Beautiful Chemistry: Hoye's HDDA + Napth Trap

Every so often, a reaction behaves so well that you just publish the crude NMR spectrum.

Professor Tom Hoye's HDDA* reaction, first reported in 2012, apparently fits the bill rather well, wouldn't you say?

From Org. Lett. 2015, ASAP.

Amazing - heat up a heavily conjugated triyne for 2 days, and it just does one thing, reproducibly and immaculately. I wonder whether Hoye and his group have any further tricks up their sleeve to try and control the diastereo  enantioselectivity of that sweet new quaternary center...time will tell.

--

*Please allow me touch of professional jealousy - this reaction opened up so many different questions for the Hoye group that they've published 10 manuscripts on it in just the last 3 years. Damn.

**Perhaps I've developed a love affair with barrelenes. Hmm.

Thanks for the catch, Per-Ola!

Cubanes! Get Your Cubanes, Here!

A cube of med-chem cubanes**

It's not often you see drug candidates advanced with cubane substructures.* A collaborative group from the UK branch of AstraZeneca and Oxford University aims to change that: a report in Organic Letters indicates they've produced gram-scale quantities of cubane derivatives with common med-chem handles already "baked in."

Starting from a 1,4-cubane diester, Burton, Davies, and Wlochal take turns elaborating each side into thiazoles, beta-diketones, nitriles, amine salts, and ynones. Though more cautious readers might expect the cubed synthons to go up in smoke, they actually seem to survive fairly rigorous conditions - boiling water, phosphoryl and oxalyl chloride, TMS triflate, LDA.

I'd be most interested to hear from any readers who integrate these new building blocks (sorry, couldn't resist!) into their research. It's hip to be...cubic.

* On Twitter, CJ (rightly) points out that the authors could have done some DSC (stability) and solubility assays, just to put minds at ease that these synthons really could be integrated into a drug campaign.

**Not a real substance (but wouldn't that be something???)

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:

.@cenmag 's Bethany Halford interviews Prof. Fukuyama about NMR spectra issues. Do you buy it? http://t.co/NMvzkofYmW
— Unstable Isotope (@UnstableIsotope) April 12, 2014

[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.

Fukuyama Mea Culpa in Organic Letters Corrections

Remember all the recent dust-ups over potentially doctored NMR spectra? How about when Organic Letters EIC Amos Smith went on the offensive, hiring a full-time data analyst to sniff out fishy details?

Well, we have a major opening salvo in the war on sketchy Supporting Information (thanks to an anonymous JLC commenter for the tip-off). Seems that Prof. Tohru Fukuyama (U. Tokyo) has issued six simultaneous Org. Lett. corrections in yesterday's ASAP section. (1, 2, 3, 4, 5, 6).

This is a big deal, not least because Prof. Fukuyama's reputation looms large in the synthetic community, but more because the corrections impact challenging targets from his group (manzamine A, huperzine A, lysergic acid, histrionicotoxin) and span multiple years (2008-2013).

Shockingly, the corrections all admit deletion of solvent peaks or impurities from final, published spectra. This correction announces 20 such "edits." In some instances, when the group re-examines the spectra, they're so unreliable that they cannot correct the record: "Samples included some unknown impurities, thus the exact purity could not be determined."

I'm not sure whether to applaud or condemn the Fukuyama group - if they chose to come forward voluntarily to correct the record, I applaud the effort. However, if they were instead strong-armed by the OL Data Analyst, then a culture of data manipulation has been uncovered at the highest levels of our field (reminder: this is just one journal, hold on for the slate of corrections in other venues).

Wish I could say that this meant "Case Closed," but I think we're only seeing the tip of the corrections iceberg in Organic Letters.

New Tricks for Old Reagents: Oxygen Everywhere!

Passed a time, not too long ago, when if you wanted to oxygenate a selected C-C or C-H bond, you had to jump through several hoops: Over-oxidize (read: DESTROY!) then reduce again. Convert it to another functional group first, then use an expensive catalyst. Use toxic heavy metals (Cr, Hg, Pb, anyone?) in their highest oxidation states...and, oh yeah, heat the heck out of it.

