Optimal ATRP‐Made Soluble Polymer Supports for Phosphoramidite Chemistry

Soluble polystyrene supports with optimal molecular structures for iterative phosphoramidite chemistry were prepared by atom‐transfer radical polymerization (ATRP) and subsequent chain‐end modification steps. The controlled radical polymerization of styrene was first performed in the presence of an 9‐fluorenylmethoxycarbonyl (Fmoc)‐protected amino‐functional ATRP initiator. Soluble supports of different molecular weight were prepared. Size‐exclusion chromatography and NMR analysis indicated formation of well‐defined polymers with controlled chain lengths and narrow dispersity. After synthesis, the bromo ω end group of the ATRP polymer was removed by dehalogenation in the presence of tributyltin hydride, and the Fmoc protecting group of the α moiety was subsequently cleaved with piperidine. The resulting α‐primary amine was afterwards treated with a linker containing a carboxyl group, a cleavable ester site, and a dimethoxytrityl‐protected hydroxyl group to afford ideal soluble supports for phosphoramidite chemistry. NMR analysis indicated that these chain‐end modifications were quantitative. The supports were tested for the synthesis of a non‐natural sequence‐defined oligophosphates. High‐resolution ESI‐MS analysis of the cleaved oligomers indicated formation of uniform species, and thus confirmed the efficiency of the ATRP‐made soluble polymer supports. In addition, the synthesis of a thymidine‐loaded soluble support was achieved.