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Must Read Papers 2015. Part 2.

help 2At the end of 2015 I wrote a post (Must read papers 2015) including my favourite paper of the year and recommendations of a few nice reviews/highlights to read during Christmas. During 2015 I selected several papers I wanted to write about in the blog but unfortunately I have less time than I would like and I couldn’t write a line about many of them. Now 2015 is gone and I already have a few nice papers selected this year to comment in the blog. So all these nice papers are piling up and haunt me in my dreams because I don’t have enough time (or maybe because I’m just lazy).

To make a long story short I have decided to write a follow-up post of the Must read papers 2015 to comment a little bit on the best papers I selected during 2015 that for one reason or the other attracted my attention (click on the pictures if you want to go to the paper’s websites).

The first two papers of the post fit perfectly in the section Cool Synthesis under the topic Impossible Molecules. The Impossible Molecules topic is dedicated to molecules with exotic structures, elusive molecules and synthetically challenging molecules in general.  The first paper describes the first example of an amazing corannulene derivative bearing an internal heteroatom. The second paper describes a creative strategy to stabilise long cumulenes with a phenanthroline-based macrocycle.

1_ACIE_Benzene=Fused Azacorann

2_Cumulene rotaxanes

If you have ever read this blog before, you already know I’m a bit (just a bit) obsessed with halogenating reactions so you will find several posts on the topic. There are 2 papers I couldn’t write about during 2015 that I want to highlight. The first one describes a one-pot vicinal fluorination-iodination of arynes using the diphenyliodonium salt as a catalyst and CsF as a fluorine source. The second paper describes the synthesis of the molecules Halomon, Plocamenone and Isoplocamenone using a dihalogenating reaction I wrote about in a previous post.

3_iodofluorination

3_sintesis total dihalogenacion

Another of my obsessions is the chemistry of Frustrated Lewis Pairs (FLP), and just as I said in one of my previous posts “This is not the first time and probably will not be the last time I post about Frustrated Lewis Pairs”. One of the papers I didn’t have time to write about is this nice contribution by Stephan’s group on the catalytic hydrogenation and reductive deoxygenation of ketones and aldehydes.

4_FLP reduction

The next paper is another creative contribution by Alcarazo and coworkers. The paper describes an interesting alternative to hipervalent iodine species, Dihalo(imidazolium)sulfuranes that are versatile electrophilic group-transfers reagents.

6_paper alcarazo

The last paper I want to mention in this post caught my attention because of the interesting fact that the selectivity of the two products obtained in a copper-catalysed arylation is controlled by the choice of the reaction vessel.

7_reaction vessel

 

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Must read papers 2015

Now that 2015 is ending I remember a nice tradition we used to have in the research centre where I did my first postdoc. At the end of December we had a “Reaction of the year” seminar in which everyone of us had to present a paper we thought it was the most important contribution of the year.

I would like to use a similar idea in this post to open a discussion in which everyone can say their #favouritepaperof2015 and why. So I am going first…

Yeah, the main reason I liked so much this paper is that I may have a bit of an obsession with halogenation reactions in general. Anyway it is a must read paper in this year 2015, I’ve recently wrote a post about it if you are interested.

Besides my favourite paper of the year, for those who want to read a bit of chemistry during the Christmas break I would like to recommend you a couple of reviews and highlights on topics I really like and I hope you also enjoy (click on the pictures to go to the links).

