Enantioselective Transformations in the Synthesis of Therapeutic Agents

Abstract

The proportion of approved chiral drugs and drug candidates under medical studies has surged dramatically over the past two decades. As a consequence, the efficient synthesis of enantiopure pharmaceuticals or their synthetic intermediates poses a profound challenge to medicinal and process chemists. The significant advancement in asymmetric catalysis has provided an effective and reliable solution to this challenge. The successful application of transition metal catalysis, organocatalysis, and biocatalysis to the medicinal and pharmaceutical industries has promoted drug discovery by efficient and precise preparation of enantio-enriched therapeutic agents, and facilitated the industrial production of active pharmaceutical ingredient in an economic and environmentally friendly fashion. The present review summarizes the most recent applications (2008–2022) of asymmetric catalysis in the pharmaceutical industry ranging from process scales to pilot and industrial levels. It also showcases the latest achievements and trends in the asymmetric synthesis of therapeutic agents with state of the art technologies of asymmetric catalysis.

Lead-halide perovskite quantum dots embedded in mesoporous silica as heterogeneous photocatalysts combined with organocatalysts for asymmetric catalysis

“…Chirality is closely related to the origin of life and occupies a significant position in our daily lives. 1 Asymmetric catalysis is one successful chiral amplification route among numerous chiral synthesis routes, and represents the use of trace amounts of chiral catalysts to obtain non-stoichiometric enantiomers in high yields. 2,3 Photoredox reactions in asymmetric catalysis bring new opportunities for developing highly efficient green synthesis of molecules with high stereoenantioselectivity.…”

De-epimerizing DyKAT of β-lactones generated by isothiourea-catalysed enantioselective [2 + 2] cycloaddition

“…Building upon these principles and the growing impact of organocatalysis in the pharmaceutical industry, 38–42 in this manuscript an effective synthetic strategy for the preparation of functionalised β-hydroxy-β-pyrazolone amides in high dr and er (up to >95 : 5 dr, >99 : 1 er) is described. Given that nitrogen-containing heterocycles are incorporated into an array of biologically relevant compounds, 43–46 and with pyrazole derivatives a prevalent heterocycle of widespread relevance, 47–52 the generation of catalytic enantioselective methods that would lead to chiral pyrazolone heterocycle derivatives was targeted.…”

Finding Relevant Retrosynthetic Disconnections for Stereocontrolled Reactions

“…Drug development has transitioned away from the “flatland” of therapeutic agents that were largely devoid of stereochemical features to modern drug discovery and manufacturing, where specific enantiomers and diastereomers have to be synthesized in high stereochemical purity. , It is, for example, well established that opposite enantiomers of chiral drugs may have greatly different biological activities whereby one enantiomer has desired therapeutic properties, but the other may have lower activity or even undesired toxic effects. The importance of enantioselective synthesis in the discovery and development of therapeutic agents was recognized, for example, by the award of the 2001 Nobel Prize in Chemistry to Knowles, Noyori, and Sharpless, who developed some the earliest and most important enantioselective methods while working in a combination of industrial and academic settings …”