Wednesday, July 24, 2013

Sixteen Columns

Vittorio over at Labsolutely has a very clever and amusing post up re-imagining the X-Men as chemists.

So what other media genres share cross-over with our field?

The modern art form deemed the "chick flick" shares key features with tactics used to recruit students into graduate school in chemistry. Namely: (1) hopelessly romantic view of the content; (2) focus on idolizing the celebrities of the subfield (e.g. Tom Hanks, Phil Baran); and (3) careful shielding of the subject from reality of life/lab. And of course, both chick flicks and science place an emphasis on diaries.

In a salute to both, here are some chick flicks in the context of science:*

  1. How to Lose a Grant in 10 Days
  2. Unemployed Going on 30
  3. The Proposal
  4. Never Been Published
  5. 27 Postdocs
  6. What's Reproducibility Got to Do with It
  7. The Devil Wears PPE
  8. Sixteen Columns
  9. My Best Friend's Defense
  10. What PIs Want
  11. Save the Last Authorship
  12. Bridget Jones's Lab Notebook
  13. When Harry Met Sally at an ACS Regional Meeting
  14. The Lab Notebook
  15. Out of Academia
  16. Sleepless in Grant Season
  17. The English Postdoc
  18. Gloves Actually
  19. How Stella Got Her Glassware Back
  20. 10 Things I Hate About U...niversities
  21. Pride & PNAS
  22. Crazy, Stupid, Reaction Mechanisms
  23. Peggy Sue Got Funded
  24. P.S. I Love the Combiflash
  25. Flashcolumn

* Note: these are in no particular order; the author claims no expertship on relative merits of chick flicks.



Thursday, July 11, 2013

Why Steve Strauss should stop hiring English majors and hire some scientists instead

Recently, a few people I know shared this column on Facebook. Written by Steve Strauss, a lawyer/author and self-described "small business expert", the short piece from the Huffington Post makes the case that English majors are pretty much the bee's knees. Strauss prefers to hire English majors for a variety of roles, as he explains:
I love English majors. I love how smart they are. I love their intellectual curiosity. And I love their bold choice for a major. Most of all, I love to hire them. 
A recent article by the great David Brooks in the New York Times about the changing nature of the Humanities in higher education just reinforced why, when given my druthers, English majors are my employee of choice. 
And the reason is not that I am a writer; I more consider myself an entrepreneur than anything else. I run a small business and the people I hire do a variety of tasks -- SEO, project management, social media, and so forth. 
For my money (literally and figuratively), for my needs, and I suggest the needs of most small businesses, English majors are easily the top choice when it comes to getting the type of teammate who can make us all better, as they say in basketball.
Strauss goes on specify some key traits apparently endemic to the English major population. These are: (1) English majors are smart and creative independent thinkers, more so than business majors; (2) English majors are bolder risk-takers than others; (3) English majors are always better writers; and (4) English majors are easy to work with.

I suspect many scientists will disagree. I take issue with the broadness of Strauss's assertions--though he never claims to have broadly surveyed skillsets of humanities scholars, his descriptors read like mere feel-good fluff. Yes, there are English majors who have those characteristics, and many English majors are successful. But "rigor" and "difficult assignments" are not essential traits of the undergraduate English experience.  While English may allow deep thinking, it doesn't absolutely require it, and it's certainly easier to skate through an English degree than, say, one in chemical physics or organic chemistry.

You see more chemists who also know literature than you see literary analysts who know molecular orbital theory. But isn't that just because science is more specialized? Well, yes and no. Individual fields of science certainly have their own jargon, methodology, and bodies of knowledge. But the scientific process is fairly universal, and you see people switch fields in their BS/PhD and PhD/postdoc transitions.

That all sounds harsh, of course, and borders on the increasingly-prevalent-but-misguided attitude of "cut the humanities, boost only employable fields". So to clarify: I like the humanities. I really do. I've always enjoyed literature and music (both production and consumption), and I think their study is vital for making a person more culturally aware and well-rounded. I have opinions on writers and composers. I was one of those people who didn't whine about general-education requirements interfering with "real" coursework. But assigning top general employability status to English majors overlooks a key group of students who, when successful, possess all the abovementioned skills and more: science majors.

The case for hiring science majors

As previously mentioned, Strauss touted the creativity of English majors and their ability to think analytically. Creativity is essential to good science as well; skilled researchers tend to be creative people who see alternate ways to solve problems. Moreover, scientists find solutions that work, based on reality and reproducibility. This clarification is important, because "analysis" means very different things in scientific and non-scientific circles. However, scientists are quite good at two things: (1) finding information; and (2) evaluating information.

Strauss also claims English majors are superior risk-takers. But scientists are too. They have to be. Good research is always at the edge of knowledge--which means it might not work. Bench time might be wasted. A six-year PhD might produce no results and lead to no job. Ideas might get defunded and banished to obscurity. Going to grad school is a tremendous risk. So is working for an untenured professor, or starting a brand-new project. So the advantage here again goes to scientists. Additionally, scientific risk-taking is grounded in reality--helpful for businesses.

What other employable traits do scientists tend to have? Work ethic: long hours are the norm and determination over long periods of time (ca. 5 years) is required. Versatility: the scientific method is employable between variant research areas but also to management and business decisions. Technical skills: this probably goes without saying, but intimate knowledge of scientific theory and technique isn't easily gleaned from Google. Even in non-bench roles, this can be quite important. Teamwork: whereas writing English papers is a solitary venture, lab research is done in groups, and collaboration between students and labs on the experiment or project scale is commonplace. Objectivity: whereas the humanities stress the voice and identity of the individual (subjectivity), science emphasizes minimization of bias. This is useful in risk assessment, evaluation, project design, etc.

All in all, I think science majors sound pretty employable.

What we can learn from our English-wrangling colleagues

The claim about English majors being superior writers is also worth examining. Do English majors write? Yes. Do they write a lot? Most of them. Do they write well? The good ones write academic papers well, but an increased vocabulary and flowery verbiage doesn't mean good communication. Of course, many English majors are good communicators, but the degree doesn't guarantee that. And not having an English degree doesn't mean you can't write just as well as someone who has one.

It's worth noting that significant differences exist between scientific/technical and academic (non-scientific) writing. In another life, I worked closely with undergraduate writing tutors. Most were English majors, and as a lot they were very intelligent. But all of them were horrid at actually helping science students improve their communication skills. The result was a continuous stream of frustrated chemistry students with half-mangled lab reports. The writing process is fundamentally different across the humanities/science divide, which makes me skeptical that the garden-variety English major would be good at writing in a technical or scientific context (where content is highly specific, highly technical, and verbal economy is vital). Some are good at it, but it's not because of Chaucer.

That being said, scientists themselves are very commonly awful writers. Those who deny this or think it's not important are simply either ignorant or delusional. Then again, scientists are perhaps more likely to be blunt and direct, which has its appeal. Regardless, it's probably good for budding scientists to take all the writing experience they can get and to pay attention not only to the facts of what they write but the organization and presentation. Clear communication makes ideas easier to sell, cuts down on wasted time, and improves work efficiency. The ability to write well (more than just JACS communications) can be a huge selling-point when building an employment skillset, as it extends to grants, business proposals, technical reports, and intellectual property claims.

A final anecdote.

A friend of mine switched from pre-med to business during undergrad and found himself in a business database systems class. The class entailed a team-based project wherein each group of students needed to create a database system for a local business. Several of the born-and-bred business majors insisted that the class was probably the most difficult in the university. Having taken two years of pre-med coursework, my friend pointed out the difficulty and rigor in the hard sciences, especially in independent research. Oh, no way, the business majors insisted, scientific research is just following recipes.

