Cao Qiao, Tibbetts Joshua D, Wrigley Gail L, Smalley Adam P, Cresswell Alexander J
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge, CB4 0WG, UK.
Commun Chem. 2023 Oct 4;6(1):215. doi: 10.1038/s42004-023-01012-2.
Spirocyclic tetrahydronaphthyridines (THNs) are valuable scaffolds for drug discovery campaigns, but access to this 3D chemical space is hampered by a lack of modular and scalable synthetic methods. We hereby report an automated, continuous flow synthesis of α-alkylated and spirocyclic 1,2,3,4-tetrahydro-1,8-naphthyridines ("1,8-THNs"), in addition to their regioisomeric 1,6-THN analogues, from abundant primary amine feedstocks. An annulative disconnection approach based on photoredox-catalysed hydroaminoalkylation (HAA) of halogenated vinylpyridines is sequenced in combination with intramolecular SAr N-arylation. To access the remaining 1,7- and 1,5-THN isomers, a photoredox-catalysed HAA step is telescoped with a palladium-catalysed C-N bond formation. Altogether, this provides a highly modular access to four isomeric THN cores from a common set of unprotected primary amine starting materials, using the same bond disconnections. The simplifying power of the methodology is illustrated by a concise synthesis of the spirocyclic THN core of Pfizer's MC4R antagonist PF-07258669.
螺环四氢萘啶（THNs）是药物研发中很有价值的骨架结构，但由于缺乏模块化且可扩展的合成方法，进入这个三维化学空间受到了阻碍。我们在此报告了一种自动化的连续流动合成方法，可从丰富的伯胺原料出发，合成α-烷基化和螺环的1,2,3,4-四氢-1,8-萘啶（“1,8-THNs”）及其区域异构体1,6-THN类似物。基于卤代乙烯基吡啶的光氧化还原催化氢胺烷基化（HAA）的环化切断方法与分子内SAr N-芳基化相结合进行排序。为了获得其余的1,7-和1,5-THN异构体，光氧化还原催化的HAA步骤与钯催化的C-N键形成相结合。总之，这提供了一种高度模块化的方法，可从一组常见的未保护伯胺起始原料出发，通过相同的键切断来获得四种异构体THN核心结构。辉瑞公司的MC4R拮抗剂PF-07258669的螺环THN核心结构的简洁合成说明了该方法的简化能力。