Conia

FLP

ammonia

asymmetric chlor

Quick guide to get your synthetic methodology in a top journal

Nowadays thousands of “gurus” share their expertise to offer guidance in topics ranging from beauty and health to how to succeed in life. Chemistry of course is not an exception, we have our own gurus to seek for a piece of advice on many chemistry-related topics. Well, I am not a guru but still for my post today I would like to write a few lines on how I think you can improve your chances to get your synthetic methodology published in a good journal. I have also included one beautiful Yes-No flow diagram so my post is taken more seriously.

get published

Even in the case you have developed a new methodology to solve a very challenging synthetic problem, you may not get your results published in the top journals if you don’t include all the relevant information. For example, sometimes including a mechanism proposal is as important as getting excellent yields. I have considered two main scenarios:

Your synthetic methodology is new: The best scenario possible. You are the first one that solved the puzzle, but make sure the problem you are working in has relevance. And make sure that you are the first, so you did a good and meticulous literature research. Let’s say your method is good and your research is relevant, now is time to be creative. Select challenging and varied substrates and explore functional groups tolerance. If you are using a catalyst or a reagent developed by you it has to be fully characterized, an X-Ray structure can make the difference to get to the top journals. A new methodology might mean new reaction pathways or mechanisms. In my opinion at least a mechanism proposal should be always included. More and more often publications in synthetic methodology include now theoretical calculations to support mechanistic proposals.

Your methodology is not new but is way better than the others: Now is time to show your muscles. Besides being creative with substrates, having a full characterization or good mechanistic studies, now more than ever you have to include “extra toppings” to strengthen your chemistry. Stablish clear comparisons between your methodology and current methods using tables, explore recyclability or robustness of your catalyst, reagent or conditions. In other words try to highlight all your methodology’s strengths. Show off, put some efforts trying to scale-up to multi-gram levels “I synthesised 500 g at once, why? Because I can”. Apply your methodology to the synthesis of products of interests.

To conclude this post what could be better than showing a very good example of how to get your synthetic methodology in a good journal? This great work by Snyder and co-workers (click the link) speaks for itself: Et2SBr⋅SbCl5Br: An Effective Reagent for Direct Bromonium-Induced Polyene Cyclizations (Angew.Chem.Int.Ed.2009,48, 7899 –7903). In their paper, Snyder and co-workers describe a new reagent for well known reactions of bromocyclization. They describe the synthesis of their reagent with a full characterization including an X-Ray structure and more importantly they don’t hesitate to show muscle. They compare their reagent with the existing methods at that time to clearly show their reagent is in general better than the others, they also explore the scaleability of their methodology and apply it to the synthesis of natural products.

Syn-dichlorination of alkenes

Another post for the series “This blog is obsessed with dihalogenation reactions”. In previous posts I presented some of the reactions I consider of great relevance on the subject of enantioselective dihalogenation reactions (you can take a look here and here as well :D).  All these reactions having in common the synthesis of vicinal halides resulting from anti-addition as an inevitable consequence  of the ionic nature of the addition reaction of elemental halogens and related reagents to alkenes.

In other words, the challenge I’d like to highlight in this post is the difficulty of the development of straightforward methodologies for the syn-halogenation of alkenes. A great contribution to this topic is the first catalytic, syn-stereospecific dichlorination of alkenes developed by Denmark and co-workers.

challenge

The strategy used is based on a first step of anti-addition of an in-situ generated PhSeCl3 to an alkene followed by a nucleophilic displacement with a chloride ion source leading to a syn-dichlorination product overall. The process is made catalytic by adding an oxidant to the Ph-Se-Se-Ph precatalyst.

mechanism syn

This new methodology could be very useful for the synthesis of oligo- and polychlorinated compounds such as chlorosulfolipids, a family of synthetically challenging compounds originally discovered from the membranes of freshwater algae and associated to diarrhetic shellfish poisoning.

fosfolipids

Do you want to know more? Take a look to the original paper:

Catalytic, stereospecific syn-dichlorination of alkenes. Alexander J. Cresswell,              Stanley T.-C. Eey & Scott E. Denmark. Nature Chemistry 7, 146–152 (2015).

