Undergrad Tech: Remember When?

Recently, I sat with a friend sipping coffee, watching passers-by hurriedly moving from one tall building to another. Remarks drifted back towards research - as they're wont to do when chatting with chemists - and she said: "Remember how hard it was just to order things?"

I knew exactly what she meant. Lab tech changes quickly, and you may not even notice until you take a step away from the bench. I'm not part of the generation who spent hours sketching molecules by hand from a rubber template pre-ChemDraw, but nor am I a grad student in the era of tablet computers that can access PDB or Aldrich from a free wireless connection in any lecture hall.

Maybe I'll take a quick stroll down memory lane to see how different things really were when I first started undergraduate research...

Planning: Then, as now, most projects kicked off using pen-and-paper or chalkboard sessions; whiteboards were in about 30% of classrooms and gaining ground, but my first experiences with drawing molecules for my coworkers covered my fingers in tacky powder. I can still smell lab chalk: musty, earthy, sometimes tinged with a faint amine odor if stored too near the reagents cabinet.

Courtesy of Dr. Freddy, at Synthetic Remarks, who seems to recall
chalkboards much more fondly than I.

Once you'd had the discussion, you transcribed it into a lab notebook - usually bound with black vinyl, perhaps featuring brown or maroon faux-leather accents and a bookmark string - and signed the page. Then it was time to dive into the literature. First, you staked out some territory at one of the few hulking beige monitors attached to your shared lab computers. Plan for coffee, since reboots and blue-screen crashes could usually be expected to last 10 minutes, with accompanying Windows jingles or goofy Mac cursor wheels.

(Why were operating systems always a generation behind on shared computers?)

Your 10-minute excuse to go grab a coffee.

Beilstein and SciFinder both offered installed systems with single-user seats. This meant you walked down your lab hallway, shouting "Does anyone need anything on SciFinder?" before logging in. The user interfaces were very Internet 1.0 - muted grey windows, inscrutable black text, fuzzy structures. Mostly, you would up transcribing the reference into your notebook alongside the idea. To get the paper, you usually brought a stack of dimes down to the reference library, and spent the next 20 minutes finding and then copying (don't forget to rotate every other page!) the journal article. The still-warm, toner-scented stapled copies were lugged back to your wooden desk to be pored over until evening. My fingers would often be tinged with more than one color of highlighter or colored pen after a night of intense study.

SciFinder Scholar, 1999. Source: ISTL.org

Synthesis: OK, you know what you want to make, so you need some reagents. Maybe first you glanced through the 2,000-row Excel file your lab has as its de facto "inventory" system. I remember some groups also had a dog-eared, yellowing notebook dangling from a rope of masking tape that listed all the chemicals no one needed any longer - hope you enjoy distillation! Failing these approaches, the trusty catalogs are all lined up against the single lab window, effectively blocking out 20% of the available visual real estate. Names of vendors I remember included Fisher, VWR, Aldrich, Sigma, TCI, and Columbia. Each one had different account reps, pricing, and delivery specs; you'd better believe your boss would ask if you looked up pricey, boutique reagents in more than one source. Someone had the lab job of calling these vendors every few days, providing the lab P.O. number or group credit card, and then taking delivery later that week. Collections of cardboard boxes large and small would be piled near the front door, and every week was Christmas (even if it was just your reagent-grade TEA).

The first and last physical Aldrich catalogs I remember ordering from.
Source: Alfred Bader, Sigma-Aldrich

At some point, you'd have everything needed to run your experiment. Hours passed, TLCs ran, and you scribbled long-hand in that same lined lab notebook. I'm fairly certain I spent thousands of hours hunched over, detailing exactly how the workup went, or scrawling single-line corrections (with initials!) for changes and errors.

Analysis: Instruments fell largely into two camps - things you ran and printed out to later affix into 3-ring binders, or numbers on an LED screen you hastily scribbled onto a Post-it note. UV-Vis and optical rotation fell into this latter camp; I still smile whenever I see a forgotten, tucked-away bookmark reading "+8.75 deg."