The piece is short, so it's worth reading.  Do also peruse the comment section, which is rife with people praising Strauss's words and/or correcting each others' grammar/diction. 



Tuesday, June 25, 2013

Stop using that word: Accordance

Consider "accordance". It's a sleek, shiny word. But it's terribly misused in scientific manuscripts.

To pick on just one example, take the following text from a recent publication by Neil Kelleher's group at Northwestern (bold emphasis mine):
Our observations were in accordance with a previous study on nostocyclopeptide, where certain amino acids in the peptide sequence were found essential for the spontaneous macrocyclization of the peptidyl aldehyde intermediate into a cyclic imine.
And another example from a total synthesis of daptomycin by Xuechen Li:
The spectrum was in full accordance with those in the literature.
Not quite right.

"Accord" implies agreement. It's what writers usually mean when they use "accordance". For instance:
His dismal personal life was in accord with his excellent progress in total synthesis.
"Accordance", in contrast, implied obedience. It refers to compliance with a rule.
My one day of vacation per year is in accordance with group policy.
Examples of the correct use of "accordance" are actually hard to find. Consider this paper by Robert West at Wisconsin. An excerpt (bold emphasis mine):
In accordance with Bent’s rule, the increased R–O bond polarities of permethylated species lead to increased oxygen hybrid s-character and R–O–R bending angles in both ethers and siloxanes.
That one is arguably correct.

The difficulty is probably that "in accord with" doesn't flow quite smoothly. Perhaps a better option would be simply to say "in agreement with". Either way, reviewers probably won't catch it.

This has been a public service announcement.

Thursday, June 20, 2013

Carbenes: turns out, nature has them, too

Enzymes are like nature's little gloveboxes. It's really quite interesting what kind of chemistries are possible in aqueous, biological conditions just by manipulation of the local electronic and steric environment by the structure of enzymatic active sites.

Take carbenes. Everybody likes a carbene--it's a lone pair on carbon, but it's formally neutral, and it does interesting reactions like alkene insertion (cyclopropanation), C-H insertion, rearrangements, and the like.

One of the more interesting aspects of carbenes is their variable reactivity. They can exist in a singlet (depicted as lone-pair) or triplet (depicted as diradical) form. Depending on their electronic environment, they can react as nucleophiles (aided by a high-lying HOMO) or electrophiles (encouraged by lowering the LUMO). Their reactions can be stereospecific through concerted pathways (singlet carbenes) or non-stereospecific through stepwise mechanisms (triplet carbenes). All of this is tuned, not surprisingly, through the electronic/steric environment around the carbon in question.

Carbenes are typically highly reactive and short-lived, though examples of persistent carbenes are now well-known. N-heterocyclic carbenes (NHCs) make a prime example. The electron-rich di-adamantyl NHC shown above, for instance, was described in 1991 and can be crystallized (it melts, by the way, at 240 degrees Celsius).

Note the electronic nature of the carbene: the carbon is flanked by two nitrogens, each bearing lone pairs capable of donating electron density into the carbene's p orbital. This acts to stabilize the singlet state and imbues NHCs with admirable properties as metal ligands (electron rich sigma donors which bond quite strongly to metal centers) The most famous of these is probably Grubbs' second-generation catalyst, which bears an NHC in lieu of one of the phosphine ligands of the first-generation counterpart. Besides olefin metathesis, though, persistent carbenes (as NHCs) are quite useful ligands for tricky C-C cross-couplings. Specifically, the so-called Pd-PEPPSI complexes are useful for coupling of tetrahedral carbon centers to each other.

It turns out that nature utilizes carbenes as well. Take a look at vitamin B1--also known as thiamin. It's an essential coenzyme which, as it turns out, we can't make and must obtain in our diet. There's several forms consisting of various decorations, usually of the hydroxyl moiety. One of these is thiamin diphosphate (ThDP), which, if you didn't guess, is thiamin with diphosphate attached (it also goes by the name thiamin pyrophosphate, or TPP, which is definitely not confusing at all). ThDP is a coenzyme for pyruvate decarboxylate and pyruvate oxidase, among other enzymes.

If you look at thiamine, there's a place--right between that sulfur and its neighborly nitrogen--that seems like a nice candidate for a carbene. There's been a debate in the literature; that carbon must be deprotonated for catalytic activity, and it hasn't been clear whether the associated enzymatic reaction proceeds via a carbanion or the short-lived carbene. A recent report in Nature Chemical Biology provides evidence for the latter. The authors examined thiamin diphosphate with the enzyme pyruvate oxidase (from bacterial origins). Phosphate was employed as a mimic of the substrate (pyruvate) that would bind similarly but not form a covalent adduct--this was to see if substrate binding might correspond with the formation of a carbene.

Via circular dichroism (CD), and X-ray diffraction, the authors give evidence that although the coenzyme is C-protonated in its resting state, binding of phosphate results in accumulation of either the carbanion/carbene form. This is narrowed down to the carbene chiefly through analysis of the XRD structure. Not only was the electron density consistent, but the bond lengths and angles were similar to synthetic thiazolium carbenes previously reported. The authors mention similar results upon analysis of the ThDP/cyclohexane-1,2-dione hydrolase complex.

Essentially, under physiologically relevant equilibrium conditions, the thiamine/enzyme complex can accumulate a carbene. In water. That's quite cool.

Wednesday, May 22, 2013

Academic salaries: some numbers and graphs

The topic of academic salaries came up recently and I figured I'd look a little further. Where does chemistry stand? After all, jobs are scarce--how do academic positions pay compared to other disciplines?

Lots of resources exist for salary issues that are much more data-thorough, so take the following numbers with a grain of salt. For more in-depth info, a few resources include HigherEdJobs, The Chronicle of Higher Education, or a web search.

I took a (somewhat) random single institution (Bowling Green State University, Ohio) of medium size (ca. 15,000 undergraduates) that also offers graduate degrees (in chemistry, an M.S. in chemistry and a Ph.D in photochemical sciences are available). Ohio was chosen as an example state simply because of the ready availability of data.

Salary information (for a few years back) is available for all Ohio's higher ed institutions through the Buckeye Institute. I grabbed the 2010 info for the university and present below the averages for four standard academic ranks (lecturer/instructor, assistant professor, associate professor, and full professor) across 14 broad but somewhat arbitrarily chosen disciplines. Standard deviations aren't included and sample sizes were small in some cases, so caveat emptor and all that. (NB: click any chart for a larger view)

First, a graph of the disciplines ranked by associate professor salaries. It's quite interesting to me that chemistry is near the top--ahead of biology but also physics and geology. Moreover, associate professor salaries in chemistry rank a little short of computer science (by about $7,000) but above economics (by about $8,000). As would probably be expected, two business disciplines (management and accounting/M&IS) are way ahead. I don't know if that's endemic to the particular school or a general trend. Regardless (and probably again to no one's surprise), it looks like chemistry and the other sciences are pretty far ahead of the humanities by as much as business-related fields are ahead of science.


Ranking by full professor puts chemistry more in the middle of the pack:


Quite interestingly, though, are the salaries for assistant professor positions (typically the first 3-6 years of an academic appointment). Here the distribution is almost bimodal, with chemistry falling in a group ranging from  about $50,000 to $66,000. Then there's a $24,000 jump to the business disciplines and computer science, which compensate assistant professors on average from $89,000 up to a whopping $119,000! (For the math-challenged organic chemists, that's about double the chemistry salary for the first five years).

