Thursday, May 29, 2014

Who Would YOU Invite to the NOS?

Plans for the 2015 ACS National Organic Symposium (U. Maryland) have ramped up recently. The Division of Organic Chemistry sent out some feelers last week, requesting nominees for speaking invitations.

Source: University of Maryland, 2015 NOS website
Judging by early suggestions, I think they'd especially like to hear about up-and-coming* chemists, both in the U.S. and abroad. So, readers, I'll put two questions to you:

1. Which early-career (<10 years' experience) U.S. organic chemist would you recommend?

From the comments: Jeff Johnson (UNC), Guangbin Dong (UT-Austin), Chris Vanderwal (Irvine), Rob Knowles (Princeton)

2. Which international** early-career organic chemist's work most excites you?

From the comments: Masayuki Inoue (Tokyo), Weisheng Tian (SIOC), Nicolai Cramer, Michael Willis, Shu-Li You (SIOC), Jerome Waser (EPFL), Nuno Maulide, N. Yoshikai (Nanyang), M. Niggeman (EWTH Aachen), Ang Li (SIOC)

Please leave your thoughts in the comments. Thanks!

*Presumably, this serves to generate a more inclusive environment, and also (hopefully) helps NOS to reverse the steep declines in attendance. 
In 2003, 1081 chemists traveled to Bloomington, IN; only 636 made it to Seattle, WA in 2013.

**Bonus points if they're from outside the U.K. or Europe.

Thursday, May 22, 2014

Antibiotic Purple Rain

Did you know scientists used Clostridium species to produce industrial solvents from cellulose?
Did you know anaerobic (oxygen-free) bacteria produced polyketides?
(I didn't!)

This Angewandte Chemie article by Prof. Christian Hertweck (HKI, Germany) held many such surprises for me. While poking around in bacterial genomes, Hertweck and team discovered gene sequences for secondary metabolites, or what organic chemists usually call "natural products". When they cultured a certain Clostridium strain from their collection, a deep purple dye emerged.

Dubbed clostrubin (see right), the pigment possesses several striking features. First, its shape: this five-ring topology, dubbed a benzo[a]tetraphene, has never been documented from living organisms. Second, although polyketides commonly come from other microbes, this is the first the team had ever observed in an anaerobe. To compound the mystery further, the folding pattern itself - polyketides come from long chains of simple precursors - had never been seen.

Most exciting for all involved: the compound shows high activity in assays against MRSA and VRE, two highly resistant strains feared for their prevalence in hospital-based infections.

So, who wants to be the first to make it?

Wednesday, May 21, 2014

Satori Makes Good (Steroids)

Whether it's because of the evergreen interest in Carl Djerassi, the discovery of a (new-to-me!) blog, or Percy Julian's recent Google Doodle, everything in the blogosphere seems to be coming up steroids.

Take a peek at these back-to-back OPRD articles, both from chemists at the former Satori Pharmaceuticals.

As a "cub blogger" for CENtral Science, I still remember gaping at how radically different their root-derived phytosterols were from the rest of the anti-Alzheimer's medicines. Now, almost a year to the day after Satori shut its doors, we have some insight from the team responsible, just before they scattered to the winds.*

So, that means 6.99 tons of plant waste to dispose? [rubs eyes]

To access their preclinical candidate, Satori scientists first needed a reliable supply of the glycosylated intermediate. Enter seven metric tons of dried black cohosh, a traditional medicine used as a pain reliever by Native American healers. A third-party vendor crushed the root and sent it to another firm, where they extracted it with ethanol, passing about 300 kg of "solids" back to Satori. Suspension in brine / DCM partitioned the desired compounds into the organic phase, which was treated with triethylamine and catalytic zirconium tetrachloride. This ejects the pesky E-ring alcohol, and the resulting compound performs a net oxidation to yield a diastereomeric mixture of ketones (above).

(Warning: I guess you haven't lived 'til you've purified 70 kg of crude, brown extract with DCM over silica...yuck!)

