An exploration of “greener” alternatives for oligonucleotide synthesis University of York in United Kingdom

The solid phase synthesis of oligonucleotides, historically conducted on controlled pore glass, but more recently on polystyrene, typically proceeds in a 3' to 5' direction by a four-step synthesis cycle with each step followed by a solvent wash. Waste has long been highlighted as a signi?cant issue for oligonucleotide manufacturing. Excess starting materials and reagents are used to drive the reactions to completion, and wash solvents are used to remove them. Puri?cation is often by reverse-phase preparative chromatography using large volumes of mobile phase which are discarded as waste. In addition to the volume of the waste produced, there are also concerns about the nature of the solvents and reagents used, and the waste that results. DCM had historically been used as a solvent for the detritylation step, but this has largely been replaced with toluene in large-scale manufacture. However, toluene is suspected of causing damage to the unborn child and is restricted under REACH Annex XVII, so further substitution would be preferred. Acetonitrile is used in large amounts in reverse phase chromatography, and acrylonitrile, generated during the backbone deprotection step, may cause cancer, and is suspected of damaging fertility or the unborn child.   Previous and current expertise in the group includes several areas of relevance, including: exploration of a bioderived alternative to toluene, tetramethyloxolane (TMO); use of Hansen Solubility Parameters to predict solvents (and solvent mixtures) that facilitate solubility in general, and swelling of polystyrene supports in particular; exploration of alternatives to acetonitrile for reversed phased column chromatography; and mindful that “drop-in” solvent replacements are rarely achievable, optimisation of protecting groups, protection coupling and deprotection conditions under different solvent regimes. It is proposed that this project will bring together many of these strands, as well as oligonucleotide specific challenges – e.g. exploring alternative acids for more efficient DMT group removal (and subsequent washing); exploration of bioderived routes to phosphoramidites; to explore and quantify alternative potentially “greener” solid phase and solution phase oligonucleotide synthesis protocols Useful links:Sneddon research group: https://www.york.ac.uk/chemistry/people/hsneddon/ Key publications: Greener solvents for solid-phase synthesis (Green Chem. 2017, 19, 952–962) Greenness Assessment and Synthesis for the Bio-Based Production of the Solvent 2,2,5,5-Tetramethyloxolane (TMO) (Sustain. Chem. 2021, 2, 392–406) Further information The EPSRC Centre for Doctoral Training in Chemical Synthesis for a Healthy Planet (CSHP CDT) is a new EPSRC-funded centre focused on training the next generation of synthetic chemists, developing a sustainable, innovative chemistry culture that equips students to address major emerging and future global challenges in Human Health, Energy & Materials, and Food Security. We offer a fully-funded four year PhD programme, delivered jointly by the Universities of Oxford and York, comprised of taught courses and a substantive research project. Student cohorts will work together in a 4-month training period at both Oxford and York, before embarking on their main PhD projects. These substantive projects will be industry co-supervised, and based at either the Department of Chemistry in Oxford, or the Green Chemistry Centre of Excellence at York and the associated Department of Chemistry. This PhD project will primarily be based at the University of York.  The first application deadline is 15th November 2024. We will continue to receive applications following this deadline, however some of the projects may be filled following the assessment of the first round of applications. We therefore encourage you to submit your application early to ensure that your first-choice project is available. A full list of CSHP CDT projects on offer for 2025 entry can be found here. All project partners recognise the importance of equal participation, progression and success for all. We strive to provide a working, learning, social and living environment that will enable all our staff and students to contribute fully, to flourish and to excel - a place where we can ALL be ourselves. The Department of Chemistry in York holds an Athena SWAN Gold Award, and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel; for more details, see: https://www.york.ac.uk/chemistry/ed/. In particular, we recognise the importance of the equal participation of women at all levels in a subject that has traditionally been male-dominated. We also particularly encourage applications from people who identify as Black, Asian or from a Minority Ethnic background, who are underrepresented in science.