I worked in lab right at the death knell of chart-recorders - little red pens in threaded holders that traced a curve based on numeric readouts from an IR or GC. NMR, graciously, always emerged on an ink-jet printer in the corner of a sub-level lab. I was a Bruker shim-jockey for quite a while, bragging that I could shim, acquire, FT, pick, and integrate an 8-scan 1H in under 2 minutes. Of course, many academic labs now have robotic cherry-pickers and automatic data transfer, which must save tons of time (unless you're a biophysicist or monitor kinetics; we might as well chain you to the 600MHz).

Source: Cal State LA / Bruker Instruments

Presentation: My first lab group still owned an overhead transparency viewer, and we were encouraged to print or sketch acetate slides each week for discussion. As these smudged easily when warm or done hastily, there were many grumblings and thrown elbows at the photocopier from fellow labmates on group meeting day. PowerPoint was reserved for "big" talks - oral exams, defense seminars, or preparing a poster for ACS meetings. Once saved and laid out the way you wanted, these were burned onto a CD-R or stored on a 100MB USB flash drive your boss might loan you. The walk to FedEx felt tense, because you didn't want to lose this uncomfortable piece of plastic, which contained the only copy of your slides.

Just don't write on the glass itself, or the PI will get really angry. Trust me.
Source: Amazon

I'm sure that I'm missing more fun events from lab life and technology from the late 20th century. Readers, if you have a special memory from back in the day, please feel free to share it in the comments. I'll update the post if I've missed something vital.

Chemical Space Explorers

One startling omission from my Acc. Chem. Res. post? Jean-Louis Reymond's review on the vastness of his generated database GDB-17, a.k.a. The Chemical Space Project. With over 166 billion compounds  Reymond claims to have produced the largest virtual library ever assembled. The best part? It's 99.9% new-to-science compounds. As Derek has quipped, chemical space truly is "Big. Really big."

Trudging along through chemical space, using Dr. Reymond's MQN-browser.
(I realize there's no way some of these are stable - 49? 54? - but they sure do look cool!)

Of these innumerable options, how do we decide what to make next? It's like that old Wall Street saw about how "Buy low, sell high" sounds easy, but takes a lifetime to figure out. It seems straightforward to say that you've generated billions of druglike compounds in silico, but how do you find out which ones are actually drugs?

You have to start somewhere. I still recall the first "chemical space exploration" paper that truly caught my eye - a 2009 J. Med. Chem. scribed by Will Pitt and colleagues at UCB (I still keep a dog-eared copy in my file cabinet). Using machine learning, the team constructed a library (VEHICLe) containing synthetically feasible heterocyclic compounds, most of which had never been made.

Offering a partial update to Will Pitt's "Figure 6" from his 2009 J. Med. Chem. I searched SciFinder for each ring system as a substructure of reaction products, allowing for certain substitutions (say, fused phenyl in place of endocyclic olefin) and considering tautomers. By my count: 10 down, 12 to go!

Pitt issued a challenge in the introduction:

"With this work, we aim to provide fresh stimulus to creative organic chemists by highlighting a small set of apparently simple ring systems that are predicted to be tractable but are, to the best of our knowledge, unconquered."

Heady stuff. So, who will step forward to try these tantalizing targets? Someone certainly should, as Prof. Reymond seems to suggest with his own forward-leaning graphic:

GDB-17 "nearest neighbors" - closely related to known drugs, but not yet synthesized.
(I couldn't find anything similar in SciFinder, either)
Source: J-L Reymond, 2015 Acc. Chem. Res.

Do you suppose an academic candidate could make a convincing case? I'd be tickled pink if something along these lines were sent off to the NIH R01 office:

"Dear [insert funding agency] - Listen, I really want to develop novel molecules to improve human health, but I'm not collecting plants or culturing microbes, and it's too tough to compete with industry head-on. But say, there's this guy who's looked at more compounds than any other human being alive, and he says there's some structures that look really close to existing drugs that nobody's ever tried making. Mind giving me some cash for that?"

Good luck, chemical space explorers. 

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...

