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

Wednesday, 31 December 2014

How can we prepare a chiral compound? PART II. Resolution of racemates.

As shown in the previous post (see how can we prepare a chiral compound? PART I, 15 Dec 2014) one of the main approaches to access chiral compounds is the so-called chiral (or optical, or classical) resolution of racemic mixtures.
The classical resolution involves the physical separation of the pair of enantiomers contained in a racemic mixture (i.e. a 50/50 mixture of both enantiomers). The isolation of one of the enantiomer from the racemic mixture is achieved by using a physical method (e.g. crystallization) combined with a chemical reaction in some cases.

Obtaining chiral compounds with tweezers!

Louis Pasteur performed the first optical resolution in 1848, and was able to manually separate two kinds of crystals of racemic tartaric acid salts by using magnifying glasses and tweezers. This fact represented the discovery of molecular chirality and the spontaneous resolution. The process consists of crystallizing a supersaturated solution of racemic sodium ammonium tartrate below 28 ºC. Then, he was able to identify the different shapes of the crystals for each enantiomer. In this case, there is no chemical reaction involved in the resolution. In spite of the simplicity of this separation technique, it is limited to conglomerates. In fact, just only 5-10% of all racemates are known to crystallize as mixtures of enantiopure crystals.



Another interesting process is the so-called preferential crystallization (also called resolution by entrainment). Again, Pasteur in 1882 demonstrated that by seeding a supersaturated solution of sodium ammonium tartrate with one of its enantiomers crystallized preferably the same enantiomer he used as a seed.
Again, there is no chemical reaction involved; we just only take advantage of the different solubility of one enantiomer compared to the other. This means that the crystallization rate of one enantiomer is faster than the other one, crystallizing out from the solution. The microscopic nature of the process of crystallization let us identify that in some specific examples enantiomers can self-recognize better than recognize each other yielding the pure enantiomers in the solid state separately.


Crystallization of conglomerates and resolution by entrainment are reliable processes for the obtention of chiral compounds at the pharma industry mainly because they are easy and economical to implement and scale-up. However, the maximum yield for these processes is 50% (we "lose" the enantiomer we are not interested in) . In addition, our chiral compound of interest should crystallize as conglomerate and as stated above this is restricted to ca. 10% of chiral compounds.

Crystallization of diastereomeric salts

Notably, the vast majority of resolutions involve the conversion of a racemate, by treatment with an enantiomer of a chiral substance (the so-called chiral resolving agent), into diastereomeric salts. Diastereoisomers differ from enantiomers that the latter have the same physical properties. The different solubility of diastereoisomers allow the separation of both products and subsequent treatment with an acid or a base give access to both pure enantiomers. Derivatization to diastereoisomers is possible by salt formation between an amine and a carboxylic acid. The method was introduced (again) by Louis Pasteur in 1853 by resolving racemic tartaric acid with optically active (+)-cinchotoxine.



The use of this method circumvents the issue of crystallization as conglomerate, and allows the use of a broad range of chiral resolving agents from the chiral pool. Even chiral synthetic reagents increase the options of finding the most suitable chiral substance to react with our enantiomer of interest. It is considered the most traditional method of resolving racemates, also easily implemented in the chemical industry. However, we still keep the maximum chemical yield for this process up to 50%.

Towards the "perfect" chiral resolution

Apart from the aforementioned classical resolution process based on physical properties like solubility there are other resolution processes that can led to the separation of both enantiomers with yields above the 50%, ideally up to 100%.
As opposed to chiral resolution, kinetic resolution (KR) does not rely on different physical properties of diastereomeric products, but rather on the different chemical properties of the racemic starting materials.
In particular, kinetic resolution relies on the different reaction rate of the enantiomers with a chiral non racemic reagent. In this case, the reaction rates should differ enough to recover the less reactive or non-reactive enantiomer. The maximum chemical yield for this process is 50% for each enantiomer and one of them is chemically modified. Kinetic resolution reactions utilizing purely synthetic reagents and catalysts are less common than the use of enzymes although a number of useful synthetic catalysts have been developed achieving excellent performances.
Again, Louis Pasteur accomplished the first reported kinetic resolution. After reacting aqueous racemic ammonium tartrate with a mold from Penicillium glaucum, he reisolated the remaining tartrate and found it was enantiomerically pure. The chiral microorganisms present in the mold catalyzed the reaction of (R,R)-tartrate selectively, leaving an excess of (S,S)-tartrate.

