DNA and RNA oligonucleotides are molecules of great interest due to their potential
application as antisense and RNAi drugs. Currently, solid phase synthesis (SPS) is the
method of choice for their synthesis due to its simplicity, automation, and simple
intermediate purification. However, large scale synthesis is challenging due to its 2-
phase reaction medium. This research investigates a novel method – Membrane
Enhanced Oligonucleotide Synthesis (MEOS) – for the synthesis of DNA
oligonucleotides. This novel process combines synthesis on a soluble polymeric
support with the emergent separation technology Organic Solvent Nanofiltration
(OSN). The synthesis of support-bound oligonucleotide dimers was first attempted
using linear MeOPEG112 as the soluble support, and ceramic and cross-linked
polyimide OSN membranes. The performance of OSN membranes was characterised
prior to synthesis in order to selected membranes with appropriate performance
properties. Poor process yields lead to the development of novel branched PEG
supports. PEG silyl ethers, phosphate and carboxylic esters were prepared in a novel
methodology using an OSN membrane for the separation of the branched PEG from
excess PEG diol. The use of branched PEGs resulted in an increase of the MEOS
process yields in the range of ~3 to 6 fold. Best results for the MEOS process were
obtained in the synthesis of a fully unprotected dimer, dApdA, using a 3-arm PEG
carboxylic ester with MW of ~ 9,000 g mol-1 [benzene-1,3,5-(CO2-PEG67)3]. The
synthesis of DNA monomers using OSN was also investigated. This investigation
also describes a novel synthetic method for the synthesis of heterobifunctional PEGs.
PEGs of MW of ~ 2,000 g mol-1 were prepared and characterised with
monophthalimide, monoamine, and monoazide functionalities. Overall, this research
investigates the use of OSN in two different applications for organic synthesis,
namely the synthesis of DNA oligonucleotides and derivatised (branched and linear)
PEGs.