The past decade has seen kinder, gentler oxidations emerge in rapid succession. Cobalt. P-450s. Iron. Now, two recent papers bring new wrinkles to the oxygenation of organic molecules in unexpected ways.

The first, from the Concellon / del Amo group in Org. Lett., relates a neat trick performed by Oxone, usually a reagent reserved to make other oxidants.

The researchers deal with their serendipitous discovery with humility and class:

"This work was not originally intended..[but]...was worth studying. [We] remark that Oxone is a crystalline solid oxidant, easy to handle, non-toxic...and, above all, stable and cheap."

All great reasons to run these reactions, which are formally derivatives of the classic Baeyer-Villiger reaction. They blast through a brief substrate table (26 entries, 33-95% yields), and seem pretty excited about investigating the mechanism.

The second reaction, hot off the Nature presses, involves another legacy reagent: phthaloyl peroxide. I suspect the Siegel group was looking for sp3 C-H activation conditions, but instead discovered a serendipitous site-selective arene activation, reliably producing phenols.

The reaction works across a broad functional group palette - azides, silyl groups, boronate esters, primary halogens - that other oxidants would tear apart. They ultimately do about 50 substrates, including 3 natural product-like scaffolds, with yields ranging from 45-95%.

Deciphering the mechanism requires Ken Houk's computational super-powers. The researchers discover a "reverse-rebound" mechanism operates, meaning an oxygen radical from phthaloyl peroxide adds into the ring, the electron bounces around in the pi cloud, and then ejects the ipso hydrogen in a two-step process. Interestingly, other radical oxygen oxidants (di-benzoyl peroxide) led to primarily sp3 oxidation, showing that the structure of the radical precursor plays a big role here.

Friday Fun: How to Fund Your Data Analyst

Remember Amos Smith's Editorial, discussed here yesterday?

(and here, and here, and here)

I wondered, on Twitter: How many submissions does Organic Letters get in a year, anyway?

Sonja Krane, a JACS editor, set me straight:

@seearroh Journal submission statistics aren't publicly available. Sorry I can't be more helpful in this case!
— Sonja Krane (@sonjakrane) June 6, 2013

Rats, foiled again! But then, an interesting tidbit from Stu Cantrill over at Nature Chemistry
(N.B. Stu used to work at OL):

@seearroh When I was there, accept rate was getting down to 50%. I suspect now 30-40%, so look at papers published in 2012 & go from there.
— Stuart Cantrill (@stuartcantrill) June 7, 2013 

Hmm, so all I have to do is count. In 2012, Organic Letters published 24 issues, which seem to have an average article count ~80 / per.* So that's 2,000 articles / year, give or take 100. Now, let's assume Stu's lower range (30% acceptance) - that's 7,000 submissions. Back of the envelope, I'd guess an average Supporting Info section to clock in at around 40 pages nowadays.

That's 280,000 pages of SI.
Pity the poor Data Analyst.

But...what a great way to FUND this potentially burgeoning "alternative" career! A nominal fee of, say, $0.10 / SI page - price of a photocopy from way back, kids - would immediately bring $30K into the journal's coffers. A $3 "data verification" fee per manuscript brings another $21K. Not big money, but we're now into the realm of serious subsidy for someone's salary.


Readers: Would you pay $7.00 to submit your OL manuscript?

* [(Dec 21 + July 6 + Jan 6 + Apr 20) - (corrections + editorials)] = 318 articles / 4 = 79.5

OL's Smith Stands Up for Data Integrity

Did you know Org Lett had hired a full-time Data Analyst? I didn't.

All I can say is: What took so long?

Esteemed professor and Editor Amos Smith wrote a terse, pointed piece for OL ASAP yesterday. Titled "Data Integrity," it explores ethical conduct for article submissions in the wake of several (!!) recently uncovered instances of data manipulation. Smith doesn't pull punches:

"Even if the experimental yields and conclusions of a study are not affected, ANY manipulation of research data casts doubts on the overall integrity and validity of the work reported."

