Tuesday, January 8, 2013

Bytesize Science: Day-Glo Tour

Glass-lined reactors? Particle dispersion? 'Blaze' Orange? Soft jazz?
Count me in!


Bytesize Science, an outreach offshoot of the ACS, produced this video, which takes you on a 7-minute tour of the brightly-colored Cleveland-based Day-Glo corp (Slogan: "Color. Only Better.")

If you've ever wondered why process chemists need to consult with plant engineers about "pipes and tubes" all the time, this video will clear that right up. My favorite quote (6:40), which takes place in front of a 5,000-gallon reactor:
"Y'know, the dye industry isn't like the pharmaceutical industry [where] everything has to be pure and cutting-edge. We need a pot, and we need to heat it." 
Have a look, and let the ACS know what you think!

Credit due to Reddit Chemistry, where I first saw this posted.

Monday, January 7, 2013

What-a-Ouabagenin! Grams on Demand

I can't believe I got back from New Year's without finding a single post on ouabagenin* [wah-bah-jenn-in], the latest from Phil & Co. in Science this past week:


Ouabagenin, a polyhydroxylated (>5 -OH groups) cardenolide (steroid with an appended lactone) positive inotrope (helps heart pump more forcefully) had been completed only once before, in a 40+ step relay synthesis by Deslongchamps in 2008 (got all that?!?). Only a few mg were prepared, and those of you familiar with the Baran group know that the only real way to make natural products is with a shovel and bucket - gram-scale, baby!

Hulkster - Quite interested in
gram-scale ouabagenin precursors...
So, we start out with 20 g of cortisone acetate - just one reduction shy of Preparation H - and two steps later have a fully protected version of adrenosterone. The group first tries a porphyrin-catalyzed C(19) hydroxylation (the bottom-left methyl), which doesn't work, so they opt instead for some fancy solid-state photochem to generate a cyclobutane ring, which selectively pops open with NIS under sunlamp irradiation.

Selective de-ketalization and iodide hydrolysis sets the stage for a three-step sequence (peroxide, SeO2, peroxide) to generate a diepoxide (right, top), a.k.a. the "most difficult transformation to secure on scale." They toss a "gamut of conditions" at the molecule, only to receive mixtures of enones. Finally, they find that using in situ Al-Hg amalgam (we're talking foil / scissors here!) combined with Sharpless "on water" suspension produces the desired triol, which they wrap up as an acetonide.

Next, "superhydride" reduction both reduces the ketone and protects - as a boronic ester - the remaining two hydroxyl groups. A little Saegusa-esque dehydrogenation, a fluorous solvent-enabled bond migration, and a Co-catalyzed hydration produces 'protected ouabageninone' (right, bottom).

Endgame - We're not out of the woods yet, folks! Conversion of that lone ketone into the vinyl iodide (hydrazine, iodine, TEA) followed by a modified Stille returns a butenolide diene. They again toss in a 'kitchen sinkful' of reductants, only to find that dicobalt-borane (cool!) followed by Barton's base (N-tert-Bu-TMG) produces the correct butenolide orientation (3:1 dr). A touch of HCl in methanol liberates the natural product.

Despite the fact that they report the last few steps on just 30-60 mg, the group claims that they have >0.5 g parked at the protected ouabageninone (vide supra). With this synthesis, Baran also alludes to the overall usefulness of his "redox-relay" strategy, which has certainly served him well before.

*Bonus - In the Scripps press release, Phil calls ouabagenin "probably the most polyhydroxylated steroid known on planet Earth." Billions of yet-undiscovered microorganisms could not be reached for comment.

Escalation: Authors Respond

Regular readers know I sent out an inquiry to the Fe-S authors a few days back:

Dear Prof. Nguyen:

Good afternoon. My name is See Arr Oh (a pseudonym), and I write a chemistry blog called Just Like Cooking. I've posted about one of your recent publications in JACS ASAP:


Another chemist at Princeton graciously offered to repeat one of your reactions (Table 2, entry 2), and could not duplicate your group's yield or purity. Further discussion can be found in the comments section of the second post. Additionally several other members of the chemistry community have expressed an interest in running it themselves, with the intention of aggregating data under the Twitter hashtag #RealTimeChem.

Please share some more information - do you have any hints or tips for successful duplication? 

Thank you in advance,
See Arr Oh

Unfortunately, my spam filter ate the (prompt) response, and thus I'm posting it a few days later than when I received it back on 1/2/13:


Dear See Arr Oh,

Thank you for your mail. First, you should carry out the reaction in the same scale as described, otherwise, sulfur is comsumed by reacting with methylhetarene before combining with iron. Second, a vigorous stirring is necessary to disperse iron powder into the reaction mixture. At this temperature, the reaction mixture is homogeneous except iron powder. Third, the reaction should be carried out under Ar atmosphere because oxygen is not an innocent impurity. Oxygen in the reaction tube is best removed in vacuo (10 mmHg is ok) then the tube is filled with Ar. This cycle is repeated twice. Before running an NMR spectrum of the crude mixture, paramagnetic iron residue should be removed by syringe filtration to avoid any magnetic pertubation. In most cases, the products were formed as black solid. The prduct is fluorescent with UV lamp.

Sincerely


Nguyen

Interesting tidbits: vigorous stirring, as opposed to a debate in the comments over whether we should stir the reaction at all, scalability issues, and recommendations for NMR analysis - Fe junk really does mess that up!

Methinks this advice might come too late* for anyone trying the reaction today; sorry, B.R.S.M.!

*Addendum - That's a lot of "insider info" in that email, and I'd argue a lot of the online discussion we've had on this reaction could have been avoided by a more complete Supporting Information file. None of that info was available either there or in the paper, nearest I can tell. Readers?