Thin Layer Consternation

Earlier today, I was involved in a minor dust-up with some commenters over at Derek's blog. A central issue concerned my (admittedly quick'n'dirty) TLC, which meant to indicate the complete consumption of the acrylate starting material for Blog Syn #002.

Well, since I was already running another entry for #003, I decided to pause and take stock of my TLC tool-box: yes, I should use a ruler, and yes, a classic TLC would have lots more info (solvent system, stain, clearer labels, etc).

So, I took a sample from my IBX oxidation of methylnaphthalene to 2-naphthaldehyde (12 h timepoint, set up in straight DMSO with 0.1 volume of H2O). Results below:

Before anyone goes crazy, that's DMSO / H2O on the baseline, and the SM at Rf ~0.8. It's stained in potassium permanganate, which forms pale yellow spots upon heating. I circled the "UV-only" spots with a pencil before staining.

I'm guessing that the tiny new spot (Rf ~0.45) represents trace aldehyde. But, as you can tell, we're still a long, long way away from completion. Sad, because it was a lot more homogeneous this time!

Readers: How's my technique? Have any more pointers?

Nitration Surprise

(File under "Learn something new every day")

Boom goes the peptide!

For some light bedtime reading, I chose Life Technologies' Molecular Probes handbook, a 1,000-page opus of how to make anything and everything biological light up in brilliant hues of Texas Red or Cascade Blue. Flipping to Chapter 1, I quickly glanced at the very first scheme in the entire catalog, and did a double-take: tyrosine nitration...by tetranitromethane!

TNM: First time's the charm!
Source: Molecular Probes Handbook

Not to tread on Derek - who has a good thing going with his "Things I Won't Work With" tales - but doesn't this look like it should be grandfathered in to his list?

"Rule of Six" violation? Check. Potentially explosive byproducts? Check Check. A brief glance at the MSDS shows some of the more exciting Hazard Codes ("H330 - Fatal if Inhaled"), and the Merck Index (#9305) ain't much better: TNM "attacks iron, copper, brass, and rubber" and "Has been proposed as [an] irritant war gas."

Fun!

But, lest I lapse into my own fit of hypocritical chemophobia, I should point out that this compound is apparently 'par for the course' for stalwart chemical biologists - it's been used since the 1920s to label proteins, and a 1966 JACS article dubs it "stable, specific, and gentle." Even PubMed brings up >600 references, so I suppose my initial gut-check was a bit unwarranted - TNM looks OK when used in dilute solutions. But, I'd still say you should think twice before considering it for routine bench work.

Gotta Chelate 'Em All

Quick, someone call TOC ROFL; there's a fantastic new abstract graphic in town:

Source: JOC | B. Fischer, Bar-Ilan

Yes, that's Pac-Man, in all his NAMCO glory, chomping on a chelated soft metal ion. Turns out these compounds excel at wrapping up "soft/borderline" metals (Cu, Zn, Pb, Hg, Fe) and stopping radical reactions in their tracks.

Maybe this entry might also complement Derek's "Things I won't work with," since cooking up these (wait for it) methylenediphosphonotetrathioates proceeds as follows: Add super-stoichiometric ethanedithiol to hot bromoform and aluminum salts, and stir in starting material (a bis-phosphoryl-dichloride); heat for 5 days.

P.S. - Don't forget that the two-step process evolves four equivalents of thiirane....yum!

Chem Coach Carnival, Day Three

Chemists everywhere! It's not too late to play. Send an email along to seearroh_AT_gmail if you still want to take part.

Day 1

Day 2

Pushing ever onwards. Just after posting the round-up last night, a fresh new batch of recruits showed up! (Not that I'm complaining). Apparently, waaay more folks than I ever thought do Raman spectroscopy for a living. Today, we hear from self-acclaimed 'super-villains,' postdocs, IP counsel, Lecturers, a very familiar Fellow, and two in-silico dudes.