What do authors say when faced with the facts? They throw their students under the bus!

"In some of the cases that we have investigated further, the  Corresponding Author asserted that a student had edited the spectra without the Corresponding Author's knowledge. This is not an acceptable excuse!"

(Perhaps we should label these "Sezen situations.")

I highly recommend reading the whole thing, if for no other reason than the righteous feeling of good-triumphing-over-evil washing over you by the end. For those interested in alternative #chemjobs, might "Data Analyst" be a pretty good use of your lab skillz?

The Pterodactyl Flies Again

I'll admit it: I was a bit bummed out to read B.R.S.M.'s tweet regarding Totally Synthetic's untimely demise:

As a young pup, I cut my teeth in a few guest posts over at Paul's place. Since I saw a sexy, streamlined version of one molecule go by in Org. Lett. last week, I decided to do a (memorial? celebratory?) post in true Tot Syn style.

Folks who've read the other syntheses might agree with me that the trigonoliimines, as drawn by Tambar, resemble a terrifying pterodactyl:

Respectfully stolen from Tot Syn

Both Tambar and Movassaghi aimed for asymmetric syntheses, and started from a [2,2] fusion point between differentially-functionalized tryps. They're aiming to make the whole lot (Trig A-C), so this semi-biosynthetic approach makes sense. But Hao's latest paper sets its sights squarely on (all together now!) the (6/5/7/5/6/6) core of Trig A - sadly, a much "flatter" molecule with less 'dinosaur' character. But, the target still shows moderate antiviral activity, so the group reasons a shortened synthesis may expedite analog generation.

Hao aims to use two fairly well-known reactions to join his tryptamines: a modified Strecker, followed by a Houben-Hoesch cyclization. First, the group pops open a methoxylated, phthalamide-protected Trp precursor using CuCl under oxidative conditions (the 'cool' kids use blue LEDs now). Now they've set the stage for the really short racemic synthesis:

Initial TMS-promoted imine condensation with the aryl ketone sets up a CN alkylation, which cyclizes on the nearby formamide (probably through an isonitrile). Now here comes a 7-membered Houben-Hoesch ring closure, which they perform in a one-pot prep due to instability of the methoxy-Strecker intermediate. Basic workup, followed by hydrazine deprotection / cyclization, produces Trigonoliimine A, in a respectable 35% yield (4 steps, 3 pots).

Godspeed Dr. Docherty, wherever you are...

Update: Neil posits that Paul is still alive and well, and writing for Chemistry World.

Stump Your Friends! A Devious Diels-Alder

You may have noticed a lot of chatter about the "turbo-charged" Diels-Alder (Chemistry World, C&EN) recently reported by Prof. Thomas Hoye and colleagues at UMN. With all the fuss, another equally exciting, albeit subtler D-A development might have been overlooked.

Introducing: the metathesis-modified Himbert reaction!

Wait...the what?

Browse on over to Org. Lett. ASAP for a crazy two-stepper you're sure to love. Here's the opening scheme, so sharpen those pencils, and try some electron-pushing before I tell you the secret:

*

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*****

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*

Give up? I tried all sorts of pi-arene cyclizations, and drew out amide tautomers until my eyes bled. But the real answer, clues author Prof. Chris Vanderwal, lies 30 years in the past. A brief (2/3 page!) 1982 communication in ACIEE related a rare bird indeed: an unactivated benzene ring participating as a diene, with no added metal catalysts, pressure, acids, or bases. Upon heating, the tethered alkyne isomerizes to an allenamide, which gladly serves as the dienophile (somewhere, Richard Hsung is smiling).

Source: Himbert, Henn ACIEE 1982, p. 620

Vanderwal's insight comes next: seeing a strained [2.2.2] diene, he figures he can pop it open with some metathesis magic. A touch of Hoveyda-Grubbs, some ethylene, and a little heat rearrange the strained system to a complex 7-6-5 tricyclic lactam. His group prepares quite a few of these scaffolds, and hopes to utilize them to access several of the Erythrina alkaloids. 

P.S. First one to use this problem for 'mechanisms' group meeting wins!