This research is supported by a Marie Curie Action

This research is supported by a Marie Curie Action
This research has received funding from the People Programme (Marie Curie Actions) of the EU (FP7/2007-2013) under REA grant agreement nº PIEF-GA-2013-622413

Saturday, 12 December 2015

How to dry molecular sieves?

In this post, I will move from the topic of asymmetric catalysis and I will explain a basic operation in organic chemistry lab.
Laboratories involved with organic synthesis require efficient methods with which to dry (i.e. removal of water) organic solvents. In some cases, water present in organic solvents can be deleterious for the chemical reaction since reactants and/or reagents can react faster with water being deactivated with the consequent loss of performance of the reaction.
Among the different methods available for drying solvents, the use of molecular sieves is one of the most efficient ones. A molecular sieve is a material with pores (very small holes) of uniform size. These pore diameters are of the dimensions of small molecules, thus large molecules cannot be absorbed, while smaller molecules can.

Molecular sieves
From the chemistry point of view, molecular sieves are crystalline metal aluminosilicates having a three dimensional interconnecting network of silica and alumina tetrahedra. Natural water of hydration is removed from this network by heating to produce uniform cavities which selectively adsorb molecules of a specific size.
Commercially available molecular sieves contain water, therefore it is needed to remove this water content before use as dessicant in organic solvents. This process is called "activation" of molecular sieves.
In the following video created by my lab mate Rasmus Mose you will find a short description on how to activate molecular sieves and store solvents in a schlenk flask.
Very useful in case you work in an organic chemistry lab!

Saturday, 5 December 2015

Publication in Angewandte Chemie International Edition (this post is for specialists only)

Recently, it has been published in Angewandte Chemie International Edition research I have been involved with my lab mates Yang, Rune, and Hao.
For those who are familiar with organic chemistry, you will find the link to the original article below. Hope you enjoy reading it!

Li, Y., Tur, F., Nielsen, R. P., Jiang, H., Jensen, F. and Jørgensen, K. A. (2015), Enantioselective Formal [4+2] Cycloadditions to 3-Nitroindoles by Trienamine Catalysis: Synthesis of Chiral Dihydrocarbazoles. Angew. Chem. Int. Ed. 2015, 54, 1020-1024 doi:10.1002/anie.201509693

Tuesday, 1 September 2015

Asymmetric catalysis: how it all started? 3 key experiments.

It is difficult to establish exactly when a new research area is born. Mainly due to the fact that scientific knowledge is generated continuously over the years since a scientist (or group of scientists) achieves a major breakthrough.
However, probably, we can agree that the asymmetric catalysis area was born in 1966. Of course, during the 1950s the introduction of X-Ray crystallography, which was used to determine the absolute configuration of an organic compound by Johannes Bijvoet in 1951 and the contribution of Klem and Reed who first reported the use of chirally-modified silica gel for chiral HPLC chromatographic separation are considered crucial for the analysis of chiral compounds and the further development of asymmetric catalysis during the 60s.
Independently, three different organic chemists, William S. Knowles (USA), Ryōji Noyori (Japan) and K. Barry Sharpless (USA) were the pioneers in the asymmetric catalysis area. For their contributions to this research area they received the 2001 Nobel Prize in Chemistry.

William S. Knowles: "I suspect that no invention has ever been made without some fortuitous help".
Knowles and Noyori started working with the development of asymmetric hydrogenation, which they developed independently in 1968.
Basically, Knowles strategy consisted of replacing the achiral triphenylphosphine ligands in Wilkinson's catalyst ([RhCl(PPh3)3], used as a soluble hydrogenation catalyst for unhindered olefins) with chiral phosphine ligands. This chiral catalyst was employed in a hydrogenation reaction of α-phenylacrylic acid giving the final product with a modest 15% enantiomeric excess (ee).

