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."

USC to Acquire Scripps?

Other perspectives: The Scientist, Science, L.A. Times.

Well, that's not something you see every day.

Courtesy of U-T San Diego* - with bonus Derek Lowe quotes! - comes talk of the University of Southern California taking over gobbling up "acquiring" the Scripps Research Institute. I'm sure we'll hear much more about the motivations as events develop, but the early suggestion involves cold hard ca$h - declining NIH funding paired with expiry of major pharma partnerships on the Scripps side, billions in fundraising** on the USC side. I've been hearing about salary squabbles and shrinking department budgets at Scripps, but didn't realize things had gotten to this point.

Clouds in parking lot, 2014

I don't see the press releases on either side that U-T San Diego alludes to,
[UPDATE 6/19 - Here's the releases!]
Perhaps someone on the inside of either institution knows more? seearroh_AT_gmail

*The guys who helped break the Nicolaou to Rice saga!
** I mean, they did just get all that money from Dr. Dre...

Twisted Olefins in "Click" Chem?

Everyone digs the copper-catalyzed "click" reaction between azides and alkynes - its fruits have ripened into applications for protein labeling, drug analogs, and green synthetic approaches.

Science Express just released an intriguing read from the Fokin group, which uses reaction calorimetry (how hot? how fast?) and mass spec isotopic enrichment studies (where'd that atom come from?) to study the copper-catalyzed click. Using calorimetry, Fokin's group determines that two copper atoms must cooperate to form the desired triazole; the uncatalyzed reaction limps along (~7%) in the same amount of time that the catalyzed reaction - which gives off a brief burst of heat - reaches completion (>96%). 

To try and tease out which copper does what, the team synthesized an isotopically-enriched ⁶³Cu catalyst, which they added to a "normal" (⁶³Cu / ⁶⁵Cu) isotope blend of a copper-bound acetylide. Time-of-flight mass spec showed isotopic enrichment of copper in the resulting isolated copper species. How the heck can that happen?!? 

Well, it can't. . . unless, of course, there's an intermediate where the two copper atoms interchange. Enter the crazy, wild world of gem-dimetalation, a concept several groups (Fürstner, Blum,  Gagné) have recently studied for a variety of d¹⁰ metals (Pd, Ag, Au). Even more crazy, the enrichment indicates that an NHC ligand "jumps" between the two copper atoms, hardly usual behavior for such a strong donor ligand. To explain these results, Fokin constructs a modified catalytic cycle, shown below:

Source: Science | Fokin group, Scripps

Check out that prism-shaped intermediate in the lower left. Anything seem strange about it?

Think, for a moment, about axial chirality. What comes to mind? BINAP, certainly, or the M and P descriptors for allene (cumulated double bonds) chemistry. Well, unless I'm missing something, this intermediate may be the first representation of olefinic axial chirality I've seen. To invoke this intermediate, the alkene in question must really be something special, since the azide has to be disposed roughly 90 degrees out-of-plane! 

Usually, alkenes like to sit in sp² -hybridized space - flat, like a sheet of paper. Rotational energy barriers exist to interchange E to Z olefins, but they usually need lots of energy (heat, light) or a charged intermediate. Here, we have an almost-room-temp, neutral, 3D alkene intermediate: a rare duck indeed.

A Few More Thoughts on Faculty Moves

While looking back at the map I made for my earlier post today, I had a few "deeper thoughts" about the faculty moving process.

- Is it just me, or do all the moves seem to be to warmer places? Even funnier, some mention it in the press releases following their moves. Take this gem, from Greg Fu:

"...it does not hurt, [Fu] adds, that he gets to leave those cold Cambridge winters behind."

A future Prof practices
for his first faculty move

- Although I claim that the moves are often prestige-based, i.e. to move into a highly-ranked university, several of these moves buck the trend. Finn moved from Scripps (#7) to Georgia Tech (#26), and Woerpel from Irvine (#26) to NYU (#67). If Nicolaou does indeed move to Rice, he'll be moving from #7 to #33. Now, I realize there's other rankings in town (see Chronicle, Times), and the "big fish" mentality suggests these rankings will improve once the new recruit sets foot on campus. But I'd still argue that some of these were lateral moves at best.

- What's up with the Pacific Northwest? The South? The Rockies? How come nobody from these places seems to move around? Either everyone in these locations is completely satisfied with their lives, positions, and income, or there's some dynamics between the East and Left Coast that I haven't yet figured out. 

Readers, what do you think?

Chemistry Bumper Cars

By now, most folks on the chemblogosphere have heard the rumbles about K.C. Nicolaou's possible departure from Scripps. His landing spot looks to be Rice University, in Houston, aided by a generous multi-million dollar "golden parachute." Followup comments posted on Chemjobber and In the Pipeline saw speculation run rampant regarding other Scripps synthetic chemists, including M.G. Finn, Jin-Quan Yu, Phil Baran, and Dale Boger.

Wow. Does everyone have the moving bug?

I seem to recall Kyle over at The Chem Blog drawing us a convenient map a few years back, during another busy moving season (2005, I believe?). The past two years have proven quite busy as well, with no less than an entire ChemBark post entitled "Nocera to Harvard!" (vide infra).

Without further ado, I present my highly-researched, but definitely not-to-scale, map of synthetic faculty moves, 2011-2012.