As you can observe from the methods above the maximum chemical yield for the enantiomer of interest is 50%. In order to avoid this “loss” of material there is a type of kinetic resolution called dynamic kinetic resolution (DKR) where 100% of a racemic compound can be converted into an enantiopure compound. The same principles of KR applies to DKR. In addition, DKR utilizes a chemical reaction to interconvert the (R) and (S) enantiomers throughout the reaction process (this is called epimerization). At this point, the catalyst can selectively react with a single enantiomer, leading to almost 100% chemical yield.


It is necessary to consider the practicality of utilizing resolutions (classical or kinetic ones) for the preparation of enantiopure products. Even for a chiral molecule, which can be attained through other methods, the racemate may be significantly less expensive than the enantiopure material, resulting in heightened cost-effectiveness even with the inherent "loss" of 50% of the material. The main important aspects to evaluate the effectiveness of these methodologies are: 
  • Inexpensive racemate (and chiral catalyst in KR, DKR). 
  • No appropriate enantioselective synthesis available. 
  • Straightforward separation of starting material and the target enantiomer. 
  • Resolution proceeds selectively at low catalyst loadings (i.e. using small amounts of catalyst).
To date, a number of catalysts for kinetic resolution have been developed that satisfy most, if not all of the above criteria, making them highly practical for use in organic synthesis of chiral compounds.

Monday, 15 December 2014

How can we prepare a chiral compound? PART I

In past blog entries I have shown that chirality is an important property of molecules. In molecules intended to be used as drugs, chirality may be extremely important since the biological effect directly depending on the stereochemistry of the compound (e.g. the thalidomide).
The administration of enantiopure drugs brings benefits in terms of improved efficacy, and reduced toxicity. Consequently, it is not strange that 7 out of the top 10 most selling-drugs worldwide in 2010 are commercialized as enantiopure forms. Therefore, it is relevant to have synthetic methods to access these chiral compounds obtaining just only the enantiomer we are interested in.

Let’s "cook" chiral molecules!

The synthesis of chiral compounds is addressed by an area of chemistry called enantioselective synthesis. Simply: it is the synthesis of a compound by a method that favours the formation of a specific enantiomer. Enantioselective synthesis is a key process in modern chemistry and is particularly important in the field of pharmaceuticals. It has also a prominent role in the food, agrochemical, and perfumery industries.


On the other hand, we must recognize that the social demands on the current chemistry are increasingly higher. Selectivity should be applied to every single stage of chemical production. It is useless to produce the enantiomer with no biological effect (and/or toxic effects). In fact, it is considered waste, so it is worth focusing on obtaining the useful enantiomer only. Chemical waste is not a trivial issue considering that usually chemical synthesis is scaled-up (e.g. production of pharmaceuticals or agrochemicals) and this may be very costly in industrial processes where the economic aspects are crucial.

Chirality cannot be created in molecules by a random chemical process. When a random chemical reaction is used to prepare molecules having chirality, there is an equal opportunity to prepare the left-handed isomer as well as the right-handed isomer. In addition, and more relevant, the preferential formation in a chemical reaction of one enantiomer over the other is result of the influence of a chiral feature present in the substrate, reagent, catalyst or environment. Chemical synthesis of a chiral molecule from simpler non-chiral precursors usually produces equal amounts of both enantiomers. For this reason, we strictly need a source of chirality.

