The chiral portfolio of abcr
The abcr catalogue portfolio encompasses about 15,000 chiral compounds in various categories,
which includes the broad field of natural and unnatural amino acids with various substitution patterns and downstream chemistry based on chiral amino alcohols. Building blocks are available with various protection groups (Fmoc, Boc, cbz, …) as well as in various halogenated forms with sulfonyl or azido groups, etc.
We will gladly provide you with information about our offer in the brochure “New Chirals for Drug Design”, which gives an outline of a few core structures with a multitude of variation examples including inaccessible naphthalene derivates, aminochromanes or aminoindanes.
Benefit from our network: This area is continually being expanded with new structural motifs based on close cooperation.
We will gladly provide you with information about abcr’s chiral molecules and their varied application areas.
1. What does chirality mean?
Chirality refers to the spatial structure of atoms (stereochemistry) within a molecule. The mirroring at the molecular level leads to two different forms that are not identical or congruent such as the right and left hand. These forms are referred to as “right-handed” or “left-handed” rotating molecules. In the molecule name, the rotational movement is referred to as R and S-forms or as D and L-forms. The 1:1 mixture of molecule forms is referred to as racemate. The prefix in the designation of the active ingredient indicates which isomer is used within an active ingredient. The prefix dex, dextro stands for the D-enantiomer of an active ingredient, e.g. dextromethorphan. The prefix levo stands for the L-enantiomer of an active ingredient, e.g. levocabastine, levodopa.
Chiral molecules behave differently with respect to polarised light, which is referred to as optically active substances (optical rotation). For the R-enantiomer or R-configuration, the ray of light is guided clockwise to the right (lat. rectus – the prefix/antonym dex, dextro stands for the D-isomer by analogy). For the S-configuration, the light is turned to the left (lat. sinister - the prefix/antonym levo stands for the L-isomer by analogy). The rotation of the polarised light cancels itself out in the racemate in which both enantiomers are contained. It does not exhibit any optical activity.
2. Properties of enantiomer pairs
The properties of the enantiomers of a molecule can be very different.
The amino acid valine has a bitter taste as an (S)-valine while the (R)-valine is sweet. In lemons, the S-form tastes like lemons and the R-form like oranges. Terpene (S)-(+) carvone smells like caraway while its enantiomer (R)-(−) carvone smells like mint. The various pharmacological properties are the determinative characteristics of enantiomers. For beta blockers, the (S)-enantiomer selectively affects the heart while the (R)-enantiomer affects the cell membrane of the eye. A very well-known example as to how different the pharmacological properties of enantiomers can be is the active ingredient thalidomide in the medication Contergan whose fruit-damaging (teratogenic) effect (malformations) can alone be attributed to the S-isomer.
The molecule 3-methoxy-N-methylmorphinan (methorphan) is another example of the pharmacological application and varied effect of enantiomers. The L-isomer levomethorphan is a narcotic with a five-times stronger effect than morphine. However, the D-isomer dextromethorphan is available without prescription in many cough suppressants as a synthetic codeine analogue.
This example shows how important it is to develop efficient, environmentally friendly, and economic synthesis procedures that selectively only create the desired enantiomer. Another issue is the high enantiomer purity required for pharmaceutical substances.
3. Synthesis of chiral building blocks
In 2001, the Royal Swedish Academy of Sciences honoured the work of the researchers William Knowles, Ryoji Noyori and Barry Sharpless with the Nobel Prize in Chemistry. The research of the three scientists was focused on the catalytic production of asymmetric molecules. With this award, the Nobel Committee concurrently emphasised the importance of chiral substances.
3.1 Natural substances as the basis for the “chiral pool”
An enantiomer is preferred or exclusively used in all natural substances. Naturally occurring amino acids, the L-amino acids and glucose that occur almost exclusively as D-glucose in nature are examples of this. Chiral building blocks can be used as starting materials and modified subsequently based on this naturally occurring reservoir of enantiopure substances, the “chiral pool”.
These also include amino acids with protection groups, halogenated amino acids and the respective downstream chemistry such as amino alcohols, halogen-substituted amines, etc.
3.2 Classic separation
Mixtures of enantiomers can be separated into the R and S-isomer by means of salt separation. Various separating reagents are used for this purpose. Separation is based on various properties of diastereoisomers that the racemate enters into with the separating reagents.
