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? 

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.

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?

Precious Serendipity

Serendipity often drives scientific inquiry.

Ask a famous scientist - Feynman, Archimedes, Fleming, to name a few beneficiaries - they'd tell you it's better to be lucky than good. But Pasteur's paraphrased "Fortune favors the prepared mind" spells things out more clearly; diving into the nitty-gritty of chemical transformations often brings up a chance pearl of wisdom.

Such is the case for a recent JACS ASAP, out of the Wang group at Xiamen University in China. Let's set the stage: the scientists attempt to create a stabilized bimetallic cluster compound from gold, silver, and hemilabile P-N ligands. When the starting Ag-Au complex meets acetonitrile and methanol, something interesting occurs: a dimeric crystalline compound forms, bridged by two fully deprotonated acetonitriles!

Those golden pyramids are pretty schnazzy.
Source: JACS | Wang group

So, why am I so excited?

1. That's a CCN (3-) anion stuck in there! What if you could, say, build a tetra-substituted carbon center just by adding electrophiles in sequence?

2. C-H activation of sp3 bonds = hard. Especially at room temp.
Well, there's (technically) 6 sp3 C-H bonds missing in that complex!

3. The authors note that water forms as the reaction progresses. Most nitriles, in the presence of Au/Ag catalysts and water, will hydrate to form amides. Not so here.

4. The authors point out that a gold oxo intermediate must be present for the cluster to form. They also point out that similar gold oxo catalysts (and silver oxide bases) pop up in the literature. Perhaps crazy intermediates like this commonly arise in gold-catalyzed reactions?

The best part? Studies like this always leave you with more questions than answers.
Perfect fodder for future projects.

Pd Bites Back! Isopropyl Surprise

Although we don't always admit it, we chemists love a good surprise.

That's the feeling I got reading through a recent JACS ASAP, from the Chen group at PSU. They've been playing with an easy-to-remove C-H activation auxiliary (PA) first developed by Daugulis back in 2005. They've taught it some pretty neat tricks thus far: C-H amination, alkoxylation, and even alkylation reactions using simple primary iodides.

Their latest extends the chemistry to methyl iodide, which, when combined with some silver salts and a phosphate additive, usually plunks a new CH3 on an unhindered, kinetically-accessible gamma-methyl (i.e. the chain grows by one). However, in the case of norbornene, something wild happens: the Pd catalyst activates a secondary C-H bond, sticks a methyl on, but doesn't stop there; it "bites" into the newly formed methyl and adds on two more, to produce an isopropyl group. Sweet!

     
       Source: JACS ASAP 2013 | Chen group, PSU

Chen's group shows that the position of the new i-Pr depends upon exo ("up") or endo ("down") relationships of the initial amine, but doesn't speculate much on mechanism.

O Norbornene Tree, O Norbornene Tree;
I do not grok your sterics.

Well, allow me! I wonder what happens if you keep feeding iodomethane into the system. I'm sure there's a limit (likely steric) that prohibits additional branching past a certain point, but currently nothing completely rules out a dendrimeric "norbornene tree" compound, right?

Readers, can someone disabuse me of this crazy notion?

Here We Go Again!

Well, it's been about 12 hours, and the internet 'done blown up' over allegations of plagiarism between a 2013 Chem. Eur.J. and a 2009 JACS. Now, let's say that all this blog coverage brings a lot of otherwise-unwanted attention to your group, and people start to notice other similarities...

...such as the ones between a 2012 Dalton Trans. (same gentleman) and a 2010 JACS, this time from Chuan He's group over at the University of Chicago. Holding these up face-to-face, there sure are a bunch of similarities (again!).

He (p. 2): "In this study an Amt1-based copper(I) fluorescent reporter, Amt1-FRET, was constructed by subcloning the copper-binding domain of Amt1 (residues 36-110) between a cyan fluorescent protein (CFP) and a yellow fluorescent protein (YFP), taking advantage of the copper(I)-binding-induced conformational change of Amt1 (Figure 1b). This strategy, pioneered by Tsien and co-workers, produces a genetically encoded fluorescent reporter by inserting a sensing domain, which undergoes a conformational change upon target binding, between two fluorescent proteins that are fluorescence resonance energy transfer (FRET) pairs.10,11,21 Amt1-FRET was expressed in E. coli in the presence of 1.4 mM CuSO4 and purified to yield the copper(I)-bound Amt1-FRET (Amt1-FRET-Cu) (Figure S2, Supporting Information). The fluorescence spectra of both copper(I)-bound and apo-Amt1-FRET were taken by exciting the FRET donor CFP (433 nm) and recording the fluorescence intensities of the YFP (527 nm) and CFP (477 nm) emissions. An increase in FRET between YFP and CFP in Amt1-FRET in the presence of Cu+ was observed through the increase of the peak ratios (I527/I477) from 1.95 to 2.26 as soon as metal was added (Figure 1c), supporting the proposed copper(I)-binding-induced conformational change of Amt1"