This modest result was of no preparative value at that time. However, it established for the first time that by using a chiral catalyst the reaction course could be controlled to give an asymmetric bias on the final product. Further development of the chiral catalyst let control the enantioselectivity of the reaction efficiently. Knowles was also the first to apply asymmetric catalysis to industrial-scale synthesis; while working for the Monsanto Company and he developed an enantioselective hydrogenation step for the production of L-DOPA. This molecule is a precursor to neurotransmitters, e.g. dopamine, noradrenaline, and epadrenaline. As a drug, it is used in the clinical treatment of Parkinson's disease.
Ryōji Noyori: "Our ability to devise straightforward and practical chemical syntheses is indispensable to the survival of our species."
Noyori conceived a copper complex using a chiral Schiff base ligand, which he used for the metal-carbenoid cyclopropanation of styrene. Noyori's results for the enantiomeric excess for this first-generation ligand were disappointingly low: 6% ee. However, he continued developing this research that eventually led to the development of the Noyori asymmetric hydrogenation reaction.
Noyori also developed an asymmetric catalysis process at industrial scale in collaboration between Nagoya University and Takasago International Co. for the production of (-)-menthol.

K. Barry Sharpless: "...when I started doing chemistry I did it the way I fished – for the excitement, the discovery, the adventure, for going after the most elusive catch imaginable in uncharted seas".
Sharpless complemented these reduction reactions by developing a range of asymmetric oxidations (the so-called Sharpless epoxidation, Sharpless asymmetric dihydroxylation, and Sharpless oxyamination during the 1970s to 1980's.

Note: Part of the contents of this post has been extracted from Knowles, Noyori, and Sharpless Nobel Laurate Lectures. References below:

Angew. Chem. Int. Ed. 2002, 41, 1998.
Angew. Chem. Int. Ed. 2002, 41, 2008.
Angew. Chem. Int. Ed. 2002, 41, 2024.

Wednesday, 1 July 2015

Publication in Angewandte Chemie International Edition (this post is for specialists only)

Recently, it has been published in Angewandte Chemie International Edition research I have been involved with my lab mates Line, Kim, and Sofie.
For those who are familiar with organic chemistry, you will find the link to the original article below. Hope you enjoy reading it!

Næsborg, L., Halskov, K. S., Tur, F., Mønsted, S. M. N. and Jørgensen, K. A. (2015), Asymmetric γ-Allylation of α,β-Unsaturated Aldehydes by Combined Organocatalysis and Transition-Metal Catalysis. Angew. Chem. Int. Ed., 54: 10193–10197. doi: 10.1002/anie.201504749

Sunday, 1 March 2015

Then, why asymmetric catalysis?

In the previous posts, I have shown different approaches to access chiral compounds. Moreover, I stressed that the demand for chiral compounds, often as single enantiomers, has escalated sharply in recent years, driven particularly by the demands of the pharmaceutical industry, but also by other applications, including agricultural chemicals, flavours, fragrances, and materials. Two-thirds of prescription drugs are chiral, with the majority of new chiral drugs being single enantiomers. This widespread demand for chiral compounds has stimulated intensive research to develop improved methods for synthesizing such compounds.

So, then what is asymmetric catalysis and most important why is relevant for the synthesis of chiral compounds?

To get started, firstly, we should define the term asymmetric catalysis.

Catalysis is the increase in the rate of a chemical reaction due to the participation of an additional substance called a catalyst. By using a catalyst, the chemical reaction occur faster and require less activation energy. Because catalysts are not consumed after promoting the reaction, they can further catalyse the reaction of further quantities of reactant. Therefore, often only tiny amounts are required.

The term asymmetric when linked to catalysis refers to the phenomenon whereby a chiral catalyst promotes the conversion of an achiral substrate to a chiral product with a preference for the formation of one of the mirror image isomers (enantiomers).

In simple words, the rate of a chemical reaction is increased biasing the process towards the formation of just only one single enantiomer.

Historically, enantiomerically enriched compounds were generated either by chemical transformation of an enantiomerically enriched precursor, often derived directly or indirectly from nature's chiral pool, or by resolving an equimolar (racemic) mixture of the two enantiomers. Both of these approaches suffer from potentially severe drawbacks, the former in requiring stoichiometric amounts of a suitable precursor and the latter in typically yielding only up to 50% of the desired enantiomer.

Asymmetric catalysis, in which each molecule of chiral catalyst, by virtue of being continually regenerated, can yield many molecules of chiral product, has significant potential advantages over these older procedures. Indeed, enantiomerically pure compounds are produced in nature by such chirality transfer from enzymes.