The three main approaches to access chiral compounds are:

Chiral (or optical) resolution of racemic mixtures:

Namely, physical separation of the pair of enantiomers contained in a 50/50 mixture. This involves the isolation of one enantiomer from the racemic mixture by any of a number of methods. Where the cost in time and money of making such racemic mixtures is low, or if both enantiomers may find use, this approach may remain cost-effective.



Synthetic transformations from an enantiomerically pure starting compound:

In the particular case of using an easily available natural compound as starting material it is called chiral pool synthesis. This methodology is more useful when the desired final product and the chiral compound used are structurally similar. Carbohydrates, amino acids, hydroxy acids and terpenes integrate the chiral pool arsenal.



Stereoselective synthesis:

This approach involves the use of a prochiral substrate and an enantiopure reagent as a source of chirality, in stoichiometric (auxiliary) or substoichiometric (catalytic) amounts, which is not included in the final product.


In the next blog entries we are going to have a close look to these three different approaches to have access to chiral compounds highlighting pros and cons of each method.

Monday, 1 December 2014

The thalidomide disaster and why chirality is important in drugs.

In past blog entries I have shown that enantiomers are optical isomers which are nonsuperimposable mirror-image structures. A mixture of equal portions (50/50) of the (+) and (-) enantiomers is called a racemic mixture. The chirality of a compound is very important when interacting with a chiral medium as the human body, the biological effect directly depending on the stereochemistry of the compound and the receptor in the body. Thus, a single-enantiomer drug can be pharmacologically interesting whereas its mirror image can be inactive or display a different desirable or non-desirable activity.
The thalidomide disaster is one of the darkest episodes in pharmaceutical research history. Chirality of molecules played a crucial role in this story and underscored its importance in organic synthesis of pharmaceuticals.
In 1957, a pharmaceutical company in West Germany introduced a new drug to the market. It was called thalidomide. The drug was sold in several countries as a sedative and sleeping drug for pregnant women. The thalidomide is a chiral molecule. However, the drug was made and marketed as a racemic mixture of the (+)-(R)-thalidomide and (-)-(S)-thalidomide.



Tragically, thalidomide was found to have serious side-effects; thousands of babies were born with missing or abnormal arms, hands, legs, or feet. It was banned by many countries in 1961. Nowadays scientists know that it is the (-)-(S)-thalidomide that caused the severe side-effects. (+)-(R)-thalidomide is a sedative, but (-)-(S)-thalidomide is a teratogen (i.e., a drug that can harm a foetus in the womb).

Thus, (-)-(S)-thalidomide is the unwanted enantiomer. You might think that pharma companies can simply purify the racemic mixture and give patients only the (+)-(R)-thalidomide. Unfortunately, the answer is not that simple in this specific case. Human liver contains an enzyme that can convert (+)-(R)-thalidomide to (-)-(S)-thalidomide. Therefore, even administration of enantiomerically pure (+)-(R)-thalidomide results in a racemic mixture. It is said that in the human body thalidomide undergoes racemization.
This disaster was a driving force behind requiring strict testing of drugs before making them available to the public. Now there is rigorous testing before launching new drugs into the market. The ban of thalidomide was lifted in 1985 by the World Health Organization. Today, thalidomide is used experimentally in all continents to treat various cancers and inflammatory diseases.

Despite of the fact of the racemization of thalidomide in the body, this example illustrates the importance of obtaining just only one single enantiomer. In fact, in the pharmaceutical field, chirality of molecules is placed in an extremely relevant position. The administration of enantiopure drugs (i.e. a pharmaceutical that is available in one specific enantiomeric form) brings benefits in terms of improved efficacy, and reduced toxicity. These advantages forced pharmaceutical companies and health authorities to place stereochemically pure substances in a privileged position.
The large demand of enantiopure products has broken out the progress of chemical synthesis. Nowadays, the number of synthetic methods available for the preparation of chiral molecules has permitted to efficiently gain access to a myriad of enantiomerically pure compounds.

Saturday, 15 November 2014

Chiral molecules in everyday life: from natural compounds to pharmaceuticals.