Why the giant divide? Market demand certainly plays a large role. Folks with graduate-level business and computer science skills are very, very employable, and generally aren't in markets plagued by the oversupply that science (and especially the humanities) face.

Lastly, check out the ranked salaries for instructors/lecturers. These are the teaching-only positions; for some disciplines this doesn't require a PhD. (For chemistry, I've seen very few lecturers without PhDs; many have postdoc or industrial experience).

Management here has the highest salary by far, but that's incidentally an n = 1 type scenario (there's only one lecturer in the management department, and they appear have an 'executive' position). Here the business gap disappears; average salaries range from $38,000 to $52,000. Interestingly, computer science ranks in at $61,000, which is probably indicative of its very high employability--you have to pay someone a lot to draw them away from an attractive industry job.


For fans of seeing-it-all, here's a ranked-by-associate graph including all four ranks.


Lastly, here's the average salaries for most of the public university chemistry departments in that particular state (Ohio) [note--data was not easily harvestable for Ohio University, Shawnee State, Central State, or Youngstown State].

This itself is somewhat interesting, as there's a wide distribution (assistant ranges from an average of $55,000 to $78,000; associate from $70,000 to $97,000; full professor from $101,000 to $131,000). Moreover, salary averages don't appear to correlate to institutional prestige (cf. Ohio State and University of Akron, for instance) nor to cost-of-living.





The ordering of schools even changes by faculty rank--Cleveland State tops out the assistant professor category, but Bowling Green wins for associate professor and University of Toledo for full professor. The only consistent element, it seems, is that Kent State pays the lowest for chemistry professors, across the board, of all the state schools shown.

Again, take all this data with a grain of salt; I just think it's interesting stuff.

Saturday, April 27, 2013

The Office and the lab

Just as the #ChemMovieCarnival drew to a close, chemistry made another appearance on national television!

In the most recent episode of The Office (a mockumentary about a paper company; it's usually hit-or-miss but still funnier than the British version*), the branch manager, Andy Bernard, was cast in a chemical safety video ("HRPDC Chemical Handling Protocol") in an attempt to break into an acting career.

The on-screen lab was pretty clearly a molecular biology or chemical biology space -- you can see microscopes, centrifuges, Pipetmans,** a cold-room, 96-well plates, and plenty of buffers; additionally, the glassware is largely Erlenmeyers, graduated cylinders, and volumetric flasks.

Unlike most featured lab spaces on TV (we're looking at you, NCIS and CSI...), it looks like the producers used an actual lab. If not an actual lab, it's a very good replica (as evidenced by the abundant bench clutter).

For the sake of the chemical community, I present a graphical abstract below.

Drying rack contains an appropriate mix of glassware.

What lab would be complete without an egregious safety violation?
(note the presence of snacks in the lower left corner)

Benchtop clutter looks about right.

Note the scientist in the far background using proper PPE.
\
Demonstration of eyewash station use, plus screaming.
Note that undergraduates usually have the same aversion to the eyewash station that Andy Bernard does.

And my favorite exchange of dialogue:

Director 1: Okay, stop. Why are you smiling?
Andy: I just made a character choice to be a scientist who really likes what he does and enjoys his job.
Director 2: Okay, well, maybe no smiling on this one.


* Note: some people get really upset when you say this to them. Try it!
** I love me some Pipetmans.

Wednesday, April 24, 2013

Chemical Fun from 1921

What's more fun than historical documents? Historical chemistry documents! From one such document: the following tongue-in-cheek paragraph appeared in the April edition of the briefly-published and mostly-otherwise-serious quarterly departmental (U of I) magazine The Illinois Chemist 1921, 5(3), 12.


The text (written out):

CHEMICAL FUN. Procedure (to be followed with extreme carelessness): Select several choice cut medium sized hydrogen ions from a bottle and scour until thoroughly clean. Wipe and dry carefully. Avoid handling. Lay aside. Now soak a few large chunks of metallic sodium in a beaker of distilled water and allow to stand quietly. In the meantime be collecting a pailful of cathode rays. Filter these, using suction. Beat them to a froth with two and three-quarters pounds of green radium (the red variety is highly unsuitable for this experiment). Now stir in the hydrogen ions, one at a time. Drain the sodium and put it in above mixture. Grind up with T. N. T. and put in a mortar and add all at once. Thus the mixture will become catalyzed. -- Voodoo, M. I. T.

Chemical fun, indeed. Sounds like a job for Blog Syn!
 

Thursday, April 18, 2013

#ChemMovieCarnival: Chocolate and chemical academia

It's time for the #ChemMovieCarnival, as organized by See Arr Oh (who posted this first day round-up). So far we've seen chemistry featured in Fight Club, Iron Man 2, The Great Escape, The Absent Minded Professor, G.I. Joe, Real Genius, and MacGyver, among others.

Some of the above examples highlight some pretty bad movie science. I thought I'd share a movie clip that was on the other end of the spectrum!

Everyone's familiar with Willy Wonka and the Chocolate Factory--the 1971 musical film starring the immortal Gene Wilder. The film's protagonist is Charlie Bucket, a child from a poor family whose genuine heart leads him to success where several other spoiled/privileged children fail. Early on, we're shown Charlie's education, including the following chemistry demonstration. The clip is a little modified from the original at the end (it was the only one I could find!).



It's a remarkably accurate portrayal of life in chemical academia. After all, all the hallmarks are there:

  • Disregard for proper PPE/lab safety.
  • Intellectual snobbery/faculty egotism.
  • Over-eager undergrads who don't know what they're doing.
  • Secrecy and irreproducibility.

Just like life in the lab! (Of course, Pure Imagination is perhaps more apt to describe the pragmatism of many projects).

Carrots, chlorine, and chemophobia

On a recent lunchtime "survey of the literature" (i.e. Facebook break) I noticed that an old classmate posted the following paragraph (it's not new--but I hadn't seen it before):

“DANGER TO YOUR FAMILY!!

From the Department of Life Education:

Baby Carrots:

The following is information from a farmer who grows and packages carrots for IGA, METRO, LOBLAWS, etc.

The small cocktail (baby) carrots you buy in small plastic bags are made using the larger crooked or deformed carrots which are put through a machine which cuts and shapes them into cocktail carrots – most people probably know this already.

What you may not know and should know is the following:

Once the carrots are cut and shaped into cocktail carrots they are dipped in a solution of water and chlorine in order to preserve them (this is the same chlorine used in your pool).

Since they do not have their skin or natural protective covering, they give them a higher dose of chlorine.

You will notice that once you keep these carrots in your refrigerator for a few days, a white covering will form on the carrots. This is the chlorine which resurfaces. At what cost do we put our health at risk to have esthetically pleasing vegetables?

Chlorine is a very well-known carcinogen, which causes Cancer. I thought this was worth passing on. Pass it on to as many people as possible in hopes of informing them where these carrots come from and how they are processed.

I used to buy those baby carrots for vegetable dips. I know that I will never buy them again!!!!”

First, it should be noted that the person who shared the post works in a biomedical profession and probably should know better. Second, this looks like a classic chemophobic recipe: (1) take familiar concept; (2) point out chemical; (3) extol nastiness of chemical, real or imaginary; (4) panic.

