Late-stage meta-C–H alkylation of pharmaceuticals to modulate biological properties and expedite molecular optimisation in a single step

Lucas Guillemard, Lutz Ackermann () and Magnus J. Johansson ()
Additional contact information
Lucas Guillemard: Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca
Lutz Ackermann: Georg-August-Universität Göttingen
Magnus J. Johansson: Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Catalysed C–H activation has emerged as a transformative platform for molecular synthesis and provides new opportunities in drug discovery by late-stage functionalisation (LSF) of complex molecules. Notably, small aliphatic motifs have gained significant interest in medicinal chemistry for their beneficial properties and applications as sp3-rich functional group bioisosteres. In this context, we disclose a versatile strategy with broad applicability for the ruthenium-catalysed late-stage meta-C(sp2)–H alkylation of pharmaceuticals. This general protocol leverages numerous directing groups inherently part of bioactive scaffolds to selectivity install a variety of medicinally relevant bifunctional alkyl units within drug compounds. Our strategy enables the direct modification of unprotected lead structures to quickly generate an array of pharmaceutically useful analogues without resorting to de novo syntheses. Moreover, productive late-stage modulation of key biological characteristics of drug candidates upon remote C–H alkylation proves viable, highlighting the major benefits of our approach to offer in drug development programmes.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-46697-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46697-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-46697-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().