Conia-ene Nostalgia

I’ve seen very recently a nice review on the Conia-ene reaction by Dieter Enders and co-workers and I couldn’t avoid feeling some nostalgia. A very important part of my PhD project was related to the Conia-ene reaction so today I felt like wanting to write a few lines in a post…

nostalgia

The Conia-ene reaction was, at its origins, a thermal cyclization reaction of unsaturated carbonyl compounds usually in an exo mode. An intramolecular cousin of the Ene Reaction. This reaction usually required temperatures in excess of 300 oC limiting its utility in the synthesis of complex molecules.

conia mechanism

The potential of the Conia-ene reaction attracted the interest of many groups on the development of milder variants. We can find very encouraging contributions in the literature of Conia-ene reactions catalysed at much lower temperatures by Mo, Sn, Ti, Pd, Hg or Co, however these reactions usually required hard conditions in the presence of acid, bases, photochemical activation and were limited to the exo cyclization mode.

endo vs exo

It wasn’t until the seminal works of Toste’s group using the catalytic system AuPPh3Cl/ AgOTf that we can find a general method at room temperature that can lead to both endo and exo cyclization modes.

It seems natural that the next step in the study of a reaction is an enantioselective variant. Toste and co-workers, always one step ahead, developed in 2005 the first asymmetric version of the Conia-ene reaction. The strategy: Electrophilic activation of the acetylenic moiety of b-Ketoesters with a DTBM-SEGPHOS Palladium complex as chiral promoter in the presence of the Lewis acid Yb(OTf)3.

chiral strategies

A different approach is the generation of a chiral enolate. Dixon and co-workers used this strategy in their work by combining Cu(OTf)2 with a Brønsted base.

enantioselective conia

The Conia-ene reaction has proved to be a very useful synthetic tool toward the synthesis of cyclopentanoid products. Just to name one example (of many), Toste’s group application to the synthesis of (+)-Lycopladine A.

Conia aplicacion sintesis

Do you want to know more? Take a look to these papers:

The review of the nostalgia:

Catalytic Conia-ene and related reactions. Daniel Hack, Marcus Blümel, Pankaj Chauhan, Arne R. Philipps and Dieter Enders, Chem. Soc. Rev., 2015,44, 6059-6093

Where it all begun:

The Thermal Cyclisation of Unsaturated Carbonyl Compounds. J. M. Conia, P. Le Perchec, Synthesis 1975, 1 – 19

Seminal works in gold catalysis

Gold(I)-Catalyzed 5-endo-dig Carbocyclization of Acetylenic Dicarbonyl Compounds. Steven T. Staben, Joshua J. Kennedy-Smith andF. Dean Toste, Angew. Chem. Int. Ed. 2004, 43, 5350 –5352.

Gold(I)-Catalyzed Conia-Ene Reaction of β-Ketoesters with Alkynes. Joshua J. Kennedy-Smith , Steven T. Staben , and F. Dean Toste, J. Am. Chem. Soc., 2004, 126, 4526–4527.

Enantioselective Conia-eno

Catalytic Enantioselective Conia-Ene Reaction. Britton K. Corkey and F. Dean Toste, J. Am. Chem. Soc., 2005, 127,17168–17169.

Brønsted Base/Lewis Acid Cooperative Catalysis in the Enantioselective Conia-Ene Reaction. Ting Yang, Alessandro Ferrali, Filippo Sladojevich, Leonie Campbell and Darren J. Dixon. J. Am. Chem. Soc., 2009, 131 (26), 9140–9141.

And a bonus track, one application in synthesis

Gold(I)-Catalyzed Cyclizations of Silyl Enol Ethers: Application to the Synthesis of (+)-Lycopladine A. Steven T. Staben, Joshua J. Kennedy-Smith, David Huang, Britton K. Corkey, Rebecca L. LaLonde andF. Dean Toste. Angew. Chem., Int. Ed., 2006,45, 5991.

Enantioselective Dihalogenation of Allylic Alcohols

The development of a catalytic enantioselective reaction of bromination of alkenes can be at least as complicated as the corresponding dichlorination variant. The background reaction of bromine and other common dibrominating reagents capable of reacting rapidly with alkenes with no need of catalyst and the fact that bromonium ions can rapidly racemize in the presence of alkene do not make it any easier.