It should be pointed out, of course, that the "warning" is alarmist and exaggerated. Most fruits/veggies are rinsed in water containing low-ppm chlorine -- levels comparable to drinking water -- not in a highly-chlorinated solution as implied. Chlorine is an antimicrobial protectant in thse cases. Moreover, the white residue is, obviously to chemists, not chlorine 'resurfacing' (???) but simply dehydrated carrot. And something that needs mention: there's no evidence that chlorine is a carcinogen (see here and here for instance) (You wouldn't want to go on a date with pure chlorine, of course, but not because of a cancer danger).

The chemophobia doesn't surprise me, though, since "chlorine" sounds nasty.

I am surprised, however, by some of the responses on the internet. They're unusually fact-based! In fact, in the first two pages of Google search results for "baby carrots chlorine", only a few support the myth. But let's look at the chemophobic minority first:

The chemophobes

Angela Garrison, a writer at alternative health site The Alternative Daily, gave this warning about the carrots (also posted at RiseEarth) in 2012. She largely parrots the viral bite above, adding some nonsense about baby carrots being ground-up regular carrots (they're sliced, but certainly not ground, and it would be pretty impressive if manufacturers could reconstitute the texture like that from carrot paste). Additionally, the title ("Why Baby Carrots are Killing You") is perhaps more dramatic than warranted. She alleges that the chlorine bath gives them their orange color (and has never apparently heard of carotene). It's worth reading the article (which is characteristically factless); but I have to include this excerpt which does a smashing good job of confusing chlorine with chloroform and delightfully ignores both citation and any discussion of dosage:

As defined by the EPA, Chlorine is a pesticide. Its purpose is to kill living organisms. So it would make sense that when you ingest chlorine, it kills some parts of our body like the healthy bacteria in your gut and intestinal flora for instance. Chlorine is a highly toxic, yellow-green gas most heavily used in chemical agents like household cleaners and can be found in the air near industrial areas especially around paper processing plants. Exposure to Chlorine has been linked to health problems such as sore throat, coughing, eye and skin irritation, rapid breathing, narrowing of the bronchi, wheezing, blue coloring of the skin, accumulation of fluid in the lungs, pain in the lung region, severe eye and skin burns, lung collapse, a type of asthma known as Reactive Airways Dysfunction Syndrome (RADS).

Chlorine is also added to the public water supply. So not only are you drinking it, but you are absorbing it through the largest organ in your body, your skin. In fact, 2/3 of human absorption of chlorine is from inhaling the steam in the form of chloroform and fast absorption through your open pores in the warm shower or bath. The inhalation of chloroform is a suspected cause of asthma and bronchitis, especially in children… which has increased 300% in the last two decades. Other health risks associated with chloroform is cancer, potential reproductive damage, birth defects, dizziness, fatigue, headache, liver and kidney damage. Chloroform is also found in the air and in food, like baby carrots.
While no one is encouraging anyone to go breathe the stuff, that's a bit much.

Another unsuprisingly chemophobic source is Mercola.com (website for prominent snake-oil salesman Joseph Mercola). Mercola starts (in 2009) by insisting that chlorine is a carcinogen (spoiler: it's not), delves into a litany of other nasty roles chlorine and chlorinated byproducts can play, and ends by recommending chlorine-free carrots. Total Health magazine seems to largely echo (almost plagiarize) these claims.

The chemophobia has to have been taken fairly seriously by many--indeed, Bolthouse Farms created an entire website (truthaboutbabycarrots.com) to respond to the claims. But surprisingly, the above three examples were the only two immediate negative results in my two-page Google foray.

The non-chemophobes

Interesting, the majority of responses to the chlorine-carrot allegations are non-chemophobic (and largely come from non-scientists!). Journalist Bart Van Bockstaele at Digital Journal (2008) posts a  response that includes a discussion of the confusion around the 'chlorine' nomenclature whilst dismissing all health concerns and properly pointing out that science hasn't shown chlorine to be carcinogenic anyway. (Note that some of the text is pretty similar to that found on the somewhat odd website World Carrot Museum).

At FarmProgress (2013), editor Jennifer Vincent admonishes those spreading misinformation, pointing out the public health efficacy of chlorinated water and describing how she corrected someone else who was spreading the carrot scare.

Joel Mackey of Z6Mag (2013) gives a somewhat disorganized response, but two items stand out: (1) he contacted the companies and investigated the matter himself; and (2) there's some neat Google trends graphs that show that searches for 'baby carrots chlorine' increased going into 2013.

Lisa Leake of the whole-foods effort 100 Days of Real Food (which sounds like it should be brimming with chemophobia) has a nice, accessible response in which she (1) made a point of looking up the relevant information and not just trusting 3rd party information; and (2) explained some of the layperson chemical misconceptions in the carrot-chlorine scare.

Other, shorter responses include those by Dr. Andrew WeillLinda Golodner of the Water Quality & Health Council (she points out the health-protective benefits of low levels of chlorine in water!), Megan Loberg of Eat, Pray, Farm (who points out that even 'organic' producers use chemicals to wash carrots), and Consumer Reports, Moms Against Cooties.

And of course, anti-hoax websites such as Snopes and wafflesatnoon dismiss the claims (Snopes is itself a little chemically misleading, implying that neat chlorine is used to treat the carrots).

Overall, the responses are encouragingly NOT chemophobic in general. That's a relief to see, I think: engagement by the non-chemical community is probably more convincing to the general public than engagement by chemists (whether we like it or not).





Thursday, April 4, 2013

Analytical chemistry and the dinner table

I saw this headline recently on NPR: "Food Fraud Database Lets Us All Play Detective." From the description, I expected some degree of chemophobia (habit):
Spices colored with carcinogens? Milk that "never saw a cow"? A free global database opens the door on the many ways that people adulterate [food]
Though I expected the carcinogen to be simply "chemicals" or something, it turned out to be the (indeed carcinogenic) Sudan dyes. In fact, NPR avoided chemophobia on this one!

The article is worth checking out -- it's a brief read, and it points to a really interesting resource: the USP Food Fraud Database. I'm not going to delve much into what the database is, since the NPR highlight already did that. But it's worth pointing out a feature I found interesting (and perhaps contrary to my experience with the food world, where anecdotal claims are usually key)--the database lists food items (ingredients), what the adulterant was, and the method of detection (PCR, Raman, NMR, etc.). Moreover, the scholarly or other reference in question is listed, for those interested in further clickthroughs. Makes for a nice highlight of how analytical chemistry techniques are used in real-world applications--and how particularly techniques are uniquely suited for different classes of analytes.

But now I'm going to be burning some time searching all the ingredients in my kitchen.

Monday, April 1, 2013

Total synthesis funding declared top national priority

WASHINGTON -- Among recent changes to the federal budget was a joint announcement by the White House and the Congressional Budget Office (CBO) that along with postmodernist literature critique and intermediate basketweaving, natural product total synthesis has been declared a "top funding priority" for the nation.

The news of the funding priority shift Monday morning came as welcome news to thousands of synthetic chemists in academia, who had worried in recent years that federal belt-tightening might divert funds away from their activities.

Although the funding measures have been laid out in detail in a 6000-page document readily accessible on the CBO website, several government officials gave public statements early on Monday to clarify the scope and magnitude of the announcement.

From the White House's press room, President Barack Obama spoke to reporters. "I consider this my most important contribution to the nation's interest so far," he said, stepping away from his prepared script and wiping a hint of a tear from his eye as he addressed the cameras earnestly. "For too long, our federal government has prioritized translational and applied research. And while contributions to medicine and energy are somewhat important, or something, I guess, we've too long neglected the biggest questions in science that will keep our country great. For example, there are so many alkaloid and polyketides that have been isolated from sea sponges that we just don't know the absolute stereochemical configuration of. And a few of these have some sort of cytotoxic activity or something at millimolar concentrations," the President added.

