Better Than Word of Mouth

Hello, dear readers. It's been...a while. I promise the blog is not dead, just sleeping for now. My 2017 New Year's resolutions include sculpting specific time out for all the sci-writing goodness. Stay tuned.

Enough maudlin overtures. Now, on to the fun!

Strem has, as any synthetic guru would attest, the highest-quality metal precursors in the biz.* Now, you could spend a weekend cracking ampoules to find out, or just open to the Supporting Information of one of Jeff Bode's recent publications in Org. Lett. Perhaps you remember this reaction - SnAP synthesis of saturated heterocycles - best from a cheeky Derek Lowe tweet:

That's in reference to the stoichiometric incorporation of tin** in the reagent, which serves as a linchpin for the eventual transmetalation to a copper species and ring closure, neatly without disturbance of the ipso heteroatomic group.

Well, much to my surprise, Prof. Bode has climbed on the recent trend of showing one's work through tactful inclusion of smartphone pics to buoy up procedure adoption. Especially with fussy transition metals, valency, contaminants, poor environment, and a whole host of other factors lead to catalyst poisoning and color changes. In the SnAP case, the litmus test seems to be formation of a correctly ligated Cu(II) ion in lutidine relative to the (probable) hexaaquo cuprate species formed as a blue heterogeneous train wreck.

The kicker? The fairly indiscreet preference for the Strem copper(II) precursor over all other suppliers. Look at the change! Night and day, and key to making these reactions work.

You couldn't buy better advertising than this....right, Strem?
Bravo, Bode group! I look forward to seeing your colorful coupling chemistry in future reads.

--

*Dear Strem: please send non-sequential $50 bills to See Arr Oh at Big City Company, USA
**SnAP. Get it? [drum kit]

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. 

Desert Island Chemistry: Simple as Fe-S

"Damnit, Jim, I'm a Professor,
not a chemist!"

(cue the Gilligan's Island theme music)

Quick! You're on a desert island, and you have to make a heteroatom-rich drug compound. You don't have any of your fancy Pd, Pt, or Ni complexes - those unfortunately went down with the ship. Since your phone is made from coconuts, no access to Aldrich, either; boronic acids and bromoarenes are out. Your scouting party reports finding a simmering sulfur-encrusted thermal vent, and you still have a few hand warmers in your pockets...

...What do you do?

Well, if you were lucky enough to bring the latest JACS ASAP, you'd know right away: grab a jar, stir a 2-nitroaniline and a methyl-heteroarene together with equal parts iron powder and sulfur, toss the mixture into the thermal vent, and wait - about a day should do it. Et voilà! Just about any benzimidazole you can think of, courtesy of a catalytic iron sulfide species formed in situ. 

The authors present 21 entries, most in the ~50-80% range, which includes examples where normally labile bromo- or chloroarenes (Suzuki classics!) survive the procedure unharmed. The only catch? The heteroatom must be at the 2- or 4-position of the methyl-arene (sorry, no meta). 

Source: JACS | Prof. Nguyen, CNRS

So what's going on here? The authors invoke a biologically-inspired iron sulfide cluster, like the kind one finds in redox proteins underpinning essential processes like respiration or DNA repair. Though the mechanistic details haven't been fully teased out, they claim a six-electron (6e-) reductive transfer, using evolved water and the iron sulfide cluster as electron and proton shuttles, followed by ring closure. (Extra bonus: many of the products can be directly triturated out of the reaction mixture!)

Reader challenge: I'm itching to try this reaction, but don't have any iron powder, sulfur, or nitroanilines handy. Anyone want to give it a shot, and let me know how it turns out?

Be a #RealTimeChem hero!