So, once Satori had in hand ~11 kg of compounds 1 + 2 (see right), they needed to advance the structures to their desired candidate (below) which you'll notice has a few little changes from the plant-derived drug. Gone are the acetyl group. Reduced is the ketone. Ripped apart is the sugar, making way for a morpholine.

The scientists' first-gen synthesis, an 8-step sequence, wasn't up to snuff for kilogram work. The trouble? Too many chemically similar hydroxyls, prompting some protecting group manipulation to target one or two selectively. Process work on the ethyl ether step - utilizing diethylsulfate / tert-butoxide in place of an earlier NaH / EtI mix - allowed a telescoped 5 step route, cutting out 2 silica gel columns and upgrading the final process purity to >95%.

Interestingly, the authors, ever circumspect, reflected on the limitations of their final process:
"While this reported route was sufficient to provide the kg-scale quantities of target compound for preclinical studies, we acknowledge that it has limitations that would make it impractical at the 100 kg scale."
Silica gel chromatography strikes again! Still, their candidate came through on 1 kilo, at about 30% overall yield after HCl salt formation. Not too shabby.

Update (5/30/14): Want to see how Satori chose these molecules? One of the authors (Hubbs) writes in to recommend their 2012 J. Med. Chem. optimization paper.

*According to the author lists, everyone on the team ended up in a different place: Enanta, AstraZeneca, Celgene, ETH, Genzyme, Resilientx, Sanofi.

WWWTP? Travel Edition

JLC hit the road a few weeks back, and collected a bit of chemical mayhem along the way!

First, a follow-on to a strange beauty products ad used by Kiehl's. First noticed by ChemBark and Stu Cantrill, I've now managed to find the full structure in (photonegative?) a completely different airport:

I'm willing to take bets on what readers think Kiehl's might be trying to draw; I don't have access to SciFinder until tomorrow morning. First blush? Looks like a strange, mangled version of digoxigenin, which I certainly wouldn't want in my face creams!

Second, a comparison of two toothpastes: one manufactured in the ol' US of A, and the other in Thailand. Same brand. Notice anything different?

Different fluoride sources! I hadn't realized that the FDA allows MFP, or even stannous fluoride, in place of sodium fluoride in toothpaste. Huh.

Friday, May 16, 2014

Friday Fun: Backhanded Compliment

From a recent correction in OPRD, an odd bit of recognition.

In a 2014 paper, Burgard and Turconi, two Sanofi process chemists, laid out their vision for a high-yielding, industrial-scale semisynthesis of artemisinin. Somewhere along the way, a reference to another semisynthesis (Tetrahedron, 2013) got missed. Here's how the overlooked authors find themselves incorporated (emphasis mine):
"Bearing major breakthroughs in synthetic methodology, we are confident that this hybrid approach is far superior to a total synthesis and none of the many total syntheses published [insert ref here] appears to even approach providing a basis for a commercially viable process."
 Ouch. Them's fightin' words.

Happy Friday,

*One wonders if the first word should be "barring," as in, the authors allow that synthesis might one day catch up. As written, it's much more of a boast.

Wednesday, May 14, 2014

Elemental Roll-Call

Inspired by posts from JessTheChemist and the esteemed Dr. Lowe, I've tallied mine below.
(N.B. I came up in an organometallic lab where we made many precursors from scratch...)

Hydrogen (obvious)
Helium (carrier gas)
Lithium (Li-Hal exchange)
Carbon (Darco)
Oxygen (ozonolysis)
Aluminum (form'n Friedel Crafts salts)
Sulfur (mercury spills)
Chlorine (oxidant)
Potassium (N-K form'n)
Manganese (reductant)
Iron (reductant)
Nickel (Ra nickel)
Copper (forming amalgams)
Zinc (organozincs, reductant)
Bromine (distilled, even...yuck!)
Palladium (hydrogenation, salts)
Silver (foil, to make salts)
Indium (reductant)
Cerium (cross-coupling...failed)
Samarium (to make SmI2)
Platinum (hydrogenation, catalysts)
Gold (dissolve in aqua regia)
Mercury (old pressure eqpt)

So, I count 28. Pitiful against 118, but a varied lot nonetheless.