21. Dr. Bodwin, Prof. and Dept. Chair, "Mysterious State U. Midwest." Dr. Bodwin blogs at Everything Under the Copper Sun, Science of Cooking (hmmm...), and maintains electronic lab notebooks at Dr. Bodwin's Electronic Notebook. Call him a faculty leader, recruiter, teacher, budget-maker, just don't call him an "administrator." Dr. Bodwin's story of a grad school "mistake" led him to a whole bunch of unexpected papers...and half his thesis. 

22. Chad, physical chemistry graduate student. Chad blogs at The Collapsed Wavefunction. He claims, like many, that there's no "standard day," and his hours seem to run to grad school extremes. Chad, like many, did a two-year stint in industry before returning to grad school. He plays card games while the laser warms up. Chad recommends learning how to pronounce names of famous chemists before you have to speak them aloud at oral presentations (Good advice!).

23. Dr. Rubidium, Evil Genius / Supervillain. Dr. Rb blogs at JAYFK, Thirty-Seven, and maintains a rockin' Twitter feed. I'm fairly certain she has the henchmen claimed in the post, somewhere deep underground. Dr. Rb walks us through the convoluted world of villains: hierarchy, daily routine, and career objectives. Oh yeah, and forensic science appears in there, somehow. BWAHAHAHA!

24. Michael, grad student / blogger. He blogs at The Organometallic Reader and Cheersical Education. Michael's interests lean heavily towards pedagogy, as one can see from his fantastic organometallic lectures (online). For those who want to teach? "Start early; there's a tired old fogey out there waiting for your youth and enthusiasm." He enjoys long walks on the beach, being recognized on campus solely by voice, and anthropomorphizing chemical events.

25. Marcel, Research Prof. / Computational Chemist, University of Girona. Marcel blogs at Trends in Science. He's an "excellent scientist, performing breathtaking research." Marcel inherited a love of numbers from his accountant father, and feels his postdoc(s) taught him a lot concerning project management. Ask him about how chemistry miraculously 'cured' him of mono...

26. Derek, Research Fellow, Vertex. Derek blogs at In the Pipeline - we consider him the "blogfather" for the chemblogosphere. Derek provides a fantastic med-chem primer, touching briefly on the joys of bench work, project management, binding pockets, and what it's like to bounce around multiple companies. Some of his reactions still form sticky maroon tars; not just yours and mine. Some caveats? "Never talk yourself out of an easy experiment," and "never assume your future grad advisor won't call you in the middle of the night." ; )

27. Darren, Patent Attorney, EIP Elements. Darren blogs at The IP Alchemist (catchy!). He shows us bench types a different aspect, namely examining prior art, and how new ideas become patentable. He's fluent in Japanese; a fringe benefit of the trade (and a postdoc spent in Japan!). Darren's frequent travel to fun and exciting locales makes me dream of a career in the IP office.

28. Janet, Science Philosopher, SJSU. Janet blogs at SciAm's Doing Good Science, as well as Scientopia's Adventures in Ethics and Science. She helps people who are "scared of science" learn about where it comes from. Janet's actually a "double Doctor" - chemistry and philosophy - which you certainly don't see every day. Have a peek at her Philo 133 syllabus, quiz her about the importance of lab safety, or ask about rubbing elbows with Nobelists (twice!).

29. Mark, Applications Scientist, Rigaku Raman. Mark's full entry is published below:

Your current job: I’m working as an Applications Scientist for a portable Raman instrument company.  I’ve enjoyed spectroscopy since graduate school and this position is a good fit for my scientific interests. Because my company is a small startup, it will be a great learning opportunity to develop business skills. The company has a unique product offering for their market, and I’m confident that we’ll be successful. 

What you do in a standard work day: My current position is new, so most of my initial activities have involved training on our equipment and software, sharing insight with coworkers into the c-GMP environment, getting to know our sales force, and learning key marketing messages for the product.  I’ve also begun writing an application note and trade publication articles, as well as helping to edit the user manual.  Because I am a field based employee, I participate in a lot of teleconferences.  I’ll also travel to visit customers, help to train the sales force, and work at trade shows. My position will involve product marketing and seeking out business development opportunities.