Cries of "USA! USA!" could be heard from several reporters in the audience who were briefly overtaken with emotion.

NIH director Francis S. Collins issued a statement later in the day on behalf of the National Institute of Health. "We are allied with the President on this strategic historic decision," the report reads. "While some might object to the fact that the NIH has completely defunded cancer research, antibiotic research, and genetics projects, we caution the public that the money invested in total synthesis will reap much richer rewards for the scientific community and the public. For instance, one of the total syntheses might contribute a valuable synthetic method that can be used in a different total synthesis from the same lab group."

The NSF did not issue a statement but a source within the organization pointed out that all NSF predoctoral fellowships this year were awarded to students studying total synthesis.

Despite the billions of dollars of refocused funding, not everyone is happy with the move. The American Physics Society issued a formal letter of protest against the measures, which are estimated to result in the closure of 99.5% of physics labs across the country. Said the report: "What's a carbon?"

Surprising to many was an announcement by the Pentagon that drastic military funding cuts would be made to support the total synthesis effort. US Defense Secretary Chuck Hagel addressed troops worldwide via a televised message. "Um, yeah, so, guys, we appreciate your hard work and whatnot, but you can all go home. We're cancelling all this 'war' business, honestly. It's a money sink." In one video of an Army base in Afghanistan, soldiers were seen reacting to the news with elation. Hagel continued: "And let's be honest. Enlarging the postdoc pool is the true route to national security."

In other news, job prospects for chemists look to be increasingly encouraging. In 2013 alone, twelve of the fifteen largest pharmaceutical companies have launched massive hiring campaigns, resulting in nearly complete employment among recent PhD graduates.


Thursday, March 28, 2013

Stipends: A waste of funding?

A little while ago the subject of teaching assignments came up among some colleagues (as it is wont to do).  Specifically, we were discussing which PIs had habits of sticking their students on repeated teaching assignments and which PIs didn't have their students teach unless they really wanted to.

I was a little surprised that one of the very well-funded synthesis groups here had an abundance of TAs. One of the students (him/herself a TA) explained it thus: "We don't like to waste money on paying people." The point was that they viewed grant money as primarily for supplies and fancy instrumentation. For instance, they'd shelled out quite a bit of cash recently for some fancy chromatography and microscopy equipment.

It was an interesting perspective, and I'm not sure what to think of the philosophy.

I've seen PIs before who tended to put students on TA quite frequently -- for their entire PhD, in many cases. But those have typically been groups with little-to-no funding, where available grant money wouldn't even cover a meager grad student stipend.

I've also seen well-funded PIs who limit their students to two semesters of teaching (or whatever the departmental requirement happened to be), regardless of external fellowships available to the individuals in their lab. In those cases, a large portion of the available grant money is devoted to stipend/tuition expenses.

So a lab that has plenty of cash that it needs to burn and decides to burn it by buying valuable (but not essential) upgrades--that's different.

It might be a subdiscipline thing. I suspect that "hard" synthesis groups -- methodology and total synthesis -- tend to rely more on a TA culture (perhaps the funding situation is less predictable here?). In contrast, most biologically-oriented organic groups seem to find the funding (from training grants and other sources) to keep their lab RA-based. Additionally, some grants have specifications.

Even so--can personnel costs be considered a "waste"? The word I would suggest is "investment." But it might be because I think a well-trained, happy chemist with decent instrumentation/supplies is more valuable than a slightly nicer MPLC.

Monday, March 18, 2013

Singers and musicians, apocryphal quotes, and chemists

Recently, I saw the following quote get shared widely among my acquaintances on a particular social media outlet:
Singers and Musicians are some of the most driven, courageous people on the face of the earth. They deal with more day-to-day rejection in one year than most people do in a lifetime. Every day, they face the financial challenge of living a freelance lifestyle, the disrespect of people who think they should get real jobs, and their own fear that they’ll never work again. Every day, they have to ignore the possibility that the vision they have dedicated their lives to is a pipe dream. With every note, they stretch themselves, emotionally and physically, risking criticism and judgment. With every passing year, many of them watch as the other people their age achieve the predictable milestones of normal life - the car, the family, the house, the nest egg. Why? Because musicians and singers are willing to give their entire lives to a moment - to that melody, that lyric, that chord, or that interpretation that will stir the audience’s soul. Singers and Musicians are beings who have tasted life’s nectar in that crystal moment when they poured out their creative spirit and touched another’s heart. In that instant, they were as close to magic, God, and perfection as anyone could ever be. And in their own hearts, they know that to dedicate oneself to that moment is worth a thousand lifetimes.
-David Ackert, LA Times
I kind of hate to reproduce it--not because it's pandering and indulgent*, necessarily, but because I can't find the original source, and as a scientist, that bothers me. It's attributed to David Ackert of the LA Times. No one seems to mention that the LA Times website doesn't even mention a David Ackert, much less this quote. So the authenticity/origin is dubious (that doesn't seem to matter to those who push it along). 

A quick search of the internet reveals several modifications of the quote, wherein people have substituted 'actors' and 'artists' for 'singers and musicians'. So, I figured: why not 'chemists'? (We do use instruments). Let's try.
[Chemists] are some of the most driven, courageous people on the face of the earth. They deal with more day-to-day rejection in one [group meeting] than most people do in a lifetime. Every day, they face the financial challenge of living a [STEM] lifestyle, the disrespect of people who think they should get real jobs, and their own fear that they’ll never work again. Every day, they have to ignore the possibility that the vision they have dedicated their lives to is a pipe dream. With every [column], they stretch themselves, emotionally and physically, risking criticism and judgment. With every passing year, many of them watch as the other people their age achieve the predictable milestones of normal life - the car, the family, the house, the nest egg. Why? Because [chemists] are willing to give their entire lives to a [synthesis] - to that [ring], that [stereocenter], that [functional group], or that [weird perfluorinated tail] that will [get them into JACS, or Org. Lett., or heck, Tet. Lett., it's gonna get ignored anyway]. [Chemists] are beings who have tasted life’s nectar in that crystal moment when they poured out their [organic layer by mistake] and [broke] another’s [favorite sep. funnel]. In that instant, they were as close to [unemployment] as anyone could ever be. And in their own hearts, they know that to dedicate oneself to that moment is worth a thousand lifetimes [...PSYCH! Hahahahahahaahahaah. Heh.].
-David Ackert, LA Times
Seems to fit.

Update: 11:05 PM. Re: source of original, for those interested (thanks to Chemjobber for the legwork). According to David Ackert:

* Caveat: I've done a lot of music stuff myself; I'm not hating on musicians here. Just saying.

Monday, March 4, 2013

JACS comment section? Back to the future

It's been a very interesting couple of weeks in the realm of Blog Syn (the beginning of Blog Syn #003A has a roundup for anyone who hasn't been following). People across a number of blogs have noted the importance (or at the very least, usefulness) of chemists participating in social media and rapid web communication (indeed, even Phil Baran's lab has started a blog, despite hegemonic bias against blogging in the field of organic synthesis). 

