oxygen, initially forming a 6-membered endoperoxide they fragment / rearrange with base. A gentle oxidation (DMP) sets them up for the wild step: stitching together a 7-membered endoperoxide using Mn(III)*, a radical source, a silane reducing agent, and even more oxygen. Simple phosphine reduction knocks down the last hydroperoxide into an alcohol, and the whole target (7 stereocenters!) falls out as a single stereoisomer.

Pretty sweet.

P.S. - Since the group's made over half a gram in just this first push, I'd assume an efficacy paper against live Plasmodium parasite hot on the heels of this one...

*We're apparently already calling this the "Shenvi catalyst"...wasn't this only two months ago?