Nature is chiral exemplified by the fact that molecules of living organisms (both plants and animals) such as amino acids, peptides, proteins, enzymes, carbohydrates and nucleic acids are chiral. However, not only these biomolecules are chiral but also many other molecules we find on a daily basis are chiral. Most of these molecules are artificial coming from the human activity who synthesized these compounds in order to be used as agrochemicals, or pharmaceuticals just only to cite two relevant applications.



Independently of its origin (natural or artificial) these chiral molecules (namely, their enantiomers) may have different biological activity. This can be illustrated by means of the following examples:

The enantiomers of limonene, both formed naturally, smell differently. One of the enantiomers (S)-limonene smells of lemon while its mirror image compound (R)-limonene smells of oranges. We distinguish between these two enantiomers because our nasal receptors are also made up of chiral molecules that recognise the difference.




Chirality also plays a role on odorants such as (4S)-(+)-carvone, which has a distinct caraway odour, as compared to (4R)-(-)-carvone which has a characteristically sweet spearmint odour. Again our nasal receptors let us to allow us to distinguish the difference in smell.

   
These two odorants possess different odours due to the role of chirality on bioactivity, in this case a different 3-D fit on an odour receptor and/or on different odour receptors. Although the role of chirality in odour perception is still a rather modern area of interest, it should be noted that more than 285 enantiomeric pairs (570 enantiomers) are known to exhibit either differing odours or odour intensities.

Insects use chiral chemical messengers (called pheromones) as sex attractants. Similarly to odorants, in the case of insect pheromones chirality can influence the degree of attractiveness of the insect. (S)-Olean is the female-attracting sex pheromone of the olive fruit fly (Bactrocera oleae Gmelin). On the other hand, the (R)-enantiomer attracts males of the species.



The same principals are important for herbicides and pesticides containing chiral molecules. For example, the (R)-(+)-enantiomer of the herbicide dichlorprop is the active enantiomer in killing the weeds, while the (S)-(-)-enantiomer is inactive as an herbicide.



Thus, biology is very sensitive to chirality and the activity of pharmaceuticals depends on which enantiomer is used. Most drugs consist of chiral molecules. And since a drug must match the receptor in the cell, it is often only one of the enantiomers that is of interest.
One of the earliest known uses of a chiral compound to cure a disease is the case of Quinine (and other Cinchona alkaloids). These compounds possess anti-malarial properties and were used as a medicine since the XVII century. Cinchona extracts and quinine are also used in tonic waters, which were popularized in the British colonies as both a malaria prophylactic and for enjoyment in the form of a “Gin & Tonic”. Tonic water is now one of the largest industrial uses of quinine.



Another early use of a chiral compound to cure a disease is the case of Vitamin C (albeit from foodstuffs). Natural Vitamin C (chemically named (+)-ascorbic acid) has anti-scurvy activity and shows strong anti-oxidant properties.




In certain cases, one of the enantiomers may even be harmful. This was the case, for example, with the drug thalidomide, which was sold in the 1960s to pregnant women. One of the enantiomers of thalidomide helped against nausea, while the other one could cause fetal damage.




Since the two enantiomers of a chiral molecule often have very different effects on cells, it is important to be able to produce each of the two forms pure. These are key processes in modern chemistry and is particularly important in the field of pharmaceuticals.

Saturday, 1 November 2014

What is chirality? Importance in Nature.

It is all about symmetry!

Chirality is a property of asymmetry of objects. The word chirality is derived from the Greek word  χειρ (kheir), which means "hand".
An object (or a system) is chiral if it is not identical to its mirror image, that is, it cannot be superposed onto it. A chiral object and its mirror image are called enantiomorphs (Greek opposite forms) or, when referring to molecules, enantiomers. A non-chiral object is called achiral and can be superposed on its mirror image.