How can chemists use social media to the greater benefit? Take, for instance, the first comment in Chemjobber's reply to the IBX+water conclusion. Polychem says (bold emphasis mine):
This work makes me think that every paper published on pubs.acs.org deserves its own comment section. I can imagine it being abused, but there may be some good insights by having essentially a wider peer review where you don't have to pay to print your rebuttal.
Good job Blog Syn people!
 Hmm... a comment section at JACS? Check out this 1996 editorial from the journal! For those stuck outside the paywall, an excerpt:
There is no question that digital computers have had a large impact on the publication of scientific research. JACS uses computers in the management of the journal data base and in production of the journal. Most manuscripts are now submitted in final form as floppy disks, and e-mail is often used for correspondence with authors and reviewers. Recently, especially with the wide accessibility and usage of the World Wide Web (WWW), interest has turned to electronic publishing, i.e., to the posting of manuscripts on the web rather than, or in addition to, producing a hard copy (print) journal. The advantages of electronic publishing include the faster appearance of a paper at a presumed lower cost than printing (with the attendant possibility of wider distribution) as well as the ability to provide materials, like computer programs, movies, color figures, and large amounts of experimental data, not available in the hard copy. Concerns about electronic publishing include the maintenance of the quality and integrity of the published literature, providing for the long-term archiving of papers, and assuring that financial support is available to carry out the needed peer review and maintenance of the archive. These points are discussed in a booklet available from ACS Publications: Will Science Publishing Perish?
Interesting that the ACS proposed lower cost and wider distribution--I wonder if that worked out that way? The last section of the editorial is also a fun read:
JACS Web Page -- An Experiment. The JACS web page (accessible via the ACS publications page at http://pubs.acs.org) displays instructions for authors, links to supporting information, and the table of contents for the latest issue of the journal. As an experiment we will also try out a section for selected correspondence and comments. Readers can submit, by way of a form available on the web page, scientific comments pertaining to recently published JACS papers. Authors will be asked to reply. Posting of comments will not be automatic. Comments for posting will be selected by the editors and they will not be sent out for review. There will be no appeals for comments not selected. Comments will not be published in hard copy or CD versions of the journal nor will they be archived. We hope these comments will generate interesting discussions and help amplify and clarify ideas and results published in JACS papers. They are not meant to discuss priorities or present still unpublished ideas or results. Additions and corrections will still be published in the printed version of JACS. We hope the level of discussion on the JACS page will be significantly higher than the average WWW newsgroup! This experiment will be terminated if the community feels it is not useful (or if it becomes too burdensome for the editors). At this time we cannot accept manuscripts submitted electronically for review; however, we are investigating the possibility of doing this in the future. As stated at the outset, the science publication field is evolving rapidly. The new possibilities are intriguing, but the community will best be served by an orderly evolution that involves the best features of both the print and electronic media.
It's quite revealing to see the difference between scientific publishing just 17 years ago (oh wow, 1996 was 17 years ago??) and now--after all, electronic submission is de rigueur not only for SI but for main text and for correspondence with reviewers.

More interesting, though: there was a comment section on JACS before the journal even started putting the manuscripts themselves online. Seems like unusually progressive thinking by the ACS!

But if you go to the JACS website now, there's no comment section. What happened to it? A search of editorials from the journal gives no relevant hits and a 2002 editorial discussing other web-based aspects of JACS makes no mention of it. Did it die a quick, fiery death?

Indeed, there's a lot of room for publishers to include the community in scientific discourse. Some do a little: Nature Chemistry, for instance, has a good metrics section that indexes blogs (but no comment section). The ACS journals don't have comments, nor do Taylor & Francis, the RSC journals, Elsevier, or PNAS.

Does anyone do comments?

Yes! Take a look at PLoS One (example article): they have comment section built in to a very slick web interface.

It'll be interesting to see how the face of scientific communication changes over the next few years.

Sunday, February 24, 2013

Reading assignments, vol. 11

Communication of science


Peer review and publication

  • Neuroskeptic writes about the perhaps-sensical, perhaps-counterintuitive situation of stats quality in journals. It seems that high-impact journals (e.g. Science and especially Nature) are more likely than many low-impact journals to have insufficient statistical analysis. This may not be surprising, given the incentive for those journals to publish hyped-up work. Is there a similar trend in chemistry? I suspect that many medium-tier journals provide more solid experimental characterization and writeup than some of the flashier ones.
  • Scientists unsatisfied with the status quo of journal publishing practices will find this development interesting. Biologist Michael Eisen has declared that he will publicly post each paper from his lab prior to journal submission for pre-publication, community-oriented peer review. It's a refreshing idea--hopefully others will follow suit.
  • Derek Lowe points to the disappearance of the electronic-only open-access publication Journal of Advances in Developmental Research. Although he notes the relative unimportance of that particular journal, he brings up some points that open-access advocates should pay close attention to: predatory publishing and digital preservation. On a related note, Kevin Bonham writes about the premiere of a new prominent online-only journal, PeerJ.
  • The story of the recent Xi Yan plagariasm endeavor (and the journal's lackluster, non-punitive response) has been written about with proper consternation by See Arr Oh. This kind of case is amazing, as it's the kind of thing routinely warned against in undergraduate writing courses and in orientation lectures at grad programs. Despite this, the plagiarists quite often win (for another plagiarist who 'won', check out Jonah Lehrer). For those with a spare half-hour, check out the Chemjobber/See Arr Oh podcast about plagiarism and peer review. Also, the comments section at the relevant In the Pipeline posting contains a discussion of the ethics of paper submission and whose fault plagiarism is (one commenter seems to think it lies with editors/reviewers and not  professors).
  • In the last two weeks, two more entries came out at Blog Syn (a Pd-catalyzed site-selective C-H olefination and an IBX-mediated benzylic oxidation). Give them a read--and submit your comments if you have suggestions or questions! Blog Syn is supposed to be a discussion-oriented endeavor (and the further updated to Blog Syn #003 illustrate that, I think). On another note, despite broad support (including from more than one big-name prof), Blog Syn does have its critics. See particularly the comments section at In The Pipeline, which is brimming with vitriol (so much that Derek Lowe jumped in to defend Blog Syn).
  • Science librarian Bonnie Swoger discusses common metrics of scientific publishing, such as h-index and impact factor, citing the importance of context in any comparisons. 

The job market


Research highlights

Thursday, February 14, 2013

A rose by any other IUPAC name...

Today is Valentine's Day, and what's more quintessentially appropriate than roses? If you're enjoying the scent of flowers today, you have chemicals (*gasp*) to thank!

Here's a few of those chemicals found naturally in the scent of various rose cultivars:


Enjoy your terpenes, everyone!

References (further reading for the brave)
  1. Flament, I., Debonneville, C., and Furrer, A. (1993). Volatile constituents of roses: Characterization of cultivars based on the headspace analysis of living flower emissions. In Bioactive Volatile Compounds from Plants, R. Teranishi, R.G. Buttery, and H. Sugisawa, eds (Washington, DC: American Chemical Society), pp. 269–281. DOI: 10.1021/bk-1993-0525.ch019
  2. Charles S. Sell. (2003). A fragrant introduction to terpenoid chemistry. Cambridge: RSC, Royal Society of Chemistry. pp. 256–257. ISBN 978-0-85404-681-2.

Tuesday, February 12, 2013

Stop using that word: Facile

Certain words tend to catch on in the scientific literature, such as "novel", which increased exponentially in usage starting in the 1980s. One of those catchy words is one that I previously* used like candy: facile.