Yan (p. 2): "In this paper a PMtb-based copper(I) fluorescent reporter, PMtb-FRET, was constructed by subcloning the copper(I)- binding domain of Mtb CDC 1551 (residues 1–162) between cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP), taking advantage of the copper(I)-binding induced conformation change of PMtb (Fig. 1) to determine the free concentration of the copper(I) in Mtb protein. This strategy, pioneered by Tsien and coworkers,31 33 produced a genetically encoded fluorescent reporter by inserting a sensing protein domain, which went through a conformational change upon target binding, between two fluorescent proteins that were FRET (fluorescence resonance energy transfer) pairs.31–34 PMtb-FRET was expressed in E. coli in the presence of 1.5 mM CuSO4 and purified to yield the copper(I)-bound PMtb-FRET (PMtb-FRET-Cu) (Fig. S2, ESI†). The fluorescence spectra of both PMtb-FRET-Cu and PMtb- FRET without copper(I) were taken by exciting the FRET donor CFP (433 nm) and recording the fluorescence intensities of the YFP (527 nm) and CFP (477 nm) emissions. An increase in FRET between YFP and CFP in PMtb-FRET in the presence of Cu(I) was observed through the increase of the peak ratios (I527/I477) from 2.01 to 2.45, supporting the proposed copper(I)- binding induced the conformational change of PMtb-FRET (Fig. 1)."

Or how about this swatch?

He (p. 2): "To further investigate if different metal ions interfere with the Cu+ binding, the copper(I)-binding-induced FRET changes were measured in the presence of an equal amount of other metal ions. First, the signal for other metal ions after the addition of 5 equiv of metal to Amt1-FRET was measured, followed by the addition of an equal amount of Cu+ (Figure 2b). In all cases, 100% of the signal was recovered, showing that Cu+ binding is tighter compared to that of other metal ions tested and that the presence of other metal ions does not interfere with copper(I) binding to Amt1-FRET. Also, common anions were shown not to interfere with copper(I) binding"

Yan (p. 3): "To further investigate whether different metal ions would interfere with the Cu(I) binding, the copper(I)-binding-induced FRET changes were measured in the presence of an equal amount of othermetal ions. Firstly, the signal for other metal ions after the addition of 5 equiv ofmetal to PMtb-FRET was measured, followed by the addition of an equal amount of Cu(I) (Fig. 5). In all cases, 100% of the signal was recovered, showing that Cu(I) binding was tighter compared to that of other metal ions tested and that the presence of other metal ions does not interfere with copper(I) binding..."

*Even worse? This time, the forgers couldn't even manage a citation!

I didn't have time today to cantrill the whole thing, but look forward to a lively (continuing!) debate in the Comments. Thanks again to Shawn at WPI for alerting me to the later papers.

Update (1/23/13) - Thanks also to Prof. Chris Goldsmith for the initial hat-tip on this round!

Escalation

Dr. Sonja Krane, Managing Editor at JACS, contacted me to encourage dialogue with the authors of the Fe-S redox catalysis paper. In the interest of full disclosure, I've reprinted my email to the lead author, and I will re-post any response I receive.

Dear Prof. Nguyen:

Good afternoon. My name is See Arr Oh (a pseudonym), and I write a chemistry blog called Just Like Cooking. I've posted about one of your recent publications in JACS ASAP:

http://justlikecooking.blogspot.com/2012/12/desert-island-chemistry-simple-as-fe-s.html

http://justlikecooking.blogspot.com/2012/12/call-to-arms.html

Another chemist at Princeton graciously offered to repeat one of your reactions (Table 2, entry 2), and could not duplicate your group's yield or purity. Further discussion can be found in the comments section of the second post. Additionally several other members of the chemistry community have expressed an interest in running it themselves, with the intention of aggregating data under the Twitter hashtag #RealTimeChem.

Please share some more information - do you have any hints or tips for successful duplication? 

Thank you in advance,

See Arr Oh

seearroh@gmail.com

Cross your fingers!