A Tale by Mail

Long-time readers will no doubt be aware of my running affectation with the "Profiles, Pathways, and Dreams" series of books from ACS; books which, had I not read them in grad school, would probably cause this blog to never exist.

So I have a sneaky hobby: scouring the Internet's used book counter to assemble an entire set. Thus far, I've collected 17 of the 22 from the original 1990-1995 run. As I'm simultaneously trying for thrift, I'm proud to say the most I've paid for one of these books was around $25.

One of the best came in the mail only today - a first-edition, basically mint copy of Djerassi's Steroids Made it Possible. You know, the one with the picture of Nobelist R.B. Woodward going Mike Tyson's Punch-Out! on another esteemed chemist?

Steroids Made it Possible, ACS Books, p. 60

I open the plastic packaging, breathe in the old-book-paper smell.  But wait, there's no library markings. And the book is, what, 26 years old, and is basically undamaged? Curiously, I opened the cover, and realized that Djerassi himself had dedicated it:

To whom, exactly? Why, to Larry Lehmkuhl, the previous president of St. Jude Medical, according to Bloomberg. And is that really Carl's signature? I've compared it against two *for sale* on eBay and at Amazon - $89 euro and $39.85, as of this writing, respectively - it's the real McCoy.

This, of course, raises more questions: Did Lehmkuhl ever read his gift? Was he from a chemistry background? (I can't find much about him through the usual channels).

Did Djerassi mail out copies of his books, en masse, to anyone interested? If so, perhaps other signed treasures are out there, waiting to be found.

Hyperspeed Hyperforin

Kudos to the Maimone group (UC-Berkeley), who have published in JACS ASAP what seems to be the speediest synthesis of a hyperforin on record - just ten steps!

Perhaps this lends more credence to the Eastgate's "current complexity" index, which measures synthetic simplification over time thanks to improved methods. But who would have guessed that in just five short years this synthesis would telescope from 50 steps down to just 10? Strychnine, albeit a very different challenge, took nearly 60 years to simplify from 30 steps down to Vanderwal's highly-convergent six.

For Chemists: Steps of interest include a highly-oxidized [4+2] diketene cycloaddition, a iodoacetate-promoted ring expansion, and a highly modular synthesis widely amenable to analogue production.

For Everyone Else: Why should I care that this ungainly-looking molecule was made faster than before? First, hyperforin and related secondary metabolites (natural products produced by living organisms) isolated from famous folk remedy St. John's wort suggest new avenues for the treatment of of malaria and certain forms of depression. Second, if chemists can make variations on this molecule in roughly one-fifth the time, we can expect a venturesome start-up somewhere to begin fleshing out the SAR (what chemical modifications product what activities?) in record time.

WWWTP? BBC's Sherlock Edition

Chemical degradation by microscope? Incorrectly-scrawled structures? Wikipedia analyses?
Looks like Scotland Yard should send their consulting detective back to University.

I'm referring, of course, to Sherlock, the BBC reboot that re-imagines Detective Sherlock Holmes and his partner Dr. John H. Watson as modern* Londoners, with text messages and nicotine patches in place of telegrams and pipes. Quick reminder: the Sherlock of Sir Arthur Conan Doyle's original books represents the first fictional character ever recognized by the Royal Society of Chemistry for contributions to science.

Sherlock Holmes hacks into a secret British government database and finds...pyridine and phenol!
Credit: Benedict Cumberbatch and BBC-One

In "The Hounds of Baskerville," Holmes and Watson investigate claims of a giant, red-eyed monster lurking outside - wait for it - a secret military research laboratory called Baskerville. Naturally, the dynamic duo break into the lab under false pretenses, questioning a scientist accused of genetically re-engineering a pet bunny to glow green.**

They later return to Baskerville with a hypothesis: a psychoactive drug, perhaps hidden in an innocuous foodstuff. Holmes sets to work using the analytical instrument of choice for modern chemists - the light microscope. Using nothing more than a pipette and glass window that would have made Bob Woodward proud, Sherlock performs some crude chemical degradation studies:

Who needs NMR, kinetic studies, or a mass spectrometer? I have a mallet and a watch-glass.
Credit: BBC-One

(I'm guessing Sherlock wrote "D-Deuterium?" at the top left to remind himself that the evil research agency might have tried improving their mind-control drug's physicochemical properties : )

The silly Hollywood chemistry builds to a peak when Dr. Watson timidly investigates a scary chemical structure on the lab wall. Don't blink; it's only on-screen for about a second:

"Vancomycin" - Close enough for television?
Source: BBC-One

Well, at least the creators got something right - vancomycin certainly ranks as a "chemical weapon," but it's for killing marauding bacteria, not innocent townsfolk. That chlorocyclohexane on the right *should* be fully aromatic, and I'm sure if I had a higher-res image, I'd start to spot some more structural snafus.

I won't spoil any more of the show, but there's a few other chemical flights of fancy, such as Sherlock analyzing multiple components of floor wax using nothing more than some colored test tubes and his nose. Readers, cue up your online streaming service of choice, and have a look at episode 2.2 - let me know if I've missed more molecular mishaps.

--

* Spoiler - the goofy hat remains. Not a bad look, if you ask me.

**The show does mention that the green fluorescent protein was isolated from a jellyfish, which might be the most accurate science in the entire episode.

