NUCLEOSIDE PHOSPHORYLATION IN FLOW: A PHYSICAL ORGANIC APPROACH

This programme will offer training in synthetic and flow chemistry applied to nucleosides, alongside experience of kinetics and associated analytical techniques.
BACKGROUND AND OPPORTUNITY
Synthetic approaches towards nucleoside phosphates are cumbersome, with users relying heavily on methods established 25-50 years ago. Critically, the field lacks quantitative comparative data and is burdened with laborious synthetic methods that sequester systematic method development and innovation. Furthermore, there has been a remarkable lack of adoption of flow-based technologies, which offer excellent reagent and reaction control, with the possibility of direct, in-line reaction analyses.
PROGRAMME AIMS
Gain Quantitative Reactivity Data
The field of nucleoside phosphorylation is marked by qualitative descriptions of the relative electrophilicities of P-reagents and nucleophilicities of sugar-OH groups. Quantitative data will facilitate informed reagent choices for selective phosphorylations that avoid wasteful protecting group strategies.
Explore Flow Phosphorylation
Remarkably, beyond the well-established use of gene-machines to prepare CPG-supported oligos with (poly)phosphorylated termini, there is very limited enquiry into the application of flow technologies to phosphorylation in solution. Flow technologies offer excellent reagent mixing, and consistent control of reaction temperatures and solvent moisture content. Furthermore, automation alongside in-line analysis, will offer the opportunity to systematically explore the reactivities of existing and new reagents in a consistent, higher throughput manner than has previously been the case.
New Reagents and Strategies Required
Recent innovations, such as the development of the moisture-tolerant phosphoramidite strategy presented by Jessen and co-workers, illustrate that there is significant opportunity to develop new reagents for nucleoside phosphorylations. Our approaches will facilitate the design and exhaustive testing of potential new reagents, with flow control allowing more reactive reagents to be used without protecting groups.