Advancing Chiral Chemistry in API Synthesis

Functionalized supramolecular catalysts and an enantioselective route to unnatural amino acids are some recent developments.
Nov 02, 2009
Volume 33, Issue 11

Patricia Van Arnum
The goal of reaching desired enantioselectivity of active pharmaceutical ingredients (APIs) is an ongoing challenge for process chemists. Chemocatalysis and biocatalysis play an important role in asymmetric synthesis, and there have been several interesting developments in these areas.

Supramolecular catalysts

Researchers at the Graduate School of Engineering at Nagoya University in Nagoya, Japan, recently reported that they developed an asymmetric catalyst that assembles spontaneously, a development that lays the groundwork for further designing functional supramolecular catalysts. Their work involved using chiral organic ion-pair catalysts assembled through a hydrogen-bonding network (1). The researchers pointed out that overall development of structurally discrete, chiral supramolecular catalysts for asymmetric organic transformations has been met with limited success. In their work, however, the researchers reported that a chiral tetraaminophosphonium cation, two phenols, and a phenoxide anion appeared to have self-assembled into a catalytically active supramolecular architecture through intermolecular hydrogen bonding. The researchers developed the catalyst for the highly enantioselective conjugate addition of acyl anion equivalents to α-, β-unsaturated ester surrogates (1).

Catalytic asymmetric synthesis for nonnatural amino acids

Eric Jacobsen, professor of chemistry at Harvard University, and his research team detailed an improved method for making bulky nonnatural amino acids, which are used as building blocks for APIs and in chiral catalysts (2). The researchers point out that although there are efficient chemo–enzymatic methods for producing enantioenriched α-amino acids, obtaining nonnatural amino acids has been more difficult. The researchers explained that although alkene hydrogenation is useful for the enantioselective catalytic synthesis of many amino acids, it is not possible to obtain α-amino acids with aryl or quarternary alkyl α-substituents with this approach (2).

The researchers addressed this problem by developing a scaleable catalytic asymmetric Strecker synthesis of unnatural α-amino acids. The Strecker synthesis is an approach to produce racemic α-amino acids, but catalytic asymmetric methods have been limited to small scales. The Strecker synthesis involves the reaction of an imine or imine equivalent with hydrogen cyanide followed by nitrile hydrolysis. Existing catalytic methods and the use of hazardous cyanide materials in the asymmetric Strecker reaction however, limits its application in large-scale reactions (2).

To resolve that issue, Jacobsen and his team developed a new catalytic asymmetric method for producing enantiomerically rich nonnatural amino acids using a chiral amidothiourea catalyst to control the hydrocyanation step. The researchers report that this approach is compatible with aqueous cyanide salts, which are safer than other cyanide sources, which allows the process to be run at larger scales (2).

Ligand selection in asymmetric transition-metal catalysis

Chiral separations.
Researchers at McGill University in Montreal reported on an approach for ligand selection in asymmetric transition-metal catalysis. The approach in chiral catalyst formation involved coupling a pool of Brønsted acids, specifically amino-acid derivatives, with adjustable ligands on copper catalysts. The researchers reported that the system can be used to generate various chiral environments by changing the amino acid or ligand and therefore is a suitable approach for screening and identification of possible combinations to achieve high enantioselectivity. An example of this approach is shown with the copper-catalyzed alkynylation of imines in enantiomeric excess of up to 99% (3).