Patricia Van Arnum
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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
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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.
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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).
