Friday, July 29, 2016

Synthetic Endgame

Inspired by this paper from Melanie Sanford's rocking organometallic group at Michigan.

*Pun contest! I could also have called this post...

Gotta Make 'Em All
Poke-Ball and Stick Models
Chantix Charmander
Putting the Fun in C-H FUNctionalization
'All Thumbs' Synthesis

Friday Fun: Semi-Legal Starting Materials

I ran across this entertaining anecdote today while researching Lord Todd's research into vitamin B1.

From Todd's 1997 obituary in the Independent, written by fellow Nobelist "Kappa" Cornforth:
"[Todd] also worked on cannabis, and in his excellent autobiography A Time to Remember (1983) he tells with relish the story that, having naively imported 6 lb of distilled cannabis resin donated by the Indian police, he had to promise Customs that he would send 25 copies of any ensuing paper to their Bureau of Drugs and Indecent Publications."
Apparently, the "ask forgiveness, not permission" dictum applied in mid-1930s London. It bears reminding that this same choice, made today, would result the appearance of severe gentlemen in dark suits with thick briefcases and Summons in hand at the lab entrance...

Happy Friday,
See Arr Oh

Sunday, July 17, 2016

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:

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.

Saturday, July 9, 2016

Big Fish, New Ponds?

Have you kept your ear to the ground? Felt something on the breeze? Getting a "gut feeling"?

The most recent edition of Chemistry Bumper Cars - Faculty Moves, for the uninitiated - leans towards bigger deals and dramatic poaches as the Fall term looms over the Summer horizon. Here's the latest I've heard about, with my own opinion about whether the rumor holds water.

Dave MacMillan to leave Princeton, for...?
Odds: Low

I hear what you're saying: MacMillan has already moved twice (Berkeley -> Caltech -> Princeton), and we're talking about a researcher who averages an award every year and a new named professorship every four. However, he's fairly well settled into a tight relationship with Merck, who are local to NJ. He's also helped propel Princeton back up in the rankings over the past decade. I can think of only one university that sounds like any kind of a step up, and they have plenty of organic power at the moment.

Dirk Trauner to NYU
Odds: Medium

Though I've heard this more than once, I'm scratching my head about how it makes sense for Trauner. Part of his motivation in returning to LMU was to continue the Mulzer mystique: the powerhouse European natural products group that makes densely-functionalized products appear as if by magic. Then again, NYU seems to be aggressively searching for a certain kind of chemist; maybe Dirk is slated to be the new Phil Baran of the East Coast?*

Update: As seen in the comments, Dirk himself confirms. My gracious thanks to the Professor.

Tom Rovis to Columbia
Odds: Certain

Signed, sealed, and delivered to Columbia back in the Spring.

Dave Liu to Broad from Harvard
Odds: Low

First he was an undergraduate wunderkind with Corey, now one of the youngest Full Professors and an HHMI scholar, all before age 40. He's already a core faculty member with Broad while managing his Harvard group, and I see no reason for Harvard (or for Liu) to wish to terminate his current position. This may sound like wild speculation or stargazing, but I fully suspect Liu's name goes on a nomination for a Big Prize within ~5 yrs, and I think Harvard would do everything they could to keep him in the fold for that day.

Update: As noted in the comments, does appear Liu will have to be physically present on the Broad's campus.

Karen Goldberg to leave U. Washington
Odds: Low

I very much want to believe, especially since UW lost Jim Mayer a few years back, that they can retain Goldberg, a C-H activation and general OM superstar. She boasts a local Center and a named professorship, as well as a Department with plenty of talented young blood: Boydston, Bush, Cossairt, Fu, Lalic, Schlenker, Theberge, Zalatan, all hired in just the last 6 years, doubtless some drawn there through her influence. I'm sure she'd succeed at a Caltech or an MIT, but I really don't know enough about her motivations to say any more conclusively.

Greg Verdine leaves Harvard to run companies full-time 
Odds: High

It's said you can throw a rock in Cambridge these days and hit a VC. Seeing how much apparent fun and success Verdine has had with his previous ventures into the private sector, I'm betting he continues this line full-time and slowly winds down managing theses and group meetings.

*Today's ridiculous statistic: In the past 20 years, Baran and Trauner have authored a combined 372 research papers. That's 2-3 entire careers, and these are guys with 20+ years ahead of them. Damn.

Tuesday, July 5, 2016

Sudden Tamiflu

Hey there, JLC fans! Long time, no post.

Today's inspiration comes from a molecule I've enjoyed watching the synthetic, process, and educational chemistry communities go to town on for the past 18 years: (-)-oseltamivir, also known by the trade name Tamiflu. See that cyclohexene in the middle? This molecule mimics the transition state of a mostly-flat oxonium cation derived from sialic acid, so well that it interrupts the flu virus's ability to release further infectious particles, allowing the body to "catch up" and reduce overall time spent hovered over a steaming bowl of chicken noodle soup.

But enough about the Why, let's get to the How; as the authors of this paper pitch in their opening line: Time is Money!

Hayashi and Ogasawara, no strangers to Tamiflu themselves (syntheses in 2009, 2010, and 2013), report in Org. Lett. ASAP a synthetic economy we don't always consider: time. They claim a one-pot Tamiflu synthesis, five steps, average step yield around 70%...finished in just 1 hour.*

Compare that against the benchmark of the previous 1-pot reaction - 57 hours. Wow!

Several interesting modifications to their previous syntheses have enabled this savings. First, addition of a hydrogen-bond donor catalyst to a nitro-Michael addition, which accelerates the reaction 3x. Second, swap of a base in an HWE reaction: 3.5 hours in cesium carbonate becomes 20 mins in tBuOK. Finally, a sacrificial move - rapid epimerization of the penultimate nitrohexene, knowing that only 50% of the product will successfully reduce to the desired diastereomer.** A short silica column completes the rapid realization of this antiviral drug.

Lest you believe that I'm hornswoggled by a synthetic sprint, a quick glance at the Supporting Info*** provides a cold shower. There's some lingering impurities in those 1H NMRs, enough to make me believe that the yield, even at gram-scale, isn't really 16%. And the reagent equivalencies used to drive these nitro-boosters aren't pretty: 30 parts Zn, 3 parts phosphonate, 15 aliquots of TMSCl. To touch upon an allusion the authors themselves make - perhaps a Jamison-style flow reactor is the next logical step for this speed-demon of a route.

*As I wrote this line, I couldn't stop comparing this to other "just 1 hour!" claims from consumer products: teeth whitening, photo development, tax preparation, LensCrafters, oil changes, and pizza delivery can all refer to the 2016 Hayashi Tamiflu synthesis as a spiritual brother of sorts.

**I don't believe that there's a spontaneous kinetic resolution here, but if any sharp-eyed reader can prove differently, I'm all ears.

***Counter-counterpoint: The one-pot is so streamlined that it now takes only 281 words to synthesize Tamiflu.