Click reaction under scrutiny

It is amazing how Huisgen azide-alkyne cycloaddition, once resurrected and reinvented by K. Barry Sharpless, generated so many application papers while we are still digging to understand its copper-catalyzed mechanism.

A recent JACS paper from Don Tilley lab sheds some more light on the catalytic cycle. And it’s not that easy as setting up the reaction itself. Disrupting catalytic cycle in step-by-step fashion is a tricky business but it was beautifully done in this study. First, trapping elusive cycloadduct within dinuclear copper complex:

Then displacing it with a fresh alkyne to get the product and the complex ready for another catalytic cycle:

But then look at the scheme below, which is arguably the least dramatic change one can imaging from a chemical transformation (involving organic compounds).

For those still scratching their head about what did actually happen here, it’s a one-electron oxidation of Cu(I)-Cu(I) dicopper complex into mixed-valence Cu(I)-Cu(II). That slight tilt of the bridging alkyne ligand seems to be the only indicator that reaction indeed took place without much of competing disproportionation or whatever could happen to the complex. Yes, it takes X-ray crystallography to prove that, and I wonder if Micah Ziegler, the first author, a priori knew what to look for to monitor the reaction success. EPR? Cyclic voltammetry? Maybe color change was enough?[1]

Anyway, attempts to get the mixed complex 3 to react with tolylazide didn’t succeed. So authors concluded that CuAAC does not involve mixed-valence dicopper complexes. In addition, they excluded a bunch of alternatively proposed intermediates. This was in fact contradicting with earlier results published by Jin et al of Bertrand lab. The key difference between papers was that in the latest study authors forced two copper atoms to sit close to each other, while Jin et al used mononuclear copper complex to initiate the reaction [2]. This may bring up a discussion of what study is more relevant for ‘real world’ cycloaddition. I wonder more, however, if knowing the exact mechanism will help one to improve the reaction in any way. It already is pretty well-optimized and reliable (to a point).

More generally, it seems like the dissociation of practical application from (strictly unambiguous) theoretical explanation is a genuine feature of science. Take for instance CRISPR-Cas9, which leading experts are still trying to understand how it works in native systems (i.e. bacteria) while other scientists are ready to tweak human embryos with it.

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[1] 19F NMR had enough difference due to different stoichiometry of triflimide anions.

[2] It still might be that both results are ‘right’ and one intermediate can turn into the other.

OC tidbits #7

Mose et al. (Jørgensen lab) [Nature Chemistry]

There are whole bunch of messy electrocyclic reactions in the paper and nice projections explaining diastereoselectivity. They made me nostalgic about reading OC texbooks.

Hugelshofer and Magauer [JACS]

Want something even cooler, here’s a dyotropic reaction! Characterizing the side-products must have been a lot of fun. As well as monitoring the progress (the major undesired product had the same Rf as the starting material, and good luck with crude NMR). Heads up from amphoteros.

Hall, Roche, and West [OL]

Was this reversible photo-switch discovered by accidentally shining a wrong UV lamp onto the final product?  The authors say it was expected. [Note: UVA = 350 nm; UVC = 254 nm]. TOC graphic:

Chen et al. (Yu lab) [ACIE]

OK, enough electrocyclic reactions. Here’s some C-H activation work from Jin-Quan Yu lab. From [phthalimide-protected] alanine to [phthalimide-protected] substituted phenylalanines in one step! The conditions are somewhat peculiar though. A lot of silver (and quite a lot of palladium) was consumed for this to happen.

Shi, Jiang, and Tian [JOC]

Tellurium is not very popular among chemists (and even less among anybody else for that matter), so each successful use of it is worth attention. The authors of this paper managed to find an application for sodium hydrotelluride. As an excuse they wrote this last sentence of discussion: ‘Reduction of the α-azido ketone 31 with PPh3, as in the Staudinger reduction, followed by stirring in air could not deliver 34 in our hands.’

