Friday Fun: Sweet Cardamom (Peroxide)

Rice pudding. Ginger snaps. And...malaria?

That's what'll be going through my head next time I cook with cardamom, thanks to Tom Maimone and coworkers (UC-Berkeley) and their under-the-wire JACS ASAP from yesterday afternoon. The title and abstract scratch all the Baran lab alumni itches: 1) biosynthetically inspired, 2) novel mechanisms, 3) scalable, 4) just four steps! And hey, we're making stable endoperoxides, which all the cool kids are into nowadays.



Not their actual abstract graphic...

As Maimone points out, the latent symmetry of the final product offers a really neat assembly strategy. The group McMurrys together two units of (-)-myrtenal, then hits it with singlet oxygen, initially forming a 6-membered endoperoxide they fragment / rearrange with base. A gentle oxidation (DMP) sets them up for the wild step: stitching together a 7-membered endoperoxide using Mn(III)*, a radical source, a silane reducing agent, and even more oxygen. Simple phosphine reduction knocks down the last hydroperoxide into an alcohol, and the whole target (7 stereocenters!) falls out as a single stereoisomer.

Pretty sweet.

P.S. - Since the group's made over half a gram in just this first push, I'd assume an efficacy paper against live Plasmodium parasite hot on the heels of this one...

*We're apparently already calling this the "Shenvi catalyst"...wasn't this only two months ago?

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.

Making It

It's Official: Phil Baran has finally "made it."

You could have 120 papers before your 40th birthday, profiles in Nature, and win a bunch of international awards. You could run a ridiculously bright group at a Top 5 program. You could have finished pala'uamine. But the real arbiter of success?

Your very own reagents, and a splash page at Sigma-Aldrich.

Strange Brews

While leafing through the latest magnum opus by Prof. Phil Baran and his Super Group (Nature, 2012, 492, p.95), I came across this playful graphic* near the bottom of page 4:

Source: Nature 2012 | Baran group, Scripps

Yes, that's right: Phil's "toolkit" chemistry for site-selective radical additions works in buffer, cell lysate, or oolong tea. Sounds like we need a few more entries in B.R.S.M.'s "Conditions You'll Never Try" post!

Mmm, delicious solvent...
Source: forbes.com

Perhaps a story I tossed out in his Comments section bears repeating: I once attended a conference where Profs. Paul Wender and Kazunori Koide spoke on alternate days. Wender went first, and mentioned in passing that one of his group's specialties (I think it was Rh [2+2+2], but correct me if you know otherwise...) could be performed in beer. Not to be outdone, Dr. Koide called his group the following morning, and arranged a hasty trial of his transition-metal detecting fluorescent sensor in Starbucks coffee.

Escalation followed. By the end of the conference, everyone had rung up their labs to try ever more exotic solvents, ranging from wine to paint thinner, then finally to whiskey. As explained in Adam Rogers' fantastic 2011 piece "Mystery of the Canadian Whiskey Fungus," this aged, distilled melange of organic compounds should foil up all but the most robust reactions; I'm fairly certain the reaction - another metal-catalyzed cyclization - still performed around 40%. Not too shabby.

*Just noticed that Bethany Halford beat me to it, at least as far as the tea!

Chemistry Bumper Cars

By now, most folks on the chemblogosphere have heard the rumbles about K.C. Nicolaou's possible departure from Scripps. His landing spot looks to be Rice University, in Houston, aided by a generous multi-million dollar "golden parachute." Followup comments posted on Chemjobber and In the Pipeline saw speculation run rampant regarding other Scripps synthetic chemists, including M.G. Finn, Jin-Quan Yu, Phil Baran, and Dale Boger.

Wow. Does everyone have the moving bug?

I seem to recall Kyle over at The Chem Blog drawing us a convenient map a few years back, during another busy moving season (2005, I believe?). The past two years have proven quite busy as well, with no less than an entire ChemBark post entitled "Nocera to Harvard!" (vide infra).

Without further ado, I present my highly-researched, but definitely not-to-scale, map of synthetic faculty moves, 2011-2012.

