An overview of late-stage functionalization in today’s drug discovery

Abstract

Introduction: Late-stage functionalization (LSF) can introduce important chemical groups in the very last steps of the synthesis. LSF has the potential to speed up the preparation of novel chemical entities and diverse chemical libraries and have a major impact on drug discovery. Functional group tolerance and mild conditions allows access to new molecules not easily accessible by conventional approaches without the need for laborious de novo chemical synthesis. Areas Covered: A historical overview of late-stage functionalization and its applicability to drug discovery is provided. Pioneering methodologies that laid the foundations for the field are briefly covered and archetypal examples of their application to drug discovery are discussed. Novel methodologies reported in the past few years mainly stemming from the recent renaissances of photoredox catalysis and radical chemistry are reviewed and their application to drug discovery considered. Expert opinion: It is envisioned that late-stage functionalization will improve the efficiency and efficacy of drug discovery. There is evidence of the widespread uptake of LSF by the medicinal chemistry community and it is expected that the recent and continuing endeavors of many academic laboratories and pharmaceutical companies will soon have an impact on drug development.

Synthesis of Highly Enantioenriched Sulfonimidoyl Fluorides and Sulfonimidamides by Stereospecific Sulfur–Fluorine Exchange (SuFEx) Reaction

“…Fluoride ions are demonstrated to cause racemisation of the sulfonimidoyl fluorides, which is avoided by fluoride trapping. The mild coupling reagents allow the use of neutral primary and secondary amines, and the methodology is exemplified in the functionalisation of amine containing drug compounds, showing the potential for its use to rapidly prepare novel chemical entities and diverse chemical libraries . A readily removed N‐Boc (Boc= tert ‐butyloxycarbonyl) protecting group on the imide nitrogen is employed, which also increased the electrophilicity of the sulfonimidoyl fluoride.…”

Positioning of an unprecedented spiro[5.5]undeca ring system into kinase inhibitor space

“…Such a strategy cannot disrupt the potential binding of a pharmacophore to a target, so this fragment growing strategy was benchmarked to modify 1,5-oxaza spiroquinone 1. For this purpose, we should also consider late-stage functionalization for efficient introduction of diverse substituents in the very last steps of the synthesis 44,45 . As shown in Fig.…”

Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids

“…As a critical component of many medicinal chemistry campaigns or total syntheses, LSF allows for the incorporation of important functional groups in the final steps of a synthesis, creating the need for efficient methodologies. 37 When the in situ reaction conditions were applied to the LSF of Telmisartan, a carboxylic acid-containing drug used for the treatment of hypertension, the desired ketone (4a) product was isolated in 91% yield. This direct, one-step alkylation was applied to various other pharmaceutical compounds to afford the ketone products (4b-c) in moderate-togood yields (Scheme 2).…”