Legend (Updated 9/20):
1.  Keith (purple) Woerpel, Irvine to NYU
2.  John (Berkeley blue) Hartwig, UIUC to Berkeley
3.  Vy (green) Dong, Toronto to Irvine
4.  Dan (crimson) Nocera, MIT to Harvard
5.  O(maroon) Yaghi, UCLA to Berkeley
6.  M.(Goldenrod) Finn, Scripps to Georgia Tech
7.  K.(Cyprus orange) Nicolaou, Scripps to Rice (confirmed!)
8.  Greg Fu(schia), MIT to Caltech
9.  (Rust)em Ismagilov, Chicago to Caltech
10. Paul (cyan) Chirik, Cornell to Princeton

I've been searching for a chemistry faculty movement metaphor. At the end of the NFL season, reporters write about the "coaching carousel," where coaches switch jobs circuitously, trapped on an employment merry-go-round. Well, that's not quite right here. Chemists usually move away for good, and there's clearly a directionality to the moves: towards more money, higher prestige, or warmer climes. Perhaps a Ferris wheel? Nah: it implies "up" or "down," a good view of the situation...and far too smooth a ride. Negative on the Gravitron, though grads and postdocs might feel like they're smashed by the pressing gravity* of an upcoming move.

I've got it: Bumper cars! Everyone starts out hesitantly, driving around in circles, hesitant to make first contact. After a few minutes, though, it's a free-for-all, everyone bouncing off each other, crashing, laughing, sparks flying off the ceiling. In the end, no one ends up where they started, and everyone has headaches. (Bear with me, it's a work in progress, doesn't yet have the oomph of a "Manifest Destiny" or "fiscal cliff.")

Faculty jostle for top spots like, well, you get it...

Credit: UK Telegraph

Are faculty moves unavoidable? It's true that the grass is always greener. But, if you're already a professor at a Top 20 institution, you likely receive the lion's share of grant monies, decent media coverage, and your pick from top-shelf graduate students. So why go? Some moves are nostalgia-driven - the Prof. wants to return home to a welcoming parade, having "done good." Some moves try to fix the two-body problem. Some happen because of missed tenure, or a feeling that it's "just time." Maybe in today's uncertain economy, it's just best to assume you won't be in any job longer than ten years...with a handful of exceptions.

Readers: Know of any more high-profile U-Hauls being loaded this academic season? If the "Chemistry Bumper Cars" trend persists, this might yet become an annual post.

P.S. Heard about a move I missed? Email me at seearroh_AT_gmail, and I'll add it here!

*I completely understand, having been involved with two moves in grad and postdoc.

Illegal Drugs Spur Chemists to Create Cures

White powders marketed on grocery shelves as “bath salts” are quickly becoming problematic for politicians and police, as reported in the July 17^th New York Times.  These “salts,” derivatives of a compound called methylenedioxypyrovalerone (MDPV) cause many of the same symptoms as methamphetamine intoxication. The wide availability of these new mixtures, compounded by their ease of synthesis and seemingly no lack of supply, has led to an explosion in their abuse (Note: I won’t cover the chemistry behind MDPV, the active ingredient, because my in silico mentor David Kroll’s posts on Terra Sigilata have mostly covered it).

That’s the gist of the article, in which illicit chemical synthesis fuels a new drug craze, and the public perception of chemists is dragged down again by sound bites such as “state bans thwarted by chemists who have to change only one molecule… to make [the salts] legal.” What happened to fair and balanced coverage?

For every illegal manufacturer of psychoactive compounds hoping for addiction to promote sales, there are many more chemists working on analogs of bioactive substances to treat disease.  Compounds that show high potential for abuse tend to interact with three neurotransmitters: serotonin, dopamine, and norepinephrine. In the case of bath salts, the main ingredient is a norepinephrine-dopamine reuptake inhibitor (NDRI), which allows these neurotransmitters to stay longer in the synapse, creating feelings of pleasure and wakefulness. Phenethylamines, such as MDPV, meth, or Ecstasy, the popular club drug, are one major class of compounds which activates these receptors, and are easily tweaked synthetically to prepare drug leads for Parkinson’s disease, schizophrenia, and ADHD.

Prof. David E. Nichols, of Purdue University, has devoted much of his career to understanding the mechanisms by which addictive drugs can interact with brain receptors, and designing novel compounds to take advantage of these traits (See this October 30, 2010 Wall Street Journal piece for Nichols’ comments regarding black market applications of his academic work). Prof. Nichols has synthesized variants of psilocybin, mescaline, and notably for this particular story, MMAI, a “cyclized” version of a typical methamphetamine scaffold.  On the day the NYT article went to press, Prof. Nichols had a J. Med. Chem. ASAP publication (DOI: 10.1021/jm200334c) appear online, in which his group prepared four new methylated analogs of their lead compound dihydrexidine. This analog, developed off the phenethylamine scaffold, has been shown to bind to the D₁ dopamine receptor, and both improve blood flow to the brain and to reverse Parkinson's-like symptoms.



Photo Credit: obrag.org

 Two other medicinal chemists are using methamphetamine derivatives as “Trojan horses” to trick the body into immunizing itself against the drugs. Their end goal is a vaccine that could be administered to control meth addiction. Kim Janda, of the Scripps Research Institute, and F. Ivy Carroll of the Research Triangle Institute (just down the block from David Kroll!) have both recently reported their groups’ respective efforts towards methamphetamine vaccines. Each group strategically introduces a hapten, an immunological “stamp” that latches onto a human protein, which the body can use to recruit white blood cells to the foreign substance.

Janda (JACS 2011, 6587) attaches a six-carbon chain ending in a thiol (SH) group to the amino group of (+)-methamphetamine, the more potent enantiomer, and observes high antibody titres in mouse models. Carroll (J Med Chem, 2011, ASAP) also uses a sulfur antigen, but attaches his via an amide linker connected to the aromatic core. After connecting this linker to a suitable immune-responsive protein, Carroll generates a monoclonal antibody with a 6.8 nm K_D for (+)-meth.

Update (July 30, 6:50PM) - Changed "bloodstream" to "synapse," since commenter gippgig is (again) correct that the compounds influence synaptic function, not bloodstream chemistry. Thanks!