Recently in 2013 Burns and co-workers approached this challenge with a different strategy: to formally separate Br2 into electrophilic and nucleophilic components that are unreactive on their own. Diethyl dibromomalonate as the bromonium source and titanium bromide as the bromide anion source do the trick. To induce enantiocontrol a chiral TADDOL ligand is used as a chiral promoter and allylic alcohols capable to bind to the titanium metal centre are chosen as substrates. The TADDOL-type ligand used in the reaction has been found to induce good levels of enantioselectivity when used stoichiometrically and also lowering its loading to 20 mol%.

dibromacionNot happy with this incredible contribution Burns and co-workers have very recently published a follow up paper extending the methodoly to an enantioslective Bromochlorination version. Same strategy different actors, in this case Chlorotitanium triisopropoxide as the chloride source and N-bromosuccinimide as the bromonium source serve as a non-disproportionating equivalent to bromine monochloride and a tridentate Schiff base is used as chiral promoter.

dihalogenation
These new methodology will enable enantioselective synthesis of a wide variety of polyhalogenated natural products. As a proof of concept the paper also includes a short chemo-, regio-, and enantioselective synthesis of (+)-bromochloromyrcene and model subtrates leading to bromochlorocyclohexane motifs that can be found within several natural products including obtuso and preintricatol.

natural products           Do you want to know more? Why don’t you take a look to these references?

-Dennis X. Hu , Grant M. Shibuya , and Noah Z. Burns. Catalytic Enantioselective Dibromination of Allylic Alcohols. J. Am. Chem. Soc., 2013, 135, 12960–12963.

– Dennis X. Hu , Frederick J. Seidl , Cyril Bucher , and Noah Z. Burns. Catalytic Chemo-, Regio-, and Enantioselective Bromochlorination of Allylic Alcohols. J. Am. Chem. Soc., 2015, 137, 3795–3798.

Asymmetric Chlorination of Olefins.

There is no need to argue the relevance of the study of the halogenation reactions. Alkyl halides are common and useful intermediates in organic synthesis and there are thousands of halogenated natural products with potential biological activity. But curiously and despite the chlorination of olefins is a well-known text book reaction, a general enantioselective variant is yet to be discovered. A great contribution to this challenge was the enantioselective olefin dichlorination developed by Snyder and co-workers in their total synthesis of napyradiomycin A1. The reaction requires the use of a stoichiometric chiral borane auxiliary that forms an in-situ complex with the substrate. According to the authors the enantioselectivity of the process can be due to an organizational π-stacking interaction with the substrate favouring the formation of a chloronium ion at the bottom face of the molecule. The chlorinated olefin is obtained with 87% e.e. (95% e.e. only after recrystallization) and that is a tremendous success due to the difficulty of the reaction.

Snyder

If you think that an enantioselective chlorination reaction promoted by a stoichiometric reagent is hard, try to make it catalytic. That can be just madness:

-It is strictly necessary to minimise the background reaction, chlorinating reagents can add to olefins with no need of a catalyst.

-Even in the case you are able to form enantioselectively the corresponding chloronium intermediate, complete loss of enantioselectivity can occur due to:

a) Chloronium transfer to a free olefin or

b) Non-regioselective nucleophilic opening by a chloride.

Racemization

The catalytic reaction challenge was admirably accepted by Nicolau and co-workers. Aryl-substituted allylic alcohols were wisely selected as model substrates in an attempt to overcome the difficulties of the reaction. The reaction is expected to occur via benzylic chloronium species that favour a regiocontrolled chloride attack and the hydroxyl group can serve as an anchor to the catalyst via hydrogen bonding rigidifying the system and providing stereocontrol. The reaction is also performed at low temperatures to slow down the background reaction. The best system to promote the catalytic dichlorination reaction was a combination of the cinchona alkaloid derivative (DHQ) 2PHAL (commonly used as a ligand in Sharplesasymmetric hydroxylation) with p-Ph(C6H4)ICl2 as chlorine source. Although the enantioselectivities obtained were moderate and controlled by substrate design, the work of Nicolaus group meant a great contribution to the field and there is (Im completely sure) much more to come in the future.

