Late-stage Functionalization for Improving Drug-like Molecular Properties

Abstract

The development of late-stage functionalization (LSF) methodologies, particularly C–H functionalization, has revolutionized the field of organic synthesis. Over the past decade, medicinal chemists have begun to implement LSF strategies into their drug discovery programs, allowing for the drug discovery process to become more efficient. Most reported applications of late-stage C–H functionalization of drugs and drug-like molecules have been to rapidly diversify screening libraries to explore structure–activity relationships. However, there has been a growing trend toward the use of LSF methodologies as an efficient tool for improving drug-like molecular properties of promising drug candidates. In this review, we have comprehensively reviewed recent progress in this emerging area. Particular emphasis is placed on case studies where multiple LSF techniques were implemented to generate a library of novel analogues with improved drug-like properties. We have critically analyzed the current scope of LSF strategies to improve drug-like properties and commented on how we believe LSF can transform drug discovery in the future. Overall, we aim to provide a comprehensive survey of LSF techniques as tools for efficiently improving drug-like molecular properties, anticipating its continued uptake in drug discovery programs.

Ruthenium(ii)-catalyzed C–H activation/lactonization of aromatic acids with diazonaphthoquinones: regioselective synthesis of polycyclic coumarin frameworks

“…To expand the synthetic value, benzoic acids embedded with various biologically relevant scaffolds were examined (Scheme 4). 12 Under the standard reaction conditions, pharmaceutically useful aliphatic acids such as clofibric acid, gemfibrozil, ibuprofen, and lauric-acid-linked benzoic acids efficiently reacted with diazonaphthoquinones ( 2a–2b ), supplying desired benzocoumarins 6a–6e in 77–91% yields. The functionalized benzoic-acid-bearing tryptamine scaffold was also suitable, and furnished 6f in 88% yield.…”

Total Synthesis of (−)‐5‐Deoxyenterocin and Attempted Late‐Stage Functionalization Reactions

“…After having successfully established a concise total synthetic route towards 5‐deoxyenterocin ( 1 ), we turned our attention to the possibility of its late‐stage functionalization (LSF) at position C5 (Scheme 6). Transition metal‐, [19] radical‐, [20] and photoredox‐mediated [21] C−H functionalization strategies represent versatile tools for the derivatization of natural products [22] . However, many of the transformations were reported with the reagent instead of the substrate being the limiting component.…”

“…Transition metal-, [19] radical-, [20] and photoredoxmediated [21] CÀ H functionalization strategies represent versatile tools for the derivatization of natural products. [22] However, many of the transformations were reported with the reagent instead of the substrate being the limiting component. Additional challenges associated with 5-deoxyenterocin are its instability at elevated temperature, [23] the limited availability (low substrate concentration), and several additional reactive positions (highlighted as gray spheres) apart from the desired, sp 3 -hybridized C5 position.…”

Side-Selective Solid-Phase Metallaphotoredox N(in)-Arylation of Peptides

“…Routinely, the chemical construction of modified peptide sequences is carried out through the incorporation of ncAAs during peptide elongation. , However, although advances have already been achieved for the synthesis of ncAAs, the lack of them as commercially available building blocks hampers access to diversity and therefore sets limits on structure–activity relationship (SAR) studies. − Alternatively, postsynthetic modifications of peptides through selective amino acid functionalization on specific side chains are currently under development to expedite the preparation of exogenous peptides, albeit with a limited number of side chains suitable for the intended targets. − As such, the selective postsynthetic modification at endogenous amino acid side chains has conspicuously lagged behind. − Therefore, there is a growing need for the development of selective late-stage functionalization of peptides that endows them with improved pharmacological properties.…”