During the initial work on the P(V), it was found that the standard succinate-based CPG linker (12) was unstable to DBU. Presumably, the amide N-H bond is deprotonated by DBU followed by cyclization onto the ester, cleaving the Un-yLinker and prematurely liberating the oligonucleotide from the solid-support. Based on previous reports on the instability of succinate linkers to DBU, more base stable linkers were pursued. Strategies evaluated included blocking the free N-H (N-Me linker 11) and extending the distance between the amide (linkers 13, 14) and the resin. This set of CPG linkers was then subjected to concentrations of DBU to mimic that encountered in oligonucleotide couplings steps and the % DMTr remaining was measured by absorbance (Figure ). As previously reported, the commercial, succinate-based CPG (12) was rapidly cleaved with no discernable DMTr signal after several cycles. The Qlinker ( ) also demonstrated poor stability with only 48% remaining. It was found that a Sar-Glu-based linker (11) exhibited the most favorable properties showing a 94% recovery and stability after 120 coupling cycles. The PEG4-based linker ( ) was also found to be relativelystable under the same conditions with a recovery of almost 80% after 120 cycles. To verify that linker (11) was amenable to SPOS and not just incubation with DBU, a 1µmol P(III) control synthesis between linker (11) and the commercially available succinate-based CPG (12) (see SI) was performed. Yields were comparable, 28% for (11) and 25.4% for (12), with no major differences in detected impurities. With an improved set of P(V) reagents (+ and -Ψ Br ), a process for preparing the P(V)-monomers and an SPOScompatible linker (with more resistance to DBU) in hand, attention turned to evaluating the performance of the differentially base protected monomers in SPOS.