A position like this requires soft business skills in addition to technical knowledge.  The ability to network and collaborate with project teams, organize work activity, communicate with customers and coworkers, and frequently delegate without authority are all key to succeeding.

What kind of schooling / training / experience helped you get there? I went to graduate school at a small university and earned a terminal Master’s degree in physical chemistry, specializing in FTIR and Raman spectroscopy.  I’ve held a variety of industrial and pharmaceutical R&D positions as an analytical chemist and also have prior experience as an Applications Scientist with a large analytical instrumentation company. My current position will draw upon that experience base.

I’ve learned that networking is critical career development, not only in finding a new position but also building collaborations to accomplish business goals.  Also, participation and volunteering in professional organizations, such as a local American Chemistry Society section provides opportunities to develop soft skills.

How does chemistry inform your work? I use my understanding of chemistry to help customers select the best solution for their problems or processes.

Finally, a unique, interesting, or funny anecdote about your career: I’m part of a dual chem-career couple.  My wife is a PhD chemist and is currently manager of an analytical group at a specialty chemical company.  We’ve found that geography is critical for dual chem-couples; there really needs to be enough industry where you live to support both careers.  Early in our careers, we worked at the same company.  Seeing the “writing on the wall” we found new positions and relocated before facing a dual lay-off situation.  Altogether, we’ve been really lucky with our jobs so far and work to be supportive of each other’s career growth.

30. Nathan, Computational Chemist. Nathan's full entry published below:

Your current job.

For the past 5 years I’ve led the In Silico Medicinal Chemistry research group at the Institute of Cancer Research in London. I started off as a computer scientist in my undergrad days but moved into chemistry (chemoinformatics) when I joined Prof. Peter Willett’s lab in Sheffield. I’ve had a bit of an unorthodox path to where I am today.

What do you do in a standard “work day”.

My job is now very reactive, which has changed since my time before joining the ICR when my day job was mainly programming. I support both my group and oversee support for our therapeutic projects. This involves lots of computational methods, such as: virtual library design; multi-objective prioritization; docking; pharmacophore searching; building and validating predictive models in QSAR approaches. Much of my work involves assessing the vast space of virtual compounds we could make, but we are unable to in resource-limited academia.

We are a post-graduate college of The University of London so a lot of my time is devoted to supporting our PhD students and PostDocs advising them on tools and techniques to apply in their projects. I also spend a lot of time writing papers with my colleagues, from basic computational methods right through to our teamwork on drug discovery programmes. I am also currently editing my second book, Scaffold Hopping in Medicinal Chemistry, following one that was released recently: Bioisosteres in Medicinal Chemistry.

This year we’ve also had quite a few external visitors, which has led to a few TV appearances on British television on BBC Horizon and Newsnight. You can see the programme on ‘Defeating Cancer’ here: http://www.youtube.com/watch?v=7TyB07imDug&t=42m53s

What kind of schooling / training / experience helped you get there?

I have a first degree in computer science, which was followed by a PhD from Prof. Willett’s lab in Sheffield. In my undergrad life I focused on evolutionary algorithms, particularly writing software to simulate adaptive artificial life models. It was this initial interest in ‘writing software that writes itself’ that led me to work with Peter in Sheffield. I followed this with a Marie Curie Fellowship at Avantium Technologies, Amsterdam and Prof. Johnny Gasteiger in Erlangen for two years and a Presidential Fellowship at Novartis in Basel for another three years.

I never really wanted to work in IT but wanted to use computers to answer questions in other disciplines. I think the most useful experiences I’ve had is working with colleagues from other fields. I find these interactions very rewarding, particularly if you’re unafraid to ask questions that might seem silly. An orthogonal viewpoint has put me in good stead.

Throughout my career, my academic mentors have instilled the clear importance of the scientific method. It is so important in computational sciences to ensure that we do not become beholden to our own ideas because a computer will tell you what you want to hear. At least in real chemistry Mother Nature will give you a slap and say, “No!” The computer often says, “Yes!” This can lead to what I term the ‘pretty picture’ syndrome in some computational work. I always advise my students accordingly to clearly state the hypothesis and how they’re going to test it.