Chemists like to describe reactions as "facile." By that, they usually mean easily-performed, smooth, or simple. You know, not much fuss involved. And indeed, that's one of the definitions (from the OED):
adj. (1) a. That can be achieved with little effort; straightforward, easy. In later used freq. in disparaging sense: contemptibly easy. b. Of instructions, a device, etc.: easy to understand or make use of; simple. c. Of a course of action, a method, etc.: presenting few difficulties.
That is the original, historical meaning. Another (more modern) definition carries a different implication (from the Oxford Pocket Dictionary):
adj. (1) ignoring the true complexities of an issue; superficial; or (2) (of a person) having a superficial or simplistic knowledge or approach
And if you type "facile" into Google, you get this immediately:
adj. (esp. of a theory or argument) Appearing neat and comprehensive only by ignoring the true complexities of an issue; superficial
Essentially, "facile" in modern usage (last century or so) has a negative connotation. And take a look at the synonyms for facile (Oxford again):
simplistic, superficial, oversimple, oversimplified, schematic, black and white; shallow, pat, glib, slick, jejune, naive
It's interesting to note that wiktionary has a chemistry-specific entry for "facile":
(chemistry) Of a reaction or other process, taking place readily.
Of course, language is defined by usage, so maybe I'm being picky here. But why not describe procedures as "straightforward", "robust", "easily performed", or any number of other, less ambiguous descriptors? (My intuition says those terms sound too common/"blue-collar" to many academics)

When did "facile" catch on? Well, from a crude PubMed search, it looks like the late 1990s was the tipping point (incidentally, PubMed makes it way easier than SciFinder to get data on this kind of thing. Sorry, CAS). Additionally, most of these references are (not surprisingly) from synthetic organic chemistry papers. See also this description of the two meanings of the word and their historical context.

The shrouded meaning of facile adds overlooked complication when authors start to invent words (after all, organic chemists are wont to derivatize things). There's a handful of examples from the literature that use "nonfacile" (which isn't even a word; go ahead, check the OED or Merriam-Webster).

Take this example from an otherwise-good trifluoroborate-preparation paper (Lennox, A.J.J., Lloyd-Jones, G.C. Angew. Chem. Int. Ed. 2012, 51(37), 9385-9388. doi: 10.1002/anie.201203930):
Replacing MeOH with diethyl ether led to co-precipitation of 2a with other potassium salts (KF/RCO2K etc.), thus making isolation of pure 2a nonfacile. Switching to MeCN kept trifluoroborate 2a in solution, but an excess of carboxylic acid (e.g. acetic or ortho-iodobenzoic acid) was still required (Scheme 2).
So if "facile" means "contemptibly easy" or "appearing neat and comprehensive only by ignoring the true complexities of an issue", what does "nonfacile" mean? Was isolation of 2a not contemptibly easy (just acceptably easy?). Did isolation merely appear difficult while really, under the surface, it was simple?

Stop using that word.

* i.e. before a reviewer pointed out the proper definition.

Sunday, February 10, 2013

Reading assignments, vol. 10

Here's the link roundup for the week:

Science communication

Denialism, chemophobia, and fraud

Chemical education & academia

Public policy

Other

Wednesday, February 6, 2013

Wanna buy some tetrahedral centers?

Chemists: Devise syntheses for the following molecules in enantiopure form, starting from affordable, commercially available precursors.* Oh, and make sure your routes are three steps or fewer.


As conventional total syntheses, of course, that would be a tall order, and each molecule would take a substantial amount of time and effort. But in an interesting new paper (behind paywall at Nature Chemistry) by Paul Hergenrother's group at the University of Illinois at Urbana-Champaign, the authors do just that, as well as preparing numerous other, equally complex molecules. The effort introduces a new variant on diversity-oriented synthesis (DOS) which the authors coin "Complexity to Diversity"--or CtD.

Complexity to Diversity


What CtD entails is this: the authors take stereochemically defined, readily available natural products (here from three classes of biosynthetic small molecules) and perform skeletal transformations on them, using the complexity (chirality and ring structure) present in the molecules to create new compounds that have unusually high numbers of stereocenters and structural sophistication. Moreoever, the compounds are produced in very few steps (from one to about five, averaging three), meaning that regardless of individual stepwise yield, any of the materials may be obtained in quantities sufficient for biological testing or (importantly to chemists) full analytical characterization (check out the SI; there's a lot of NMR data and even a crystal structure!). (This, of course, stands in stark contrast to total synthesis approaches, wherein 3 mg may be the sum total available at the end and making more means gallons of tears and sweat).

At first, the idea of using natural products (typically thought up as targets) as starting materials may sound odd, but (1) that's how nature does it; and (2) semi-synthesis from easily-procured natural materials is a common strategy, the most common example being paclitaxel. One note, in case this wasn't clear: the authors aren't proposing this as an alternative to traditional total synthesis; rather, it's a forward approach designed to generate a library of novel compounds.

The authors employed three starting materials readily available on multigram scales: gibberellic acid (pronounced like "jib", not "gib"), adrenosterone, and quinine. These each represent a major class of biosynthetic natural products: terpenes, steroids, and alkaloids, respectively. Of course, each of these compounds have been the subject of total synthesis efforts (indeed, quinine is covered in KCN's Classics in Total Synthesis Vol. II, while adrenosterone pops up in Carreira's Classics in Stereoselective Synthesis).


The key was the use of structurally transformative reactions (i.e. ring distortions, as in the title of the paper). Take the following example: adrenosterone was submitted to sodium azide and sulfuric acid, giving an interesting tandem ring-expansion (Schmidt reaction) and ring-cleavage. This product (already non-trivially different from adrenosterone in terms of both ring structure and functional group presence) was subjected to a Luche reduction of the unsaturated ketone, giving stereoselectively an alcohol which was then acetylated.


Another example (this one from gibberellic acid): an initial treatment of gibberellic acid with aqueous base resulted in allylic rearrangement of the lactone to give the trisubstituted alkene. The carboxylic acid moiety was then subjected to amidation and a subsequent dual-purpose treatment with in situ-generated trifluoroperacetic acid, resulting in two stereoselective epoxidations and opening of one of the epoxides via a Wagner-Meerwein rearrangement.


A third example (of course, with quinine). In a (to me) pretty neat first step, an acid-catalyzed elimination (described as similar to a Hofmann) followed by a carboxybenzyl N-protection step gives a rearranged ring system that has lost one of two fused rings but produced a ketone (via the enol tautomer). The ketone is then subjected to Petasis methylenation (aka Diet Tebbe), setting it up for a nice Grubbs-catalyzed RCM ring closure to afford the cis-decalin (sort of) moiety.



There's lots more examples than that in the paper. In fact, from those three starting compounds, the authors managed to generate a decent-sized proof-of-concept library (a cool feature of the web interface of the journal is that a list of all the compounds in the paper is available here, complete with easily accessed ChemDraw files and PubChem links. There are 169 molecules listed. The SI is big. Granted, all the combichem types and HTS folks will dismiss that as a very small library, but it covers a much wider area of chemical space than a typical HTS collection, as the authors point out--I'll get to this shortly). 

The birth of the CtD


The concept of CtD is interesting, as it has its roots in two areas of organic chemistry which haven't been in vogue recently: diversity-oriented synthesis (as mentioned before), and chiral pool synthesis.

Diversity-oriented synthesis (which is conceptually similar to combinatorial chemistry but differs in its emphasis of skeletal diversity over substituent diversity) received a lot of attention when it was first championed by Stuart Schreiber, but industry hasn't adopted it as a strategy (though Schreiber and other proponents haven't given up on the concept; check out this article for an anti-malarial 'hit' generated by DOS in 2011). Derek Lowe has written about it several times, with appropriate reservations (incidentally, I'm a little amazed at how much chemist-rage Schreiber seems to induce in Derek's comment sections).

Incidentally, Hergenrother was a postdoc for Stuart Schreiber around 1999-2001, making him part of a group of several Schreiber alumni who utilize and extend DOS methodology (including Derek Tan at Sloan-Kettering and David Spring at Cambridge).