Nicolau

Do you want to know more? Take a look to these papers:

-Scott A. Snyder, Zhen-Yu Tang and Ritu Gupta. Enantioselective Total Synthesis of (−)-Napyradiomycin A1 via Asymmetric Chlorination of an Isolated Olefin. J. Am. Chem. Soc., 2009, 131, 5744–5745.

-K.C. Nicolaou, Nicholas L. Simmons,Yongcheng Ying, Philipp M. Heretsch, and Jason S. Chen. Enantioselective Dichlorination of Allylic Alcohols. J. Am. Chem. Soc. 2011, 133, 8134–8137.

-Mattia R. Monaco and Marco Bella. A Formidable Challenge: Catalytic Asymmetric Dichlorination. Angew. Chem. Int. Ed. 2011, 50, 2–5.

Top Drugs Academy Awards.

redcarpet awardBig Pharma companies invest billions of dollars every year for a very low rate of success and still all these efforts must pay off. Only a few drugs are accepted every year as they have to pass through innumerable tests in order to guarantee, for the most obvious reasons, the safety of patients-customers.

Last September C&EN released a supplement on The Top 50 Drugs of 2014. Something I see like the academy awards of drugs, a very interesting catalogue in which you can see the ultimate tendencies in drugs research and also the direction pharma companies are taking in terms of where to invest their money. The supplement analyses the top 50 drugs according to 3 different categories: The top 10 emerging blockbusters (drugs recently approved with $1 billion plus potential),  the top 10 drugs in development (most promising drugs still in the pipeline) and the 30 top-selling drugs on the market.

Apart from my curiosity as a chemist I wanted to know what are the diseases object of research for pharma companies. When you take a closer look to the diseases treated by the top selling drugs you see that the first and second are for the treatment of rheumatoid arthritis and the third top selling  drug is for asthma and chronic obstructive pulmonary disease. A bit unexpected I have to recognise, if I had to place a bet without all that information I would have said cancer, no doubt, is top 3. You see treatment for leukemia, a type of cancer, in the fourth position. Fifth position for the treatment of diabetes and at last cancer (used as a general term) appears in the sixth position. Then when you continue going down the list you see mainly cancer, HIV, respiratory problems and pain treatments. And it is quite clear that the treatment of pain has a big part in the whole business.

Concerning the top 10 emerging blockbusters and the top 10 drugs in development the tendency is similar. Predominantly cancer with a special mention to breast cancer, HIV, diabetes and in the top positions hepatitis C.

From a more synthetic point of view, there were a few things that caught my attention. First of all, where are all the super-big molecules from the literature in total synthesis? where are all these molecules isolated from plants and algae with medicinal properties? Instead of those, the vast majority of the drugs are small to medium size molecules. Molecules dominated by nitrogenated heterocyclic structures and in a great number of cases bearing fluor atoms or fluorinated functional groups. All these facts highlight the relevance of the development of the chemistry of heterocycles which are ubiquitous in nature. And also the increasing number of papers on fluorination methodologies in the literature as it is known that fluorine atoms often enhance the pharmacological properties of organic molecules.

And with all said, it only rests to congratulate the 2014 awardees. Nevertheless, my advice to all is try to keep yourselves healthy.

Frustrating Fuel Cells.

This is not the first time and probably will not be the last time I post about Frustrated Lewis Pairs (FLPs). Due to the unquenched acidity and basicity of FLPs, these systems present an extraordinary reactivity to the cleavage and activation of small molecules. Unarguably, the most important application is the activation of hydrogen, FLPs are capable to heterolitically cleavage the strong bond of the molecule of dihydrogen resulting in a hydride adduct of the Lewis acid and a protonated Lewis base at room temperature. From the point of view of a synthetic chemist, the activation of hydrogen with FLPs opens the door to a new class of metal-free hydrogenation reactions. However, creativity in the area of FLPs seems to be endless as shown in the great contributions by Andrew Ashley and Gregory G. Wildgoose groups from the Imperial College of London and the University of East Anglia towards the oxidation of hydrogen.