Both from a conceptual and chemical efficiency point of view, the use of enantiomerically pure (chiral) catalysts instead of stoichiometric chiral auxiliaries is extremely attractive. Ideally, the final product can be obtained in a single step from a substoichiometric amount of chiral inductor (the catalyst) by transmission of the 3D information through organic reactions resulting in a chirality multiplication. In a prototype reaction a prochiral substrate (A) and an achiral reagent (R) react in the presence of a chiral catalyst to give an enantiomerically enriched (or pure) product (P*). The catalyst acts temporarily as a template coordinating starting products (A, R) transferring the chirality from the source of asymmetry to the new stereogenic centre created in the reaction (Figure 1).

Figure 1. Comparison of strategies based on chiral auxiliaries and chiral catalysts in asymmetric synthesis.

In the next posts, we will start a journey highlighting how far asymmetric catalysis has evolved and being considered one of the most prominent areas in organic chemistry.

Saturday, 28 February 2015

How can we prepare a chiral compound? PART IV. Asymmetric synthesis.

In the previous posts, (see how we can prepare a chiral compound? PART I to PART III, from 15 Dec 2014 onwards) I have shown different approaches to access chiral compounds.
Although chiral resolution and chiral pool synthesis have been used or are currently used as efficient methods for preparing chiral compounds there is a high demand of new chiral compounds for pharma, agrochemical, fragrances, fine chemicals and nutrition areas. This means that even chiral pool (chiral compounds from Nature) and/or resolutions are quite limited methods to address new challenging synthesis of chiral compounds. Therefore, innovative approaches to overcome these limitations are desirable.

The asymmetric (or stereoselective) synthesis from prochiral substrates (i.e. substrates that will be chiral after a chemical reaction) is a potent tool that allow the preparation of a broad variety of enantiopure compounds.
In order to fully understand the concept behind asymmetric synthesis we have to review some definitions in organic chemistry related to chirality:

  • Prochiral molecules are those that can be converted from achiral to chiral in a single step (i.e. one single chemical reaction).
  • Stereoisomers are isomeric molecules (from Greek ἰσομερής, isomerès; isos = "equal", méros = "part") that have the same molecular formula and sequence of bonded atoms (constitution), but that differ only in the three-dimensional orientation of their atoms in space. Importantly, we can differentiate between enantiomers and diastereoisomers.
  • Enantiomers are two stereoisomers that are mirror images of each other, which are non-superimposable. Two compounds that are enantiomers of each other have the same physical properties.
  • Diastereomers are stereoisomers that are not mirror images of each other. Diastereomers seldom have the same physical properties.
  • Chemical reactions can be stereoselective which means that can be selectively directed to one stereoisomer (enantio- or diastereoisomer) only.

Once we have a clear-cut picture of these definitions it is important to highlight that asymmetric synthesis involves chemical reactions that introduce one or more elements of chirality in a prochiral substrate generating stereoisomeric compounds (enantio- or diastereoisomers) in unequal amounts. The responsible for the asymmetric induction is the so-called chiral auxiliary (or chiral catalyst in the case of the asymmetric catalysis approach I am going to explain in next posts).

A chiral auxiliary is a chemical compound that is temporarily incorporated into an organic molecule in order to control the stereochemical outcome of the reaction. In simple words, we install a chiral molecule that “help” us to obtain our target compound.
The asymmetric synthesis methods have evolved during the years. Early methods for asymmetric synthesis introduced the chiral auxiliary in the same molecule to be transformed, generating the chiral product permanently attached to the group responsible for asymmetric induction (diastereoselective synthesis). Then, the methods further developed to those that remove the chiral auxiliary from the final chiral product and preferably recover and reuse the chiral auxiliary in future reactions.
The first step involves the incorporation of the chiral auxiliary. From a proquiral compound we move to a stereoisomer. Then, a second chemical reaction is carried out on the stereoisomer. The chirality present in the auxiliary can bias the stereoselectivity of this reaction towards one diastereoisomer only (diastereoselective synthesis). Finally, the chiral auxiliary can then be cleaved from the substrate and is typically recovered for future uses, ideally, without any loss of performance during the diastereoselective reaction.