Tartrates (salts of tartaric acid), alkaloids such as cinchonidine, amino acids such as alanine and arginine or BINAP/BINOL derivates are among the most well-known separating reagents. abcr provides both isomers of these reagents for your applications.
3.3 Usage of stereoselective catalysts
The majority of enantiopure substances is used in the production of active pharmaceutical ingredients. Homogenous precious metal catalysts based on chiral ligands are the primary cost factor of chemical production procedures.
Chiral bis(oxazoline) ligands (“BOX”) have, for the most part, proven to be usable in asymmetric synthesis. Their excellent enantioselectivity is also demonstrated in Diels-Alder, Mannich, Negishi, Kumada and Heck reactions as well as for the hydrosilylation of ketones and the allylation of aldehydes. We offer these ligands in a high optical purity in the multi-kilogramme standard (bulk).
Chiral phosphoric acids with a BINOL core structure provide access to new BUILDING BLOCKS as organocatalysts in 1,3 dipolar cycloaddition reactions as well as in Mannich, Michael and Strecker reactions.
Thus, chiral diaminocyclohexanes (“DACH” compounds) are used as ligands in metal-based pharma-active ingredients or the widely usable Jacobsen salen complexes.
The application area of chiral phosphines, e.g. ferrocenylphosphines, mainly consists in stereoselective cross-coupling and asymmetric hydrogenation. Polydentate ligands such as diphosphines can be assigned in many cases to so-called pincer ligands.
Organocatalysts are based on the catalytic effect of small organic molecules. In the chiral area, (S)-proline, (S)-naphthylamine, tartaric acid derivates (such as TADDOL derivates) or tripeptide structures are good examples of this.
3.4 Chromatographic separation
Chromatographic separation of chiral substances occurs by means of modified HPLC or GC columns. The surface of the inorganic substrate is modified with organosilanes and chiral ligands in order to produce such columns. The enantiomers to be separated interact with varying intensity with the chiral centres of the modified column material. As a consequence, the enantiomers elute at various retention times.
3.5 Enzymatic separation – biocatalysis
Biochemical reactions are catalysed through enzymes. Enzymes are able to enantioselectively guide the reaction, which makes it possible to synthetise chiral products from prochiral and achiral educts. In this manner the preference of an enantiomer and thus the chirality of the entire biochemistry and physiology is continued.
Reactions of enzymes are usually linked to physiologically leaning conditions. Environmentally hazardous solvents, toxic metal components and extreme reaction conditions are avoided for this form of catalysis. These reaction conditions are concurrently characterised by enormous cost savings in regard to traditional chemical methods, which is why the term “green chemistry” is very fitting.
4. Application of chiral substances in the area of active ingredient synthesis and diagnostics
The essential importance of chiral building blocks is in the area of molecular medicine, which explores the molecular causes of pathological processes. The development of faster and safer diagnostics as well as new active ingredients and therapy approaches is based on an understanding of key procedures at the molecular level.
A differentiation is made between
- low molecular active ingredients (small molecules)
- biopharmaceuticals or biologics
Chiral building blocks are equally important for both groups. Chirality is the precondition for the formation of ordered secondary structures in proteins such as an α-helix, which can only be established from enantiopure amino acids. The conformation of molecules is enormously important in nature. It is essentially determined by the three-dimensional structure of atoms in the molecule. Thus, the conformation of molecules decides whether an enzyme is active and can perform a reaction (catalyse) or whether it exists in an inactive form. A suitable conformation allows for an interaction of active ingredients at the receptors at the cell surface.
The term conformation is synonymous with the sum of the secondary structure and tertiary structure for biopolymers (nucleic acids, polysaccharides, proteins). These are ultimately only differentiated by the various rotations of (very many) single bonds.
4.1 Low molecular active ingredients – small molecules
The by far greatest share of the currently approved medicinal products consists of the group of low molecular active ingredients. These are also referred to as small molecules. Their molecular mass is about 800 g/mol. They are able to penetrate into cells and take effect there due to their small size (while taking the RO5 – rule of five – into account).
4.2 Biopharmaceuticals (also biologicals, biologica or biologics)
Biopharmaceuticals are regarded as “large” molecules due to their complex structure. These medicinal substances can be produced by means of biotechnology and genetically modified organisms. Biopharmaceuticals are part of the growing business fields of the pharma and biotechnology industry and also include the production of proteins (including monoclonal antibodies) and nucleic acids (DNA, RNA). Diagnostics is another application area.