Human hands are perhaps the most universally recognized example of chirality in the real world. The left hand is a non-superimposable mirror image of the right hand; no matter how the two hands are oriented, it is impossible for all the major features of both hands to coincide.
In chemistry, chirality usually refers to molecules. A chiral molecule is a type of molecule that has a non-superposable mirror image. Achiral molecules are symmetrical, identical to their mirror image. These two mirror images of a chiral molecule are called enantiomers or optical isomers. Pairs of enantiomers are often designated as "right-" and "left-handed".



Nature is chiral

One may well think that both forms of chiral molecules ought to be equally common in nature. But when we study the molecules of the cells in close-up, it is evident that nature mainly uses one of the two enantiomers. That is why we have – and this applies to all living material, both vegetable and animal – amino acids, and therefore peptides, enzymes and other proteins, only of one of the mirror image forms. Carbohydrates and nucleic acids like DNA and RNA are other examples.
Thus the enzymes in our cells are chiral, as are other receptors that play an important part in cell machinery. This means that they prefer to bind to one of the enantiomers. In other words, the receptors are extremely selective; only one of the enantiomers fits the receptor's site like a key that fits a lock.
Since the two enantiomers of a chiral molecule often have totally different effects on cells, it is important to be able to produce each of the two forms pure. Chemistry brings us solutions to achieve this goal.

For more info, see also an interesting video "What is chirality and how did it get in my molecules?" at http://ed.ted.com/lessons/michael-evans-what-is-chirality-and-how-did-it-get-in-my-molecules

Friday, 31 October 2014

Presentation of the REMOTEcat blog.

REMOTEcat is the acronym for the project entitled "Asymmetric organocatalysts for remote functionalization strategies" funded by the People Programme (Marie Curie Actions) of the EU. Currently, I am carrying out this project at the Center for Catalysis (Department of Chemistry, Aarhus University, Denmark) under the supervision of Prof. Karl Anker Jørgensen.

In line with EU research & innovation policy, REMOTEcat assumes that responsible research implies an effort to the scientific promotion of science encouraging public participation and understanding of science. The goal is to create awareness among the public about the research work performed in the Marie Curie Action and their implications in society.


About the project

REMOTEcat is a chemistry project. In particular, organic chemistry, and in more detail, asymmetric organocatalysis.
Many chemical processes would not occur (at least, not at a rate that has any practical application) without catalysts. Catalysts (i.e. a substance that modifies the rate of a chemical reaction) have thus become indispensable in a wide range of industrial reactions. But the study of these systems can offer much more: it can change our understanding of fundamental chemical concepts and challenge us to rethink the “rules” of the chemical world.
In general, enantioselective catalysis (usually known as asymmetric catalysis) mostly refers to the use of chiral metal catalysts. It is very commonly encountered, as it is effective for a broader range of transformations than any other synthetic methods. Small organic molecules without metals can also exhibit catalytic properties, In the early 2000s, these organocatalysts were considered "new generation" and are competitive to traditional metal-containing catalysts.
Research in the area of organocatalysis moves at breathtaking speed: many catalytic reactions now considered to be “standard issue” by organic chemists were almost unthinkable just 10 years ago. The ability to synthesize and selectively modify small organic molecules is crucial for many applications, including drug discovery and the search for new materials. The development of new organocatalysts often makes it possible to generate previously unattainable compounds, which could have unique physical, chemical or biological properties.

Why am I launching this blog?

Probably, there are too many weird words in just only a few lines above. However, do not be concerned about this. The idea of launching this blog is to build bridges between the research I am doing and non-specialists. It is science for non-scientists.
What I would like to do is to introduce the basic concepts of organic chemistry involved in the project through case examples and situations of our daily lives. Gradually, and later on, going into more details about the research carried out in the project in the most entertaining manner possible and understandable to everyone.
Hope you find interesting and understandable the contents of the blog. Any comments or suggestions for their improvement are welcome.

About me

LinkedIn: dk.linkedin.com/pub/fernando-tur/2a/1a8/535/
Twitter: @fernando_tur

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