Sunday, January 6, 2013

Turning Wishes into Horses

A fantastic summary crossed my desk today, courtesy of the RSC's Chemistry World. It profiled a new reaction from the Milstein group, just reported in Nat. Chem., that just looked so tempting: oxidation of a primary alcohol, using water as the "O" source, with hydrogen gas as the lone byproduct.*

And thus began what my brain usually does, "Science Wish Syndrome." Not familiar? Here's the stages:

1. Unbridled Enthusiasm - "Holy cow, that reaction looks fantastic! I'm sure it will produce 20 new analogues / help me wrap up my thesis early / solve world hunger. I can't wait to try it!"

2. Skepticism / Doubt - "Well, Blogger X tried it, and couldn't reproduce the yields. And the Supporting Info says it only works with 100 mesh hyper-refined silver powder sourced from Argentina. Still, it's in Nature / Science / JACS / Angew Chem, so it must work, right?"

3. Despair - "I ordered all the reagents, and used my last 0.3 mg of shootmenowicene in the test reaction. I barely got 10%, and it's a mixture of stereoisomers! Who the heck let this into this journal?"

Readers, does this ever happen to you? Modern chemistry publication, with ASAP format, DOI codes, PDB uploads, and overall rush to publish before the guy on the other side of the pond, seems forced somehow, and doesn't always live up to the glowing reviews crowed about in press releases.

Over at Not the Lab, Vinylogous has suggested that we compile a sort of post-hoc online review journal, playfully named "Blog Syn" (after 800-lb-gorilla-in-the-room-for-synthetic-methods Org. Syn.).

Well, how might something like this work? I'd assume that the community would have some sort of mechanism to suggest papers, say, for when too-good-to-be-true chemistry like the NaH 'oxidation' comes 'round. A central aggregation point, perhaps cultivated by an "Editor / Blogger" would then issue requests for duplication. To ensure results were processed in a timely fashion, a deadline would be suggested (2 weeks?) and the "Duplicators" would have to authenticate that they tried to cleave to the original conditions as best they could. A digital "Stamp of Approval" might then follow the reaction through the online world, indicating, much like Org. Syn., that the reaction works in others' hands.

Readers, would anyone like to be part of such an effort? Methinks the #RealTimeChem crowd could get excited about this. Yes, I know everyone's busy, and this isn't the first thing you think of when there are proposals to write, classes to teach, or conferences to attend. But the literature will only be as good (or as bad) as the folks who contribute, and we desperately need more quality control.

*Update - It occurred to me (too late!) that I sound like I'm condemning the Milstein reaction, which I have not tried, and have no reason to suspect won't work as of this writing. I just wanted to use it as a backdrop for seemingly "perfect" reactions that end up not living up to expectations. The reaction, as reported, needs some scope exploration, so only time will tell if it's as widely applicable as I'd hoped.

Saturday, January 5, 2013

WWWTP? "Unjunked" Candy

While shopping in Target (Tar-ZHAY) earlier tonight, some food in eye-popping purple & black wrappers caught my eye. UNREAL markets so-called "unjunked" candy, which contains "no corn syrup, GMOs, or artificial flavors." Naturally, I bought one ($0.89, not too shabby) and I can report that it tasted just like the intended Snickers bar facsimile.

But here's the rub: a list on the back (see picture) proudly displays corporate commitment to "chemical-free" - by transforming a bunch of scientific adjectives into pseudo-plural nouns. What, may I ask, is a single "hydrogenated?" Would you say "No Crafts" if your fridge were devoid of craft beer?

The 'organic' ingredients they've constructed the candy from include:
Milk chocolate (cane sugar, chocolate, cocoa butter, milk powder, organic blue agave inulin, skim milk, soy lecithin, vanilla extract), caramel (tapioca syrup, cane sugar, fructan (prebiotic fiber), organic palm kernel oil, whey, milk protein concentrate, organic cream, vanilla extract, salt, soy lecithin), peanuts, tapioca syrup, cane sugar, organic palm kernel oil, skim milk, peanut flour, salt, hydrolyzed milk protein, evaporated cane syrup, soy lecithin
Inulin? Fructan? New to me. Turns out both are fructose-based dietary fibers, which in this context replace some of the fats and sugars found in similar candy bars. However, these soluble fibers often aren't well-tolerated intestinally, similar to known gut troublemakers sorbitol, maltitol, or lactose. My current stomach ache indicates I might be susceptible; please think on my sacrifice when the Pulitzers go out next year...

P.S. I'm no marketing whiz, but "Unreal?" If unable = not able, and unclear = not clear, doesn't 'unreal' = not real? For a candy bar made without "artificial" ingredients? I think the intended sarcasm might be lost on the way to the checkout.

Wednesday, January 2, 2013

Christmas Chemistry Cornucopia

Here's a few things I unwrapped this past week:

I'm very lucky to have such understanding friends and family.

Escalation

Dr. Sonja Krane, Managing Editor at JACS, contacted me to encourage dialogue with the authors of the Fe-S redox catalysis paper. In the interest of full disclosure, I've reprinted my email to the lead author, and I will re-post any response I receive.

Dear Prof. Nguyen:

Good afternoon. My name is See Arr Oh (a pseudonym), and I write a chemistry blog called Just Like Cooking. I've posted about one of your recent publications in JACS ASAP:


Another chemist at Princeton graciously offered to repeat one of your reactions (Table 2, entry 2), and could not duplicate your group's yield or purity. Further discussion can be found in the comments section of the second post. Additionally several other members of the chemistry community have expressed an interest in running it themselves, with the intention of aggregating data under the Twitter hashtag #RealTimeChem.

Please share some more information - do you have any hints or tips for successful duplication? 

Thank you in advance,
See Arr Oh

Cross your fingers!