Legend (Updated 9/20):
1.  Keith (purple) Woerpel, Irvine to NYU
2.  John (Berkeley blue) Hartwig, UIUC to Berkeley
3.  Vy (green) Dong, Toronto to Irvine
4.  Dan (crimson) Nocera, MIT to Harvard
5.  O(maroon) Yaghi, UCLA to Berkeley
6.  M.(Goldenrod) Finn, Scripps to Georgia Tech
7.  K.(Cyprus orange) Nicolaou, Scripps to Rice (confirmed!)
8.  Greg Fu(schia), MIT to Caltech
9.  (Rust)em Ismagilov, Chicago to Caltech
10. Paul (cyan) Chirik, Cornell to Princeton

I've been searching for a chemistry faculty movement metaphor. At the end of the NFL season, reporters write about the "coaching carousel," where coaches switch jobs circuitously, trapped on an employment merry-go-round. Well, that's not quite right here. Chemists usually move away for good, and there's clearly a directionality to the moves: towards more money, higher prestige, or warmer climes. Perhaps a Ferris wheel? Nah: it implies "up" or "down," a good view of the situation...and far too smooth a ride. Negative on the Gravitron, though grads and postdocs might feel like they're smashed by the pressing gravity* of an upcoming move.

I've got it: Bumper cars! Everyone starts out hesitantly, driving around in circles, hesitant to make first contact. After a few minutes, though, it's a free-for-all, everyone bouncing off each other, crashing, laughing, sparks flying off the ceiling. In the end, no one ends up where they started, and everyone has headaches. (Bear with me, it's a work in progress, doesn't yet have the oomph of a "Manifest Destiny" or "fiscal cliff.")

Faculty jostle for top spots like, well, you get it...

Credit: UK Telegraph

Are faculty moves unavoidable? It's true that the grass is always greener. But, if you're already a professor at a Top 20 institution, you likely receive the lion's share of grant monies, decent media coverage, and your pick from top-shelf graduate students. So why go? Some moves are nostalgia-driven - the Prof. wants to return home to a welcoming parade, having "done good." Some moves try to fix the two-body problem. Some happen because of missed tenure, or a feeling that it's "just time." Maybe in today's uncertain economy, it's just best to assume you won't be in any job longer than ten years...with a handful of exceptions.

Readers: Know of any more high-profile U-Hauls being loaded this academic season? If the "Chemistry Bumper Cars" trend persists, this might yet become an annual post.

P.S. Heard about a move I missed? Email me at seearroh_AT_gmail, and I'll add it here!

*I completely understand, having been involved with two moves in grad and postdoc.

Baran Borole Begets Mess of Meroterpenoids

I know I'm preaching to the choir, but have you seen the latest from the Baran group?

Dr. Freddy probably said it best: Please, slow down, Phil!

Source: JACS ASAP

In today's tract, Prof. Phil Baran and company search for a molecular linchpin, trying to stick a two-ring starting material onto an aromatic group. The resulting structures, dubbed meroterpenoids, show up in the framework of several marine natural products.

The group ID's a logical starting point: sclareolide, an essential oil isolated   from various species of sage plants. Long story short - the first few avenues (iodination, carboxylate degradation, BF3 salts) are all dead ends. The "Eureka!" moment comes when they try a cyclic borole (see right), which succeeds on multigram scale and produces a med-chem-friendly crystalline white solid. Using increasingly-popular radical conditions, Baran's team readily attaches this intermediate to benzoquinone (46-60% yield).

The result? A natural product, (+)-chromazonarol, formed in 34% yield... in only six steps! Mere mortals might have called it a day, but not Dr. Phil: he goes on to make nine more natural products, most of which had previously taken >12 steps to make on their own...not too shabby for a four-page Communication.

Boroles: All the things I've
come to remember...
Source: 1000 Eighties Blog

While reading this paper, I couldn't stop staring at the "borono-sclareolide" linchpin - now where had I seen that before? A-ha! It's the major attraction in all those antibacterial compounds Anacor recently developed. Perhaps, more entrepreneurial readers might consider calling to find out if Anacor's replete pipeline might suffer further functionalization, bringing forth even more wild drug leads.