Encore, Encore!

Two hot areas of research served up second helpings online this week:

C-H Azidation: Remember John Hartwig's iron-meets hypervalent iodide combination from last March? It possessed the power to insert a late-stage amine equivalent into complex natural products. John Groves has raised the stakes, disclosing a "practical and complementary" Mn-porphyrin promoted version that takes solid sodium azide as the precursor. 

Source: Groves, JACS ASAP

The group finds it can enable late-stage azidation of a variety of complex bioactive substances (sclareolide, artemisinin, estrone, papaverine). Even more surprisingly, although likely a radical-induced transformation, using a chiral salen led to a single example of 70% ee material. Groves admits they have work to do, but the fact that this reaction operates with 1% loading in wet ethyl acetate at room temperature sure sounds promising!

Synthesis Machines: Over at Nature, Kobayashi published a flow reactor approach to syntheses of either enantiomer of rolipram, an anti-inflammatory. No MIDA-boronate 'handles' here; this is classic chemistry - olefination, 1,4 addition, reduction, hydrolysis, decarboxylation, cyclization - performed over heterogeneous catalyst beds encased in stainless steel tubes. The group spices up the synthesis by including their in-house chiral PyBOX-calcium catalyst to control the 1,4 addition, and developing a Pd / polysilane-catalyzed reduction for a troublesome nitro group. 

Kobayashi claims his synthetic engine can produce a gram of 96% ee material every 24 hours, and that the system remains stable and operable for about a week's time. In a complementary Commentary, Joel Hawkins of Pfizer presents a tantalizing future, where hood-sized continuous synthesis units chug through kilo quantities of drug precursors, using commercial reagents, sans column chromatography.

Cryptic Retraction, Uncovered

Earlier today, a curious Twitter tipster wondered aloud about an "obtuse retraction notice" in JACS:

"The structure of compound 1, the major compound, of the manuscript was mistakenly assigned. As a result the authors withdraw this manuscript."

You heard it right, folks: An entire (published) manuscript, all down to one set of spectra.

So, what went wrong here? Here's the carbon-13 spectrum, from the SI:

Source: Jang group | JACS 2008

Whoa! That's a lot of carbons for that relatively simple product. I count 39 signals, aside from solvent, despite the compound's formula - and the authors' peak lists - only accounting for 26.

Another tweet (thanks, Neil!) clued me in to this Organometallics paper, in which they prepare the same compound. Compare the spectrum above to this one:

Source: Hor group | Organometallics 2011

I count 26 major signals, about as many as should be there, given the slight magnetic inequivalency of the benzyl carbons.

So, what went wrong? One clue might be solvent; the first spectrum's taken in a highly polar solvent (d6-acetone), whereas #2 uses ol' NMR stand-by deuterated chloroform. Given the highly polar nature of the first compound, along with the extra signals (and perhaps a second benzyl group in the proton NMR), I'm guessing that spectrum #1 actually shows a quaternary ammonium salt, which might result from "over-benzylation" of the cinchonine starting material.

The real bummer here? I've looked through the rest of the SI, and most compounds appear spot on.

Certainly, the authors managed to perform a challenging radical addition with high selectivity. Even more curiously, the ammonium salt used to effect the transformation (1a) looks correct!

Tough pill to swallow. Kudos to the authors for making the right (tough) choice here, voluntary or not.

Update, 8/8/13: Over at Reddit, stop_chemistry_time has staged a fantastic, ongoing debate with me in the comments. Here's the link.

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!

MacMillan's Latest - Almost Autocatalysis?

There's been a veritable treasure trove of interesting reactions in JACS over the past month. One particular ASAP caught my eye today: the latest SOMO-organocatalysis reaction from the MacMillan group at Princeton University.

Back up a second, SOMO? Organocatalysis? For those readers normally not nose-first in organic journals, I'll explain a little. SOMO stands for singly-occupied molecular orbital, which means there's radical chemistry afoot! The initial intermediate in many of these reactions, an enamine, reacts with a single-electron oxidant to form a radical cation, which functions as a sort of chiral radical nucleophile...a rare duck.

Future Organocatalyst?
Pyrrolidine Power!

Organocatalysis utilizes small molecules - amines, urea derivatives, hydrogen-bond donors, or small peptides - to accelerate chemical reactions. MacMillan himself gives a good short course on the topic. Organocatalysis bridges the synthetic and biochemical worlds, adapting Nature's enzymatic tricks into new reactivity.

So, why highlight this reaction? Ever since the Soai reaction, a zinc-catalyzed alkylation first reported in 1995, chemists have been enthralled with autocatalysis, the idea that the product of a given reaction could serve as its own catalyst. In theory, you could start with a tiny bit of an (almost) racemic catalyst, and wind up with a fast, highly selective reaction.

Note the similarity between the catalyst (a pyrrolidinone) and the product (a pyrrolidine). Clip off the nosyl protecting group, and I'd believe that product capable of catalyzing its own formation. Now, I'm not usually a betting person, but I like to look skeptically for what's not mentioned. In this case, only two of the products exhibit the same 2,5 substitution as the catalysts, and the authors mention catalyst development only indirectly. 


I'll offer anyone 3:1 odds that, in the next year, an autocatalytic version of this reaction pops up.

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.