{"id":25614,"date":"2018-12-21T15:48:16","date_gmt":"2018-12-21T22:48:16","guid":{"rendered":"https:\/\/hepatochem.com\/enabling-synthesis-in-fragment-based-drug-discovery-by-reactivity-mapping-photoredox-mediated-cross-dehydrogenative-heteroarylation-of-cyclic-amines\/"},"modified":"2018-12-21T15:48:16","modified_gmt":"2018-12-21T22:48:16","slug":"enabling-synthesis-in-fragment-based-drug-discovery-by-reactivity-mapping-photoredox-mediated-cross-dehydrogenative-heteroarylation-of-cyclic-amines","status":"publish","type":"post","link":"https:\/\/hepatochem.com\/euro\/enabling-synthesis-in-fragment-based-drug-discovery-by-reactivity-mapping-photoredox-mediated-cross-dehydrogenative-heteroarylation-of-cyclic-amines\/","title":{"rendered":"Enabling synthesis in fragment-based drug discovery by reactivity mapping: photoredox-mediated cross-dehydrogenative heteroarylation of cyclic amines"},"content":{"rendered":"


\n<\/p>\n

\"\"

The new photoredox-mediated cross-dehydrogenative method reported herein<\/p><\/div>\n

Abstract<\/strong><\/p>\n

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 sp2<\/sup><\/small>or sp3<\/sup><\/small>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\u2013H 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 precursorsvia<\/span>Minisci-type addition of \u03b1-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\u2013reactivity 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 sp2<\/sup><\/small>\u2013sp3<\/sup><\/small>privileged architectures.<\/p>\n

Authors:<\/strong> Rachel Grainger<\/span>\"ORCID<\/a><\/span>*a<\/span><\/sup>,Tom D. Heightman<\/span>\"ORCID<\/a><\/span>a<\/span><\/sup>,StevenV. Ley<\/span>\"ORCID<\/a><\/span>b<\/span><\/sup>,Fabio Lima<\/span>\"ORCID<\/a><\/span>bc<\/span><\/sup>and<\/span>Christopher N. Johnson<\/span>\"ORCID<\/a><\/span>*a<\/span><\/sup><\/p>\n

Link:<\/strong> https:\/\/pubs.rsc.org\/en\/content\/articlehtml\/2019\/sc\/c8sc04789h<\/a><\/p>\n

<\/body><\/html><\/p>\n","protected":false},"excerpt":{"rendered":"

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 […]<\/p>\n","protected":false},"author":1,"featured_media":25616,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_et_pb_use_builder":"","_et_pb_old_content":"","_et_gb_content_width":"","_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_feature_clip_id":0,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_post_was_ever_published":false},"categories":[680],"tags":[],"class_list":["post-25614","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-featured-articles"],"yoast_head":"\nEnabling synthesis in fragment-based drug discovery by reactivity mapping: photoredox-mediated cross-dehydrogenative heteroarylation of cyclic amines<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/hepatochem.com\/euro\/enabling-synthesis-in-fragment-based-drug-discovery-by-reactivity-mapping-photoredox-mediated-cross-dehydrogenative-heteroarylation-of-cyclic-amines\/\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"admin\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"1 minute\" \/>\n<script type=\"application\/ld+json\" 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