Friday Fun: RCDEYM

Readers: Do you recognize that acronym?

Hint: It's a reaction related to RCM, with a taxane twist...

I've seen some strange nicknames in the organic literature, but this one takes the cake. How do you even pronounce it* in casual conversation? Is muttering "R-C-D-E-Y-M" actually more efficient than saying its real name?

Ye Gods.

-------
* "Racadaim?"

If you're truly stumped, click here or here for an answer. 

An "Ironic" Pauson-Khand

How would you go about making this compound?

(+)-ileabethoxazole

Taking a casual glance, I'd offer up at least a few disconnections. An epoxide-opening cascade, starting from that alcohol in the lower left hand corner. Maybe make the oxazole last, after some funky bismuth rearrangement chemistry. Perhaps you think you could stitch together the middle with some new-wave aryne technology?

Well, the Williams group (Indiana) took a completely different tack: a 9-iron. 

Not the reagent in question.

No, not the golf club, but di-iron nonacarbonyl. This dimeric "precatalyst" is thought to dissociate under the reaction conditions to Fe(CO)4, an unsaturated iron species that can complex to a variety of pi groups. It's been used for the Pauson-Khand for about 20 years, but the Williams group uncovered a new wrinkle last year: according to calculations, the iron might be initiating at the allene using a 3-membered metallacyclic ring! 

Very cool.  

Using these results, the Williams group mentally unzips the cyclopentane to this retrosynthetic intermediate (right). This wasn't the first thing they tried - that MOM ether on the oxazole came only after brominated versions of the heterocycle kept falling apart. Amazingly, the diiron complex ignores the alkyne, oxazole, and the MOM, choosing instead to complex to the end of the allene. Alkyne complexation, CO insertion, et voila! Cyclopentanone, coming right up (61% yield). Three more steps (deprotection, Swern, and base-promoted cyclization) produce the desired four-ring core.

The paper possesses blind alleys, full-stop restarts, theoretical underpinnings, and a good mission - anti-tuberculosis activity. Well worth reading the whole thing.

Chemistry Bumper Cars, 2014-2015

'Tis the season for chemistry faculty to pack up their U-Hauls, distribute plane tickets to the post-docs, and relocate their labs halfway across the country. 2014's shaping up to be not much different from previous cycles.

For this year's moves, I'm adopting the ChemBark format, picking up roughly where he left off.

**Know of someone missing? Let me know in the comments!

Moves

Sarbajit Banerjee (SUNY-Buffalo to Texas A+M)
Timothy Bertram (UCSD to Wisconsin)
Carolyn Bertozzi (Berkeley to Stanford)
Christopher Bielawski (UT-Austin to UNIST)
Erin Carlson (Indiana to Minnesota)
John Clayden (Manchester to Bristol)
Andrew Cleland (UCSB to Chicago)
Vicki Colvin (Rice to Brown, admin)
James Dalton (industry to Michigan, admin)
Scott Daly (G. Washington to Iowa)
Darren Derksen (SFX to Calgary)
Thomas Dunning (NIAC to Washington)
Katherine Faber (Northwestern to Caltech)
Eric Ferreira (Colo State to Georgia)
Joseph Francisco (Purdue to UNL, admin)
Giulia Galli (UC Davis to Chicago)
Justin Gallivan (Emory to DARPA)
Richard Gross (NYU Poly to Rensselaer)
Michael Gross (Bucknell to Wake Forest)
Mei Hong (Iowa State to MIT)
Jeffrey Hubbell (EPFL to Chicago)
Ramesh Jasti (BU to Oregon)
William Kittleman (Birmingham-Southern to Millersville)
Angela Koehler (Broad to MIT)  thanks, Anon!
Yamuna Krishnan (NCBS-Bangalore to Chicago)
Igor Larrosa (QM to Manchester)
Marcus Lay (UGA to Cooper Union)
Wenbin Lin (UNC to Chicago)
Mi Hee Lim (Michigan to UNIST)
Andrew Lyon (GA Inst. Tech to Chapman, admin)   thanks, Anon!
Lane Martin (UIUC to Berkeley)
Jim Mayer (Washington to Yale)
Phil Messersmith (Northwestern to Berkeley)
Gerald Meyer (Hopkins to UNC)   thanks, Anon!
Dan Mindiola (Indiana University to Penn)
Nouri Neamati (USC to Michigan, 2013)
Andrew Phillips (Yale to Broad)
Eran Rabani (Tel Aviv to Berkeley)  thanks, Max!
Gayan Rubasinghege (St. Cloud to New Mexico Tech)
Elizabeth Rhoades (Yale to Penn)
Tobias Ritter (Harvard to Max Planck, 2015)  thanks, Anon!
Jan-Uwe Rohde (Iowa to UNIST)   thanks, Anon!
Peter Rossky (UT-Austin to Rice, admin)   thanks, Anon!
Alan Saghatelian (Harvard to Salk)
Klaus Schmidt-Rohr (Iowa State to Brandeis)   thanks, MJ!
Gregory Scholes (Toronto to Princeton)
Dionicio Siegel (UT-Austin to UCSD Pharmacy)
Melody Swartz (EPFL to Chicago)
Paul Thompson (Scripps to UMass Medical)
Kallie Willets (UT-Austin to Temple)
Bryan Wong (Drexel to UC-Riverside)
Damian Young (Broad to Baylor)

