New catalytic technique creates key component of incontinence drug in less time

A research group at Nagoya University in Japan has developed a new catalyst that promises to revolutionize the asymmetric synthesis of pharmaceuticals called chiral macrocyclic dilithium(I) salt. It overcomes the lack of reactivity of ketones and the difficulty of getting them to organize atoms, which are common challenges in drug manufacturing.

The researchers used their technique to synthesize a key intermediate for the incontinence drug oxybutynin. Their catalyst promises to contribute to future drug discovery and development. They published their results in the Journal of the American Chemical Society.

“This research represents a major breakthrough in chiral drug synthesis,” said Professor Ishihara of Nagoya University. “Our catalyst can facilitate the rapid synthesis of complex compounds. This holds great promise for future drug discovery efforts.”

All medicines are made from chemical precursors. Ideal precursors are versatile compounds that can create a wide variety of end products. A particularly versatile precursor is the optically active tertiary propargyl alcohol. It is used to create pharmaceutical products, including anti-cancer agents, antibiotics and antivirals.

However, the production of these important chemicals is hampered by the low reactivity of ketones, precursors of tertiary propargyl alcohols. Added to this is the difficulty of their asymmetric induction, a process which favors the creation of a specific arrangement of atoms more suited than other arrangements to the manufacture of the drug.

To overcome the low reactivity of ketones, highly reactive lithium-based reagents, called lithium acetylides, are added. However, their reactivity is often insufficient for use with ketones. The development of a new catalyst was necessary to promote the reaction and control the selection of the optimal arrangement of atoms.

Enzymes are ideal for these reactions because they reduce the energy needed for the reaction to occur. However, due to their large and complex structure, the synthesis of enzymes is difficult.

The acyclic dilithium catalyst-based approach currently in use was pioneered by Makoto Nakajima of Kumamoto University. However, this approach has a limited scope on the substrate due to the self-aggregation of the catalysts and a too long reaction time of up to 12 hours. This creates a bottleneck in the production of the desired drug.

Professor Kazuaki Ishihara and his collaborators, including his graduate students, have developed a chiral macrocyclic dilithium(I) salt. It is a simple catalyst that functions like an enzyme, overcoming decreased reactivity by activating less reactive ketones.

This allows the addition of acetylides, such as lithium acetylides. The large macrocyclic structure of the catalyst allows them to catalyze even bulky ketones. This prevents aggregation between the catalyst and lithium-based reagents.

Although they are simpler than enzymes, the researchers found that their catalyst was more effective than other known catalysts. They successfully synthesized optically active tertiary propargyl alcohol from a variety of ketones. Although this industrial alcohol is difficult to produce by conventional methods, they synthesize it in 5 to 30 minutes. This is much faster than the 12 hours that Nakajima’s catalyst-based production process takes.

The addition of alkynyls to carbonyl compounds, such as ketones, provides a valuable synthetic method for the preparation of versatile chiral alcohols found widely in pharmaceuticals and natural products. This research represents a breakthrough in modern synthetic organic chemistry and a promising step forward in drug discovery.