4-Oxoheptanedioic acid: an orthogonal linker for solid-phase synthesis of base-sensitive oligonucleotides

l,6-Dioxaspiro[4,4]nonane-2,7-dione has been found to react readily with alcohols in the presence of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU). The 4-oxoheptanedioic acid tether obtained bears (l) a free carboxy group, which enables anchoring to aminoalkylated resins, and (2) a 4-oxobutanoate structural motif, which allows release of the target alcohol by a mild hydrazinium acetate treatment. To demonstrate the applicability of the procedure, nucleosides have been derivatized with this simple difunctional linker arm, anchored to a solid phase and subjected to synthesis and subsequent release of oligonucleotides bearing a base-sensitive biodegradable phosphate protection.