Chiral and inexpensive.
Chiral pool synthesis (aka chiral template synthesis), on the other hand, is simply using readily available chiral starting materials to build complex targets (sometimes called first-generation asymmetric synthesis). For instance, common "chirons" (i.e. chiral synthons) include amino acids and carbohydrates. Nowadays, this method has been somewhat largely supplanted by chiral auxiliaries and chiral catalysis (sometimes called second- and third-generation approaches) because of their broader scope and other advantages--you don't need a completely new starting material for the other enantiomer, for one, and the chiral reagent can be used in very, very small (hence reduced-cost) amounts if it's a catalyst.

So CtD seems to be a child of these two methods. Its birth was also likely motivated by biomedically-driven motives: Hergenrother's group is very involved in high-throughput screening (HTS) efforts for anticancer and antibacterial purposes. I mentioned that DOS gets a bad rap partially because it is an "academic exercise" without use in real industry; I noticed that Hergenrother has (non-CtD) licensing agreements with two companies (StemPar Sciences and startup Vanquish Oncology). It'll be revealing to see if CtD spills over into any industrial connections.

Natural product-like compound libraries


So why bother? Aren't there screening libraries out there? Aren't some of these libraries huge? Isn't combinatorial chemistry well-established? Can't you get, like, six thousand billion compounds and count on one being the magic winner?

Well, the authors conducted a significant cheminformatic analysis of screening collections and marketed drugs in order to support their strategy. They noted a recent survey article from J. Med. Chem.:
A recent study examined eight structural parameters (molecular weight, ClogP, polar surface area, rotatable bonds, hydrogen-bond donors and acceptors, and complexity and fraction of sp3-hybridized carbons (Fsp3)) of compounds synthesized by medicinal chemists over the past 50 years, and then compared them to marketed drugs
The point was this: the properties of screening collections don't generally match up well to marketed drugs, and in certain sub-categories of drugs (say, antibiotics) the mismatch is worse than for others (say, kinase inhibitors). Hence, HTS efforts using these collections are putatively destined for higher-than-expected inefficiency.

In analyzing the results of CtD, Hergenrother et al. chose to focus particularly on proportion of tetrahedral (vs. planar) carbons (Fsp3) and ClogP, comparing the CtD library to the ChemBridge 150,000-compound collection. See Figure 5 of the article (reproduced partially below) for the analysis, presented in shiny, colorful graphs. They demonstrate a clear difference between commercial libraries and the CtD compounds on three metrics: stereocenters, tetrahedral content (representing complexity), and ClogP.

Example of chemoinformatic analysis from paper, differentiating ChemBridge
library (red) from novel CtD library (blue). Click the image for a larger (i.e.
readable) version. Source: part of Figure 5 from the article (Nature).

Additionally, a matrix is shown with Tanimoto similarity coefficients (essentially a geometry-based metric of 'similarity') that indicates substantial geometrical diversification even within groups derived from a common precursor. I'm not 100% convinced on how well Tanimoto scores predict useful diversity (for instance, a compound and its enantiomer would have a coefficient of 1.0 for complete similarity, and so would brominated and fluorinated versions of each other**). Still, it's an interesting metric! Note: a Tanimoto matrix of all 169 compounds is in the SI, if you like that kind of thing.

To sum that up: the group argues that they've created a library that is more 'drug-like' (and/or natural-product-like) than traditional (read: flat and boring) screening collections. Seems reasonable, but I wish there were more chemoinformatic analysis included.

It's tricky (potential pitfalls)


The synthetic chemist in me likes this paper a lot: after all, who doesn't like a healthy dose of wedges and dashes in as few steps as possible? However, I've got a few questions. Some potential limitations:

Derivatization. Med chem efforts tend to involve lots of taking a compound and slightly modifying it a bunch of times followed by screening of the derivatives (this is why med chem articles are pretty much the most boring thing in the world to read). I worry that leads generated in this way would be difficult to conduct derivization studies on. The authors do address this:
To demonstrate that traditional derivatization strategies can be applied even to these highly complex compounds that contain an array of chemical moieties, small libraries were synthesized based on 12 of the 49 compounds. As shown in Supplementary Fig. S4, small collections of imides, N-benzylated amides, aryl amides, amides, lactones, secondary and tertiary alcohols, epoxides, triazoles, ureas and sulfonamides were created readily from these 12 small molecules, and in this manner an additional 119 highly complex compounds were synthesized.
Still, with the strategies employed here, it's very easy to envision only being able to functionalize a small area of a given molecule--and it's also feasible that the functionalizable area would be distant from the actual pharmacophore.

Throughput. Though the output here is good, the reactivity on complex materials is often, well, rather unpredictable. Accordingly, thorough purification and characterization is needed at each step. That rather limits the high-throughput aspect of an approach like this, especially compared to combi-chem and DOS approaches that use highly predictable pathways that can be automated. After all, the idea is to generate a library. Numbers-wise, it's like comparing your bookshelf to your university library (although, if your university library has three million slightly different copies of Twilight but your bookshelf has Dostoevsky, Hugo, Hemingway, Shakespeare, and Poe, numbers might not matter).

Scope/compound selection. The authors do place some guidelines for selecting CtD compounds and reactions near the end of the paper. Still, when compared to simple, achiral starting materials, the selection of multigram-available, affordable natural products with appropriate orthogonality of functional groups seems scant. It could very well be that the good CtD compounds get taken very quickly, leaving few useful options. A lot of that depends on availability of natural products, of course--but is industry really isolating and/or making enough of these for this purpose? The authors address this, somewhat, giving a list of some suggested natural products. But it's a short list.

Does CtD walk the walk? It's interesting to see that no biological screening was reported. As one of the goals of this kind of research is to expand the scope of chemical space covered in screening collections, and by doing so, to improve screening efforts, it will be important to see if that benefit comes to fruition. The chemoinformatic analysis in the paper suggests these compounds to be more natural product-like/more drug-like--will that come to anything, practically? I hope it does. But there's a big gamble here that because complexity is correlated with many drugs (e.g. antibiotics), it'll be causative too.

(End of gloom-rant).

I do think this kind of project would be an excellent training exercise for early graduate students. Routes are short, the chemist would get exposed to a variety of reactions, structural elucidation skills would get quickly strengthened, and the results could very easily be contributed to screening libraries, potentially leading to leads for biologically-driven studies.

One last thought: this work has the potential to annoy a lot of people (perhaps for bad reasons). I can see total synthesis chemists getting annoyed at the economy of steps; I can see med chemists getting annoyed at the lack of trigonal carbons and flat rings; I can see methodology or process chemists getting annoyed at the lack of optimization (since yields here aren't important); and I can see chemical biologists being confused as to whether this is or isn't just a rehash of DOS.

But I think it's a cool paper.

Comparison of synthetic approaches*** (a) Target-oriented synthesis;
(b) Medicinal chemistry/lead optimization; (c) Diversity-oriented synthesis.


Note: this journal article has also been covered in C&EN and by Chemistry Cascade.

* Of course, this instruction is disingenuous, given that retrosynthetic analysis is not really feasible here and it's not target-oriented synthesis anyway, but hey. 
** I think.
*** Alternate interpretation: total synthesis is not as good as Come On Eileen, med chem is better than but pretty much as boring as Nickelback, and DOS confuses as many people as David Bowie.
**** I'm guilty of using lots of footnotes. Sorry, See Arr Oh!

[Edit: fixed minor typographical errors.]