How does chemistry inform your work?

I use mathematics a lot to try and explain chemical phenomena. This is not all that different to scientists in the 19th century who used mathematical representations of molecules with the advent of atomistic theory. One of my mentors referred to a chemical reaction as a context-dependent mathematical graph transform, and in the abstract this is true. I like to look back over old papers and not taken common methods for granted. It is always important to understand how different computational algorithms work: with understanding comes control and can only contribute positively to our work.

There is a famous quote from Feynman: "If it disagrees with experiment it is wrong." This should be the mantra of the computational scientist in whatever field. Our models and predictions must be reduced to practice often to both test our hypotheses but also provide a feedback loop into the system. Therefore, chemistry is fundamental to this. If I suggest a compound that does not fulfil my predicted potential, I have wasted substantially more of someone's time in the lab than in my blase prediction. Due to this, I spend a lot of time doing my best to validate my methods as often as possible.

Finally, a unique, interesting, or funny anecdote about your career.

Although I’m an in silico medicinal chemist, I have been tempted into the lab on occasion. A few years ago I spent a day in the lab working on a halogen dance rearrangement. On my way home that evening I came off my bike, breaking my arm and dislocating my shoulder. Irrationally, I blame working in the lab and that was the end of my synthetic organic chemistry career to date. I knew synthesis was dangerous, but didn’t expect this to be the result.

31. Mike, Technical Editor / Webmaster, AATCC. Mike's full entry published below:

I morphed into science writing unexpectedly, and late in my 30+ year career. I have a BS, Chemistry from the University of Virginia and an MS, Chemistry from Colorado State University, and have been an ACS member since 1980.

Someone once told me that chemists can do practically anything. I didn’t believe them then. I do now!

My loves are natural products/synthetic organic chemistry, astronomy, and meteorology. Was a research chemist primarily in health care products industry. Got swept up in the lure of computer-aided chemistry tools, especially molecular modeling. Learned Unix on my own back in the 1990s. Discovered what “gophers” were, and then, hearing about the Web, realized something big was coming. Got out of the lab and became a webmaster contracting with the National Institute of Environmental Health Sciences for two years. I then rode out the internet boom and bust, until landing my current gig as technical editor of scientific articles and webmaster for the American Association of Textile Chemists and Colorists in 2003.

Adaptability is the key to success in today’s world. I would have never guessed ten years ago that I would have enjoyed being an editor and writer. These were “hidden” talents, until the opportunity presented itself. Even more surprising was finding out that I could write for the public! I had long desired to do this, but didn’t think I had the ability. Two mentors at AATCC convinced me otherwise. As a result of their encouragement, I won a Gold Tabbie Award in 2011 for one of my newsletter articles.

I write articles for AATCC News, the association’s newsletter, relating to textile science. This includes chemistry’s intersection with the larger world of textiles: including fashion! Can you imagine: science on the runway! It’s both fun, challenging, and there is so much to learn!

Most recently, I’ve been an active proponent of social media as an engagement tool. Our Association’s LinkedIn site has become a major textile industry resource. I have little time to blog, but love microblogging (Twitter).

My advice: Do what you love, no matter what, but don’t hesitate taking opportunities to test new skills that broaden your experience. If you want to write, start on Twitter. It’s a great place to meet like-minded people and get your feet wet. Finally, be sure to keep a sense of humor about yourself and what you do-it helps when times are tough.

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32. Late Addition, just under the wire: B.R.S.M., postdoc / blogger, UK (and soon to be in the US of A!). Blogs 'eponymously' at BRSM. A true synthetic chemist, he's proud to "wear the white coat" and work at the bench. I'm jealous amazed that he's achieved so much at such a young age; blame credit the shortened British Ph.D. Seriously, though, BRSM enjoys the freedom of not being bound by grants or teaching (for now). He's prepared for a lifetime of learning...and to learn organic "in-jokes" whenever possible.

For Your Consideration...