Source: U-Haul.com

New Hires

Brett Fors (Cornell)
Neil Tomson (Penn)
Sophie Rousseaux (Toronto)
Tianning Diao (NYU)
Steve Townsend (Vanderbilt)
Jeffrey Rinehart (UCSD)
Jeff van Humbeck (MIT)
Alex Shalek (MIT)
Dave Martin (UC-Riverside)
De-en Jiang (UC-Riverside)
David Sarlah (Illinois)
Jessica Anna (Penn)
Sarah Slavoff (Yale)
Hailang Wang (Yale)
Ziad Ganim (Yale)
David Nagib (Ohio State)
Sergey Pronin (UC-Irvine)
Gerald Knizia (Penn State)
Jefferson Chan (Illinois)
Brett VanVeller (Iowa State)
Vincenzo Venditti (Iowa State)
Bryan Dickinson (Chicago)
Alexander Spokoyny (UCLA)
Matthew Cain (U. Hawaii)
Raymond Moellering (Chicago)
Nicole Becker (Iowa)
Heather Jaeger (Lehigh)
Tim Cook (U Buffalo)
Melanie Chiu (Stony Brook)
Christopher Johnson (Stony Brook)
Ignacio Franco (Rochester)
Nathan Jui (Emory)
Jacob Schwartz (Arizona)
Kateri DuBay (UVA)
Michelle Dolgos (Oregon State)
Dipankar Koley (Oregon State)
Sandra Loesgen (Oregon State)
Jesse Zalatan (Washington)
Cody Schlenker (Washington)
James Prell (Oregon)
Aaron Franklin (Duke)
Alex Grenning (Florida)    thanks, Rob!
Suri Vaikuntanathan (Chicago)   thanks, Andrew!
Sarah Wengryniuk (Temple)   thanks, Brando!
Graham Dobereiner (Temple)
Zac Hudson (UBC)   thanks, Anon!
Aaron Vannucci (South Carolina)    thanks, Anon!
Laina Geary (U. Nevada-Reno)  thanks, Anon!
Ryan Rafferty (Kansas State)     thanks, SupraChem!
Chen Zhou (Central Misssouri)    thanks, UCTDM!
Jonah Jurss (Ole Miss)
Brian Michel (U. Denver)
Michael Nippe (Texas A+M)
James Frederich (FSU)
Yan-Yan Hu (FSU)
Justin Kennemur (FSU)    thanks, Vastib!
Adam Duerfeldt (Oklahoma) thanks, Alex!
Gabriela Schlau-Cohen (MIT)
Stacy Smith (BYU)
David Michaelis (BYU)
Michael Ragusa (Dartmouth)
Derek Schipper (Waterloo)
Stephen Newman (Ottawa)
Jatinder Josan (VA Tech)
Avena Ross (Queens)
Nick Kuklinski (Furman)
Christina Vizcarra (Barnard)
Emily Derbyshire (Duke)
Anton Dubrovskiy [@SynthChem] (Houston Clear Lake)
Bill Morandi (Max Planck)
Feifei Li (New Mexico State)
Thomas Teets (U Houston)
Severin Schneebeli (Vermont)
Keith Reber (Towson)
Christine Caputo (New Hampshire)
Leila Deravi (New Hampshire)
Yftah Tal-Gan (Nevada-Reno)
Marco Caricato (Kansas)
Nozomi Ando (Princeton)
Elliott Hulley (Wyoming)
Andrew McNally (Colorado State)
Martin McCullagh (Colorado State)
Eilaf Ahmed (Emory)
Ronald Grimm (WPI)
Matthew Sheldon (Texas A+M)
Julio D'Arcy (Washington U - St. Louis)
Graham Griffin (DePaul)
Zhang Wang (Albany)
Luisa Whittaker-Brooks (Utah)
Michael Grunwald (Utah)
Douglas Genna (Youngstown St.)
Abhinav Nath (Washington)
Kevin Cash (Colorado Mines)
Rebecca Scheck (Tufts)
Robyn Biggs (Oklahoma)
Kenneth Graham (Kentucky)
Peter Kekenes-Huskey (Kentucky)
Anusree Mukherjee (Alabama-Huntsville)
Ku-Lung Hsu (Virginia)
Chad Risko (Kentucky)
Kara Stowers (BYU)
Ryan Baxter (UC Merced)
Ben Stokes (UC-Merced)
Carsten Milsmann (West Virginia)
Wei Xiong (UCSD)
Wei-Tsung Lee (Loyola Chicago)
Michal Szostak (Rutgers)
Mark Chen (Lehigh)
Lina Cui (New Mexico)
Joel Yuen-Zhou (UCSD)
Ampofo Darko (UT-Knoxville)
Sharani Roy (UT-Knoxville)
Anthony Appleton (Stetson)
Kyle Friend (Washington + Lee)
Eugene Pinkhassik (UConn)
Indrajeet Sharma (Oklahoma)
Scott Geyer (Wake Forest)

--
ChemBark's fantastic 2012-2013 roundup .
For earlier faculty moves, click here.

Entertaining Tidbits

Whilst researching the new faculty moves for 2014, I came across a bevy of interesting stuff...

Negishi's Bronze Bust unveiled at Purdue. Unlike politicians, religious leaders, or football heroes, I'm sure the number of chemists honored this way could be counted on two hands.

Al Padwa funds a Named Lectureship...using a rollover IRA contribution.
(From the too-much-info department, perhaps?)

Bob Williams funds a Named Professorship (no word on funding mechanism)

Apparently, I'm the last person on the globe to see the (now-defunct) blog Sexy Science.
(Hey, they named Phil Baran an 'up-and-coming star' waaaay before MacArthur did!)

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.

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?

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]
OPRD, 2014 ASAP

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.