Fully automated flow protocol for C(sp3)–C(sp3) bond formation from tertiary amides and alkyl halides

Herein, we present a novel C(sp3)–C(sp3) bond-forming protocol via the reductive coupling of abundant tertiary amides with organozinc reagents prepared in situ from their corresponding alkyl halides. Using a multistep fully automated flow protocol, this reaction could be used for both library synthesis and target molecule synthesis on the gram-scale starting from bench-stable reagents. Additionally, excellent chemoselectivity and functional group tolerance make it ideal for late-stage diversification of druglike molecules

Continuous-flow photochemistry as an automated platform integrated with closed-loop AI/ML approaches

In this Activity article, Brenda Pijper (Horizon 2020 PhotoReAct early-stage researcher in the Chemical Technologies group at Janssen, the Pharmaceutical Companies of Johnson & Johnson) and Jesus Alcázar (head of the Chemical Technologies group at Janssen) and Gabriela Oksdath-Mansilla and Fabricio R. Bisogno (both professors at the Universidad Nacional de Córdoba and researchers at the National Scientific and Technical Research Council of Argentina [CONICET]) discuss the current state of continuous-flow photochemistry in drug discovery and its future as an automated platform integrated with closed-loop artificial intelligence and machine learning (AI/ML) approaches.Fil: Pijper, Brenda. No especifíca;Fil: Alcázar, Jesus. No especifíca;Fil: Oksdath Mansilla, Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Bisogno, Fabricio Román. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentin

Challenge and opportunity: The two edges of continuous-flow photochemistry

In this Activity article, Gabriela Oksdath-Mansilla and Fabricio R. Bisogno (both professors at the Universidad Nacional de Córdoba and researchers at the National Scientific and Technical Research Council of Argentina [CONICET]) and Brenda Pijper (Horizon 2020 PhotoReAct early-stage researcher in the Chemical Technologies group at Janssen, the Pharmaceutical Companies of Johnson & Johnson) and Jesus Alcázar (head of the Chemical Technologies group at Janssen) discuss the importance of implementing continuous-flow photochemistry as a tool in drug-discovery programs as they wonder about the next challenges in the field.Fil: Oksdath Mansilla, Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Orgánica; ArgentinaFil: Bisogno, Fabricio Román. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Pijper, Brenda. Pharmaceutical Companies of Johnson and Johnson; EspañaFil: Alcázar, Jesus. Pharmaceutical Companies of Johnson and Johnson; Españ

Automated One-pot Library Synthesis with Aldehydes as Radical Precursors

The increased demand for the synthesis of enriched hybridized Csp3 motifs and the urgency of discovering new drug molecules require the development of more efficient technologies and synthetic tools to accelerate drug discovery processes. Herein, we report a fully automated strategy for the addition of Csp3 enriched building blocks onto olefins via Giese addition to forge Csp3-Csp3 bonds. The developed fully automated protocol allowed the conversion of aldehydes (non-redox-active species) in-situ to electroactive imidazolidines and to employ them as precursors of C-centered radicals under photoredox catalyzed conditions for the synthesis of enriched fraction sp3 (Fsp3) character building blocks and bioactive compound libraries

Addressing Reproducibility Challenges in High-Throughput Photochemistry

Light-mediated reactions have emerged as an indispensable tool in organic synthesis and drug discovery, enabling novel transformations and providing access to previously unexplored chemical space. Despite their widespread application in both academic and industrial research, the utilization of light as an energy source still encounters challenges regarding reproducibility and data robustness. Herein we present a comprehensive head-to-head comparison of commercially available batch photoreactors, alongside the introduction of the use of batch and flow photoreactors in parallel synthesis. Hence, we aim to establish a reliable and consistent platform for light-mediated reactions in high-throughput mode. Herein, we showcase the identification of several platforms aligning with the rigorous demands for efficient and robust high-throughput experimentation screenings and library synthesis

Assembly line library synthesis in flow: A multistep and multivectorial approach

In drug discovery, traditional automated library synthesis has typically involved single-step synthetic procedures targeting a single vector of interest. However, achieving greater structural diversity requires exploring multistep and multivectorial approaches. These methodologies enable the preparation of compounds with varying structures in a single experiment. Here, we present a novel method for multistep library synthesis in continuous flow. This approach offers unique opportunities, such as exploring linkers between two defined vectors or rapidly mapping synergistic structure-activity relationship (SAR) by concurrently exploring multiple vectors. Our method incorporates up to eight different synthetic methodologies, including established chemistries, metal-catalysed transformations, and modern metallaphotoredox couplings. This broad range of synthetic methodologies ensures a high level of diversity in the compounds generated, providing a powerful tool to accelerate exploration of the chemical space in drug discovery programs

End-to-End Automated Synthesis of C(sp³)‑Enriched Drug-like Molecules <i>via</i> Negishi Coupling and Novel, Automated Liquid–Liquid Extraction

Herein, we report an end-to-end process including synthesis, work-up, purification, and post-purification with minimal human intervention using Negishi coupling as a key transformation to increase Fsp3 in bioactive molecules. The main advantages of this protocol are twofold. First, the automated sequential generation of organozinc reagents from readily available alkyl halides offers a large diversity of alkyl groups to functionalize (hetero)aryl halide scaffolds via Pd-catalyzed Negishi coupling in continuous flow. Second, a fully automated liquid–liquid extraction has been developed and successfully applied for unattended operations. The workflow was completed with mass-triggered preparative high-performance liquid chromatography HPLC, providing an efficient production line of compounds with enriched sp3 character and better drug-like properties. The modular nature allows a smooth adaptation to a wide variety of synthetic methods and protocols and makes it applicable to any medchem laboratory