Another unusual thing in the paper is the open call for collaborations: ‘For now, gram scale of 30 and more than 100 mg of 34 [12,12′-azo-13,13′-diepi-Ritterazine N] are available for any interested collaborators.’ I felt obliged to spread the word.

OC tidbits #6

Nicolaou et al. (JACS)

Nicolaou et al. does some medicinal chemistry on prostaglandins. Take a look at this Bobbit‘s salt protocol for deprotection/oxidation combo. It seems like they overload the reaction, compared to the original paper, which used 3 equivalents of the oxidant, but who cares if it works?

Moragas et al (ACIE)

Unprecedented (c) sigmatropic rearrangement of aziridines into sulfoximines.

And De Kimpe’s rearrangement for comparison.

Li et al (ACIE)

I’m not sure I would buy the proposed mechanism for the conversion below. The authors skip ‘−H₂‘ step and get away with it by simply writing “the imine intermediate 44 […] underwent tautomerization and a key decarboxylation to generate 45 with higher oxidation state.” Something else is clearly happening under that −CO₂ arrow and it’s not mere tautomerization.

Wappes et al (ACIE)

So similar, yet so different halogens. I guess, NaF won’t give anything useful under these conditions.

 

OC tidbits #5

Kawamura et al. (Baran lab, Nature)

A paper with a very straightforward title, “Nineteen-step total synthesis of (+)-phorbol” (neither “concise”, nor “efficient”, “elegant” nor any other vague adjective)  was published by Baran lab.

The step that impressed me the most was oxidation of compound 7. Chemo-, regio-, and stereoselectivity of this reaction was “easily predictable based on 100 years of C–H oxidation literature”, according to follow-up blog post, but I wonder how many chemists in the world would bet for this reaction to work so cleanly. Before reading the publication, of course.

Koh et al. (Hoveyda lab, Nature)

Expanding horizons of the metathesis reaction, Hoveyda lab teamed up with Schrock and developed a new catalyst and synthetic methodology for terminal Z-haloalkenes.

Battilocchio, Feist et al (Nat Chem)

Remember Morken reaction? I was daydreaming about streamlining it into bond-by-bond stitching of complex compounds. Turns out that Steven Ley was looking in the same direction, although through slightly different chemistry.

Yang et al. (Org Lett)

A nice example of ‘molecular gymnastics’ (proposed mechanism is quite a funny thing). Heads up from amphoteros blog.

Potter et al (JOC)

Safety first! Opt for hydrosulfate salt next time you prepare a diazotransfer reagent. I didn’t have problems with hydrochloride before, but will better give a try to hydrosulfate.

Adamo et al (Science)

…but hurry up with your diazotransfer, otherwise machines will soon do it for you! A fridge-sized synthesizer of known pharmaceuticals was constructed by chemists and engineers in MIT. Check out more detailed (and realistic) coverage by Derek Lowe.

 

Chemical Panoptikum #1

Creating new substances, sometimes just for the sake of the creation act itself, is an undeniable part of chemists’ nature. Having flawless analytical data of a newly prepared sample always fills one with mystical joy and feeling of omnipotence. And some chemical creatures are so bizarre that the very fact of their isolation and characterization causes reverence of fellow chemists. So welcome to the chemical Panoptikum, a collection of all sorts of weird structures from the recent literature. Don’t be surprised to meet boron very often here, it’s a really weird element.

From algae to crystalline sponge

Although not as exciting as it used to be, Fujita’s crystalline sponge technology has reached another milestone. This time the group could determine the absolute configuration of a natural product elatenyne.  Burton lab from Oxford attempted (and not once) the total synthesis of the product with a sole purpose to assign its structure and absolute configuration. But to achieve that, one needs a good reference analytical data of the natural sample in the first place. And this was the bottleneck for the featured compound. Owing to its almost symmetrical structure, the molecule doesn’t rotate the polarized light by a lot (the latest [α]_D values from Burton and Kim labs were −1.6° and +0.80° for two enantiomers). But reported data for ‘natural’ elatenyne varied from +19° to −10°. Which would make ambiguous even a qualitative judgement about the synthesized compound.