Science Blackout Poetry, Round 2

Round 1

JACS 2006, 10596

(These are really fun to do!)

R.B. Woodward's thesis

Chem. Comm. 1976, 734

The Incredibly Consistent R.B. Woodward

Fans of the blog know of my playful hero-worship of R.B. Woodward. A man so well-known for both his chemical triumphs and signature eccentricities (blue suits, cigarettes, slow lectures) should expect nothing less.

Recently, the ACS Division of Organic Chemistry gave me good reason to go goof around on their newly-designed site. I became especially intrigued with their collection of old National Organic Symposium brochures. Among male contemporaries, only E.J. Corey spoke at more NOS meetings (8) than RBW (tied with six others at 6 apiece).

Check out my slow-mo time-lapse photography, culled from appearances in the NOS brochures:

First, E.J. Corey, over a 52-year NOS span:

Next, RBW, over 28 years:

Wow. Same suit, same glasses, same haircut, same expression, far as I can tell!

(He really favored that left side, huh?)

Check out the titles of Woodward's talks:

• 1977 - "Recent Advances in the Chemistry of Natural Products"
• 1967 - "Recent Advances in the Chemistry of Natural Products"
• 1957 - "Recent Advances in the Chemistry of Natural Products"
• 1953 - "Recent Advances in the Chemistry of Natural Products"
• 1949 - "Recent Studies on the Structure of Natural Products"

(P.S. All of E.J.'s talk titles were completely different!)

Slow Down, Bob

An open letter to R.B. Woodward (RIP):
(Playfully adapted from Dr. Freddy's post)

Dear Bob,

Listen, I know you can't hear me right now, but I feel like this post may be overdue. Back in your day, the closest thing to "blogs" were the Editorial pages of the newspaper and (actual, cork) bulletin boards. Thus, I'll ask on behalf of all struggling grads and bench chemists: could you please stop being so darn productive?

Someone recently pointed me in the direction of your dual MIT theses. That doctoral title, what chutzpah!

I know, I know, things were different back then. You didn't have a single NMR in your dissertation; after all, it wasn't invented yet! Ditto mass spec or HPLC traces. You characterize everything by mp, bp, and elemental, and yet I can't believe you finished your Ph.D. in a year. 

Dissertation Stats: 64 (typewritten) pages, 23 (hand-drawn) structures, 27 references

Of course, we all know what happened next. You postdoc'd at Illinois for maybe two weeks, and jumped over to Harvard for a 40-year stint. You (almost) single-handedly applied UV and IR to molecular characterization, you made strychnine, chlorophyll, and B12, and you won a single-scientist Nobel at the ripe old age of 48. Some folks even thought you might have deserved (at least) one more! 

Your personality still towers over us today - legends of blue suits, chain smoking, and three-hour lectures abound in roughly 58.8%* of recent blog posts. Even your fashion sense is back in vogue, (perhaps) influenced** by your invisible hand.

While you were making quinine and cortisone in your 30s, we're now just trying to find good, stable jobs. So Bob, please enjoy your well-earned rest, and stop reminding us of how life could have been a few generations ago. We just can't bear the comparison.

*Studies show that roughly 95% of statistics are made up on the spot

**And Mad Men

Hi Ho, Silver! (Benzoate)

Ever feel déjà vu? You know, that feeling of having been somewhere before, or crossing a black cat twice?

Carbon dioxide - Silver benzoate "puts a ring on it"
Source: Yamada, et.al. ACIEE, 2012

I've been stalked lately by a certain catalytic reagent: silver (I) benzoate. It's everywhere! Here, Charette's using it for C-H activation, with a little dash of Pd, to produce heterocyclic drug leads. Here, Toste's group turns up the selectivity on a gold hydroamination. Just this week, Yamada and coworkers showed lactone formation via carbon dioxide fixation (see above), using a bit of pressure, some base, and...you guessed it, silver benzoate.


Makes me wonder: Did I somehow miss the signs? How long has this reagent been flying under my radar?

In 1957, the Lone Ranger
ruled the Silver Screen
Source: lonerangerfanclub.com

Quite a while, it seems. Name reaction buffs - have you heard of the Prévost? First developed in the 1930s, it produces an anti vicinal diester, forming two new C-O bonds from opposite directions on neighboring carbons. Later investigations into the "wet Prévost" reaction favored cis diols; not too shabby when you consider that the related osmium or iodonium variants were still several decades away.


In its heyday, the Prévost helped synthesize steroids, alkaloids, and polymers, and found its way into the hands of a Who's Who of the O-Chem 'golden age': Woodward, Fieser, Carothers, Winstein, Streitweiser, Gilman, Djerassi, Fries, Benkeser, Sondheimer, van Tamelen, and Witkop. Perhaps you're more of a mechanisms person? Check out this sweet ¹⁸O labeling work, courtesy of a young University of Washington chemist named Ken Wiberg (1957).

What about silver benzoate makes it so darn useful for these oxidations? First, you have a d¹⁰ late metal species, which loves to coordinate to π-bonds (alkenes, alkynes, allenes). Second, the softer nature of the resonance-stabilized benzoate might switch on different catalytic pathways, say, changing from inner- to outer-sphere. Finally, to the benzoate itself: our buddy Ken showed that it adds twice, producing a transient 5-membered, cyclic species that ultimately permits the second benzoate addition.