Recent Advances on Catalytic Asymmetric Synthesis of Molecules Bearing a Fluorine-Containing Stereogenic Carbon Center (2015–2024)

Aug 6, 2025Chemical reviews

Recent Progress in Making Molecules with Fluorine-Linked Chiral Carbon Centers Using Catalysts (2015-2024)

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Abstract

Approximately 20% of newly approved drugs contain fluorine, with only 16 out of 116 being enantiomerically pure.

Fluorine significantly alters the properties of parent molecules, enhancing its role in drug development.
Fluorine-containing drugs with aromatic substitutions are more prevalent than those with stereogenic center substitutions.
Asymmetric induction for creating fluorine-containing drugs primarily relies on the chiral pool and chiral resolution methods.
The asymmetric catalysis approach for developing these drugs remains underexplored.
Recent innovations (2015-2024) in asymmetric methods emphasize the use of organo- or organometallic catalysts for constructing fluorine-containing stereogenic centers.

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Fluorine, due to its unique ability to modify the physicochemical and biological properties of parent molecules, has found wide applications as pharmacological modulators in drug development research. Consequently, the portion of fluorine-containing drugs has increased to about 20% in recent years. Among these, fluorine-containing drugs with aromatic fluoro-substitutions are more common than those with fluoro-substitutions at stereogenic centers. In fact, in the past decade, out of 116 fluorine-containing drugs approved by the FDA only 16 drugs are enantiomerically pure, featuring fluorine-containing stereogenic carbon centers. Asymmetric induction during building these drug molecules is largely achieved through either the "chiral pool" or "chiral resolution" approach, while the "asymmetric catalysis" approach remains underexplored. In order to draw the attention of the scientific community to this disparity, this review highlights the innovations (2015-2024) in asymmetric methodologies for creating molecules bearing a fluorine-containing stereogenic carbon center in the presence of organo- or organometallic catalysts. The synthetic strategies are divided into two sections based on fluorine-containing building blocks and fluorine-containing reagents, which are further classified by the reaction types. Special attention has been paid to synthetic challenges, types of substrates, products and catalysts, functional group compatibility, transition states, mechanistic insights, as well as synthetic applications.

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Recent Advances on Catalytic Asymmetric Synthesis of Molecules Bearing a Fluorine-Containing Stereogenic Carbon Center (2015–2024)

Abstract

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