Paper of the Year (Part 2)

As I previously mentioned, the Glorius group has an annual paper of the year seminar (or two). As the first seminar is nearly upon us, and the wonderful @JessTheChemist over at The Organic Solution also yesterday called for nominations for paper of the year, I though time was ripe for posting our first nine.

It is worth bearing in mind that the Glorius groups’ primary research field is catalysis (transition metal and organocatalysis), and this is reflected in papers presented at our seminars.

So, in no particular order:

1) Selective C-H Fluorination of Pyridines and Diazines Inspired by a Classic Amination Reaction  (John F. Hartwig). This paper is just out, and as I knew it would be presented imminently I have not read it in detail, but a much sought after, safe, efficient, and broadly applicable fluorination of N-containing heterocycles seems to be the order of the day.

2) Amine(imine)diphosphine Iron Catalysts for Asymmetric Transfer Hydrogenation of Ketones and Imines (Robert H. Morris). Another paper just out that I mentioned in passing last week. The role of hydrogenation in the preparation of organic molecules is unquestionable, and moving away from the typical heavy, expensive and toxic transitional metals is essential. Asymmetric iron catalysed hydrogenations are consequently one of the holy grails of this field.

3) Aerobic Dehydrogenation of Cyclohexanone to Phenol Catalyzed by Pd(TFA)2/2-Dimethylaminopyridine: Evidence for the Role of Pd Nanoparticles (Shannon S. Stahl). My paper of the year is this beautiful mechanistic study that demonstrates a two stage reaction, in which the first step is catalysed by a homogeneous Pd(II) species, and the second stage is catalysed by Pd nanoparticles generated from the Pd (II) precursor. A really magnificent study.

4) Water-Stabilized Three- and Four-Atom Palladium Clusters as Highly Active Catalytic Species in Ligand-Free C[BOND]C Cross-Coupling Reactions (Avelino Corma). A truly remarkable study delving into the black box of active catalytic species in Pd catalysis. It turns out 3-4 atom clusters of Pd are the business for traditional cross coupling reactions.

5) Enantio- and Diastereodivergent Dual Catalysis: α-Allylation of Branched Aldehydes (Erick M. Carreira). An elegant combination of metal and amine catalysis enables “fully stereo-divergent” access to all for stereoisomers of incredibly useful highly substituted  gamma,delta-unsatuarated aldehyde building blocks.

6) Organotextile Catalysis (Benjamin List). Our first metal free catalysis paper here! Here organocatalysts are supported for the first time on one of the most ubiquitous materials of our times, Nylon. Yes, you got it, essentially we have clothes that can do chemistry!

7) Enantioselective Photoredox Catalysis Enabled by Proton-Coupled Electron Transfer: Development of an Asymmetric Aza-Pinacol Cyclization (Robert R. Knowles) This is one I missed; the paper couples photoredox catalysis and chiral phosphoric acid catalysis.

8) Photoredox Activation for the Direct β-Arylation of Ketones and Aldehydes (David W. C. MacMillan) From the most prolific British chemist abroad? A step on from alpha-functionalisation using photoredox catalysis, and a product of design rather than serendipity as far as I know.

9) Complex N-Heterocycle Synthesis via Iron-Catalyzed, Direct C–H Bond Amination (Theodore A. Betley) Iron catalysed synthesis of saturated N-containing heterocycles. A really inspirational paper, and a tour de force in organometallic chemistry. I just wonder if an organic chemist could have got away without isolating any products?


Life after small molecules

One of the many reasons cited for the contraction of the pharma giants is the difficulty in finding new drugs using the traditional small molecule research model.  This relies on synthesising ‘relatively’ simple and small (low molecular weight) molecules and investigating their potential as medicines, but unfortunately the pharmaceutical industry are finding drugs of this type are getting harder to discover and to get to market.

An alternative to this approach is the development of ‘natural products’- chemical compounds which are produced by biological organisms – as medicines. Erythromycin and Taxol are highly successful drugs of this nature, but compared to small molecules, natural product drugs are few and far between.  One of the main reasons for this is the complexity of natural products; from a chemical synthesis perspective they are very challenging to make, and would traditionally require a very large investment of both time and money, without any more guarantee of success than the small molecule approach.  Solutions to this problem are much sought after, and there may now be a very small glimmer at the end of what, as natural product chemists will tell you, is often a long and dark tunnel.

(“and now for the sciencey bit”)

Inspired by natural biosynthetic pathways in which common intermediates are synthesised enzymatically and then derivatised to a number of natural products, Macmillan (published in Nature) has shown that from  a simple tryptamine derivative it is possible to generate in a single step a fuctionalised  tetracyclic intermediate common to a number of natural products (Strychnos, Aspidosperma and Kopsia alkaloids).  This single reaction utilises – as those who know Macmillan’s work would expect- a highly efficient and atom economical organocatalytic  cascade, with the functionalised polycyclic product then successfully derivatised to  six complex natural products.  The longest linear sequence in any of these syntheses is twelve steps, and the lowest overall yield a whopping 6.4% (both for (-)-strychnine).

Not only does this paper demonstrate some amazingly powerful chemistry, but it shows us that with vision (inspired by nature in this case), natural product synthesis is not always as formidable as it once was. Maybe this can open the door a little further when considering the development of natural products as drugs, and give a little hope to an unfortunately flagging pharmaceutical industry.