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.