Structure of elatenyne is almost σ-symmetric

And as you can imagine, the molecule doesn’t easily crystallize in a conventional way. So it was an ideal case to try soaking a crystalline sponge in a solution of the compound. Remarkably, Fujita’s group needed only 5 μg of the freshly isolated compound for the analysis. As the result, they confirmed that Burton’s structure was correct.

No comments on bioactivity though.

OC tidbits #4

Büschleb et al. (ACIE)

A collection of OC tidbits selected by Hanessian and Overman groups. Featuring a dozen of natural products, each full of densely-packed stereocenters; 29 oldschoolishly lengthy synthetic schemes including three hundred intermediates that undergo all sorts of electrocyclic reactions and crazy cascades. Read in limited quantities to prevent overexcitement.

And, of course, I liked this guy (or girl?) at the frontispiece (the only thing one can get for free from Angewandte preview without subscription) in high-energy conformation overcoming some activation barrier.

Nicolaou et al (JACS)

KCN loves gold.

Picado et al. (JOC)

Turning failures into victories: if the reaction works, it’s just another row in a table. If it doesn’t, it can be a whole new paper!

Pan, Qin et al. (Org Lett)

A question without answer: how come this stereochemistry

… given this:

 

Patil et al. (JOC)

Simplicity is the new beauty (via orgchem.by).

Mishra and Biswas (JOC)

Another example of beautiful simplicity.

Babij, McCuscer et al. (OPR&D)

Expanded list of chemical shifts for commond (and not so common but green) solvents [open access!]

 

 

True power of 1D NMR

An interesting case study of a correct structure assignment for aquatolide appeared in JOC. It’s interesting from several points of view. First, it nicely shows how one can effectively use reach information from free induction decay (FID), which is lost (or masked) in Fourier-transformed spectra. Second, it emphasizes importance of data sharing and demonstrates crucial role of ‘research parasites‘ in scientific ecosystem. Third, the paper has seven-point manifest in the conclusions section.

OC tidbits #3

Giantassio, Lopchuk et al. (Baran lab) (Science)

As the legend goes, people from Pfizer approached Phil Baran and told him “You know, we figured out what our problem is. We need more propellers on our molecules.” Phil said “OK,  sounds like a good project” and put two grad students on it. Results: the 3-in-1 Science paper, with propellers spinning on every amine, SI, which is longer than my PhD thesis, and happy Pfizer counting cash.

Propellers everywhere! Source

By the way, Baran lab has a cold room for synthesis.

 Qi et al. (Porco lab) (JACS)

Electrocyclic reactions are always fun, especially when 2 in 1. See the paper for stereoselective one.

Schuler et al. (Nat Chem)

How to monitor progress of Bergman cyclization at 1.66 yoctomole scale? Atomic force microscopy is the answer.

Zhao, Ming et al. (Org Lett)

Looks trivial until you try to push the electrons. The side-product hints at the mechanism.

Feng et al. (Tet Lett)

Another magic reaction candidate for debunking? Thanks sash-2003 for heads up.

And before you rush to check it, they do report detection of molecular hydrogen in the gas mixture coming from the reaction.

 

 

OC tidbits #2

Zhu et al (Buchwald lab) (NChem)

Another great reaction that I was thinking to dedicate a separate post for but will never manage. Just check out this teaser scheme: two steps, two distant stereocenters, great chemoselectivity, and so drug-like!

Thanh Binh Nguyen (OPR&D)

Brilliant batch-washing of NMR tubes in a vacuum dessicator that has already got some good publicity in the blogosphere but probably won’t get too many citations. In theory, nothing can stop you from applying the same technique to any other glassware that has a solid bottom (flasks, beakers, etc.).

This is how vacuum washing works

 Williams & Trauner (ACIE)

Guess the name reaction (step c).

But the paper is worth checking not because of this step.

Newcomb et al (Ferreira lab): (JACS)

Some tips on increasing (E,E) yield:

Just a nice example of sigmatropic rearrangement: