Professor Peter O'Brien

01904 322535
Email: peter.obrien@york.ac.uk

Development and Use of New Methods in Asymmetric Synthesis, Medicinal Chemistry and Chemical Biology

The O’Brien group’s research focuses on contemporary organic synthesis, with a particular interest in asymmetric synthesis, namely the synthesis of single enantiomers of chiral molecules. All of the projects in the group aim to develop selective and synthetically useful methods that are technically simple, high yielding and robust.

Current research projects are focused in three distinct areas:

  • Organolithium Methodology for the Synthesis of Nitrogen Heterocycles
  • Design, Synthesis and Biological Screening of 3-D Fragments
  • Synthetic Tools for Chemical Biology

Organolithium methodology for Nitrogen Heterocycles

Organolithium Methodology for the Synthesis of Nitrogen Heterocycles

In this area, the O’Brien group carries out a distinctive, multi-disciplinary approach to mechanistic interrogation of organolithium/diamine-mediated reactions. We combine several orthogonal techniques including in situ React IR spectroscopy (for exploring lithiation and trapping reactions in real-time), NMR spectroscopy (for determining the solution structure of organolithium/diamine complexes), DFT computational modelling and more traditional reaction optimisation (e.g. solvent and temperature variation). All of this information is then utilised in optimising reaction conditions/yields and in the development of new methodology, with a focus on high levels of enantioselectivity, diastereoselectivity, regioselectivity and chemoselectivity. Then, our new methods are applied to the synthesis of nitrogen heterocycles such as pyrrolidines, piperidines and piperazines, which are amongst the most common structural motifs in blockbuster pharmaceuticals. As a result , the products we generate are of interest to medicinal chemistry groups and, since 2010, this area of research has benefitted from industrial support from AstraZeneca, GlaxoSmithKline, Merck and Pfizer.

Design, Synthesis and Biological Screening of 3-D Fragments

In this area, the O’Brien group is exploring the construction of a novel 3-D fragment library for fragment-based drug discovery. Fragments are relatively simple, small organic molecules with molecular weight of 110-250 Da, clogP values in the range –1 to 3 and total polar surface area of ≤60 Å. However, current fragment libraries are populated with a high proportion of flat, heteroaromatic structures and this can limit the exploration of fragment-protein interactions. To address this, we are designing 3-D fragments that occupy regions of under-represented 3-D pharmaceutical space. Ultimately, the new 3-D fragments are screened against protein targets of relevance to drug discovery. The synthetic element of this project benefits from support from an industrial consortium of partners, including Astex, AstraZeneca, Lilly, Pfizer and Vernalis.

Synthetic Tools for Chemical Biology

Through collaborations with members of the York Structural Biology Group, we are developing synthetic methodology for use in two chemical biology projects: fragment-based discovery of enzyme activators and protein bioconjugation.

Selected recent publications

  • 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.
  • Mechanistic Interrogation of the Asymmetric Lithiation-trapping of N-Thiopivaloyl Azetidine and Pyrrolidine
    Chem Commun, 2016, 52, 1354.
  • Silver(I) or copper(II)-mediated dearomatisation of aromatic ynones: direct access to spirocyclic scaffolds
    Angew Chem Int Ed, 2015, 54, 7640.
  • Lead-oriented synthesis: investigation of organolithium-mediated routes to 3-D scaffolds and 3-D shape analysis of a virtual lead-like library
    Bioorg Med Chem
    , 2015, 23, 2680.
  • Revisiting the sparteine surrogate: development of a resolution route to the (–)-sparteine surrogate
    Org Biomol Chem, 2014, 12, 9357.
  • Asymmetric Lithiation-Trapping of N-Boc Heterocycles at Temperatures above –78 °C
    Org Lett,
    2013, 15, 5424.
  • Preparation and Reactions of Enantiomerically Pure a-Functionalised Grignard Reagents
    J Am Chem Soc,
    2013, 135, 8071. 
  • Stereocontrolled Synthesis of the AB Rings of Samaderine C
    Org Lett, 2013, 15, 394.
  • An Experimental and In Situ IR Spectroscopic Study of the Lithiation–Substitution of N-Boc 2-phenylpyrrolidine and piperidine: Controlling the Formation of Quaternary Stereocenters
    J Am Chem Soc,
    2012, 134, 5300. 
  • Enantioselective, Palladium-Catalyzed a-Arylation of N-Boc Pyrrolidine: In Situ React IR Spectroscopic Monitoring, Scope and Synthetic Applications
    J Org Chem,
    2011, 76, 5936.