A New, Improved 47-Step Synthesis of Shootmenowicene

Editor: We originally sent a 1600 x 1200
color abstract. Just picture a 15-member
macrolide, densely functionalized with
heterocycles, five stereocenters,
 and chelated iron.

Abstract: Shootmenowicene, a heterocycle-containing polyketide macrolide polyene siderophore, was originally isolated in 0.009% from immature sprouts of the Bungus bungus tree. We report herein a significantly shortened 47-step route to the natural product (down from 48), which we believe will allow for kilo-scale synthesis for future clinical trials.

Synthetic highlights include: extensive use of Yamamoto's "super-silyl" protecting group, a Sezen C-H arylation / macrocyclization, kilo-scale flash-vacuum pyrolysis (FVP), and enantioselective tributyltin hydride reduction. Efforts to adapt "green" chemical considerations have been made - the penultimate oxidation occurs by swirling flask in open air for three days over twenty equivalents iron oxide catalyst.

This streamlined route utilizes seventeen silica gel purifications, four alumina plugs, two resolutions: D(-)-tartaric acid and 1R(-)-10-camphorsulfonic acid (the expensive ones, sorry!), and a one-pot global HF / Hg / chromic acid deprotection protocol. Overall yield was 0.0008%, as a mixture of diastereomers (brsm).

Two medicinally active methylated analogues will be reported in due course.

Thanks to Derek for the initial inspiration, with a gentle nudge courtesy of Chemjobber.

Arsenic Life Wrap-Up: The Good, the 'Not-So-Good'

"Arsenic Life," a hot-button issue for much of the past year, reemerged this week with two new papers, one propitious, and one, well...not so much.

GFAJ-1 bacteria
Source: nasa.gov

As covered by Curious Wavef(n), the first paper related Prof. Rosie Redfield's well-documented efforts coaxing the GFAJ-1 strain to flourish in arsenic-rich media, which, if successful, would imply arsenate linkages in the bacterial DNA. Redfield bursts the bubble nicely, utilizing multiple tools (LC-MS, cell growth assays, gels) to cast doubt on the earlier study, even mentioning that most of the detected arsenate could be washed away with distilled water.

Well, if timing is everything, then the second #arseniclife publication really missed the boat. Last week, a commentary appeared in the open-access online journal Biomolecules, bearing the epic title From Phosphorus to Arsenic: Changing the Classic Paradigm for the Structure of Biomolecules. Heavy stuff!

This summary takes the opposite tack, casting "Dr. Wolfe-Simon's discovery" as a fighting underdog - viewed skeptically today, but enshrined and glorified by future generations much like Copernicus or Darwin (both name-dropped inside). The prose shakes the reader with thrilling, emphatic statements, lines you might find in a rousing stump speech or an action movie. A few choice selections:

"...Some have died as a result
of these discussions..."
Image Credit: Silver Lining

"It is no surprise that this work has come under what some may consider a brutal attack in the past year; the proposed repercussions almost beg of it."

"...members outside of the scientific community may view the criticisms and other events that have transpired as superfluous, vindictive, and outright scathing." 

"...the implications of [arsenic life] have the potential to shake the foundation of biology as we have known it for centuries."

 "This discovery...would be absolutely groundbreaking to all of science."

You get the point. These excesses, coupled with a few cut-and-paste sources (N.B. Don't include "page-access" dates in references) and a passing remark to Wolfe-Simon's potential scientific martyrdom, complete the commentary. Yesterday, several Twitter denizens, led by the industrious Carmen Drahl, noted a very familiar vibe to this piece. To borrow a phrase from Derek and Leonid, it sounded suspiciously like a "term paper," final reports students submit to wrap up specific college courses.

My feelings, reading Paper #2
Source: Jobbing Scriptwriter

Was it? A very strong maybe. Check out this editorial, culled from the Colorado State University Journal of Undergraduate Research  (p. 16), scribed by the lead author. Bears a rather striking homology to the Biomolecules piece, sources* and all. The second author, currently an undergraduate at Boston University, may have interacted with the CSU authors at a conference, or perhaps on a summer REU.