FLP Fuel Cell

In the search for alternatives to fossil fuels, hydrogen has raised as a promising and a clean source for the production of electricity from chemical energy with the use of fuel cell technology. In the absence of a catalyst, the necessary process of oxidation of hydrogen is slow and require large overpotentials. Here is where the FLPs play their role as they considerably reduce the voltage required for the hydrogen oxidation due to the generation of hydride intermediates that are easier to oxidise to protons. Ashley, Wildgoose and co-workers were able to stoichiometrically oxidise hydrogen using one of the most basic FLP system B(C6F5)3/P(tBu)3 but unfortunately the system is not robust enough to complete more than one catalytic cycle. Some improvements were made recently replacing B(C6F5)3 for a borenium cation as a Lewis acid although the system is still lacking enough stability to properly catalyse the oxidation. As a proof of principle, it is indeed possible to oxidise hydrogen with an electrochemical/FLP approach. FLP systems have the advantage of their inherent “tuneability”  and there is still plenty of room for improvement in the way to develop a FLP based fuel technology.

Do you want to know more? Here you are the original papers:

Elliot J. Lawrence, Vasily S. Oganesyan, David L. Hughes, Andrew E. Ashley, and Gregory G. Wildgoose. An Electrochemical Study of Frustrated Lewis Pairs: A Metal-Free Route to Hydrogen Oxidation. J. Am. Chem. Soc., 2014, 136 , 6031–6036.

Elliot J. Lawrence, Thomas J. Herrington, Andrew E. Ashley, Gregory G. Wildgoose. Metal-Free Dihydrogen Oxidation by a Borenium Cation: A Combined Electrochemical/Frustrated Lewis Pair Approach. Angew. Chem. Int. Ed. 2014, 53, 9922 –9925.

A Catalytic Wittig Reaction.

The Wittig reaction was discovered by Georg Wittig and co-workers in 1953 and for which Wittig was awarded the chemistry Nobel Prize in 1979.  Since its discovery, the Wittig reaction has probably been the preferred choice of synthetic chemists towards the synthesis of alkenes. The formation of the alkene proceeds through the reaction of an aldehyde or ketone with a phosphonium ylide. The success of the reaction is due first to its regioselectivity, as the double bond of the alkenes is formed only between the reacting carbon of the ylide and the carbonylic partner, and second to its stereoselectivity to the formation of one of the two possible geometric isomers. The major drawback of the reaction is the generation of stoichiometric amounts of undesired triphenylphosphine oxide, a byproduct that frequently complicates the purification of the desired product.

wittig

In a very smart approach to overcome the problem of generating such a big amount of phosphine oxide waste, O’Brien and co-workers from the University of Texas designed a catalytic version of the Wittig reaction. The challenges: to generate in situ the reactive ylide and to reduce the phosphine oxide without reducing the carbonyl compounds involved in the reaction. The solution: the utilization of a cyclic phosphine that is reduced by Ph2SiH2, a reducing agent mild enough to leave the carbonyl  coupling partners intact. The catalytic version has proved effective with a series of aldehydes and stabilised or semi-stabilised ylides. The reaction represents an important first step to a general catalytic Wittig reaction and more research will be needed to achieve the same degree of effectiveness as the stoichiometric variant in terms of the scope of substrates and regioselectivity.

Do you want to know more? Take a look to the original paper:

Christopher J. OBrien, Jennifer L. Tellez, Zachary S. Nixon, Lauren J. Kang, Andra L. Carter, Stephen R. Kunkel, Katherine C. Przeworski, and Gregory A. Chass. Recycling the Waste: The Development of a Catalytic Wittig Reaction. Angew. Chem. Int. Ed. 2009, 48, 6836 –6839.