The next step was to use a chiral reagent (instead of the so-called auxiliary) and directly control the stereochemical outcome of the reaction. Nowadays, it is used a chiral catalyst to control the stereochemical outcome of the reaction.

Saturday, 31 January 2015

How can we prepare a chiral compound? PART III. Chiral pool synthesis.

In the previous post (see post How can we prepare a chiral compound? PART II, 31 Dec 2014) I have shown that one of the main approaches to access chiral compounds is the chiral resolution of racemic mixtures.
Another alternative available for obtaining chiral compound is carrying out synthetic transformations from an enantiomerically pure starting compound. In the specific case of using simply available natural compounds as starting materials, it is called chiral pool synthesis. This method is particularly interesting when the desired final product and the chiral compound used as starting material are structurally similar, i.e. the chiral natural product as starting material is wholly or partially built into the target molecule.
The main compounds from the chiral pool that have been used for this purpose are α-amino acids, hydroxyacids, carbohydrates and terpenes. These natural compounds have some advantageous properties: their optical purity is normally close to 100% they are in general non-toxic and many are inexpensive starting materials.
However, this strategy may not be especially helpful if the desired molecule does not bear a great resemblance to inexpensive enantiopure natural products. Otherwise, a long, probably difficult synthesis involving many steps may be required. In addition, it may be challenging to find a suitable enantiopure starting material, so other approaches may prove more fruitful.

Organic chemistry is like playing with Lego®

There is a high demand for ready access to chiral drugs in the pharma industry and chiral pool synthesis has been used for this purpose in some of the current well-known drugs.
Organic chemistry bring us the possibility to mimic Nature in order to have access to these natural compounds (with therapeutic properties) or modified and improved efficacy compounds. Easily and giving an example linked to our daily lives, organic synthesis resembles playing Lego®. Organic chemists have a huge toolbox filled with small Lego® bricks (our building blocks). Smart combination and assembly of these Lego® bricks let us to build up more complex structures (our targeted drug). In particular, the chiral pool synthesis rummages in Nature to find these tiny chiral blocks that fit the complex structure we want to build up by means of chemical reactions.

Chiral pool synthesis is a strategy that aims to improve the efficiency of organic synthesis. It starts the synthesis of a complex enantiopure chemical compound from a stock of readily available enantiopure substances. Let me have a look to two examples of chiral pool synthesis to illustrate the usefulness of this methodology. 

The drug Imipenem is a beta-lactam antibiotic for intravenous use administered in hospitals for the treatment of several bacterial infections. It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic healthcare system. It was discovered by Merck scientists when searching for a more stable version of the natural product thienamycin, which is produced by bacterium.

The pharma company Merck markets the drug Imipenem (in combination with cilastatin to enhance its therapeutic effect) under the trade names Primaxin® or Tienam®. The synthesis of Imipenem is carried out by using aspartic acid as starting material. Aspartic acid is one of the 20 existing natural aminoacids present in Nature (our chiral pool) commonly used in chiral pool synthesis due to its ready availability, low cost and simple structure. From aspartic acid through several chemical reactions the structure of Imipenem is built up (highlighted in red the fragment coming from the starting material incorporated into the final molecule).

The drug Oseltamivir is marketed under the trade name Tamiflu® by the pharma company Hoffmann-La Roche. It is an antiviral medication used to prevent and treat influenza A and influenza B (flu). It is also on the World Health Organization's List of Essential Medicines. Its commercial production starts from the molecule shikimic acid harvested from Chinese star anise (Illicium verum) with a limited worldwide supply (highlighted in red the fragment coming from the starting material incorporated into the final molecule).

Due to the limited supply of shikimic acid, searches for alternative synthetic routes preferably not requiring shikimic acid are underway and to date several other alternatives routes have been proposed.
Both examples, Imipenem and Oseltamivir, show us how we can take advantatge of the chiral pool for obtaining chiral drugs very useful for treating diseases.

Aarhus University

Aarhus University
Aarhus University website

Center for Catalysis, AU

Center for Catalysis, AU
Center for Catalysis, AU website

Marie Curie Actions

Marie Curie Actions
Marie Curie Actions website