As corresponding author, Prof. Mark Brown (CSU) would, I'd believe, have final say over the manuscript. Did he check it against the lead author's previous work? The journal's Author Information section mentions that five external reviewers must be named, although "...the Editor will not necessarily approach them."

So, to round up this bizarre publishing escapade, we have undergraduate authors submitting previous work in an open-access, loosely-reviewed, and barely-edited online journal, all with the benediction of a faculty member? Sounds dubious...much like arsenate linkages in DNA.

*Can someone please tell me where to find Ed "Young" at Discover Blogs? : )


Update, 6.8.12 - Commenter Stuart Cantrill (Editor, Nature Chemistry) points out on Twitter that the original piece also misspelled "phosphorous" in the title. Sigh.

No Superstars? The 'Blog Nerd' Community and 'Science Pride'

Like many in the science blogging community, I try to pay homage to the chemists who've gone before me, especially those who've found their niche and momentum. These include Derek, Ash, CJ, and recently Paul over at ChemBark, who attracts a pretty diverse, passionate, and gregarious comment base.

I took issue recently with the stance of one ChemBark commenter, eugene, who stated: 

"...I sincerely hope [the "superstar mentality"] doesn’t go to any young professors’ heads in the future. Not only will you be vastly overestimating your ‘coolness factor’ with society at large, but you should focus on the science and your job please..."

Familiar scene for the "blog nerds"
Source:  U Chicago blog Science Life

A few lines before this, eugene refers to the "hype...created by the chemistry blog nerd community." (referring, no doubt, to Chemjobber's satirical piece about Dan Nocera's move to Harvard). Let's mull on that epithet: blog nerd community. I think that, by and large, we chem-bloggers enjoy this gig, which is critical because we don't really make our living here - we're all scientists by day, and writers after hours. Our online community encourages, supports, and challenges us. And sure, we're nerds . . .didn't you hear that that's cool nowadays?

But I digress. Back to eugene's comments: "...focus on the science and your job, please." I must know, what's so wrong with wanting recognition for hard work? 

Hey, it's my grad school advisor!

You've all heard the oft-repeated stigma, chemists as introverts, passing up individual glory, monastically devoted to our work until we die at our benches, pipette in hand. There's an ingrained mentality at work here, stating that the discipline is bigger than any one scientist. Chemists write all of their procedures in passive voice, deferring credit, as if the flasks and reagents had jumped up and performed the reactions themselves. I feel like eugene's comments boil down to: "Sit down, shut up, work hard, and hope it all works out."

Derek Lowe recently wrote a telling editorial, in which he explored reasons why most students shy away from work in STEM fields. Quoth the Pipeline:

"...if money and social standing are your motivating factors, you've probably ruled out the sciences for those reasons alone...I definitely did not go into science to become rich.  

There's another factor that doesn't get as much attention as it should: It takes a certain personality type to really get into this stuff. "Yes, it does," I can hear people saying, "and it's the one that we call nerdy." That can help, true, although not all of us in the labs live the stereotype"

Happiest scientist I could find!
(Although her PPE is not quite right...)
Source: 123RF

Yes. Myself, for one: I'm firmly on the ENTJ side of the Myers-Briggs, but the thought of discovering new reactions still gets me to work in the morning. So, I ask you: why can't chemists be proud of their success? Become champions for our cause, rally around research, take credit for our role in society? If judges judge, and singers sing, why can't chemists react?


Chemists: When you go to work today, before you slip on your lab coat and gloves, pause a second to think about all the time and effort you expended to be standing in front of your hood. Enjoy it - you're a superstar.

Well, Hello There!

I love this picture, but shouldn't he be wearing gloves?
Source: Scientific American

I've noticed a recent influx of new guests 'round these parts. Many trace back to my good buddy Chemjobber, and I'm sure Derek over at In The Pipeline has helped, too!


So...welcome to my blog! Please stay awhile, have a cup of coffee, put your feet up. If you've got a crazy idea for a new post you'd like to see me cover, leave me a comment.


Be well, everyone.
-See Arr Oh