Enabling synthesis in fragment-based drug discovery by reactivity mapping: photoredox-mediated cross-dehydrogenative heteroarylation of cyclic amines. Issue 8 (14th January 2019)

• Record Type: Journal Article
• Authors: Grainger, Rachel; Heightman, Tom D.; Ley, Steven V.; Lima, Fabio; Johnson, Christopher N.
• Is Part Of: Chemical science. Volume 10:Issue 8(2019)
• Page Start: 2264
• Page End: 2271
• Publication Date: 2019-01-14
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c8sc04789h
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : A nanogram-to-gram workflow has been established for the identification and development of synthetic transformations which are enabling in Fragment-Based Drug Discovery (FBDD). In this study, we disclose a method for the synthesis of privileged sp 2 –sp 3 architectures via direct cross-dehydrogenative coupling of heterocycles. Abstract : In fragment-based drug discovery (FBDD), a weakly binding fragment hit is elaborated into a potent ligand by bespoke functionalization along specific directions (growth vectors) from the fragment core in order to complement the 3D structure of the target protein. This structure-based design approach can present significant synthetic challenges, as growth vectors often originate on sp 2 or sp 3 ring carbons which are not the most synthetically accessible points on the fragment. To address this issue and expedite synthesis in FBDD, we established a nanogram-to-gram workflow for the development of enabling synthetic transformations, such as the direct C–H functionalization of heterocycles. This novel approach deploys high-throughput experimentation (HTE) in 1536-well microtiter plates (MTPs) facilitated by liquid handling robots to screen reaction conditions on the nanomolar scale; subsequently the reaction is upscaled in a continuous flow to generate gram-quantities of the material. In this paper, we disclose the use of this powerful workflow for the development of a photoredox-mediated cross-dehydrogenative coupling of fragments and medicinally relevant heterocyclic precursors via Minisci-type addition of α-amino radicals to electron-deficient heteroarenes. The optimized reaction conditions were employed on the milligram-scale on a diverse set of 112 substrates to map out structure–reactivity relationships (SRRs) of the transformation. The coupling exhibits excellent tolerance to a variety of functional groups and N-rich heteroarenes relevant to FBDD and was upscaled in a continuous flow to afford gram-quantities of pharmaceutically relevant sp 2 –sp 3 privileged architectures.