Accessibility statement

Professor Peter O'Brien

01904 322535

Email: peter.obrien@york.ac.uk

ORCID

Development of New Methods in Synthesis and Medicinal Chemistry

The O’Brien group’s research focuses on the development of new methods for organic synthesis. Projects in the group aim to develop novel, selective and synthetically useful methods that are technically simple, high yielding and robust. Historically, the group has studied asymmetric and mechanistic organolithium chemistry in detail. More recently, efforts have included extension to stereospecific Negishi and Suzuki-Miyaura sp3-sp2 cross-coupling reactions. In all projects, we apply the newly developed methodology to the synthesis of common motifs in blockbuster pharmaceuticals. We have ongoing interests in the design and synthesis of novel 3-D fragments for use in fragment-based drug chemistry, as well as developing new synthetic approaches for fragment elaboration. In collaboration with the Diamond X-Chem facility in Oxford, York 3-D fragments have been identified as useful starting points for drug discovery against two Covid-19 proteins. Another area of interest for the group is functionalised cyclic sulfoximines for use as medicinal chemistry building blocks.

Novel 3-D Building Blocks for Elaboration of Fragments to Lead-like Compounds

Stereospecific Negishi and Suzuki-Miyaura Csp3-Csp2 Cross-Coupling Reactions

Covid-19 Drug Discovery Research Using York 3-D Fragments

Stereoselective Synthesis of Cyclic Sulfoximines

Synthesis of Nitrogen, Oxygen and Sulfur Heterocycles using Organolithium Reagents

Design, Synthesis and Biological Screening of 3-D Fragments: York 3-D Fragment Library

 

  Selected recent publications:

  • Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking

    Sci. Adv. 2021,  7, eabf8711

  • Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

    Nat. Commun. 2020, 11, 5047

  • Design and Synthesis of 56 Shape Diverse 3-D Fragments

    Chem. Eur. J., 2020, 26, 8969

  • Visible-light-induced intramolecular charge transfer in the radical spirocyclisation of indole-tethered ynones

    Chem. Sci. 2020, 11, 1353

  • Enantioselective Lithiation–substitution of nitrogen-containing heterocycles

    Org. React. 2019, 100, 255

  • Merging π-Acid and Pd Catalysis: Dearomatizing Spirocyclization/Cross-Coupling Cascade Reactions of Alkyne-Tethered Aromatics

    ACS Catal., 2019, 9, 50

  • Lead- and Fragment-oriented Synthesis, in Chemical and Biological Synthesis: Enabling Approaches for Understanding Biology, 2018, pp. 74-113

  • Gram-Scale Synthesis of the (−)-Sparteine Surrogate and (−)-Sparteine

    Angew. Chem. Int. Ed. 2018, 57, 223

  • Increase of enzyme activity through specific covalent modification with fragments

    Chem. Sci., 2017, 8, 7772

  • Silica-Supported Silver Nitrate as a Highly Activating Dearomatising Spirocyclisation Catalyst: Synergistic Alkyne Activation by Silver Nanoparticles and Silica

    Angew. Chem. Int. Ed. 2016, 55, 13798

  • Selective synthesis of six products from single indolyl α-diazocarbonyl precursors via catalyst variation

    Angew. Chem. Int. Ed. 2016, 55, 9671

  • Synthesis of Enantiopure Piperazines via Asymmetric Lithiation-Trapping of N-Boc Piperazines: Unexpected Role of the Electrophile and Distal N-Substituent

    J. Am. Chem. Soc., 2016, 138, 651

  • Silver(I) or copper(II)-mediated dearomatisation of aromatic ynones: direct access to spirocyclic scaffolds

    Angew. Chem. Int. Ed., 2015, 54, 7640