Solution-phase synthesis of short oligo-2’-deoxyribonucleotides by using clustered nucleosides as a soluble support

Oligonucleotides are currently prepared by phosphoramidite chemistry on a solid support both in the laboratory[1,2] and on a large scale.[3] Although this will likely remain the case for the near future, there seems to be space for the development of a solution-phase synthesis for specific purposes. Short oligonucleotides are sometimes needed in research laboratories in a scale of hundreds of milligrams for DNA-based material chemistry and for spectroscopic and physical organic studies on structure, modification and interaction with protein fragments or small molecular entities, including metal complexes. Convenient solution-phase methodology would undoubtedly be useful for the preparation of such oligonucleotides in-house without any special equipment. In fact, numerous strategies for the elongation of oligonucleotides on soluble supports have been developed. Phosphoramidite,[4] H-phosphonate,[5] and phosphotriester[6,7] chemistries have been used for the solution-phase synthesis of oligonucleotides and their monothioate analogues[8–10] on a soluble polyethylene glycol (PEG) support.[11] Once the coupling is performed, the PEG-supported oligonucleotides may be isolated by precipitation in diethyl ether. More recently, oligonucleotides have been attached to an imidazolium tetrafluoroborate,[12] to an adamantyl tag,[13] and to acetylated and methylated β-cyclodextrin[14] for the same purpose, facilitating purification of oligonucleotides by precipitation, extractive workup, and flash chromatography, respectively. We now report a novel soluble-support-based strategy with properties that are highly useful for the synthesis of